Steegers-Theunissen, R.P.M.

Inequalities in perinatal and maternal health (Article)

2013-04-01T00:00:00Z

Purpose of Review: To describe inequalities in perinatal and maternal mortality, and morbidity from an international high-income country perspective. Measures of inequalities are socioeconomic status, ethnic background, and living area. Recent Findings: Despite decreasing overall perinatal and maternal mortality in high-income countries, perinatal and maternal health inequalities persist. Inequalities in fetal, neonatal, and maternal adverse outcome relate to specific groups of risk factors. They commonly have a background in so-called structural risk factors, that is low level of education and income, being a migrant and living in disadvantaged areas. Structural risk factors therefore drive inequalities, and simultaneously represent the common perspective to judge perinatal and maternal health gaps. The effect of risk factors is further magnified in urban areas through risk accumulation.As mother and child share their background, neonatal, and maternal adverse health outcome patterns coincide, resulting in similar inequalities and similar epidemiological trends. The structural background explains the difficulty of improving this. Summary: Inequalities in perinatal and maternal outcome persist in women from lower socioeconomic groups, from specific ethnic groups, and from those living in deprived areas. In view of the lifelong consequences, these marked social disparities pose an important challenge for the political decision makers and the healthcare system.

Influence of maternal folate status on human fetal growth parameters (Article)

2013-04-01T00:00:00Z

Worldwide periconceptional folic acid supplement use is recommended to prevent neural tube defects. This also stimulated research on maternal folate status in association with fetal growth, an important predictor of perinatal and future development and health. We provide an overview of literature on associations between maternal folate status during pregnancy determined by folate biomarker concentrations in blood, folic acid supplement use and dietary folate intake, and fetal growth parameters. Literature was searched in PubMed up to November 2011. Some studies suggest inverse associations between serum folate, folic acid supplement use and dietary folate intake and risk of a low birth weight or small for gestational age infant. The strongest evidence, however, revealed positive associations between birth weight and red blood cell folate, folic acid supplement use and dietary folate intake. Red blood cell folate appeared to be most consistently associated with other fetal growth parameters. These findings contribute to the knowledge of the impact of maternal folate status on fetal growth, and subsequently perinatal health and disease risks in later life. Future research is recommended to examine effects of windows, duration and dose of folic acid supplement use and use of folate-rich dietary patterns in different populations on fetal growth parameters.

Ethical aspects of paternal preconception lifestyle modification (Article)

2013-01-24T00:00:00Z

This Clinical Opinion points to a potential conflict between the scarcity of evidence on paternal preconception risk factors for adverse pregnancy outcomes and the view that preconception care should be also directed at men. We argue that from an ethical perspective, responsible fatherhood starts already before conception, as long as the evidence increases on the benefits of paternal preconception lifestyle (modification). Our explorative study suggests that the strength of the evidence for paternal preconception lifestyle modification is important for men. We argue that 5 aspects together determine the moral responsibility of prospective fathers to modify their behavior: the strength of the evidence of the risk factor, the modifiability of the risk, the efforts necessary to eliminate or diminish the risk factor, the severity of harm, and the probability that harm will occur and that it will be prevented by modifying the risk factor. The case of paternal preconception smoking illustrates the analysis.

A periconceptional energy-rich dietary pattern is associated with early fetal growth: The Generation R study (Article)

2012-12-04T00:00:00Z

Objective: To identify periconceptional maternal dietary patterns associated with crown-rump length (CRL), estimated fetal weight (EFW) and birthweight. Design: Population-based prospective birth cohort study. Setting: Rotterdam, the Netherlands. Participants: For this study, 847 pregnant Dutch women were eligible. Women were included between 2001 and 2005. Methods: Information on nutritional intake was collected by a semiquantitative food frequency questionnaire. For extracting dietary patterns, principal component factor analysis was used. Fetal growth was assessed using ultrasound measurements. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used. Main outcome measures: Crown-to-rump length, estimated fetal weight in second and third trimester and birthweight. Results: An 'energy-rich dietary pattern' was identified, characterised by high intakes of bread, margarine and nuts. A significant association was shown between a high adherence to this dietary pattern (difference, mm: 2.15, 95% confidence interval 0.79-3.50) and CRL (linear trend analyses P = 0.015). No association was revealed between increasing adherence to this dietary pattern and EFW in second or third trimester, or birthweight. Conclusion: This study suggests that increasing adherence to an energy-rich dietary pattern is associated with increased CRL in the first trimester.

An urban perinatal health programme of strategies to improve perinatal health (Article)

2012-11-01T00:00:00Z

Promotion of a healthy pregnancy is a top priority of the health care policy in many European countries. Perinatal mortality is an important indicator of the success of this policy. Recently, it was shown that the Netherlands has relatively high perinatal death rates when compared to other European countries. This is in particular true for large cities where perinatal mortality rates are 20-50% higher than elsewhere. Consequently in the Netherlands, there is heated debate on how to tackle these problems. Without the introduction of measures throughout the entire perinatal health care chain, pregnancy outcomes are difficult to improve. With the support of health care professionals, the City of Rotterdam and the Erasmus University Medical Centre have taken the initiative to develop an urban perinatal health programme called 'Ready for a Baby'. The main objective of this municipal 10-year programme is to improve perinatal health and to reduce perinatal mortality in all districts to at least the current national average of 10 per 1000. Key elements are the understanding of the mechanisms of the large health differences between women living in deprived and nondeprived urban areas. Risk guided care, orientation towards shared-care and improvement of collaborations between health care professionals shapes the interventions that are being developed. Major attention is given to the development of methods to improve risk-selection before and during pregnancy and methods to reach low-educated and immigrant groups.

Determinants of the intention of preconception care use: lessons from a multi-ethnic urban population in the Netherlands (Article)

2012-08-08T00:00:00Z

Objectives: To investigate the determinants of the intention of preconception care use of women in a multi-ethnic urban population. Methods: The ASE-model-a health behaviour model-was used as an explanatory framework. A representative sample was taken from the municipal population registers of two districts in Rotterdam, the Netherlands, 2009-2010. 3,225 women (aged 15-60 years) received a questionnaire, which was returned by 631: 133 Dutch, 157 Turkish and Moroccan, and 341 Surinamese and Antillean. Descriptive, univariate and multivariate analyses were performed. Results: The multiple logistic analyses showed that intention to attend preconception care was significantly higher in women with a Turkish and Moroccan background (β 1.02, P = 0.006), a higher maternal age (β 0.04, P = 0.008) and a positive attitude (β 0.50, P < 0.001). Having no relationship (β -1.16, P = 0.004), multiparity with previous adverse perinatal outcome (β -1.32, P = 0.001), a high educational level (β -1.23, P = 0.03), having paid work (β -0.72, P = 0.01) and experienced barriers level (β -0.15, P = 0.003) were associated with less intention to use preconception care. Conclusions: Modifiable determinants as attitude and barriers can be addressed to enhance preconception care attendance.

Peptide fingerprinting of folate-responsive proteins in human B lymphoblasts and orofacial clefting (Article)

2012-07-01T00:00:00Z

Background Maternal periconceptional use of folic acid contributes to the prevention of neural crest-related congenital malformations including orofacial clefts. The underlying biological pathways affected by folic acid, however, are still not clarified. In an explorative study, we identify folate-responsive proteins and pathways by advanced proteomic techniques and their possible role in orofacial development in young children. Materials and methods At 15months of age, we obtained B lymphoblasts from 10 children with and 10 children without an orofacial cleft. Folate-responsive protein expression was determined in folate-free B-lymphoblast cultures, supplemented with 5-methyltetrahydrofolate to reach the target concentration 30nM. Folate-associated differences of peptide and protein expressions were assessed by analysing samples before and after folate addition. Samples were trypsin digested and measured by nano-liquid chromatography coupled online to a LTQ-Orbitrap mass spectrometer. Significantly differentiating peptides were determined using a McNemar's test, and correlations with proteins and existing pathways were visualized using Ingenuity Pathway Analysis. Results We found 39 folate-responsive peptides that were assigned to 30 proteins. Those proteins consisted of histones, ribosomal and heat shock proteins (HSP), and proteins involved in antioxidant reactions, cytoskeleton, glycolysis, energy production, protein processing, signal transduction and translation. Conclusions Histones, ribosomal and HSP were mainly found in the case group, and we confirm that almost 60% of these proteins were also found in a subset of the samples in our previous study using microarray on folate-responsive gene expression. The proteins were compared with known biological pathways and matched with recent relevant literature.

The effects of homocysteine and folic acid on angiogenesis and VEGF expression during chicken vascular development (Article)

2012-03-01T00:00:00Z

Homocysteine (Hcy) has been implicated in the development of cardiovascular developmental defects. Additionally, in experimental studies, vasculotoxic properties of Hcy have been described. Although Hcy has been identified as a vascular pathogen, little is known about the direct effects Hcy exerts during early embryonic vascular development. Angiogenesis is a critical process involved in embryo survival and development. There are limited studies on the effects of Hcy on early embryonic vasculogenesis and angiogenesis. Folic acid (FA) is a B vitamin essential in embryo development, and FA supplementation may lead to reduced Hcy levels. Therefore, the purpose of our study was to explore the effects of Hcy and FA on early embryonic vascular development. Embryonic day (E) 3.5 chicken embryos were treated with a sham, Hcy or FA solution. We developed a computational program for systematic analysis of microscopic images obtained from the extra embryonic vascular beds. These results were combined with real-time PCR data on the expression of VEGF-A and its receptor in these vascular beds.Our data show that Hcy exposure inhibits early vascular development, displayed by a significant reduction of vessel area and altered composition of the vascular beds. Vascular beds of Hcy embryos for the greater part consisted of vessels of the smallest diameters, compared to middle size vessels in control and FA embryos. Hcy also reduced expression of VEGF-A and VEGFR-2. No significant effects of FA were found.We conclude that Hcy exposure causes impaired early extra embryonic vascular development, shown by altered composition of the vascular beds as well as reduced expression of VEGF-A and VEGFR-2. These effects of Hcy, and the consecutive cascade of events, may be involved in the development of cardiovascular developmental defects.

Informing on prenatal screening for Down syndrome prior to conception. An empirical and ethical perspective (Article)

2012-03-01T00:00:00Z

In most Western countries, information on prenatal screening for Down syndrome is provided in the first-trimester of pregnancy. The purpose of this study was to examine whether this information should additionally be provided before pregnancy to improve the informed decision-making process. In an empirical study, we obtained data from pregnant women with respect to their preferences regarding information on prenatal screening preconceptionally. Questionnaire data (n=510) showed that 55.7% of responding women considered participating in prenatal screening for Down syndrome before pregnancy. 28.0% of women possessed information on prenatal screening preconceptionally. 84.6% preferred not to receive information preconceptionally in retrospect. In an ethical analysis, we elaborated on these preferences by weighing pros and cons. We considered two arguments against the provision of information on prenatal screening preconceptionally: women's preference to receive information in a step-by-step manner, and the risk of providing a directive message. We identified three reasons supporting its provision preconceptionally: the likelihood of making an informed decision could, firstly, be increased by "unchaining" the initial information from possible subsequent decisions, and, secondly, by providing women sufficient time to deliberate. Thirdly, the probability of equal access to prenatal screening may increase. To conclude with, we propose to incorporate an information offer on prenatal screening for Down syndrome in preconception care consultations. By offering information, instead of providing information, prospective parents are enabled to either accept or decline the information, which respects both their right to know and their right not-to-know.

Pregnancy in multiple sclerosis: clinical and self-report scales (Article)

2012-02-01T00:00:00Z

Relapse rate is decreased during pregnancy in multiple sclerosis (MS). Risk for postpartum relapse is increased in the first 3 months after delivery. We aimed to study clinical course of MS around pregnancy, using clinical as well as self-report scales, including data on quality of life (QoL), and to identify clinical factors predisposing for postpartum relapse . We performed a prospective, longitudinal study among 35 MS patients and 20 controls. In patients we assessed expanded disability status scale (EDSS), the Guy's neurological disability scale (GNDS) and the multiple sclerosis impact scale 29 (MSIS-29). In patients and controls we assessed the MOS 36 item short form health survey questionnaire (SF36), consisting of eight domains. The previously described surge in relapses after delivery was also obvious in this study (p = 0.005). At group level EDSS and MSIS-29 did not show overt fluctuations over time. The GNDS, however, improved during the third trimester, compared to the first trimester (p = 0.003). A concomitant improvement in the SF36 domains vitality (p < 0.001) and general health (p = 0.001) was found in patients. At the final visit, at least 9 months after delivery, no worsening of EDSS, GNDS, MSIS-29 or SF36 was observed compared with the (for MS, beneficial) third trimester. Duration of disease, relapses in the year preceding pregnancy or relapses during pregnancy were not associated with postpartum relapse. QoL is improved during pregnancy. Although relapse rate was increased directly after delivery, in the mid long term after delivery no adverse effects of pregnancy on MS were found.

Comparable levels of folate-induced aneusomy in B-lymphoblasts from oral-cleft patients and controls (Article)

2012-01-24T00:00:00Z

Background: Peri-conceptional use of folic acid contributes to protection against congenital malformations, such as neural tube defects and cleft lip with or without cleft palate (CL/P). Previous studies showed that low folate levels cause DNA damage, leading to chromosomal instability and aneusomy. This study seeks to confirm this finding and investigates whether the in vitro sensitivity towards aneusomy of chromosome 17 and 21 in the folate-deficient state differs between CL/P patients and controls. Methods: Epstein-Barr virus-immortalized B-lymphoblasts derived from 15 CL/P children and 15 controls, were cultured in medium with high and low concentrations - approximately 40. nM and 5. nM - of 5-methyltetrahydrofolate, respectively. Fluorescence in situ hybridization was used to detect specific fluorescence signals for chromosomes 17 and 21. Results: A significant increase in aneusomy of chromosomes 17 (2.3% vs 7.6%; p≤ 0.001) and 21 (2.5% vs 7.0%; p≤ 0.001) was observed after 10 days of culturing in low folate. These results were comparable in cell lines from patients and controls. Interestingly, for chromosome 17 the folate deficiency mainly resulted in an increase of monosomy (6%, p≤ 0.001), while for chromosome 21 the increase of trisomy was larger (4.9%, p≤ 0.001). Conclusions: These data suggest that folate deficiency is a significant risk factor in the development of aneusomy and may affect the distribution of chromosomes during cell division. The comparable aneusomy frequencies in CL/P and in controls suggest that other folate-related processes are involved in the pathogenesis of CL/P, and additional investigations are needed to identify the causal mechanisms.

Reproducibility of echocardiographic measurements of human fetal left ventricular volumes and ejection fractions using four-dimensional ultrasound with the spatio-temporal image correlation modality (Article)

2012-01-01T00:00:00Z

Objectives: To determine the reproducibility, both reliability and agreement, of measurements of fetal left ventricular parameters from volumes obtained by spatio-temporal image correlation (STIC) acquisition applying virtual organ computer-aided analysis (VOCAL) and Simpson's rule (method of discs). Furthermore the success rate of STIC acquisition was determined. Study design: In 84 pregnancies between 20 and 34 weeks of gestation the fetal heart was scanned using the STIC modality. An optimal four-chamber view in end-diastole and end-systole was obtained. Left ventricular end-diastolic volume, left ventricular end-systolic volume, stroke volume and ejection fraction were determined. For calculations based on Simpson's rule only one plane was traced, whereas for VOCAL six planes were traced. To quantify the reliability intraclass correlation coefficients were calculated for both intra- and inter-observer measurements. Agreement of measurements was evaluated by Bland-Altman plots. Results: The STIC volumes of 54 women (64%) were excluded from the study because of poor quality, leaving 30 volumes for further analysis. Intraclass correlation coefficients for intra-observer reliability for VOCAL and Simpson were 0.99 and 0.99 for left ventricular end-diastolic volume, 0.95 and 0.92 for left ventricular end-systolic volume, 0.98 and 0.97 for stroke volume, 0.76 and 0.77 for ejection fraction, respectively. Intraclass correlation coefficients for inter-observer reliability for VOCAL and Simpson were 0.97 and 0.86 for left ventricular end-diastolic volume, 0.97 and 0.86 for left ventricular end-systolic volume, 0.95 and 0.81 for stroke volume, 0.68 and 0.63 for ejection fraction, respectively. According to Bland-Altman plots, the mean percentage difference and 95% limits of intra- and inter-observer agreement for left ventricular stroke volume measurements using VOCAL were -0.2 (-25.1, 24.7)% and 2.8 (-34.2, 39.8)%, respectively. For left ventricular stroke volume measured with Simpson versus VOCAL the mean percentage difference and 95% limits of agreement were -1.8 (-22.1, 18.5)%. Conclusions: 4D STIC enables reproducible measurements of left ventricular volumes. Reliability of the VOCAL mode is not essentially different from the single-plane method used in Simpson's rule. The large percentage of poor quality STIC volumes and the wide limits of inter-observer agreement would create obstacles for the clinical applicability of this technique.

Maternal mortality attributable to vascular dissection and rupture in the Netherlands: A nationwide confidential enquiry (Article)

2012-01-01T00:00:00Z

Objective To determine the incidence of maternal deaths attributable to vascular dissection and rupture in the Netherlands, and to assess clinical features, risk factors and the frequency of substandard care in the cases identified. Design Confidential enquiry into the causes of maternal deaths. Setting Nationwide in the Netherlands. Population A total of 3,108,235 live births. Methods Data analysis of all cases of maternal death from vascular dissection and rupture in the period 1993-2008. A literature review was also performed. Main outcome measures Incidence, clinical features, risk factors and frequency of substandard care. Results A total of 23 maternal deaths attributable to vascular dissection and rupture were reported. In most cases the location was aortic (n = 13), followed by coronary (n = 4) and splenic (n = 3) arteries. Clinical features were various, but most women presented with sudden unexplainable pain. Risk factors were present in 14 cases (61%), with hypertension being most frequently reported in ten cases (43%). Substandard care was determined to have been received in 13 cases (56%), inadequate assessment of complaints and a delay in diagnosis being the most frequent problems identified. Conclusions Vascular dissection and rupture in pregnancy, although rare, carry a high risk of maternal and fetal morbidity and mortality. Because of the rarity of this condition and its variety in presentation, diagnosis is easily missed. A high index of suspicion when a woman presents with suggestive complaints, leading to an early diagnosis, may improve the prognosis for the woman and her child.

Folic acid supplements modify the adverse effects of maternal smoking on fetal growth and neonatal complications (Article)

2011-12-01T00:00:00Z

Maternal smoking during pregnancy leads to increased risks of neonatal complications. The use of folic acid supplements might reduce the adverse effects of smoking. We examined whether folic acid supplement use modifies the associations of maternal smoking with first trimester plasma homocysteine concentrations, fetal growth characteristics, and risks of neonatal complications. The associations were studied in 6294 mothers participating in a prospective population-based cohort study in The Netherlands. Main outcomes measurements were first trimester plasma homocysteine concentrations, fetal growth characteristics, and neonatal complications, including preterm birth, low birth weight, and small-sizefor-gestational-age. Continued maternal smoking was associated with higher first trimester plasma homocysteine concentrations [difference 0.52 μmol/L (95% range = 0.20, 2.14)], lower third trimester fetal weight (difference -44 g (95% CI = -57, -31)], and birth weight [difference -148 g (95% CI = -179, -118)]. There were significant interactions between maternal smoking and folic acid supplements on all outcome measures (all P-interaction <0.040). Among mothers who continued smoking during pregnancy, those who did not use folic acid supplements had the highest risk of delivering a child with low birth weight [OR = 3.45 (95% CI = 1.25, 9.54)] compared to those who did use periconceptional folic acid supplements. No significant effects were observed for the risks of preterm birth and small-size-for-gestationalage at birth. Our results suggest that some adverse effects of maternal smoking on fetal growth and neonatal outcomes might be reduced by the use of folic acid supplements. The observed interaction seems to be mainly driven by smoking in the first trimester only.

Gestational sac fluid volume measurements in virtual reality (Article)

2011-11-01T00:00:00Z

Objectives: To evaluate a virtual reality (VR) application for gestational sac fluid volume (GSFV) measurements in first-trimester pregnancies and to study the correlation between different embryonic growth parameters. Methods: This was a prospective cohort study analyzing 180 three-dimensional (3D) ultrasound scans of 42 healthy women, performed between 5 +5 and 12 + 6 weeks' gestational age (GA). The 3D datasets were transferred to the I-Space immersive VR system. The V-Scope application was used to create a 'hologram' of the ultrasound image, allowing depth perception and interaction with the rendered objects. Volumes were measured semi-automatically using a segmentation algorithm. In addition to the GSFV, the total gestational sac volume (GSV) and its diameter (GSD) were measured. The GSV was also calculated using the ellipsoid formula. Previously obtained measurements of embryonic volume and crown-rump length (CRL) were included in the study. The outcomes were analyzed using repeated-measures analysis of variance. Results: The GSFV was measured in 78 scans, and varied from 434 to 81 491 mm3. A positive correlation between GSFV and GA, CRL and GSD was found. Comparison of the GSD formula constructed in our study in relation to GA with a formula that is commonly used clinically showed an increasing difference with increasing GA either side of 8 + 5 weeks. The GSFV/embryonic volume ratio showed a decrease with GA. The GSV calculated using the ellipsoid formula was on average 19.8% larger compared with the GSV measured in VR. Conclusion: New charts for first-trimester GSFV were constructed using VR. These growth charts could be promising tools for studying normal and abnormal embryonic development. Copyright

Quantitative cardiovascular magnetic resonance in pregnant women: cross-sectional analysis of physiological parameters throughout pregnancy and the impact of the supine position. (Article)

2011-10-11T00:00:00Z

There are physiological reasons for the effects of positioning on hemodynamic variables and cardiac dimensions related to altered intra-abdominal and intra-thoracic pressures. This problem is especially evident in pregnant women due to the additional aorto-caval compression by the enlarged uterus. The purpose of this study was to investigate the effect of postural changes on cardiac dimensions and function during mid and late pregnancy using cardiovascular magnetic resonance (CMR). Healthy non-pregnant women, pregnant women at 20th week of gestation and at 32nd week of gestation without history of cardiac disease were recruited to the study and underwent CMR in supine and left lateral positions. Cardiac hemodynamic parameters and dimensions were measured and compared between both positions. Five non-pregnant women, 6 healthy pregnant women at mid pregnancy and 8 healthy pregnant women at late pregnancy were enrolled in the study. In the group of non-pregnant women left ventricular (LV) cardiac output (CO) significantly decreased by 9% (p=0.043) and right ventricular (RV) end-diastolic volume (EDV) significantly increased by 5% (p=0.043) from the supine to the left lateral position. During mid pregnancy LV ejection fraction (EF), stroke volume (SV), left atrium lateral diameter and left atrial supero-inferior diameter increased significantly from the supine position to the left lateral position: 8%, 27%, 5% and 11%, respectively (p<0.05). RV EDV, SV and right atrium supero-inferior diameter significantly increased from the supine to the left lateral position: 25%, 31% and 13% (p<0.05), respectively. During late pregnancy a significant increment of LV EF, EDV, SV and CO was observed in the left lateral position: 11%, 21%, 35% and 24% (p<0.05), respectively. Left atrial diameters were significantly larger in the left lateral position compared to the supine position (p<0.05). RV CO was significantly increased in the left lateral position compared to the supine position (p<0.05). During pregnancy positional changes affect significantly cardiac hemodynamic parameters and dimensions. Pregnant women who need serial studies by CMR should be imaged in a consistent position. From as early as 20 weeks the left lateral position should be preferred on the supine position because it positively affects venous return, SV and CO.

Tailored preconceptional dietary and lifestyle counselling in a tertiary outpatient clinic in the Netherlands (Article)

2011-09-01T00:00:00Z

Background Adverse reproductive performance has been linked to unhealthy dietary intake and lifestyles. Our objectives were to investigate the prevalence of unhealthy dietary intake and lifestyles before conception and to evaluate whether tailored preconception counselling modifies these behaviours. Methods Between October 2007 and April 2009, 419 couples received tailored preconception dietary and lifestyle counselling at the outpatient clinic of Obstetrics and Gynaecology of the Erasmus University Medical Center Rotterdam, the Netherlands. A subgroup (n = 110 couples) was counselled twice with a fixed time interval of 3 months. Self-administered questionnaires were used for tailored dietary and lifestyle counselling. A cumulative score based on six Dutch dietary guidelines was displayed in the personal Preconception Dietary Risk score (PDR score). In a similar manner, the Rotterdam Reproduction Risk score (R3 score) was calculated from lifestyle factors (women: 13 items, men: 10 items). Univariate and paired tests were used. Results Most couples (93.8) were subfertile. At the second counselling, the percentage consuming the recommended intake of fruit had increased from 65 to 80 in women and from 49 to 68 in men and the percentage of women getting the recommended intake of fish increased from 39 to 52. As a consequence, the median PDR score was decreased [women: 2.6 (95 CI 2.4-2.9) to 2.4 (95 CI 2.1-2.6), men: 2.5 (95 CI 2.3-2.7) to 2.2 (95 CI 1.9-2.4), both P < 0.05]. The median R3 scores were also lower [women: 4.7 (95 CI 4.3-5.0) to 3.1 (95 CI 2.8-3.4), men: 3.0 (95 CI 2.8-3.3) to 2.0 (95 CI 1.7-2.3), both P < 0.01] due to less alcohol use (-14.6), more physical exercise and folic acid use in women, and less alcohol use in men (-19.4) (all P < 0.01). The R3 scores in women and men were decreased in all ethnicity, educational level, neighbourhood and BMI categories. However, low educated women appeared to show a larger reduction than better educated women and men with a normal BMI to show a larger decrease than overweight men. The reduction in the PDR score of women was similar in both ethnic groups. More than 85 women and men found the counselling useful and around 70 would recommend it to others. Conclusions Tailored preconception counselling about unhealthy dietary and lifestyle behaviours of subfertile couples in an outpatient tertiary clinic is feasible and seems to decrease the prevalence of harmful behaviours in the short term. These Results with subfertile couples are promising and illustrate their opportunities to contribute to reproductive performance and pregnancy outcome.

A maternal dietary pattern characterised by fish and seafood in association with the risk of congenital heart defects in the offspring (Article)

2011-09-01T00:00:00Z

Objective To identify maternal dietary patterns related to biomarkers of methylation and to investigate associations between these dietary patterns and the risk of congenital heart defects (CHDs) in the offspring. Design Case-control study. Setting Western part of the Netherlands, 2003-08. Population One hundred and seventy-nine mothers of children with CHD and 231 mothers of children without a congenital malformation. Methods Food intake was obtained by food frequency questionnaires. The reduced rank regression method was used to identify dietary patterns related to the biomarker concentrations of methylation in blood. Main outcome measures Dietary patterns, vitamin B and homocysteine concentrations, biomarkers of methylation (S-adenosylmethionine [SAM] and S-adenosylhomocysteine [SAH]) and the risk of CHD estimated by odds ratios and 95% confidence intervals. Results The one-carbon-poor dietary pattern, comprising a high intake of snacks, sugar-rich products and beverages, was associated with SAH (β = 0.92, P < 0.001). The one-carbon-rich dietary pattern with high fish and seafood intake was associated with SAM (β = 0.44, P < 0.001) and inversely with SAH (β = -0.08, P < 0.001). Strong adherence to this dietary pattern resulted in higher serum (P < 0.05) and red blood cell (P < 0.01) folate and a reduced risk of CHD in offspring: odds ratio, 0.3 (95% confidence interval, 0.2-0.6). Conclusions The one-carbon-rich dietary pattern, characterised by the high intake of fish and seafood, is associated with a reduced risk of CHD. This finding warrants further investigation in a randomised intervention trial. © 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology

Major dietary patterns and blood pressure patterns during pregnancy: the Generation R Study (Article)

2011-08-18T00:00:00Z

Objective: We sought to evaluate associations between dietary patterns and systolic blood pressure (SBP) and diastolic blood pressure during pregnancy. Study design: This was a prospective study of 3187 pregnant women. Participants completed a food-frequency questionnaire in early pregnancy. The Mediterranean dietary pattern, comprising high intake of vegetables, vegetable oils, pasta, fish, and legumes, and the Traditional dietary pattern, comprising high intake of meat and potatoes, were identified using factor analysis. Results: A higher SBP was observed among mothers with high Traditional pattern adherence. Low adherence to the Mediterranean pattern was also associated with higher SBP but only in early and mid pregnancy. A higher diastolic blood pressure throughout pregnancy was observed in mothers with high adherence to the Traditional pattern and low adherence to the Mediterranean pattern. These effect estimates were most pronounced in mid pregnancy. Conclusion: Low adherence to a Mediterranean and high adherence to a Traditional dietary pattern is associated with a higher blood pressure in pregnancy.

Informed decision-making in prenatal screening for Down's syndrome: What knowledge is relevant? (Article)

2011-08-01T00:00:00Z

Objective: To determine the content of decision-relevant knowledge needed for informed decision-making about (non-) participation in prenatal screening for Down's syndrome (DS), in order to develop a knowledge questionnaire for routine application in large-scale programme evaluations. Methods: A generic list of content domains for knowledge about screening was extracted from the literature. Items reflecting specific knowledge domains were constructed. An expert group of professionals and pregnant women expressed whether domains and items represented decision-relevant information. Results: All presented domains were scored as (very) important. Options when receiving an 'increased probability for DS' test result, the meaning of this result, the aim of the screening, and voluntary nature of the test were scored as most important. The condition being screened for, prevalence, and the screening procedure were scored as relatively less important, with a high amount of expert consensus. Conclusion: A knowledge measure for prenatal screening for DS was developed, based on domains and items acquired by expert consensus. Practice implications: This measure of decision-relevant knowledge can be used in routine, large-scale evaluations of the procedure for offering information about prenatal screening for DS.

Preconception care: An essential preventive strategy to improve children's and women's health (Article)

2011-08-01T00:00:00Z

Reproductive health has improved little in the last few decades. The Netherlands, particularly in large cities, has relatively high perinatal death rates compared with other European countries. Lack of improvement in reproductive outcomes despite improved quality of and better access to prenatal care strongly suggests that prenatal care alone is insufficient. We discuss how preconception care offers new strategies for improving reproductive health, how it usefully connects the life course of the affected individual and many health-care disciplines, and the benefits of combining a top-down policy structure and bottom-up organisation around caregivers. Given the likely benefits and cost savings calculated for the Netherlands, we conclude that failing to facilitate preconception care would reflect a breakdown of both professional and governmental responsibilities.

C-reactive protein levels in early pregnancy, fetal growth patterns, and the risk for neonatal complications: The Generation R Study (Article)

2011-08-01T00:00:00Z

Objective: We sought to examine the associations of maternal C-reactive protein (CRP) levels with fetal growth and the risks of neonatal complications. Study Design: CRP levels were measured in early pregnancy in 6016 women. Main outcome measures were fetal growth in each trimester and neonatal complications. Results: As compared to the reference group (CRP levels <5 mg/L), elevated maternal CRP levels (<25 mg/L) were associated with lower estimated fetal weight in third trimester and lower weight at birth (differences: -29 g, 95% confidence interval [CI], -58 to 0 and -128 g, 95% CI, -195 to -60, respectively). Elevated maternal CRP levels were also associated with an increased risk of a small size for gestational age in the offspring (adjusted odds ratio, 2.94; 95% CI, 1.615.36). Conclusion: Maternal CRP levels in early pregnancy are associated with fetal growth restriction and increased risks of neonatal complications.

Authors' reply (Article)

2011-08-01T00:00:00Z

Chlamydia trachomatis infection during pregnancy associated with preterm delivery: A population-based prospective cohort study (Article)

2011-06-01T00:00:00Z

Chlamydia trachomatis infection is the most prevalent bacterial sexually transmitted infection and may influence pregnancy outcome. This study was conducted to assess the effect of chlamydial infection during pregnancy on premature delivery and birthweight. Pregnant women attending a participating midwifery practice or antenatal clinic between February 2003 and January 2005 were eligible for the study. From 4,055 women self-administered questionnaires and urine samples, tested by PCR, were analysed for C. trachomatis infection. Pregnancy outcomes were obtained from midwives and hospital registries. Gestational ages and birthweights were analysed for 3,913 newborns. The C. trachomatis prevalence was 3.9%, but varied by age and socio-economic background. Chlamydial infection was, after adjustment for potential confounders, associated with preterm delivery before 32 weeks (OR 4.35 [95% CI 1.3, 15.2]) and 35 weeks gestation (OR 2.66 [95% CI 1.1, 6.5]), but not with low birthweight. Of all deliveries before 32 weeks and 35 weeks gestation 14.9% [95% CI 4.5, 39.5] and 7.4% [95% CI 2.5, 20.1] was attributable to C. trachomatis infection. Chlamydia trachomatis infection contributes significantly to early premature delivery and should be considered a public health problem, especially in young women and others at increased risk of C. trachomatis infection.

Informed decision-making about the fetal anomaly scan: What knowledge is relevant? (Article)

2011-06-01T00:00:00Z

Objectives This study had two objectives. The first was to determine the contents of relevant knowledge needed for informed decision-making (IDM) in second-trimester ultrasound screening for fetal anomalies, with the goal of developing a knowledge measure for use in large-scale program evaluations. The second was to compare the contents of decision-relevant knowledge for second-trimester ultrasound screening with those for first-trimester screening for Down syndrome using the combined test. Methods A generic list of content domains for knowledge about screening was extracted from the literature. Items reflecting specific knowledge domains for second-trimester ultrasound screening were constructed. An expert group of professionals and pregnant women expressed whether domains and items represented decision-relevant knowledge. Results Regarding second-trimester ultrasound screening, the experts scored all knowledge domains as (very) important. The meaning of an abnormal test result, the disorders being screened for, and the purpose of the screening were rated as very important for IDM, along with the voluntary nature of the test. All knowledge domains were included in the final measure. Importance ratings of knowledge domains for first-trimester Down syndrome screening and for second-trimester ultrasound screening were highly correlated (Pearson's r = 0.71). The domain 'consequences of a positive test result' was considered more important in first-trimester Down syndrome screening than in second-trimester ultrasound screening. Conclusions We have developed a knowledge measure for second-trimester ultrasound screening for fetal anomalies for use in routine, large-scale program evaluations.

Placental vascularization in early onset small for gestational age and preeclampsia (Article)

2011-06-01T00:00:00Z

The objective was to determine whether chorionic villous vascularization is diminished in cases of early onset (<34 weeks) small for gestational age (SGA) and/or preeclampsia (PE). Placental morphometrical measurements were performed in 4 gestational-age-matched groups complicated by SGA, SGA with PE, PE, and spontaneous preterm delivery without SGA or PE as the reference group. Using a video image analysis system, in randomly selected intermediate and terminal villi, the stromal area and the following villous vascular parameters were manually traced and analyzed: number of total, centrally and peripherally localized vessels, vascular area, and vascular area density. No differences were observed in intermediate and terminal villous vascular area. Preeclampsia was associated with smaller terminal villous stromal area (reference 2299 μm2, SGA 2412 μm2, SGA + PE 2073 μm2, and PE 2164 μm2, P =.011), whereas SGA was associated with an increased terminal villous vascular area density (reference 26.1%, SGA 35.7%, SGA + PE 33.4%, and PE 32.0%, P =.029). Compared with preserved flow, lower terminal villous vascular area density was found in cases with absent or reversed end-diastolic (ARED) umbilical artery flow (39.3% vs 30.3%, P =.013). These data demonstrate that villous vascularization was not influenced by PE, whereas in terminal villi an increased vascular area density was associated with SGA. Lower terminal villous vascular area density was associated with ARED flow in SGA pregnancies, indicating an increased risk of fetal compromise.

Defective deacetylation of histone 4 K12 in human oocytes is associated with advanced maternal age and chromosome misalignment (Article)

2011-05-01T00:00:00Z

Background: Chromosome segregation errors during human oocyte meiosis are associated with low fertility in humans and the incidence of these errors increases with advancing maternal age. Studies of mitosis and meiosis suggest that defective remodeling of chromatin plays a causative role in aneuploidy. We analyzed the histone deacetylation pattern during the final stages of human oocyte maturation to investigate whether defective epigenetic regulation of chromatin remodeling in human oocytes is related to maternal age and leads to segregation errors.MethodsHuman surplus oocytes of different meiotic maturation stages [germinal vesicle (GV), metaphase (M)I and MII] were collected from standard IVF/ICSI treatments. Oocytes were analyzed for acetylation of different lysines of histone 4 (H4K5, H4K8, H4K12 and H4K16) and for α-tubulin. ResultsHuman GV oocytes had an intense staining of the chromatin for all four histone 4 lysine acetylations. MI and MII stage oocytes showed either normal deacetylation or various amounts of defective histone deacetylation. Residual H4K12 acetylation was more frequently found in oocytes obtained from older women, with a significant correlation between defective deacetylation and maternal age (r 0.185, P 0.007). Eighty-eight percent of the oocytes with residual acetylation had misaligned chromosomes, whereas only 33 of the oocytes that showed correct deacetylated chromatin had misaligned chromosomes (P < 0.001). Conclusions We conclude that defective deacetylation during human female meiosis increases with maternal age and is correlated with misaligned chromosomes. As chromosome misalignment predisposes to segregation errors, our data imply that defective regulation of histone deacetylation could be an important factor in age-related aneuploidy.

Maternal thyroid function during pregnancy and behavioral problems in the offspring: The generation R study (Article)

2011-05-01T00:00:00Z

Maternal thyroid function during pregnancy is implicated in the neurodevelopment of the offspring, yet little is known about the effect of maternal thyroid parameters on the behavior of children. We investigated the association of maternal thyroid function during the first half of pregnancy with parent-reported problem behavior of the offspring up to age of 3 y. In the Generation R study, a population-based cohort of 3736 children and their mothers, data on maternal thyroid function and child's behavior were examined. The degree of internalizing and externalizing problems in the children were assessed with the Child Behavior Checklist at ages 11/2 and 3 y. Higher levels of maternal TSH during pregnancy predicted a higher externalizing scores in children at 11/2 and 3 y (B = 0.22 per SD of TSH; 95% CI: 0.04, 0.40; B = 0.10 per SD for internalizing scores; 95% CI:-0.01, 0.21). Maternal free thyroxine (T4) and total T4 were not associated with internalizing or externalizing scores of children. The linear relationship with more externalizing scores was across the range of TSH; this implies that subtle impairments of maternal thyroid function may affect the child. The results suggest that thyroid function is crucial for fetal brain development, which determines problem behavior later in life. Copyright

Growth, obesity, and cardiac structures in early childhood: The generation r study (Article)

2011-05-01T00:00:00Z

Cardiac structural adaptations in response to physical growth and obesity in older children have been identified and might have long-term consequences. We examined the associations of growth and obesity with cardiac structures during the first 2 years of life. In a population-based prospective cohort study among 974 children, left atrial diameter, left ventricular diastolic diameter, left ventricular mass, aortic root diameter, and fractional shortening were repeatedly measured by ultrasound at the ages of 1.5, 6, and 24 months. Height, weight, and subcutaneous fat mass were measured at the same visits, and blood pressure was measured at the age of 24 months. Height, weight, body mass index, and body surface area were positively associated with all of the cardiac structures during the first 2 years of life. At the age of 24 months, as compared with normal weight children, obese children had a greater left ventricular mass (1.04 SD score [95% CI: 0.20 to 1.89]) and a higher fractional shortening (0.91 SD score [95% CI: 0.02 to 1.80]). Nonsignificant tendencies were found for left atrial diameter, left ventricular diastolic diameter, and aortic root diameter. Our results suggest that normal variation in growth affects cardiac structures in early life. Overweight and obese children show cardiac adaptations already at the age of 2 years. Further studies are needed to assess whether these structural adaptations influence the risk of cardiovascular disease in later life.

Associations of maternal obesity with blood pressure and the risks of gestational hypertensive disorders. the Generation R Study (Article)

2011-05-01T00:00:00Z

Objective: We examined the associations of maternal prepregnancy BMI and gestational weight gain with SBP and DBP in different trimesters of pregnancy and the risks of pregnancy-induced hypertension and preeclampsia in a population-based prospective cohort study among 6902 mothers. Methods: Information about maternal weight just before pregnancy was obtained by questionnaires. Maternal anthropometrics and blood pressure were measured in each trimester. Information about gestational hypertensive disorders was available from medical records. Results: As compared to mothers with a normal weight, maternal obesity (BMI 30-34.9 kg/m) and morbid obesity (BMI â‰1 35 kg/m) were associated with higher first trimester SBP [differences for obese women and morbidly obese women: 10.80 mmHg (95% confidence interval: 9.44-12.17) and 13.07 mmHg (95% confidence interval: 10.91-15.23), respectively] and DBP [differences for obese women and morbidly obese women: 8.69 mmHg (95% confidence interval: 7.63-9.74) and 13.12 mmHg (95% confidence interval: 11.44-14.79), respectively]. Similar differences were observed during second and third trimester. The risks of pregnancy-induced hypertension and preeclampsia were increased among obese mothers [odds ratio 4.67 (95% confidence interval: 3.07-7.09) and odds ratio 2.49 (95% confidence interval: 1.29-4.78), respectively] and morbidly obese mothers [odds ratio 11.34 (95% confidence interval: 6.80-18.86) and odds ratio 3.40 (95% confidence interval: 1.39-8.28), respectively]. Maternal weight gain was associated with the risk of pregnancy-induced hypertension. Conclusion: Maternal obesity and morbid obesity are strongly associated with blood pressure in each trimester, and increased risks of gestational hypertensive disorders.

Re: Three-dimensional power Doppler: Validity and reliability (Article)

2011-05-01T00:00:00Z

Maternal smoking during pregnancy and subcutaneous fat mass in early childhood. The Generation R Study (Article)

2011-04-01T00:00:00Z

Maternal smoking during pregnancy increases the risk of obesity in the offspring. Not much is known about the associations with other measures of body composition. We assessed the associations of maternal smoking during pregnancy with the development of subcutaneous fat mass measured as peripheral and central skinfold thickness measurements in early childhood, in a population-based prospective cohort study from early fetal life onward in the city of Rotterdam, The Netherlands. The study was performed in 907 mothers and their children at the ages of 1.5, 6 and 24 months. As compared to non-smoking mothers, mothers who continued smoking during pregnancy were more likely to have a younger age and a lower educational level. Their children had a lower birth weight, higher risk of small size for gestational age and were breastfed for a shorter duration (P-values <0.01). We did not observe differences in peripheral, central and total subcutaneous fat mass between the offspring of non-smoking mothers, mothers who smoked in first trimester only and mothers who continued smoking during pregnancy (P > 0.05). Also, the reported number of cigarettes smoked by mothers in both first and third trimester of pregnancy were not associated with peripheral, central and total subcutaneous fat mass in the offspring at the ages of 1.5, 6 and 24 months. Our findings suggest that fetal exposure to cigarette smoke during pregnancy does not influence subcutaneous fat mass in early childhood. Follow-up studies are needed in children at older ages and to identify associations of maternal smoking during pregnancy with other measures of body composition.

The monocyte transcriptome during pregnancy in multiple sclerosis: Prominent expression of the Fc-receptor CD64 (Article)

2011-04-01T00:00:00Z

Background: During the third trimester of pregnancy multiple sclerosis (MS) disease activity is reduced. It is not fully understood which factors mediate this disease amelioration. Objective: To study alterations of the monocyte transcriptome during pregnancy in MS patients, using a genomewide approach to identify differentially regulated genes. Methods: Women with MS and healthy controls were longitudinally studied, including a visit before pregnancy. Results: RNA-microarray analysis was performed in six patients. We found a significant increase of CD64 (Fc gamma receptor 1a, FcgR1a) during the third trimester compared with baseline, confirmed by RT-PCR in a group of ten patients. Analysis with Ingenuity software was performed using all genes expression of which was altered at least 1.5-fold in at least five out of six patients. Major networks that were altered during MS pregnancy were: cell-to-cell signalling and interaction, immune response, and cell signalling. From the genes selected for Ingenuity analysis, seven additional candidate genes, selected for their biological interest, were tested using RT-PCR in ten patients with MS and nine controls. We found an increased expression of JAK2 and STAT1 directly postpartum in patients with MS and in controls. Conclusion: The increased CD64 expression during pregnancy is indicative of enhanced innate immune functions.

Urban perinatal health inequalities (Article)

2011-04-01T00:00:00Z

Objective. Large urban areas have higher perinatal mortality rates. In attaining a better understanding, we conducted an analysis on a neighborhood level in Rotterdam, the second largest city of The Netherlands. Methods. Perinatal outcome of all single pregnancies (50,000) was analyzed for the period of 2000-2006. The prevalences of perinatal mortality and perinatal morbidity were determined for every neighborhood. Results. Large perinatal health inequalities exist between neighborhoods in the city of Rotterdam with perinatal mortality rates as high as 37 per 1000 births. The highest risks were observed in deprived neighborhoods. Conclusion. We observed high levels of perinatal health inequalities in the city of Rotterdam which have not been previously described in the Western world. Accumulation of medical risk factors as well as socioeconomic and urban risk factors seems to be a likely contributor.

General maternal medication use, folic acid, the MDR1 C3435T polymorphism, and the risk of a child with a congenital heart defect (Article)

2011-03-01T00:00:00Z

Objective We sought to investigate maternal and child functional MDR1 C3435T polymorphism, periconception medication, folic acid use, and the risk of a congenital heart defect (CHD) in the offspring. Study Design MDR1 3435C>T genotyping was performed in 283 case triads (mother, father, child) and 308 control triads. Information on periconception medication and folic acid use was obtained through questionnaires. Results Mothers with MDR1 3435CT/TT genotype and using medication showed a significant association with the risk of a child with CHD (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.34.3) compared to mothers with MDR1 3435CC genotype not using medication. This risk increased without folic acid use (OR, 2.8; 95% CI, 1.26.4), and decreased in folic acid users (OR, 1.7; 95% CI, 0.83.7). Children carrying the MDR1 3435CT/TT genotype and periconceptionally exposed to medication without folic acid did not show significant risks. Conclusion Mothers carrying the MDR1 3435T allele, using medication without folic acid, are at nearly 3-fold increased risk for CHD in the offspring.

Air pollution, blood pressure, and the risk of hypertensive complications during pregnancy: The generation r study (Article)

2011-03-01T00:00:00Z

Exposure to air pollution is associated with elevated blood pressure and cardiovascular disease. We assessed the associations of exposure to particulate matter (PM10) and nitrogen dioxide (NO2) levels with blood pressure measured in each trimester of pregnancy and the risks of pregnancy-induced hypertension and preeclampsia in 7006 women participating in a prospective cohort study in the Netherlands. Information on gestational hypertensive disorders was obtained from medical records. PM10 exposure was not associated with first trimester systolic and diastolic blood pressure, but a 10-μg/m increase in PM10 levels was associated with a 1.11-mm Hg (95% confidence interval [CI] 0.43 to 1.79) and 2.11-mm Hg (95% CI 1.34 to 2.89) increase in systolic blood pressure in the second and third trimester, respectively. Longitudinal analyses showed that elevated PM10 exposure levels were associated with a steeper increase in systolic blood pressure throughout pregnancy (P<0.01), but not with diastolic blood pressure patterns. Elevated NO2exposure was associated with higher systolic blood pressure levels in the first, second, and third trimester (P<0.05), and with a more gradual increase when analyzed longitudinally (P<0.01). PM10 exposure, but not NO2exposure, was associated with an increased risk of pregnancy-induced hypertension (odds ratio 1.72 [95% CI 1.12 to 2.63] per 10-μg/m increase). In conclusion, our results suggest that air pollution may affect maternal cardiovascular health during pregnancy. The effects might be small but relevant on a population level.

Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation (Article)

2011-02-01T00:00:00Z

Background: Folate is a methyl donor. Availability of folate affects DNA methylation profiles and thereby gene expression profiles. We investigated the effects of low-dose folic acid use (0.4 mg/d) on the ovarian response to mild and conventional ovarian stimulation in women. Methods: In a randomized trial among subfertile women, 24 and 26 subjects received conventional and mild ovarian stimulation, respectively. Blood samples were taken during the early follicular phase of the cycle prior to treatment and on the day of human chorionic gonadotropin administration for determination of serum total homocysteine, anti-Müllerian hormone (AMH), estradiol, and folate. Folic acid use was validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian response was assessed using linear regression analysis. Results: Folic acid use modified the ovarian response to ovarian stimulation treatment. The estradiol response was higher in nonfolic acid users receiving conventional treatment [βinteraction=0.52 (0.07- 0.97); P = 0.03], and this effect was independent of serum AMH levels and the preovulatory follicle count. In the conventional treatment, themeanfolliclenumberwasalso greater in nonusers compared with the users group (14.1 vs. 8.9, P = 0.03). Conclusion: Low-dose folic acid use attenuates follicular and endocrine responses to conventional stimulation, independent of AMH and follicle count. The nature of this observation suggests that the effect of folic acid is most prominent during early follicle development, affecting immature follicles. Deleterious effects of folate deficiency, like DNA hypomethylation and oxidative stress, can help to explain our observations.

Congenital heart defects and biomarkers of methylation in children: A case-control study (Article)

2011-02-01T00:00:00Z

Eur J Clin Invest 2011; 41 (2): 143-150Background Derangements in the maternal methylation pathway, expressed by global hypomethylation and hyperhomocysteinemia, are associated with the risk of having a child with a congenital heart defect (CHD). It is not known whether periconception exposure to these metabolic derangements contributes to chromosome segregation and metabolic programming of this pathway in the foetus.Design In a Dutch population-based case-control study of 143 children with CHD and 186 healthy children, we investigated S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), total homocysteine (tHcy), the vitamins folate and B12 and the functional single nucleotide polymorphisms in the folate gene MTHFR 677C>T and 1298A>C. Comparisons were made between cases and controls adjusting for age, medication, vitamin use and CHD family history.Results In the overall CHD group, the median concentrations of SAM (P = 0.011), folate in serum (P = 0.021) and RBC (P = 0.030) were significantly higher than in the controls. Subgroup analysis showed that this was mainly attributable to complex CHD with higher SAM (P < 0.001), SAH (P = 0.012) and serum folate (P = 0.010) independent of carriership of MTHFR polymorphisms. Highest concentrations of SAM, SAH and folate RBC were observed in complex syndromic CHD. The subgroup of children with Down syndrome, however, showed significantly higher SAH (P = 0.037) and significantly lower SAM:SAH ratio (P = 0.034) compared with other complex CHD, suggesting a state of global hypomethylation.Conclusion High concentrations of methylation biomarkers in very young children are associated with complex CHD. Down syndrome and CHD may be associated with a global hypomethylation status, which has to be confirmed in tissues and global DNA methylation in future studies.

Preferences for postpartum lifestyle counseling among women sharing an increased cardiovascular and metabolic risk: A focus group study (Article)

2011-02-01T00:00:00Z

Objective. To describe women's preferences for postpartum lifestyle counseling after a pregnancy complicated by preeclampsia, intrauterine growth restriction, and/or gestational diabetes. Methods. Thirty-six women who had experienced these pregnancy complications participated in six focus group interviews. Results. All women expressed a need for participation in postpartum lifestyle counseling. They preferred participation to be tailored to individual preferences. A combination of face-to-face counseling supported by computer-tailored lifestyle advice appealed to them. Conclusion. Postpartum lifestyle counseling aimed at these women should be tailored to individual needs and preferences.

Individual accumulation of heterogeneous risks explains perinatal inequalities within deprived neighbourhoods (Article)

2011-02-01T00:00:00Z

Dutch' figures on perinatal mortality and morbidity are poor compared to EU-standards. Considerable within-country differences have been reported too, with decreased perinatal health in deprived urban areas. We investigated associations between perinatal risk factors and adverse perinatal outcomes in 7,359 pregnant women participating in population-based prospective cohort study, to establish the independent role, if any, for living within a deprived urban neighbourhood. Main outcome measures included perinatal death, intrauterine growth restriction (IUGR), prematurity, congenital malformations, Apgar at 5 min < 7, and pre-eclampsia. Information regarding individual risk factors was obtained from questionnaires, physical examinations, ultrasounds, biological samples, and medical records. The dichotomous Dutch deprivation indicator was additionally used to test for unexplained deprived urban area effects. Pregnancies from a deprived neighbourhood had an increased risk for perinatal death (RR 1.8, 95% CI [1.1; 3.1]). IUGR, prematurity, Apgar at 5 min < 7, and pre-eclampsia also showed higher prevalences (P < 0.05). Residing within a deprived neighbourhood was associated with increased prevalence of all measured risk factors. Regression analysis showed that the observed neighbourhood related differences in perinatal outcomes could be attributed to the increased risk factor prevalence only, without a separated role for living within a deprived neighbourhood. Women from a deprived neighbourhood had significantly more 'possibly avoidable' risk factors. To conclude, women from a socioeconomically deprived neighbourhood are at an increased risk for adverse pregnancy outcomes. Differences regarding possibly avoidable risk factors imply that preventive strategies may prove effective.

Foetal and postnatal growth and bone mass at 6 months: The Generation R Study (Article)

2011-02-01T00:00:00Z

Objective To examine whether parental, foetal and postnatal characteristics and growth patterns in foetal life and infancy are associated with bone mass at 6 months, as bone acquisition seems to be associated with genetic and environmental factors. Design This study was embedded in the Generation R Study, a prospective cohort from early foetal life onwards. Patients and measurements Bone mineral density (BMD) and bone mineral content (BMC) total body (TB) and BMD lumbar spine (LS) were measured by dual-energy X-ray absorptiometry in 252 infants at 6 months. Parental, foetal and postnatal data were collected by physical and foetal ultrasound examinations and questionnaires. Results Maternal, foetal and postnatal anthropometrics were positively associated with BMDTBand BMCTBat 6 months, but only postnatal anthropometrics were associated with BMDLS. A gain in weight-SD-score during foetal life and prenatal catch-up in weight were positively associated with BMDTB. After birth, a gain in weight-SD-score was positively associated with BMDLSand bone mineral apparent density (BMADLS). The effect was strongest between 6 weeks and 6 months. Catch-up in weight was associated with a lower probability of low (lowest quartile of) BMDTBand BMDLS. Children remaining in the first tertile of weight from birth to 6 months had a much higher risk of low BMDTBat 6 months [OR (95% CI): 15 (2, 88)]. Conclusions Our findings suggest that growth patterns in foetal and postnatal life are associated with bone mass in infancy and may have consequences for bone mass in later life. Follow-up studies are needed to assess whether and to what extent maternal anthropometrics, foetal and postnatal growth patterns have an effect on bone status in adulthood.

Sperm quality decline among men below 60 years of age undergoing IVF or ICSI treatment (Article)

2011-01-01T00:00:00Z

Because of changes in the society, couples in Western countries are increasingly delaying reproduction. This is accompanied by unhealthy lifestyles that may be detrimental not only to general health but also to reproductive capacity. It is well known that maternal age has detrimental effects on fertility; the paternal influence on this outcome is largely unknown. This study aims to investigate associations between a paternal age below 60 years, lifestyles, and sperm quality. In a periconceptional prospective cohort study we included 227 men undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Age at sperm collection, lifestyles, cause of subfertility, ethnicity, sperm DNA fragmentation index (DFI; as marker of sperm DNA damage), and sperm parameters were determined. Linear regression analyses showed a positive association between a rising age from 26 to 59 years and DFI (P ≤ .01) and an inverse association with ejaculate volume (P ≤ .05). Inverse associations were determined between DFI and all conventional sperm parameters (all P ≤ .01). There were no associations between smoking, alcohol use, body mass index, and DFI and sperm parameters. Dutch men compared to migrants, however, showed a higher DFI (P ≤ .05) independent of lifestyles. We conclude that the trend of delaying fatherhood in men undergoing IVF or ICSI treatment is detrimental to sperm quality. Copyright

A derangement of the maternal lipid profile is associated with an elevated risk of congenital heart disease in the offspring (Article)

2010-12-27T00:00:00Z

Background and aims: Maternal hyperglycaemia and hyperhomocysteinaemia are risk factors for congenital heart disease (CHD). These metabolic derangements and deranged lipid levels are associated with adult cardiovascular disease. We examined whether maternal lipid levels are associated with the risk of CHD offspring. Methods and Results: From 2003 onwards, a case-control study was conducted. Participants were mothers of children with (n = 261) and without (n = 325) CHD. At around 16 months after the index-pregnancy, maternal lipid levels were determined. Maternal characteristics and lipid levels were compared by Student's t-test. In a multivariable logistic regression model, risk estimates were calculated for associations between CHD and lipid levels. Adjustments were made for maternal age, diabetes, ethnicity, body mass index (BMI), parity, periconception folic acid use and total homocysteine levels. Outcome measures are presented in (geometric) means (p5-p95) and odds ratios (ORs) with 95% confidence intervals (CIs). Case mothers showed higher cholesterol (4.9 vs. 4.7 mmol l-1, P < 0.05), low-density lipoprotein (LDL)-cholesterol (3.2 vs. 3.0 mmol l-1, P < 0.05), apolipoprotein B (84.0 vs. 80.0 mg dl-1, P < 0.01) and homocysteine (10.8 vs. 10.2 μmol l-1, P < 0.05) than controls. LDL-cholesterol above 3.3 mmol l-1(OR 1.6 (95%CI, 1.1-2.3)) and apolipoprotein B above 85.0 mg dl-1were associated with an almost twofold increased CHD risk (OR 1.8 (95%CI, 1.2-2.6)). This was supported by elevated CHD risks per unit standard deviation increase in cholesterol (OR 1.2 (95% CI 1.03-1.5)), LDL-cholesterol (OR 1.3 (95%CI, 1.1-1.6) and apolipoprotein B (OR 1.3 (95% CI 1.1-1.6)). Apolipoprotein B was most strongly associated with CHD risk. Conclusion: A mildly deranged maternal lipid profile is associated with an increased risk of CHD offspring.

Calcium reduces risk of pre-eclampsia - Authors' reply (Article)

2010-12-11T00:00:00Z

The preconception nutritional status of women undergoing fertility treatment: Use of a one-year post-delivery assessment (Article)

2010-12-01T00:00:00Z

Background&Aims: A poor maternal nutritional status in the preconception period is associated with adverse pregnancy outcomes. A valid standardized assessment period after pregnancy reflecting the preconception nutritional status is missing. Therefore, this study aimed to validate the assessment period at around 1 year after delivery in women undergoing fertility treatment. Methods: In a prospective study including 30 women with a fertility problem, we compared nutrient intakes from a food frequency questionnaire and biomarkers related to the homocysteine pathway in blood, at two assessment periods, i.e., preconceptionally and 1 year after delivery. We used a linear mixed model and adjusted for possible confounders, such as body mass index and folic acid supplement use. Results: The energy-adjusted nutrient intakes were not significantly different between the two assessment periods, except for higher retinol, alcohol and vitamin B2 and lower carbohydrate intakes at around 1 year after delivery. The intraclass correlation coefficients of the nutrients ranged from 0.3 to 0.7. After adjustment, none of the biomarkers was significantly different between the two assessment periods. The intraclass correlation coefficients of the biomarkers were all ≥0.5. Conclusions: An assessment at around 1 year after delivery seems to adequately reflect the preconception nutritional status of women with a fertility problem, however larger confirmatory studies are required.

The preconception nutritional status of women undergoing fertility treatment: Use of a one-year post-delivery assessment (Article)

2010-12-01T00:00:00Z

Electroencephalography during normotensive and hypertensive pregnancy: A systematic review (Article)

2010-12-01T00:00:00Z

The objective of this review was to evaluate the available medical literature concerning the electroencephalogram (EEG) during hypertensive disorders of pregnancy. All articles found during a MEDLINE and Embase database search on the subject of EEG differences associated with hypertensive disorders in pregnancy were screened for eligibility. In all, 22 articles which describe the EEG during preeclampsia (PE)/eclampsia were retrieved. Abnormal EEG findings were observed in the majority of the preeclamptic/eclamptic patients, consisting of slow waves most frequently localized in the occipital lobe, as well as spike discharges. The EEG abnormalities in PE/eclampsia were reversible in the majority of the cases. We conclude that these described abnormalities may be interpreted as a warning sign of deterioration of brain function in PE/eclampsia. However, some caution regarding this conclusion is advised because most of the retrieved articles were published in the 1950s and 1960s, and were not consistent with current clinical guidelines or medical terminology. Further research is needed to establish the clinical value of implementing EEGs in the assessment of the preeclamptic/eclamptic patient. Target Audience: Obstetricians & Gynecologists, Neurologists, Family Physicians Learning Objectives: After completion of this educational activity, the obstetrician, gynecologist and neurologist should be better able to evaluate whether the EEG is normal for pregnancy; distinguish EEG abnormalities in hypertensive disorders in pregnancy, and assess the value of EEG abnormalities in preeclampsia (PE)/eclampsia for the detection of early signs of ischemia. Copyright

Omphalocele: Comparison of outcome following prenatal or postnatal diagnosis (Article)

2010-12-01T00:00:00Z

Objectives To assess the impact of prenatal compared with postnatal diagnosis on outcome for liveborn infants with an isolated or with a non-isolated omphalocele. Methods This was a retrospective analysis of 101 prenatally and 45 postnatally diagnosed cases of omphalocele. Cases were collected from the ultrasound database of the Division of Obstetrics and Prenatal Medicine and the patient database of the Department of Pediatric Surgery. Results Following confirmation at delivery or autopsy, prenatally diagnosed omphaloceles included 21 isolated cases, 44 non-isolated cases with a normal karyotype and 36 non-isolated cases with an abnormal karyotype. Of the prenatally diagnosed apparently isolated cases (n = 31), 12 (39%; 95% CI, 22-58%) revealed associated anomalies after delivery. Liveborn infants with an isolated omphalocele had significantly worse short-term morbidity following prenatal diagnosis (n = 14) compared with diagnosis at birth (n = 29), having a lower gestational age at delivery, lower Apgar scores, longer duration of ventilation and parenteral nutrition, more readmissions and a longer hospital stay. The prenatally diagnosed subset contained more infants with a giant omphalocele (9/14 vs. 3/29, P = 0.001) and liver herniation (8/14 vs. 6/29, P = 0.02). The outcome of liveborn infants with a non-isolated omphalocele diagnosed prenatally (n = 17) was not different from that of those diagnosed at birth (n = 16), except for a greater need for ventilation and parenteral nutrition in the prenatal subset. Conclusion When counseling patients with a prenatal diagnosis of isolated omphalocele, it is important to remember that over one third could turn out to have associated anomalies. Liveborn infants with an isolated omphalocele detected prenatally have worse short-term morbidity than do cases detected at birth. Those with non-isolated omphaloceles detected prenatally have an increased need for ventilation and parenteral nutrition compared with those detected at birth. Copyright

Maternal smoking and blood pressure in different trimesters of pregnancy: The Generation R Study (Article)

2010-11-01T00:00:00Z

Objective: Smoking during pregnancy is a risk factor for various adverse birth outcomes but lowers the risk of preeclampsia. Cardiovascular adaptations might underlie these associations. We examined the associations of smoking in different trimesters of pregnancy with repeatedly measured blood pressure and the risks of preeclampsia and pregnancy-induced hypertension in a low-risk population-based cohort of 7106 pregnant women. Methods: This study was embedded in a population-based prospective cohort study from early pregnancy onwards. Smoking and systolic and diastolic blood pressures were assessed by questionnaires and physical examinations in each trimester of pregnancy. Information about preeclampsia and pregnancy-induced hypertension was obtained from medical records. Results: Compared to nonsmoking women, both first-trimester-only and continued smoking were associated with a steeper increase for systolic blood pressure and a lowest mid-pregnancy level and steeper increase thereafter for diastolic blood pressure throughout pregnancy. We did not find any significant associations in risk of preeclampsia for first-trimester-only smoking (odds ratio of 1.28, 95% confidence interval 0.74, 2.21) and continued smoking (odds ratio of 0.83, 95% confidence interval 0.50, 1.36), respectively. Conclusions: Our results suggest that both first-trimester-only and continued smoking are associated with persistent maternal cardiovascular adaptations during pregnancy. Strategies for prevention of smoking during pregnancy should be focused on the preconception period. The effects of early and late-pregnancy smoking on the risk of preeclampsia should be further explored. Our results should be carefully interpreted to the general population of pregnant women.

The Generation R Study: Design and cohort update 2010 (Article)

2010-11-01T00:00:00Z

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health during fetal life, childhood and adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. General follow-up rates until the age of 4 years exceed 75%. Data collection in mothers, fathers and preschool children included questionnaires, detailed physical and ultrasound examinations, behavioural observations, and biological samples. A genome wide association screen is available in the participating children. Regular detailed hands on assessment are performed from the age of 5 years onwards. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

Retinol status of newborn infants is associated with congenital diaphragmatic hernia (Article)

2010-10-01T00:00:00Z

OBJECTIVE: Genetic analyses in humans suggest a role for retinoid-related genes in the pathogenesis of congenital diaphragmatic hernia (CDH). The goal of this study was to investigate the vitamin A status of mothers and their newborns in association with CDH. METHODS: We conducted a hospital-based, case-control study with 22 case and 34 control mothers and their newborns. In maternal and cord blood samples, retinol and retinol-binding protein (RBP) levels were measured with high-performance liquid chromatography and an enzyme-linked immunosorbent assay, respectively. Univariate and multivariate logistic regression analyses were performed to determine crude and adjusted risk estimates. RESULTS: Case newborns had significantly lower levels of retinol (0.60 vs 0.76 μmol/L; P=.003) and RBP (5.42 vs 7.11 mg/L; P=.02) than did control newborns. The multivariate logistic regression analysis showed lower levels of retinol and RBP in association with CDH risk; the odds ratio for retinol levels of <15th percentile (<0.61 μmol/L) was 11.11 (95% confidence interval: 2.54-48.66; P=.001), and that for RBP levels of <15th percentile (<4.54 mg/L) was 4.00 (95% confidence interval: 1.00 -15.99; P=.05). Retinol and RBP levels were not different between case and control mothers. CONCLUSIONS: CDH is strongly associated with low retinol and RBP levels in newborns, independent of maternal retinol status. This is an important finding supporting the idea that human CDH is linked with abnormal retinoid homeostasis.

Effect of postpartum lifestyle interventions on weight loss, smoking cessation, and prevention of smoking relapse: A systematic review (Article)

2010-10-01T00:00:00Z

Postpartum lifestyle interventions are recommended for women after pregnancies complicated by preeclampsia, intrauterine growth restriction, and/or gestational diabetes, since they are at increased cardiovascular risk. To identify potential intervention strategies to reduce this risk, a systematic review of the literature is presented on the effectiveness of postpartum lifestyle interventions aimed at weight loss, smoking cessation, and smoking relapse prevention. The main characteristics of these postpartum lifestyle interventions are briefly described. The PubMed, Embase, Web of Science, PsychInfo, and Cinahl databases were searched for studies on the effects of postpartum lifestyle interventions on weight loss, and smoking cessation or prevention of smoking relapse, initiated for up to 1 year postpartum. No studies on the effectiveness of postpartum lifestyle interventions after the aforementioned specific pregnancy complications were found. However, 21 studies are included that describe existing postpartum lifestyle interventions, which were applied to unselected (on the basis of pregnancy complications) postpartum women. Copyright

Mother's educational level and fetal growth: The genesis of health inequalities (Article)

2010-10-01T00:00:00Z

Background: Women of low socio-economic status (SES) give birth to lighter babies. It is unknown from which moment during pregnancy socio-economic differences in fetal weight can be observed, whether low SES equally affects different fetal-growth components, or what the effect of low SES is after taking into account mediating factors. Methods: In 3545 pregnant women participating in the Generation R Study, we studied the association of maternal educational level (high, mid-high, mid-low and low) as a measure of SES with fetal weight, head circumference, abdominal circumference and femur length. We did this before and after adjusting for potential mediators, including maternal height, pre-pregnancy body mass index and smoking. Results: In fetuses of low-educated women relative to those of high-educated women, fetal growth was slower, leading to a lower fetal weight that was observable from late pregnancy onwards. In these fetuses, growth of the head [-0.16 mm/week; 95% confidence interval (CI): -0.25 to -0.07; P = 0.0004], abdomen (-0.10 mm/week; 95% CI: -0.21 to 0.01; P = 0.08) and femur (-0.03 mm/week; 95% CI: -0.05 to -0.006; P = 0.01) were all slower; from mid-pregnancy onwards, head circumference was smaller, and from late pregnancy onwards, femur length was also smaller. The negative effect of low education was greatest for head circumference (difference in standard deviation score in late pregnancy: -0.26; 95% CI: -0.36 to -0.15; P < 0.0001). This effect persevered even after adjustment for the potential mediators (adjusted difference: -0.14; 95% CI: -0.25 to -0.03; P = 0.01). Conclusions: Low maternal education is associated with a slower fetal growth and this effect appears stronger for growth of the head than for other body parts. Published by Oxford University Press on behalf of the International Epidemiological Association

Perinatal complications increase the risk of postpartum depression. The Generation R Study (Article)

2010-10-01T00:00:00Z

Objective: To examine whether specific pregnancy and delivery complications are risk factors for postpartum depression. Design: A prospective longitudinal study. Setting: Rotterdam, the Netherlands. Population A cohort of 4941 pregnant women who enrolled in the Generation R Study. Methods: Information on perinatal complications was obtained from the midwife and hospital registries or by questionnaire. Logistic regression analyses were used to calculate the risk of postpartum depression for the separate perinatal complications. Main outcome measures: Postpartum psychiatric symptoms were assessed 2 months after delivery using the Edinburgh postnatal depression scale. Results: Several perinatal complications were significantly associated with postpartum depression, namely: pre-eclampsia (adjusted OR, aOR 2.58, 95% CI 1.30-5.14), hospitalization during pregnancy (aOR 2.25, 95% CI 1.19-4.26), emergency caesarean section (aOR 1.53, 95% CI 1.02-2.31), suspicion of fetal distress (aOR 1.56, 95% CI 1.08-2.27), a medically indicated delivery provided by an obstetrician (aOR 2.43, 95% CI 1.56-3.78), and hospital admission of the baby (aOR 1.45, 95% CI 1.10-1.92). Unplanned pregnancy, thrombosis, meconium-stained amniotic fluid, and Apgar score were not associated with postpartum depression after adjustment for confounding factors, such as pre-existing psychopathological symptoms and sociodemographic characteristics. The risk of postpartum depression increased with the number of perinatal complications women experienced (P < 0.001). Conclusions: We showed that several pregnancy and delivery complications present a risk for women's mental health in the postpartum period. Obstetricians, midwives, general practitioners, and staff at baby well clinics should be aware that women who experienced perinatal complications-especially those with a number of perinatal complications-are at risk for developing postpartum depression.

Study protocol: Cost effectiveness of two strategies to implement the NVOG guidelines on hypertension in pregnancy: An innovative strategy including a computerised decision support system compared to a common strategy of professional audit and feedback, a randomized controlled trial (Article)

2010-09-06T00:00:00Z

Background: Hypertensive disease in pregnancy remains the leading cause of maternal mortality in the Netherlands. Seventeen percent of the clinical pregnancies are complicated by hypertension and 2% by preeclampsia. The Dutch Society of Obstetrics and Gynaecology (NVOG) has developed evidence-based guidelines on the management of hypertension in pregnancy and chronic hypertension. Previous studies showed a low adherence rate to other NVOG guidelines and a large variation in usual care in the different hospitals. An explanation is that the NVOG has no general strategy of practical implementation and evaluation of its guidelines. The development of an effective and cost effective implementation strategy to improve adherence to the guidelines on hypertension in pregnancy is needed.Methods/Design: The objective of this study is to assess the cost effectiveness of an innovative implementation strategy of the NVOG guidelines on hypertension including a computerised decision support system (BOS) compared to a common strategy of professional audit and feedback. A cluster randomised controlled trial with an economic evaluation alongside will be performed. Both pregnant women who develop severe hypertension or pre-eclampsia and professionals involved in the care for these women will participate. The main outcome measures are a combined rate of major maternal complications and process indicators extracted from the guidelines. A total of 472 patients will be included in both groups. For analysis, descriptive as well as regression techniques will be used. A cost effectiveness and cost utility analysis will be performed according to the intention-to-treat principle and from a societal perspective. Cost effectiveness ratios will be calculated using bootstrapping techniques.

Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: The generation R study (Article)

2010-09-01T00:00:00Z

Context: Thyroid hormones are essential for neurodevelopment from early pregnancy onward. Yet population-based data on the association between maternal thyroid function in early pregnancy and children's cognitive development are sparse. Objective: Our objective was to study associations of maternal hypothyroxinemia and of early pregnancy maternal TSH and free T4(FT4) levels across the entire range with cognitive functioning in early childhood. Design and Setting: We conducted a population-based cohort in The Netherlands. Participants: Participants included 3659 children and their mothers. Main Measures: In pregnant women with normal TSH levels at 13 wk gestation (SD = 1.7), mild and severe maternal hypothyroxinemia were defined as FT4concentrations below the 10th and 5th percentile, respectively. Children's expressive vocabulary at 18 months was reported by mothers using the MacArthur Communicative Development Inventory. At 30 months, mothers completed the Language Development Survey and the Parent Report of Children's Abilities measuring verbal and nonverbal cognitive functioning. Results: Maternal TSH was not related to the cognitive outcomes. An increase in maternal FT4predicted a lower risk of expressive language delay at 30 months only. However, both mild and severe maternal hypothyroxinemia was associated with a higher risk of expressive language delay across all ages [odds ratio (OR) = 1.44; 95% confidence interval (CI) = 1.09-1.91; P = 0.010 and OR = 1.80; 95% CI = 1.24-2.61; P = 0.002, respectively]. Severe maternal hypothyroxinemia also predicted a higher risk of nonverbal cognitive delay (OR = 2.03; 95% CI = 1.22-3.39; P = 0.007). Conclusions: Maternal hypothyroxinemia is a risk factor for cognitive delay in early childhood. Copyright

Pregnancy-induced fluctuations in functional T-cell subsets in multiple sclerosis patients (Article)

2010-09-01T00:00:00Z

Background: During pregnancy, especially during the third trimester, multiple sclerosis (MS) disease activity is reduced. It is not known which factors mediate this disease amelioration. Objective: To study whether the frequency of two important T-cell subsets, T-helper 17 (Th17) and regulatory T-cells (Treg), is altered in relation to pregnancy-induced MS disease amelioration. Methods: Each individual was tested longitudinally, after sampling of blood at timepoints before pregnancy, during the first and third trimester, and in the early post-partum period. Frequencies of Th17 cells were assessed after short (4 hours) re-stimulation of peripheral blood lymphocytes with PMA and ionomycin, followed by flow cytometry using CD4, CD45RO and IL-17A antibodies. To assess peripheral blood Treg frequencies, we used six-colour flow cytometry with antibodies against CD3, CD4, CD25, CD127, FoxP3 and HLA-DR, to specifically identify Treg. Results: Both MS patients (n = 9) and controls (n = 8) displayed unaltered Th17 frequencies during pregnancy. In contrast, circulating Treg frequency significantly decreased in MS patients (n = 15) during the first and third (p < 0.001) trimesters compared with the period before pregnancy. In the post-partum period, the frequency of circulating Treg again resurged back to near pre-pregnancy levels. In controls (n = 15) comparable frequency kinetics were observed in that post-partum a significant increase in circulating Treg frequency was detected compared with the first (p < 0.001) and third (p = 0.012) trimester. Conclusions: Third trimester amelioration is not related to the fluctuation of circulating Th17 cells. Furthermore, a paradoxical decrease of immunosuppressive circulating Tregs can be observed during this phase, both in MS patients and controls.

Teratogenicity and underlying mechanisms of homocysteine in animal models: A review (Article)

2010-08-19T00:00:00Z

Background: Hyperhomocysteinemia in humans is a risk factor for adverse pregnancy outcome, especially congenital malformations. This review summarizes the studies directed on the teratogenicity of homocysteine carried out in animal studies, and elaborates on the underlying mechanisms. Methods: Literature was searched in Pubmed (NCBI) through January 2010 and selected manually. Keywords comprised homocysteine, congenital abnormalities and animals. Results: Increased frequencies of a wide range of congenital malformations are reported especially in the chicken embryo after exposure to homocysteine (Hcy) in various dosages and forms. Reduced embryonic growth and abnormalities of the vascularization of the yolk sac are described in mouse studies. A study in rats revealed a reduced development of blastocysts. The congenital malformations observed in the chicken embryo model share the mutual involvement of Hcy sensitive neural crest cells. Derangements in the behavior of these cells by interactions between Hcy and pathways involved in vascularization, growth, metabolism, signaling, and DNA synthesis and methylation may explain the wide range of effects on embryonic organs, the yolk sac and placental tissues. Conclusions: The associations between human hyperhomocysteinemia and congenital malformations are substantiated by chicken and rodent studies. Moreover, derangements of several pathways induced by Hcy are demonstrated with adverse effects on both reproduction and long term health. Because of the high prevalence of hyperhomocysteinemia in both the reproductive and general population, research on underlying epigenetic mechanisms is warranted.

Indirect maternal mortality increases in the Netherlands (Article)

2010-06-01T00:00:00Z

Objective. To assess causes, trends, and substandard care in indirect maternal mortality in the Netherlands. Design. Confidential enquiry into causes of maternal death. Setting. Nationwide in the Netherlands. Population. A total of 2,557,208 live births. Methods. Data analysis of indirect maternal deaths in the period 1993-2005. Main outcome measures. Indirect maternal mortality. Results. Of the study subjects, 97 were classified as indirect deaths, representing a maternal mortality ratio of 3.3/100,000 live births, a significant increase compared to the preceding enquiry in the period 1983-1992 (MMR 2.4, OR 1.5, 95%CI 1.0-2.1). The percentage of cases not directly reported to the Maternal Mortality Committee decreased from 15 to 5%. Cardiovascular disorders were the leading cause of indirect maternal mortality, followed by cerebrovascular disorders. Vascular dissection (n=19) was the most frequent specified cause of death. Risk factors were advanced maternal age, non-indigenous origin (Surinam and Dutch Antilles), and medical health risks before pregnancy. Substandard care was present in 35%, mainly being misjudgment of the severity of the condition and delay in initiating therapy. Conclusion. The rise of mortality due to indirect causes is considered a reflection of the change in risk profile of women of childbearing age and the result of demographic alterations concerning ethnicity and maternal age. The identification of high risk groups, preferably by programs of preconception care, should lead to improved care for these women, with a multidisciplinary approach when needed.

Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: The Generation R Study (Article)

2010-06-01T00:00:00Z

Background: Caffeine is a widely used and accepted pharmacologically active substance. The effect of caffeine intake during pregnancy on fetal growth and development is still unclear. Objective: We examined the associations of maternal caffeine intake, on the basis of coffee and tea consumption, with fetal growth characteristics measured in each trimester of pregnancy and the risks of adverse birth outcomes. Design: Associations were studied in 7346 pregnant women participating in a population-based prospective cohort study from early pregnancy onward in the Netherlands (2001-2005). Caffeine intake in the first, second, and third trimesters was on the basis of coffee and tea consumption and was assessed by questionnaires. Fetal growth characteristics were repeatedly measured by ultrasound. Information about birth outcomes was obtained from hospital records. Results: We observed no consistent associations of caffeine intake with fetal head circumference or estimated fetal weight in any trimester. Higher caffeine intake was associated with smaller first-trimester crown-rump length, second- and third-trimester femur length, and birth length (P for trend <0.05). Offspring of mothers who consumed ≥6 caffeine units/d tended to have increased risks of small-for-gestational-age infants at birth. Conclusions: Our results suggest that caffeine intake of ≥6 units/d during pregnancy is associated with impaired fetal length growth. Caffeine exposure might preferentially adversely affect fetal skeletal growth. Further studies are needed to assess these associations in non-European populations and to assess the postnatal consequences.

Innovative virtual reality measurements for embryonic growth and development (Article)

2010-06-01T00:00:00Z

Background Innovative imaging techniques, using up-to-date ultrasonic equipment, necessitate specific biometry. The aim of our study was to test the possibility of detailed human embryonic biometry using a virtual reality (VR) technique. Methods In a longitudinal study, three-dimensional (3D) measurements were performed from 6 to 14 weeks gestational age in 32 pregnancies (n = 16 spontaneous conception, n = 16 IVF/ICSI). A total of 125 3D volumes were analysed in the I-Space VR system, which allows binocular depth perception, providing a realistic 3D illusion. Crown-rump length (CRL), biparietal diameter (BPD), occipito-frontal diameter (OFD), head circumference (HC) and abdominal circumference (AC) were measured as well as arm length, shoulder width, elbow width, hip width and knee width. Result SCRL, BPD, OFD and HC could be measured in more than 96 of patients, and AC in 78. Shoulder width, elbow width, hip width and knee width could be measured in more than 95 of cases, and arm length in 82 of cases. Growth curves were constructed for all variables. Ear and foot measurements were only possible beyond 9 weeks gestation. Conclusions This study provides a detailed, longitudinal description of normal human embryonic growth, facilitated by a VR system. Growth curves were created for embryonic biometry of the CRL, BPD, HC and AC early in pregnancy and also of several 'new' biometric measurements. Applying virtual embryoscopy will enable us to diagnose growth and/or developmental delay earlier and more accurately. This is especially important for pregnancies at risk of severe complications, such as recurrent late miscarriage and early growth restriction.

Pharmacokinetics of clindamycin in pregnant women in the peripartum period (Article)

2010-05-01T00:00:00Z

The study presented here was performed to determine the pharmacokinetics of intravenously administered clindamycin in pregnant women. Seven pregnant women treated with clindamycin were recruited. Maternal blood and arterial and venous umbilical cord blood samples were obtained. Maternal clindamycin concentrations were analyzed by nonlinear mixed-effects modeling with the NONMEM program. The data were best described by a linear three-compartment model. The clearance and the volume of distribution at steady state were 10.0 liters/h and 6.32 × 103liters, respectively. Monte Carlo simulations were performed to determine the area under the concentration curve (AUC) for the free (unbound) drug (f) in maternal serum for 24 h divided by the MIC (fAUC0-24/MIC) . At a MIC of 0.5 mg/liter, which is the EUCAST breakpoint, the attainment at the lower 95% confidence interval (CI) was 24.6 if the level of protein binding was 65%, and this value concurred well with the target value of 27. However, for higher degrees of protein binding, as has been described in the literature, the attainment was lower, down to 10.2 for a protein binding level of 85% (lower 95% CI). The concentrations in umbilical cord blood were lower than those in maternal blood. The concentration-time profiles in maternal serum indicate that the level of exposure to clindamycin may be too low in these patients. Together with the lower concentrations in umbilical cord blood, this finding suggests that the current dosing regimen may not be adequate to protect all neonates from group B streptococcal disease. Copyright

Growth in foetal life and infancy is associated with abdominal adiposity at the age of 2 years: The generation R study (Article)

2010-05-01T00:00:00Z

Objective Early weight gain is associated with an increased risk of obesity. It is not known whether rapid weight gain in foetal life and infancy is also associated with increased abdominal adiposity. We examined the associations of foetal and postnatal growth characteristics with abdominal fat mass at the age of 2 years. Design This study was performed in 481 children participating in a prospective cohort study from early foetal life onward. Measurements Foetal and postnatal growth characteristics in second and third trimester, at birth and at the age of 2 years were related to abdominal fat mass (subcutaneous distance and area, preperitoneal distance and area) measured by ultrasound at the age of 2 years. Results Foetal and birth weight were not associated with abdominal subcutaneous fat mass. Estimated foetal weight in second trimester of pregnancy was inversely associated with preperitoneal fat area [-3·73% (95% confidence interval -7·23, -0·10)] per standard deviation score increase in weight. Weight gain from birth to the age of 2 years was positively associated with preperitoneal fat mass measures. These associations remained significant after adjustment for age, sex, breastfeeding and body mass index. Positive associations were found between catch-up growth in weight and abdominal fat mass measures. Conclusions Our results suggest that rapid growth rates during foetal life and infancy are associated with increased abdominal subcutaneous and preperitoneal fat mass in healthy children. Further studies need to explore whether these associations persist in later life and are related to metabolic syndrome outcomes.

Variants in ADCY5 and near CCNL1 are associated with fetal growth and birth weight (Article)

2010-05-01T00:00:00Z

To identify genetic variants associated with birth weight, we meta-analyzed six genome-wide association (GWA) studies (n = 10,623 Europeans from pregnancy/birth cohorts) and followed up two lead signals in 13 replication studies (n = 27,591). rs900400 near LEKR1 and CCNL1 (P = 2 × 10 35) and rs9883204 in ADCY5 (P = 7 × 10 15) were robustly associated with birth weight. Correlated SNPs in ADCY5 were recently implicated in regulation of glucose levels and susceptibility to type 2 diabetes, providing evidence that the well-described association between lower birth weight and subsequent type 2 diabetes has a genetic component, distinct from the proposed role of programming by maternal nutrition. Using data from both SNPs, we found that the 9% of Europeans carrying four birth weight-lowering alleles were, on average, 113g (95% CI 89-137g) lighter at birth than the 24% with zero or one alleles (P trend = 7 × 10 30). The impact on birth weight is similar to that of a mother smoking 4-5 cigarettes per day in the third trimester of pregnancy.

Pregnancy outcome in women with repaired versus unrepaired isolated ventricular septal defect (Article)

2010-05-01T00:00:00Z

Objective To compare the risks of pregnancy complications in women with repaired and unrepaired isolated ventricular septal defect (VSD). Design A retrospective multicentre study. Setting Tertiary centres in the Netherlands and Belgium. Methods Women were identified using two congenital heart disease registries. Eighty-eight women were identified who had experienced 202 pregnancies, including 46 miscarriages and nine terminations of pregnancy. Information on each completed pregnancy (n = 147; unrepaired VSD, n = 104; repaired VSD, n = 43) was obtained using medical records and telephone interviews. Data from the Generation R database (prospective cohort study; n = 9667) were used to determine the background risk (controls). Odds ratios and 95% CI were estimated using general estimation equation analysis adjusted for multiple pregnancies per woman, maternal age and parity status. Main outcome measures Adjusted odds ratios (AORs) for developing pregnancy complications in relation to corrective status. Results Pregnancies in women with an unrepaired VSD were associated with a higher risk of pre-eclampsia (AOR 4.59, 95% CI 2.01-10.5, P < 0.001) compared with controls. No differences were observed when comparing women with repaired VSD and controls. Pregnancies in women with repaired VSD were associated with a higher risk of premature labour (AOR 4.02, 95% CI 1.12-14.4, P = 0.03) and small-for-gestational-age (SGA) births (AOR 4.09, 95% CI 1.27-13.2, P = 0.02) compared with women with unrepaired VSD. Conclusions Women with unrepaired VSD are at increased risk of pre-eclampsia, which suggests that it is not a benign condition. In addition, women with repaired VSD are at increased risk of premature labour and SGA births compared with women with unrepaired VSD.

A prospective study on intrauterine cannabis exposure and fetal blood flow (Article)

2010-04-01T00:00:00Z

Background: Cannabis is commonly used among pregnant women. It is unclear whether cannabis exposure causes hemodynamic modifications in the fetus, like tobacco does. Aims: This study aims to ascertain fetal blood redistribution due to intrauterine cannabis exposure. Methods: This study was embedded in the Generation R Focus Study, a population-based cohort of parents and children followed from pregnancy onwards. In late pregnancy, fetal hemodynamics was assessed with ultrasound measurements in cannabis-exposed and non-exposed fetuses. Pregnant women reported about substance use during pregnancy. A distinction was made between continued cannabis use (n=9), cannabis use only in early pregnancy (n=14), continued tobacco use (n=85), tobacco use only in early pregnancy (n=92), and no tobacco or cannabis use during pregnancy (n=85). Results: Continued cannabis use was associated with an increased pulsatility and resistance index of the uterine artery, while discontinued cannabis use was associated with a decreased pulsatility, and resistance index, as compared to controls. Additionally, continued cannabis exposure resulted in a significantly higher uterine pulsatility index and uterine resistance index compared to tobacco exposure. Continued cannabis use was found to be associated with a smaller aortic diameter, as well. No association between intrauterine cannabis exposure and the fetal cerebral vascular system was found. Conclusions: Our findings suggest that intrauterine cannabis exposure was associated with changes in hemodynamic programming of the vascular system of the fetus in late pregnancy mainly due to tobacco exposure, but intrauterine cannabis exposure did demonstrate a specific effect on the uterine blood flow.

Prevalence of double incontinence, risks and influence on quality of life in a general female population (Article)

2010-04-01T00:00:00Z

Background: Urinary incontinence (UI) and anal incontinence (AI) are complaints with impact on quality of life (QOL). Few data are available on prevalence of double incontinence (DI) in the general female population. Objective: To determine prevalence of UI, AI, and DI, their associations with age, parity, and effects on QOL. Design, Setting, and Participants: Cross-sectional study on a general female population, aged 45-85 years. Measurements: Validated questionnaires measuring pelvic floor dysfunction and QOL. A short questionnaire was used for non-responders. Analyses were performed with Chi-square tests, ANOVA, and logistic regression. Results: Response rate was 62.7% (1,869/2,979); 59% of non-responders filled in the short questionnaire (620/1,051). No significant differences in stress urinary incontinence, vaginal bulging, solid stool incontinence and parity were found between responders and non-responders. DI with and without flatal incontinence were reported by 7.7% and 35.4%, respectively. Women with urge urinary incontinence (UUI) alone had an OR of 4.3 (95% CI 2.4-7.9) for liquid stool incontinence, 1.6 (95% CI 0.5-4.9) for solid stool incontinence and 2.4 for flatal incontinence (95% CI 1.5-3.8). Women with AI had an OR of 5.8 (95% CI 1.8-18.2) for UUI. Women with DIincluding flatus reported significantly poorer QOL. Limitation of the study was the lack of objective clinical validation of symptoms, which may have influenced the real prevalence data. Conclusions: Most important relation was found between UUI and liquid stool incontinence (OR 4.3). We recommend that clinicians take the history of patients with UUI or mixed urinary incontinence to exclude the co-existence of AI. Neurourol. Urodynam. 29:545-550, 2010.

Glucocorticoid receptor gene polymorphisms do not affect growth in fetal and early postnatal life. The Generation R Study (Article)

2010-03-03T00:00:00Z

Background: Glucocorticoids have an important role in early growth and development. Glucocorticoid receptor gene polymorphisms have been identified that contribute to the variability in glucocorticoid sensitivity. We examined whether these glucocorticoid receptor gene polymorphisms are associated with growth in fetal and early postnatal life.Methods: This study was embedded in a population-based prospective cohort study from fetal life onwards. The studied glucocorticoid receptor gene polymorphisms included BclI (rs41423247), TthIIII (rs10052957), GR-9β (rs6198), N363S (rs6195) and R23K (rs6789 and6190). Fetal growth was assessed by ultrasounds in second and third trimester of pregnancy. Anthropometric measurements in early childhood were performed at birth and at the ages of 6, 14 and 24 months postnatally. Analyses focused on weight, length and head circumference. Analyses were based on 2,414 healthy, Caucasian children.Results: Glucocorticoid receptor gene polymorphisms were not associated with fetal weight, birth weight and early postnatal weight. Also, no associations were found with length and head circumference. Neither were these polymorphisms associated with the risks of low birth weight or growth acceleration from birth to 24 months of age.Conclusions: We found in a large population-based cohort no evidence for an effect of known glucocorticoid receptor gene polymorphisms on fetal and early postnatal growth characteristics. Further systematic searches for common genetic variants by means of genome-wide association studies will enable us to obtain a more complete understanding of what genes and polymorphisms are involved in growth in fetal life and infancy.

Pelvic floor muscle function in a general population of women with and without pelvic organ prolapse (Article)

2010-03-01T00:00:00Z

Introduction and hypothesis: This study aims to examine the relationship between pelvic floor muscle function (PFMF) and pelvic organ prolapse (POP) in a general female population. Methods: Cross-sectional study on women aged 45-85 years. Validated questionnaires were used to assess pelvic floor muscle function. POP and PFMF were evaluated with vaginal examination. For statistical analysis chi-squared test for trend and analysis of variance were used. Results: Response rate to the questionnaire was 62.7% (1,869/2,979). No significant differences were found in muscle strength and endurance during voluntary muscle contraction between the POP stages. Women with POP stages I and II were significantly less able to achieve effective involuntary muscle contraction during coughing (38.3% and 37.7%) than women without POP (75.2%). Conclusion: Involuntary contraction of the PFM during coughing (that resulted in stabilization of the perineum) was significantly weaker in the women with POP stage I and II than in the women without POP.

Erratum: Prediction model and prognostic index to estimate clinically relevant pelvic organ prolapse in a general female population (International Urogynecology Journal and Pelvic Floor Dysfunction DOI: 10.1007/s00192-009-0903- 0) (Article)

2010-03-01T00:00:00Z

Ethnic differences in informed decision-making about prenatal screening for Down's syndrome (Article)

2010-03-01T00:00:00Z

Background: The aim of this study was to assess ethnic variations in informed decision-making about prenatal screening for Down's syndrome and to examine the contribution of background and decision-making variables. Methods: Pregnant women of Dutch, Turkish and Surinamese origin were recruited between 2006 and 2008 from community midwifery or obstetrical practices in The Netherlands. Each woman was personally interviewed 3 weeks (mean) after booking for prenatal care. Knowledge, attitude and participation in prenatal screening were assessed following the 'Multidimensional Measure of Informed Choice' that has been developed and applied in the UK. Results: In total, 71% of the Dutch women were classified as informed decision-makers, compared with 5% of the Turkish and 26% of the Surinamese women. Differences between Surinamese and Dutch women could largely be attributed to differences in educational level and age. Differences between Dutch and Turkish women could mainly be attributed to differences in language skills and gender emancipation. Conclusion: Women from ethnic minority groups less often made an informed decision whether or not to participate in prenatal screening. Interventions to decrease these ethnic differences should first of all be aimed at overcoming language barriers and increasing comprehension among women with a low education level. To further develop diversity-sensitive strategies for counselling, it should be investigated how women from different ethnic backgrounds value informed decisionmaking in prenatal screening, what decision-relevant knowledge they need and what they take into account when considering participation in prenatal screening.

Rise in maternal mortality in the Netherlands (Article)

2010-03-01T00:00:00Z

Objective To assess causes, trends and substandard care factors in maternal mortality in the Netherlands. Design Confidential enquiry into the causes of maternal mortality. Setting Nationwide in the Netherlands. Population 2,557,208 live births. Methods Data analysis of all maternal deaths in the period 1993-2005. Main outcome measures Maternal mortality. Results The overall maternal mortality ratio was 12.1 per 100 000 live births, which was a statistically significant rise compared with the maternal mortality ratio of 9.7 in the period 1983-1992 (OR 1.2, 95% CI 1.0-1.5). The most frequent direct causes were (pre-)eclampsia, thromboembolism, sudden death in pregnancy, sepsis, obstetric haemorrhage and amniotic fluid embolism. The number of indirect deaths also increased, mainly caused by an increase in cardiovascular disorders (OR 2.5, 95% CI 1.4-4.6). Women younger than 20 years and older than 45 years, those with high parity or from nonwestern immigrant populations were at higher risk. Most substandard care was found in women with pre-eclampsia (91%) and in immigrant populations (62%). Conclusions Maternal mortality in the Netherlands has increased since 1983-1992. Pre-eclampsia remains the number one cause. Groups at higher risk for complications during pregnancy should be better identified early in pregnancy or before conception, in order to receive preconception advice and more frequent antenatal visits. There is an urgent need for the better education of women and professionals concerning the danger signs, and for the training of professionals in order to improve maternal health care.

Kidney growth curves in healthy children from the third trimester of pregnancy until the age of two years. The Generation R Study (Article)

2010-02-01T00:00:00Z

Information about growth of kidney structures in early life is limited. In a population-based prospective cohort study, from foetal life onwards, we constructed reference curves for kidney growth from the third trimester of pregnancy until early childhood, using data from 1,158 healthy children. Kidney size, defined as length, width, depth and volume, was measured in the third trimester of pregnancy and at the postnatal ages of 6 months and 24 months. Analyses were based on more than 2,500 kidney measurements. In the third trimester of pregnancy and at 6 months of age all kidney measurements were larger in boys than in girls. At 24 months of age, these gender differences were only significant for left kidney structures and right kidney length. Both groups showed trends towards smaller left kidney measurements than right kidney measurements at all ages. Gender-specific reference curves based on post-conceptional and postnatal ages were constructed for left and right kidney length, width, depth and volume. We concluded that kidney size is influenced by age and gender. Left kidney size tended to be smaller than right kidney size, except for kidney length. The reference curves can be used for assessing kidney structures by ultrasound in foetal life and early childhood.

Insulin VNTR and IGF-1 promoter region polymorphisms are not associated with body composition in early childhood: The generation R study (Article)

2010-02-01T00:00:00Z

Objective: The objective of this study was to examine the associations between insulin gene variable number of tandem repeats (INS VNTR) and insulin-like growth factor 1 (IGF1) gene promoter region polymorphisms with body composition in early childhood. Methods: This study was embedded in an ongoing prospective cohort study. Growth in early childhood (body mass index, total subcutaneous fat mass and waist-hip ratio) was assessed at birth and at the ages of 6 weeks and 24 months. DNA for genotyping was available in 738 children. Results: The genotype distribution of the INS VNTR gene was I/I 50.4%, I/III 40.4%, and III/III 9.2%. IGF1 genotypes were categorized in the following categories based on their 192-bp allele: homozygous (wild-type) 43.1%, heterozygous 45.8%, and noncarrier 11.2%. No differences were found in body mass index, total subcutaneous fat mass and waist-hip ratio in early childhood between the three groups for both the INS VNTR and IGF1 genotypes. We also did not find interactions between these genotypes and gender or birth weight on the effects of body composition measures. Conclusions: Our results do not support previous studies showing associations between INS VNTR and IGF1 promoter region polymorphisms with body composition in early childhood. Copyright

Proteomic analyses of the developing chicken cardiovascular system (Article)

2010-01-04T00:00:00Z

Up until today, no proteomics approaches have been described for heart muscle development. We describe a proteomics method to study the proteome of different heart structures at three stages of chicken embryonic development. For this purpose, a combination of gel separation, nanoLC separation and mass spectrometry was used. With this method, we identified in total 267 proteins in different tissue structures of chicken heart. We observed differences in protein abundance for a number of proteins between the different tissue structures and time points of development using spectral counting as a semiquantitative measure of protein abundance. For myosin-heavy chain 6, myosin-heavy chain 7, titin, connectin, collagen alpha-1, and xin, differences in protein levels for the different stages and structures (great arteries, outflow tract and ventricles) have been observed. A pathway analysis is performed in which the identified proteins are related to theoretical protein networks. Most prominent was the 'cardiovascular system development and function' network with the abundantly present proteins myosin 6 and myosin 7. We showed that myosin 6 is highly regulated in a stage and heart tissue specific manner. In conclusion, this method can be used to study changes in protein levels of chicken heart tissue in a spatiotemporal manner.

Increased preconception omega-3 polyunsaturated fatty acid intake improves embryo morphology (Article)

2010-01-01T00:00:00Z

The association between preconception dietary intake of the polyunsaturated fatty acids (LC-PUFAs) omega-6 and omega-3 and the E2 levels and IVF/intracytoplasmic sperm injection (ICSI) outcome were investigated in women in a prospective study. It revealed that high intakes of omega-3 LC-PUFA alpha-linolenic acid increase baseline E2, high intakes of eicosapentaenoic acid and docosahexaenoic acid reduce E2 response and the number of follicles after ovarian stimulation, and total omega-3 intake, in particular alpha-linolenic acid and docosahexaenoic acid, improve embryo morphology.

Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate (Article)

2010-01-01T00:00:00Z

We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10-8, relative risk in homozygotes = 1.84, 95% CI 1.342.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10-8, relative risk in homozygotes = 2.17, 95% CI 1.323.56).

VEGF polymorphisms are associated with endocardial cushion defects: A family-based case-control study (Article)

2010-01-01T00:00:00Z

Endocardial cushion defects (ECDs) of the cardiac outflow tract are among the most common congenital heart disease phenotypes. VEGF is essential for endocardial cushion formation and derangements in VEGF synthesis lead to ECD. Three functional single nucleotide polymorphisms (SNPs) in the VEGF gene-2578 C>A,-1154 G>A, and-634 G>C play a role in cardiogenesis. In a Dutch case-control family study of triads, 190 case and 317 control children with both parents, we investigated linkage and association between these VEGF SNPs and ECD. Allele frequencies for the three VEGF SNPs were comparable between ECD children and controls. However, VEGF alleles-2578 C and-1154 G were transmitted more frequently to children with ECD (p = 0.003 and p = 0.002), in particular perimembranous ventricular septal defects (p = 0.012 and p = 0.006). The-2578A/-1154A/-634G haplotype was associated with a reduced risk of ECD (OR 0.7; 95% CI, 0.6-1.0) and was significantly less transmitted to children with ECD (p = 0.002). In a Dutch population, we show that the VEGF 2578 C,-1154 G alleles, and the AAG haplotype are associated with ECD. Possible VEGF gene-environment interactions exposures are discussed. Copyright

Ethnic differences in considerations whether or not to participate in prenatal screening for Down syndrome (Article)

2009-12-01T00:00:00Z

Objective: To evaluate ethnic differences in considerations whether or not to participate in prenatal screening for Down syndrome and to relate these to differences in participation. Method: The study population consisted of 270 pregnant women from Dutch, Turkish and Surinamese (African and South Asian) ethnic origin, attending midwifery or obstetrical practices in the Netherlands. Women were interviewed after booking for prenatal care. Considerations were assessed by one open-ended question and 18 statements that were derived from focus group interviews. Actual participation was assessed several months later. Results: Women from ethnic minorities were less likely to participate in prenatal screening, which could be attributed to differences in age and religious identity. They more often reported acceptance of 'what God gives', low risk of having a child with Down syndrome and costs of screening as considerations not to participate in prenatal screening. They also reported many considerations in favour of participation, which did not differ from those of Dutch women but were less often consistent with actual participation in screening. Conclusions: Women from ethnic minorities should not be stereotyped as being uninterested in prenatal screening, but should be better informed about the consequences of prenatal screening and Down syndrome. Copyright

Pelvic floor muscle function in a general female population in relation with age and parity and the relation between voluntary and involuntary contractions of the pelvic floor musculature. (Article)

2009-12-01T00:00:00Z

INTRODUCTION AND HYPOTHESIS: The objective of this study is to describe pelvic floor muscle function (PFMF) in relation to age and parity in a general female population and to test whether strength/endurance measurements represent all functions of the pelvic floor musculature. METHODS: A cross-sectional study was performed on 95% of the women aged 45-85 years from a small Dutch town. Validated questionnaires were used to obtain general information, and vaginal examination to test PFMF was performed on 649 women. Chi-square tests were used to analyse the relation between PFMF versus age and parity. Analysis of variance was used to compare muscle strength and endurance to the other PFMF items. RESULTS: Response rate to the questionnaire was 62.7% (1,869/2,979). PFM strength and endurance are not positively associated with the effective involuntary muscle contractions during coughing. CONCLUSIONS: Voluntary muscle contractions decreased with age, but there was no relation with parity. Muscle strength and endurance measurements alone are not sensitive enough to determine PFMF.

Resolution of hypertension and proteinuria after preeclampsia (Article)

2009-12-01T00:00:00Z

OBJECTIVE: To estimate the time required for hypertension and proteinuria to resolve after preeclampsia, and to estimate how this time to resolution correlates with the levels of blood pressure and proteinuria during preeclampsia and prolonging pregnancy after the development of preeclampsia. METHODS: This is a historic prospective cohort study of 205 preeclamptic women who were admitted between 1990 and 1992 at the Erasmus MC Medical Centre, Rotterdam, The Netherlands. Data were collected at 1.5, 3, 6, 12, 18, and 24 months after delivery. Hypertension was defined as a blood pressure 140/90 mm Hg or higher or use of antihypertensive drugs. Proteinuria was defined as 0.3 g/d or more. Resolution of hypertension and proteinuria were analyzed with the Turnbull extension to the Kaplan-Meier procedure. Correlations were calculated with an accelerated failure time model. RESULTS: At 3 months postpartum, 39% of women still had hypertension, which decreased to 18% at 2 years postpartum. Resolution time increased by 60% (P<.001) for every 10-mm Hg increase in maximal systolic blood pressure, 40% (P=.044) for every 10-mm Hg increase in maximal diastolic blood pressure, and 3.6% (P=.001) for every 1-day increase in the diagnosis-to-delivery interval. At 3 months postpartum, 14% still had proteinuria, which decreased to 2% at 2 years postpartum. Resolution time increased by 16% (P=.001) for every 1-g/d increase in maximal proteinuria. Gestational age at onset of preeclampsia was not correlated with resolution time of hypertension and proteinuria. CONCLUSION: The severity of preeclampsia and the time interval between diagnosis and delivery are associated with postpartum time to resolution of hypertension and proteinuria. After preeclampsia, it can take up to 2 years for hypertension and proteinuria to resolve. Therefore, the authors suggest that further invasive diagnostic tests for underlying renal disease may be postponed until 2 years postpartum.

Validation of an internet questionnaire for risk assessment in preconception care (Article)

2009-12-01T00:00:00Z

Aim: Validation of a self-administered Internet questionnaire for preconception risk assessment. Methods: Women with an appointment at the outpatient clinics for preconception care or fertility at the Erasmus Medical Center Rotterdam were requested to fill out the online questionnaire prior to attendance. Subsequently, the items of the questionnaire were verified by history taking during the first or next appointment. Agreement between the 2 screening methods (Internet vs. history taking) was calculated using Kappa statistic. Results: Most lifestyle variables, including smoking, alcohol, and dietary items, showed a good to high level of agreement when compared to the interview. Most medical history and obstetric history items also showed a good to high level of agreement. The use of over-the-counter drugs revealed a poor level of agreement (Kappa = 0.21). The items pertaining to women's family history showed a reasonable level of agreement; however, the partner's family history was unreliable and should be checked at the interview. Conclusion: The online questionnaire www.zwangerwijzer.nl is a useful tool for the identification of a number of potential risk factors in the preconception care setting and was found to be a an efficient and clear screening instrument by the majority of women. However, additional history taking by trained professionals is necessary to verify several items and to further explore identified risk factors for an adverse pregnancy outcome.

Residential traffic exposure and pregnancy-related outcomes: A prospective birth cohort study (Article)

2009-12-01T00:00:00Z

Background. The effects of ambient air pollution on pregnancy outcomes are under debate. Previous studies have used different air pollution exposure assessment methods. The considerable traffic-related intra-urban spatial variation needs to be considered in exposure assessment. Residential proximity to traffic is a proxy for traffic-related exposures that takes into account within-city contrasts. Methods. We investigated the association between residential proximity to traffic and various birth and pregnancy outcomes in 7,339 pregnant women and their children participating in a population-based cohort study. Residential proximity to traffic was defined as 1) distance-weighted traffic density in a 150 meter radius, and 2) proximity to a major road. We estimated associations of these exposures with birth weight, and with the risks of preterm birth and small size for gestational age at birth. Additionally, we examined associations with pregnancy-induced hypertension, (pre)eclampsia, and gestational diabetes. Results. There was considerable variation in distance-weighted traffic density. Almost fifteen percent of the participants lived within 50 m of a major road. Residential proximity to traffic was not associated with birth and pregnancy outcomes in the main analysis and in various sensitivity analyses. Conclusions. Mothers exposed to residential traffic had no higher risk of adverse birth outcomes or pregnancy complications in this study. Future studies may be refined by taking both temporal and spatial variation in air pollution exposure into account.

Body mass index is an important determinant of methylation biomarkers in women of reproductive ages (Article)

2009-12-01T00:00:00Z

B vitamin deficiencies lead to moderate hyperhomocysteinemia, which has been associated with health and disease. However, concomitant derangements in cellular methylation, reflected by altered plasma S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) concentrations, may be the primary cause. Therefore, we identified determinants of homocysteine, SAM, and SAH concentrations in 336 women, aged 20-48 y, as part of a large study focusing on risk factors for reproductive disorders. Blood was obtained to determine plasma SAM, SAH, and total homocysteine (tHcy), serum vitamin B-12 and folate, RBC folate concentrations, and the related single nucleotide polymorphisms 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C . T and 1298A . C, methionine synthase reductase (MTRR) 66A . G, and nicotinamide N-methyltransferase IVS1-151G . A. Questionnaires provided information on demographics, lifestyles, and nutrient intakes. Correlation coefficients were calculated and multivariable associations were assessed with a general linear model. Serum folate was positively correlated with SAM concentrations (r = 0.159; P = 0.004). Folate and vitamin B-12 were not correlated with SAH concentrations or the SAM:SAH ratio but were inversely correlated with tHcy concentrations (serum folate r = 20.324; RBC folate r = 20.294; vitamin B-12 r = 20.307; P , 0.01). From the multivariable analysis, BMI was the strongest determinant of SAM (standardized b = 19.145; P , 0.001) and SAH concentrations (standardized b = 3.241; P = 0.010). MTHFR 677TT (standardized b = 0.195; P = 0.001), B vitamin supplement use (standardized b = 20.156; P , 0.001) and dietary protein intake (standardized b = 20.011; P , 0.001) were the strongest determinants of tHcy concentrations. Thus, the determinants of SAM and SAH differ from those of tHcy concentrations. Given that BMI was a strong determinant of SAM concentrations, it should be included in future studies on cellular methylation.

Pelvic floor muscle function in a general female population in relation with age and parity and the relation between voluntary and involuntary contractions of the pelvic floor musculature. (Article)

2009-12-01T00:00:00Z

Role of nutrition, lifestyle factors, and genes in the pathogenesis of congenital diaphragmatic hernia: Human and animal studies (Article)

2009-12-01T00:00:00Z

Congenital diaphragmatic hernia (CDH) is a severe malformation with a largely unknown pathogenesis. Because an unequivocal genetic relation is diagnosed only in a minority of patients, the involvement of multiple genetic and environmental factors is suggested. Although periconceptional environmental exposures, such as maternal malnutrition and unhealthy lifestyle factors, are associated with several birth defects, they have scarcely been investigated in CDH. Nutrition and lifestyle factors can be modified and may, therefore, contribute to the prevention of CDH. This review provides an overview of the human studies in which the influences of nutrition and some related lifestyle factors during embryogenesis of the diaphragm are described. In addition, the findings in humans are further substantiated by animal studies and the nutrient-gene interactions involved are elaborated upon. The information presented here contributes to the elucidation of the pathogenesis of CDH and will assist the development of preventive nutritional strategies in the future.

First trimester interleukin 8 levels are associated with postpartum relapse in multiple sclerosis (Article)

2009-11-27T00:00:00Z

Pregnancy has an ameliorating effect on multiple sclerosis (MS), but directly after delivery the risk of a relapse is increased. The pro-inflammatory chemokine interleukin 8 is associated with disease activity. We aimed to investigate whether pregnancy-induced fluctuations of interleukin 8 correlate with periods of enhanced and diminished disease activity. Thirty-six women with MS were prospectively studied before, during and after pregnancy. Serum levels of interleukin 8 were significantly decreased during the third trimester (p = 0.03). High first trimester serum levels of interleukin 8 were associated with a high risk of postpartum relapse (p = 0.007). These results help us to further understand the altered disease course during pregnancy.

Periconceptional maternal folic acid use of 400 μg per day is related to increased methylation of the IGF2 gene in the very young child (Article)

2009-11-16T00:00:00Z

Background: Countries worldwide recommend women planning pregnancy to use daily 400 mg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. Methodology/Principal Findings: IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). Conclusions: Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use.

Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: Results of a national prospective study (Article)

2009-11-01T00:00:00Z

Objective. To determine the outcome of pregnancy in women with rheumatoid arthritis (RA) in relation to disease activity and medication use during the pregnancy. Methods. In a prospective study, pregnant women with RA were evaluated before conception (when possible), during each trimester of the pregnancy, and postpartum. Clinical characteristics, disease activity, medication use, and pregnancy outcome were analyzed. To examine the independent influence of prednisone use and disease activity on birth weight, regression analyses were performed, with adjustments for gestational age of the child at delivery, the sex of the newborn, and the mother's smoking status, education level, parity, and use of an assisted reproduction technique. Kaplan-Meier curve analyses were performed to examine the association between medication use and gestational age at delivery. Results. Data from 152 Caucasian RA patients with singleton pregnancies were available. Both the mean ± SD birth weight (3,379 ± 564 gm) and the mean ± SD birth weight standard deviation score (SDS; +0.1 ± 1.1), which is the birth weight adjusted for the gestational age and sex of the newborn, were comparable with those in the general population. On multiple linear regression analyses of birth weight and birth weight SDS, both of which were adjusted for covariates, only disease activity was associated with lower birth weight (P = 0.025). The gestational age at delivery was significantly lower in women who were taking prednisone (38.8 versus 39.9 weeks; P = 0.001), and their delivery was more often premature (<37 weeks; P = 0.004). Conclusion. Pregnancy outcome in women with well-controlled RA is comparable with that in the general population. The effect of prednisone on birth weight is mediated by a lower gestational age at delivery, whereas a higher level of disease activity independently influences birth weight negatively, suggesting an immune-mediated mechanism.

Comparison of pregnancy outcomes in women with repaired versus unrepaired atrial septal defect (Article)

2009-11-01T00:00:00Z

Objective To compare the risks of complications during pregnancy in women with repaired andunrepaired atrial septal defects (ASDs) without associated complex cardiac lesions. Design A retrospective multicentre study. Setting Tertiary centres in the Netherlands and Belgium. Population Women with ASD without associated complex cardiac lesions. Methods Women were identified using two congenital heart disease registries. One hundred women were identified who had 243 pregnancies, including 49 miscarriages and six terminations of pregnancy. Detailed information on each completed pregnancy (n = 188; unrepaired ASD, n = 133; repaired ASD, n = 55) was obtained using medical records and telephone interviews. In addition, data from the Generation R database (a prospective cohort study; n = 9667) were used to determine the background risk (control group). Main outcome measures Adjusted odds ratios (AORs) for cardiac, obstetric and neonatal events controlled for multiple pregnancies per woman using general estimating equation analysis. Results Women with an unrepaired ASD had a higher risk of neonatal events (AOR = 2.99, 95% confidence interval [CI] 1.14-7.89, P = 0.027) than women with a repaired ASD. The risk of cardiac and obstetric complications was comparable between women with unrepaired and repaired ASDs. Compared with the general population, women with an unrepaired ASD had higher risks of pre-eclampsia (AOR = 3.54, 95% CI 1.26-9.98, P = 0.017), small-for-gestational-age births (AOR = 1.95, 95% CI 1.15-3.30, P = 0.013) and fetal mortality (AOR = 5.55, 95% CI 1.77-17.4, P = 0.003). By contrast, no differences were observed when comparing women with a repaired ASD versus controls. Conclusions Women with an unrepaired ASD are at increased risk of neonatal events in comparison with women with a repaired ASD. Compared with the general population, women with an unrepaired ASD are at increased risk of pre-eclampsia, small-for-gestational-age births and fetal mortality.

Maternal medication use, carriership of the ABCB1 3435C > T polymorphism and the risk of a child with cleft lip with or without cleft palate (Article)

2009-10-01T00:00:00Z

Gene-environment interactions in the periconceptional period play an increasing role in the pathogenesis of birth defects, including cleft lip and/or cleft palate (CL/P). The P-glycoprotein, encoded by the ABCB1 gene, is suggested to protect the developing embryo from medication and other xenobiotic exposures. Furthermore, maternal medication use during early pregnancy is a significant risk factor for CL/P offspring. Therefore, the aim of this study is to investigate the association between the maternal and child's functional ABCB1 3435C > T polymorphism, periconceptional medication exposure, and the risk of a child with CL/P. A case-control study was performed among 175 mothers and 98 of their children with CL/P and 83 control mothers and their 65 children. Information on medication and folic acid use was collected. Mothers carrying the 3435TT genotype and using medication showed a 6.2-fold (95% CI = 1.6-24.2) increased risk of having a child with CL/P compared to mothers carrying the 3435CC genotype and not using medication. Periconceptional folic acid use reduced this risk by approximately 30% (OR = 3.9, 95% CI = 0.9-18.0). Mothers carrying the 3435TT genotype, using medication and not taking folic acid showed the highest risk estimate (OR = 19.2, 95% CI = 1.0-369.2). These data suggest that mothers who carry the ABCB1 3435C > T polymorphism are at significantly increased risk for having offspring with CL/P, especially mothers using medication in the periconceptional period.

Serum leptin levels during pregnancy in multiple sclerosis (Article)

2009-09-07T00:00:00Z

Background: Disease activity in patients with multiple sclerosis (MS) is suppressed during pregnancy, whereas attack frequency increases after delivery. It is yet unclear, which immuno - endocrinological processes mediate these disease fluctuations. Leptin has been identified as a hormone that can influence inflammatory activity. Objective: The aim ofthis study was to investigate whether pregnancy-induced fluctuations of serum leptin levels differed between patients with MS and controls and whether serum leptin levels correlate with periods of enhanced and diminished disease activity. Methods: Women with MS and healthy women were prospectively followed during and after pregnancy. The MS group could be studied already at a timepoint before pregnancy. Serum leptin and soluble leptin receptor (SLR) levels were measured using enzyme-linked immunosorbent assay. Results: Pre-pregnancy serum leptin levels were (mean ± SD) 22.9 ± 12.8 ng/ml in the MS group. These levels increased in the third trimester to 28.5 ± 15.0 ng/ml (P = 0.007). The third trimester serum leptin levels in healthy women were comparable, 29.4 ± 19.0 ng/ml. Serum leptin levels after delivery dropped to 18.5 ± 12.8 ng/ml in women with MS (P < 0.001) and to a lesser extend (22. ± 17.5 ng/ml) in healthy women (P = 0.04). SLR levels showed the same pattern. Remarkably, women with the highest relative decrease in serum leptin levels after delivery had more often a postpartum relapse (P = 0.008). Conclusion: In women with MS, leptin increased during late pregnancy. A postdelivery drop in leptin levels was observed in both the MS and control group. The postdelivery drop was associated with the occurrence of postpartum relapse.

The prevalence of pelvic organ prolapse symptoms and signs and their relation with bladder and bowel disorders in a general female population (Article)

2009-09-01T00:00:00Z

Introduction and hypothesis: In selected populations, pelvic organ prolapse (POP) was associated with bladder/bowel symptoms, but data on the general female population are lacking. Our aim was to obtain normative data on the prevalence of POP and pelvic floor dysfunction (PFD) symptoms and signs and to identify associations. Methods: Validated questionnaires on POP and PFD (urogenital distress inventory, (UDI) and defaecation distress inventory (DDI)) were sent to a general population of 2,979 women (aged 45-85 years). Data were analysed using the Kruskal-Wallis test, chi square test and Spearman's rank correlation coefficient. Results: Response rate was 62.7%. Associations between POP stage and parity (0.002) and vaginal bulging (<0.001) are significant. Anatomical locations of POP and PFD symptoms correlated significantly with incontinence of flatus, feeling anal prolapse, manual evacuation of stool, vaginal bulging, constipation and pain during faecal urge (p ≤ 0.005). Conclusions: Strategies should be developed to alleviate obstructive bowel disorders associated with POP.

Prediction model and prognostic index to estimate clinically relevant pelvic organ prolapse in a general female population (Article)

2009-09-01T00:00:00Z

Introduction and hypothesis: Estimation on prevalence and distribution of pelvic organ prolapse (POP) signs in a general female population is difficult. We therefore developed and validated a prediction model and prognostic instrument. Methods: Questionnaires were sent to a general female population (45-85 years). A random sample underwent vaginal examination for POP (POPQ). A prediction model was developed using multivariate analysis and validated in a subgroup of participants. Results: Positive questionnaire-response rate was 46.8% (1,397 of 2,979). From the questionnaire group, 649 women were vaginally examined (46.5%). Prevalence of clinically relevant POP was 21%. Multivariate analysis demonstrated significantly higher odds ratios on the report of vaginal bulging, parity ≥2 and a mother with POP. The receiver operating characteristic curve showed areas under the curve of 0.672 and 0.640. Conclusions: The prevalence of POP at or beyond the hymen could be estimated in a general female population using our prediction model with 17 questions and our POP score chart with eight questions.

Periconception folic acid supplementation, fetal growth and the risks of low birth weight and preterm birth: The Generation R Study (Article)

2009-09-01T00:00:00Z

Countries worldwide, including the Netherlands, recommend that women planning pregnancy use a folic acid supplement during the periconception period. Some countries even fortify staple foods with folic acid. These recommendations mainly focus on the prevention of neural tube defects, despite increasing evidence that folic acid may also influence birth weight. We examined whether periconception folic acid supplementation affects fetal growth and the risks of low birth weight, small for gestational age (SGA) and preterm birth, in the Generation R Study in Rotterdam, the Netherlands. Main outcome measures were fetal growth measured in mid- and late pregnancy by ultrasound, birth weight, SGA and preterm birth in relation to periconception folic supplementation (0.4-0.5mg). Data on 6353 pregnancies were available. Periconception folic acid supplementation was positively associated with fetal growth. Preconception folic acid supplementation was associated with 68g higher birth weight (95% CI 37.2, 99.0) and 13g higher placental weight (95% CI 1.1, 25.5), compared to no folic acid supplementation. In these analyses parity significantly modified the effect estimates. Start of folic acid supplementation after pregnancy confirmation was associated with a reduced risk of low birth weight (OR 0.61, 95% CI 0.40, 0.94). Similarly, reduced risks for low birth weight and SGA were observed for women who started supplementation preconceptionally, compared to those who did not use folic acid (OR 0.43, 95% CI 0.28, 0.69 and OR 0.40, 95% CI 0.22, 0.72). In conclusion, periconception folic acid supplementation is associated with increased fetal growth resulting in higher placental and birth weight, and decreased risks of low birth weight and SGA.

Vaginal noise: Prevalence, bother and risk factors in a general female population aged 45-85 years (Article)

2009-08-01T00:00:00Z

Introduction and hypothesis: Vaginal noise (VN) is a symptom of pelvic floor (PF) dysfunction and has been described in a few studies. No other risk factors have been described besides parity and pelvic organ prolapse (POP). Underlying mechanisms of VN are unclear. Aims of this study were to describe prevalence, bother and relation between VN and PF (muscle)(dys)function. Methods: A cross-sectional study was performed on a general population of 2,921 women (aged 45-85 years). Questionnaires were filled in by 1,397 women, and 800 were selected at random to undergo vaginal examination for POP Quantification and PF muscle function assessment. Chi-square tests, Student's t test and multivariate logistic regression were performed (P <0.05). Results: Response rate was 62.7%. Prevalence of VN was 12.8%; 72.1% reported only a little bother. Odds ratios for parity and solid stool were high. Conclusions: VN was strongly related to many symptoms of pelvic floor dysfunction, but it was only causing a little bother.

Mesenchymal hamartoma of the liver: A benign tumor with deceptive prognosis in the perinatal period: Case report and review of the literature (Article)

2009-08-01T00:00:00Z

This article reports a case of perinatal mesenchymal hepatic hamartoma and reviews the literature on the subject. A fetus presented with polyhydramnios and a large multiloculated cystic abdominal mass at 33 weeks of gestation. The ultrasound appearance was most consistent with a mesenteric cyst. Prenatal drainage was considered, due to the size of the lesion. However, a conservative management was opted for. A female infant was born at 35 weeks by classical cesarean section. The immediate postnatal period was characterized by hemodynamic instability. Laparotomy revealed a pedunculated mesenchymal hamartoma of the liver, which could not completely be resected. The infant had an uneventful postoperative recovery and is doing well at 6 months of age. Hepatic mesenchymal hamartoma are rare benign tumors. Most cases are detected in early childhood. They usually present as a cystic rapidly growing abdominal mass. Prenatal diagnosis remains challenging. In children diagnosed in the perinatal period, the outcome seems worse and determined by the compressive effect of the mass. Copyright

Reliability of echocardiographic measurements of left cardiac structures in healthy children (Article)

2009-08-01T00:00:00Z

Background: Echocardiographic measurements are widely used as outcomes of different studies. The aim of this study was to assess intraobserver and interobserver reliability of echocardiographic measurements in healthy children. Materials and methods: We studied 28 children, with a median age of 7.5 years, and inter-quartile range from 3 to 11 years. Intraobserver and interobserver reliability were assessed by repeated measurements of the diameters of the aortic root, the left atrium, and left ventricular end-diastolic structure. We also measured the ventricular end-diastolic septal thickness and the end-diastolic thickness of the left ventricular posterior wall. We calculated intraclass correlation coefficients, with corresponding 95% confidence intervals, and computed Bland and Altman plots, permitting us to derive limits of agreement plus or minus 2 standard deviations for the mean differences in cardiac measurements. Results: We found high intraobserver and interobserver intraclass correlation coefficient, ranging from 0.91 for ventricular septal thickness, with 95% confidence intervals from 0.78 to 0.96, to 0.99 for the diameter of the aortic root, 95% confidence interval from 0.97 to 1.00. Limits of agreement in the Bland and Altman plots ranged from zero millimetres for left ventricular end-diastolic posterior wall thickness to 1.60 millimeters (6.3%) for left atrial diameter. Conclusions: Our study demonstrated good repeatability and reproducibility for ultrasonic measurements of left cardiac structures in children, showing that values obtained for measurement of these structures in both clinical and epidemiological research projects can be confidently accepted. Copyright

Maternal mortality and severe morbidity from sepsis in the Netherlands (Article)

2009-07-30T00:00:00Z

Objective. To assess incidence and risk factors of maternal mortality and severe morbidity from sepsis in the Netherlands. Design. A nationwide confidential enquiry into maternal mortality from 1993 to 2006 and severe maternal morbidity from 2004 to 2006. Setting. All 98 Dutch maternity units in the Netherlands. Population. All pregnant women in the Netherlands from 1993 to 2006. Methods. All reported cases of maternal death from sepsis during 1993-2006 were reported to the Maternal Mortality Committee. Cases of severe maternal morbidity from sepsis from 2004 to 2006 were collected in a nationwide design. Main outcome measures. Incidence, case fatality rates, and possible risk factors. Results. The maternal mortality ratio from direct maternal mortality from sepsis was 0.73 per 100,000 live births (20/2,742,265). The incidence of severe maternal morbidity from sepsis was 21 per 100,000 deliveries (78/371,021), of which 79% was admitted to the intensive care unit. High age, multiple pregnancies, and the use of artificial reproduction techniques were significant risk factors for developing sepsis in univariate analysis. The overall case fatality rate for sepsis during 2004-2006 was 7.7% (6/78). Group A streptococcal infection was in 42.9% (9/21), the cause of direct maternal mortality from sepsis (1993-2006). In 31.8% (14/44), Group A streptococcal infection was the cause of obstetric morbidity from sepsis (2004-2006). Conclusions. With a case fatality rate of 7.7%, sepsis is a life threatening condition for women during pregnancy, childbirth, and puerperium.

Type 2 diabetes gene TCF7L2 polymorphism is not associated with fetal and postnatal growth in two birth cohort studies (Article)

2009-07-17T00:00:00Z

Background: An inverse association between birth weight and the risk of developing type 2 diabetes (T2D) in adulthood has been reported. This association may be explained by common genetic variants related to insulin secretion and resistance, since insulin is the most important growth factor in fetal life. The objective of this study was to examine whether T2D gene polymorphism TCF7L2 rs7903146 is associated with growth patterns from fetal life until infancy. Methods: This study was performed in two independent birth cohort studies, one prospective population-based (Generation R), and one of subjects born small-for-gestational-age (SGA cohort). Fetal growth was assessed by ultrasounds in second and third trimesters of pregnancy in Generation R. Growth in infancy was assessed in both cohorts at birth and at 6, 12 and 24 months postnatally. TCF7L2 genotype was determined in 3,419 subjects in Generation R and in 566 subjects in the SGA cohort. Results: Minor allele frequency did not differ significantly (p = 0.47)between Generation R (T-allele: 28.7%) and the SGA cohort (T-allele: 29.8%). No differences at birth were found in gestational age or size (head circumference, length, weight) between the genotypes in either cohort. TCF7L2 genotype was also not associated with any pre- or postnatal growth characteristic in either Generation R or the SGA cohort. Conclusion: We found no evidence for an association between TCF7L2 genotype and fetal and early postnatal growth. Furthermore, this TCF7L2 polymorphism was not associated with an increased risk of SGA.

Face validity and reliability of the first digital assessment scheme of pelvic floor muscle function conform the new standardized terminology of the international continence society (Article)

2009-07-13T00:00:00Z

Aims: To test the face validity and reliability of a new digital pelvic floor muscle function (PFMF) assessment scheme that was designed on the basis of the recently standardized terminology of the International Continence Society. Methods: Study participants comprised 41 women, age 18-85 years. Data on age and parity were obtained. Face validity of the new assessment scheme was tested by three senior and one junior pelvic physiotherapists, using the Delphi technique. PFMF of each woman was assessed four times by three specially trained pelvic physiotherapists. Examiners were blinded to parity and other findings. To test reliability, Kappa (K) was used for the dichotomous variables and Weighted Kappa (Kw) for the items with more than two categories. Results: Mean age of the women was 41 years (SD 10.5); 14 were nulliparous (34.1%), 6 primiparous (14.6%), and 21 multiparous (51.2%). The new assessment scheme showed satisfactory face validity and intra-observer reliability but low inter-observer reliability. Conclusions: The new assessment scheme based on the terminology of the ICS showed satisfactory face validity and intra-observer reliability. It can therefore be considered suitable for use in clinical practice. More detailed redefinition of the described outcome measures is necessary to improve the inter-observer reliability.

Interaction of PDGFRA promoter haplotypes and maternal environmental exposures in the risk of spina bifida (Article)

2009-07-01T00:00:00Z

BACKGROUND: Neural tube defects are multifactorial malformations involving both environmental exposures, such as maternal nutrition, and genetic factors. Aberrant expression of the platelet-derived growth factor alpha-receptor (PDGFRA) gene has been implicated in neural-tube-defect etiology in both mice and humans. METHODS: We investigated possible interactions between the PDGFRA promoter haplotype of mother and child, as well as maternal glucose, myo-inositol, and zinc levels, in relation to spina bifida offspring. Distributions were determined of the PDGFRA promoter haplotypes H1 and H2 in a Dutch cohort, consisting of 88 spina bifida children with 56 of their mothers, and 74 control children with 72 of their mothers, as well as maternal plasma glucose, myo-inositol, and red blood cell zinc concentrations. RESULTS: A significantly higher frequency of H1 was observed in children with spina bifida than in controls (30.1 vs. 20.3%; OR = 1.69, 95% CI 1.02-2.83). High maternal body mass index (BMI) and glucose were significant risk factors for both H1 and H2 children, whereas low myo-inositol and zinc were risk factors for H2 but not for H1 children. Stepwise multiple logistic regression analysis showed that high maternal glucose and low myo-inositol are the main risk factors for H2 spina bifida children, whereas for H1 spina bifida children, maternal BMI was the main risk factor. Interestingly, H1 mothers (median 165.5 cm) showed a significantly lower body height than H2 mothers (median 169.1 cm; p = 0.003). CONCLUSIONS: These data suggest that the child's PDGFRA promoter haplotype is differentially sensitive for periconceptional exposure to glucose, myo-inositol, and zinc in the risk of spina bifida.

Cardiac structures track during the first 2 years of life and are associated with fetal growth and hemodynamics. The Generation R Study (Article)

2009-07-01T00:00:00Z

Background: The aim of this study is to examine whether cardiac size and function track in early childhood and are associated with fetal and early postnatal growth and blood flow characteristics. Methods: This study was embedded in a population-based prospective cohort study from fetal life onward. Fetal growth and fetal and placental blood flow parameters in second and third trimester of pregnancy were measured by ultrasound and Doppler. Left cardiac structures and shortening fraction were measured postnatally at the ages of 1.5, 6, and 24 months. Analyses were based on 1,001 children. Results: Left ventricular mass tended to remain in the lowest and highest quartiles from the age of 1.5 to 24 months (odds ratio 1.70, 95% confidence interval [CI] 1.10-2.63) and 2.15 (95% CI 1.41-3.30), respectively. Similar results were found for aortic root diameter and left atrial diameter. Birth weight was positively associated with aortic root diameter (0.08 mm, 95% CI 0.01-0.17; per SD increase) and left ventricular mass (0.65 g, 95% CI 0.09-1.21; per SD increase). Resistance indices of the umbilical and uterine arteries showed weak tendencies toward inverse associations with left cardiac structures. Fetal cardiac output was positively associated with both left atrial diameter (increase of 1.96 mm, 95% CI 1.28-2.64; per mL/min increase) and left ventricular mass (increase of 1.79 g, 95% CI 0.35-3.22; per mL/min increase). Conclusions: This study suggest moderate tracking of left cardiac structures during the first 2 years and that small size and hemodynamic variations in fetal life have consequences for postnatal cardiac size and function.

Maternal symptoms of anxiety during pregnancy affect infant neuromotor development: The generation R study (Article)

2009-07-01T00:00:00Z

Several studies found that maternal symptoms of anxiety or depression are related to functioning and development of the offspring. Within a population-based study of 2,724 children, we investigated the effect of maternal anxiety or depression on infant neuromotor development. Symptoms of anxiety and depression were measured during pregnancy and after giving birth; infant neuromotor development was assessed by trained research nurses during a home visit at the age of 3 months. The current study showed that mothers who were anxious during pregnancy had an elevated risk of having an infant with non-optimal neuromotor development.

Maternal smoking during pregnancy and child behaviour problems: The generation R study (Article)

2009-06-15T00:00:00Z

Background: Several studies showed that maternal smoking in pregnancy is related to behavioural and emotional disorders in the offspring. It is unclear whether this is a causal association, or can be explained by other smoking-related vulnerability factors for child behavioural problems. Methods: Within a population-based birth cohort, both mothers and fathers reported on their smoking habits at several time-points during pregnancy. Behavioural problems were measured with the Child Behavior Checklist in 4680 children at the age of 18 months. Results: With adjustment for age and gender only, children of mothers who continued smoking during pregnancy had higher risk of Total Problems [odds ratio (OR) 1.59, 95% confidence interval (CI): 1.21-2.08] and Externalizing problems (OR 1.45, 95% CI: 1.15-1.84), compared with children of mothers who never smoked. Smoking by father when mother did not smoke, was also related to a higher risk of behavioural problems. The statistical association of parental smoking with behavioural problems was strongly confounded by parental characteristics, chiefly socioeconomic status and parental psychopathology; adjustment for these factors accounted entirely for the effect of both maternal and paternal smoking on child behavioural problems. Conclusions: Maternal smoking during pregnancy, as well as paternal smoking, occurs in the context of other factors that place the child at increased developmental risk, but may not be causally related to the child's behaviour. It is essential to include sufficient information on parental psychiatric symptoms in studies exploring the association between pre-natal cigarette smoke exposure and behavioural disorders. © Published by Oxford University Press on behalf of the International Epidemiological Association

Doppler flow velocity waveforms in the embryonic chicken heart at developmental stages corresponding to 5-8 weeks of human gestation (Article)

2009-06-01T00:00:00Z

Objectives: To obtain Doppler velocity waveforms from the early embryonic chicken heart by means of ultrasound biomicroscopy and to compare these waveforms at different stages of embryonic development. Methods: We collected cardiac waveforms using high-frequency Doppler ultrasound with a 55-MHz transducer at Hamburger-Hamilton (HH) stages 18, 21 and 23, which are comparable to humans at 5 to 8 weeks of gestation. Waveforms were obtained at the inflow tract, the primitive left ventricle, the primitive right ventricle and at the outflow tract in 10 different embryos per stage. M-mode recordings were collected to study opening and closure of the cushions. By exploring the temporal relationship between the waveforms, using a secondary Doppler device, cardiac cycle events were outlined. Results: Our results demonstrate that stage- and location-dependent intracardiac blood flow velocity waveforms can be obtained in the chicken embryo. The blood flow profiles assessed at the four locations in the embryonic heart demonstrated an increase in peak velocity with advancing developmental stage. In the primitive ventricle the 'passive' (P) filling peak decreased whereas the 'active' (A) filling peak increased, resulting in a decrease in P to A ratio with advancing developmental stage. M-mode recordings demonstrated that the fractional closure time of the atrioventricular cushions increased from 20% at stage HH 18 to 60% at stage HH 23. Conclusion: High-frequency ultrasound biomicroscopy can be used to define flow velocity waveforms in the embryonic chicken heart. This may contribute to an understanding of Doppler signals derived from valveless embryonic human hearts at 5 to 8 weeks of gestation, prior to septation. Copyright

Associations between dietary patterns and semen quality in men undergoing IVF/ICSI treatment (Article)

2009-06-01T00:00:00Z

Background: This study investigates whether dietary patterns, substantiated by biomarkers, are associated with semen quality. Methods: In 161 men of subfertile couples undergoing in vitro fertilization treatment in a tertiary referral clinic in Rotterdam, the Netherlands, we assessed nutrient intakes and performed principal component factor analysis to identify dietary patterns. Total homocysteine (tHcy), folate, vitamin B12 and B6 were measured in blood and seminal plasma. Semen quality was assessed by sperm volume, concentration, motility, morphology and DNA fragmentation index (DFI). Linear regression models analyzed associations between dietary patterns, biomarkers and sperm parameters, adjusted for age, body mass index (BMI), smoking, vitamins and varicocele. Results: The 'Health Conscious' dietary pattern shows high intakes of fruits, vegetables, fish and whole grains. The 'Traditional Dutch' dietary pattern is characterized by high intakes of meat, potatoes and whole grains and low intakes of beverages and sweets. The 'Health Conscious' diet was inversely correlated with tHcy in blood (β = -0.07, P = 0.02) and seminal plasma (β = -1.34, P = 0.02) and positively with vitamin B6 in blood (β = 0.217, P = 0.01). An inverse association was demonstrated between the 'Health Conscious' diet and DFI (β = -2.81, P = 0.05). The 'Traditional Dutch' diet was positively correlated with red blood cell folate (β = 0.06, P = 0.04) and sperm concentration (β = 13.25, P = 0.01). Conclusions: The 'Health Conscious' and 'Traditional Dutch' dietary pattern seem to be associated with semen quality in men of subfertile couples.

Fetal and postnatal growth and blood pressure at the age of 2 years. The Generation R Study (Article)

2009-06-01T00:00:00Z

Objectives To examine which fetal and postnatal growth characteristics are associated with blood pressure (BP) in children at the age of 2 years. Methods This study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards. Fetal ultrasound examinations were carried out at the visits in one of the research centers in early, mid- and late pregnancy. Fetal femur length standard deviation scores (SDS) were used as a proxy for body length SDS in the prenatal data. BP measurements were performed at the age of 2 years. Analyses were performed in 566 children. Results Inverse tendencies for fetal femur length and estimated fetal weight in mid-pregnancy and late pregnancy with SBP at the age of 2 years were found. The association was only significant for femur length in late pregnancy [-1.22 (95% confidence interval (CI), -2.09, -0.34) mmHg/femur length SDS score]. Length change from late pregnancy to the age of 2 years was positively associated with SBP and DBP [0.97 (95% CI, 0.27,1.66) mmHg and 0.82 (95% CI, 0.09, 1.55) mmHg per SDS length change, respectively]. A similar association between weight change and SBP was found. Conclusion Increased skeletal and nonskeletal growth rates from late pregnancy to the age of 2 years are associated with somewhat higher SBP and DBP in early childhood. Replication of these findings and studies examining the underlying biological pathways and the long-term consequences are needed.

Maternal anthropometrics are associated with fetal size in different periods of pregnancy and at birth. the generation R study (Article)

2009-06-01T00:00:00Z

Objective We aimed to examine the associations of maternal anthropometrics with fetal weight measured in different periods of pregnancy and with birth outcomes. Design Population-based birth cohort study. Setting Data of pregnant women and their children in Rotterdam, the Netherlands. Population In 8541 mothers, height, prepregnancy body mass index (BMI) and gestational weight gain were available. Methods Fetal growth was measured by ultrasound in mid- and late pregnancy. Regression analyses were used to assess the impact of maternal anthropometrics on fetal weight and birth outcomes. Main outcome measures Fetal weight and birth outcomes: weight (grams) and the risks of small (<5th percentile) and large (>95th percentile) size for gestational age at birth. Results Maternal BMI in pregnancy was positively associated with estimated fetal weight during pregnancy. The effect estimates increased with advancing gestational age. All maternal anthropometrics were positively associated with fetal size (P-values for trend <0.01). Mothers with both their prepregnancy BMI and gestational weight gain quartile in the lowest and highest quartiles showed the highest risks of having a small and large size for gestational age child at birth, respectively. The effect of prepregnancy BMI was strongly modified by gestational weight gain. Conclusions Fetal growth is positively affected by maternal BMI during pregnancy. Maternal height, prepregnancy BMI and gestational weight gain are all associated with increased risks of small and large size for gestational age at birth in the offspring, with an increased effect when combined.

Fetal and postnatal growth and body composition at 6 months of age (Article)

2009-06-01T00:00:00Z

Objectives: The objectives of the study was to examine which parental, fetal, and postnatal characteristics are associated with fat and lean mass at the age of 6 months and examine the effect of growth (catch-down, catch-up) in fetal life and early infancy on fat and lean mass. Design: This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. Body composition was measured by dual-energy X-ray absorptiometry in 252 infants at 6 months. Parental, fetal, and postnatal data were collected by physical and fetal ultrasound examinations and questionnaires. Results: Children with fetal catch-up in weight (gain in weight SD score >0.67) in the second trimester tended to have a higher fat mass percentage [FM(%)] at 6 months of age, whereas children with fetal catch-down in weight had a lower FM(%) compared with nonchangers. In the third trimester, both catch-up and catch-down in weight were associated with an increase in FM(%) at 6 months. Children with catch-down in the third trimester had a greater risk for postnatal catch-up in weight greater than 0.67 SD score. Birth weight and weight at 6 wk were positively associated with fat mass at 6 months. Postnatal catch-up in weight within 6 wk after birth had the highest association with total and truncal FM(%) at 6 months. Total and truncal FM were higher in girls. Conclusion: Catch-down in weight in the third trimester was strongly associated with postnatal catch-up within 6 wk after birth, and both were associated with an increase in fat mass at the age of 6 months. Our study shows that fetal as well as postnatal growth patterns are associated with body composition in early childhood. Copyright

Are starting and continuing breastfeeding related to educational background? The generation R study (Article)

2009-06-01T00:00:00Z

OBJECTIVE. To assess the effect of a woman's educational level on starting and continuing breastfeeding and to assess the role of sociodemographic, lifestyle-related, psychosocial, and birth characteristics in this association. METHODS. We used the data of 2914 participants in a population-based prospective cohort study. Information on educational level, breastfeeding, sociodemographic (maternal age, single parenthood, parity, job status), lifestyle-related (BMI, smoking, alcohol use), psychosocial (whether the pregnancy was planned, stress), and birth (gestational age, birth weight, cesarean delivery, place and type of delivery) characteristics were obtained between pregnancy and 12 months postpartum. Odds ratios and 95% confidence intervals of starting and continuing breastfeeding for educational level were obtained by logistic regression, adjusted for each group of covariates and for all covariates simultaneously. RESULTS. Of 1031 highest-educated mothers, 985 (95.5%) started breastfeeding; the percentage was 73.1% (255 of 349) in the lowest-educated mothers. At 6 months, 39.3% (405 of 1031) of highest-educated mothers and 15.2% (53 of 349) of lowest-educated mothers were still breastfeeding. Educationally related differences were present in starting breastfeeding and the continuation of breastfeeding until 2 months but not in breastfeeding continuation between 2 and 6 months. Lifestyle-related and birth characteristics attenuated the association between educational level and breastfeeding, but the association was hardly affected by sociodemographic and psychosocial characteristics. CONCLUSIONS. Decisions to breastfeed were underlain by differences in educational background. The underlying pathways require further research. For the time being, interventions on promoting breastfeeding should start early in pregnancy and should increase their focus on low-educated women. Copyright

Fetal dilated cardiomyopathy caused by persistent junctional reciprocating tachycardia (Article)

2009-05-01T00:00:00Z

Ultrasound examination of a fetus at 32 weeks' gestation revealed dilated cardiomyopathy and a heart rate of 170 beats per minute. Prenatally, this mild tachycardia was not primarily suspected to be the cause of the myocardial changes. Postnatal electrocardiography revealed a persistent junctional reciprocating tachycardia (PJRT) and the diagnosis of tachycardia-induced cardiomyopathy (TICM) became apparent. After conversion to a sinus rhythm under digoxin and amiodarone, the cardiac changes regressed. PJRT is a rare form of supraventricular tachycardia. The prenatal findings in the condition have previously been described retrospectively,but it can only be diagnosed postnatally by its characteristic electrocardiographic properties. This case indicates that TICM can occur at lower heart rates than previously assumed. Even severe prenatal cardiomyopathy may be reversible once sinus rhythm has been restored.

Effect of birth weight and postnatal weight gain on body composition in early infancy. The Generation R Study (Article)

2009-05-01T00:00:00Z

Background: Rapid postnatal weight gain is associated with obesity and type 2 diabetes in later life. The influence of rapid weight gain on body composition in early infancy is still unknown and the critical periods of weight gain for later disease are debated. Aims: To investigate the effect of birth weight and rapid weight gain on body composition in the first 6 months of life. Study design: The Generation R Study, a population-based prospective cohort study from fetal life onwards. Subjects and outcome measures: We measured body fat and fat distribution by skinfold thickness at the age of 6 weeks and 6 months in 909 Dutch term infants. Analyses were adjusted for current body mass index, sex and maternal socioeconomic status, pre-pregnancy body mass index, height and duration of breastfeeding. Results: Upward postnatal weight percentile change was associated with increased skinfold thickness, percentage body fat at 6 weeks and 6 months and a larger truncal/peripheral fat ratio at 6 months (p < 0.01 for all). Birth weight was inversely associated with truncal/peripheral fat ratio (p < 0.01) but not with relative body fat at 6 months. Conclusion: During early postnatal rapid weight gain infants do not grow in all body tissues in equal measure. Instead, they acquire relatively large amounts of fat, which is preferentially distributed to the truncal region. Long term observational studies have to assess if such changes in body composition persist into adulthood.

IVF outcomes are associated with biomarkers of the homocysteine pathway in monofollicular fluid (Article)

2009-05-01T00:00:00Z

BACKGROUNDMaternal hyperhomocysteinemia is detrimental for reproduction, but the effects on embryo quality are unknown. The aim of this study was to investigate whether biomarkers of the homocysteine pathway are associated with in vitro fertilization (IVF) outcome.METHODSIn a prospective study, we investigated biomarkers of the homocysteine pathway for associations with embryo quality and biochemical pregnancy in women undergoing IVF or intracytoplasmic sperm injection treatment (n = 181). In the treatment cycle, blood and monofollicular fluid samples were collected for determination of folate, cobalamin and total homocysteine (tHcy) concentrations.RESULTSOf all the women in the study, 67 used folic acid supplements. In blood, a significant correlation was established between high cobalamin and better embryo quality [standardized adjusted regression coefficient: -0.17, 95 confidence interval (CI): -0.30, -0.01]. In monofollicular fluid of non-supplemented women, high cobalamin correlated with better embryo quality (estimate: -0.87; 95 CI: -1.68, -0.06), whereas high tHcy resulted in poor embryo quality (estimate: 1.01; 95 CI: 0.08, 1.95). However, in monofollicular fluid of supplemented women, high tHcy correlated with better embryo quality (estimate: -0.58; 95 CI: -1.12, -0.04). In the total group, a 2-fold increase of monofollicular fluid folate corresponded with a 3.3 times higher chance (95 CI: 1.09, 9.71) of achieving pregnancy.CONCLUSIONSAn optimal homocysteine pathway in follicular fluid is associated with a better embryo quality and chance of pregnancy.

Breast-feeding modifies the association of PPARγ2 polymorphism pro12Ala with growth in early life: The generation R study (Article)

2009-04-01T00:00:00Z

OBJECTIVE-We examined whether the PPARyγ2 Ala12 allele influences growth in early life and whether this association is modified by breast-feeding. RESEARCH DESIGN AND METHODS-This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. PPARy2 was genotyped in DNA obtained from cord blood samples in 3,432 children. Information about breast-feeding was available from questionnaires. Weight, head circumference, and femur length were repeatedly measured in second and third trimesters of pregnancy, at birth, and at the ages of 1.5, 6, 11, 14, and 18 months. RESULTS-Genotype frequency distribution was 77.6% (Pro12Pro), 20.7% (Pro12Ala), and 1.7% (Ala12Ala). Growth rates in weight from second trimester of pregnancy to 18 months were higher for Pro12Ala and Ala12Ala than for Pro12Pro carriers (differences 1.11 g/week [95% CI 0.47-1.74] and 2.65 g/week [0.45-4.87], respectively). We found an interaction between genotype and breast-feeding duration (P value for interaction <0.0001). In infants who were breast-fed for >nths, PPARy2 Pro12Ala was not associated with growth rate. When breast-feeding duration was <2 months or 2-4 months, growth rate was higher in Ala12Ala than Pro12Pro carriers (differences 9.80 g/week [3.97-15.63] and 6.32 g/week [-1.04 to 13.68], respectively). CONCLUSIONS-The PPAR7gamma;2 Ala12 allele is associated with an increased growth rate in early life. This effect may be influenced by breast-feeding duration. Further studies should replicate these findings, identify the underlying mechanisms, and assess whether these effects persist into later life.

Reliability of renal ultrasound measurements in children (Article)

2009-03-12T00:00:00Z

The aim of the investigation reported here was to assess the intraobserver and interobserver variability of renal measurements in children. The study comprised 56 paired measurements in 28 children (median age 7.5 years, range 3.0-15.0 years) without renal or ureterovesical anomalies. Intraobserver and interobserver reproducibility was assessed by repeated measurements of the left and right renal length, width, and thickness. Intraclass correlation coefficients (ICCs) with the corresponding 95% confidence interval (CI) were calculated. Bland and Altman plots were computed to assess the agreement of the measurements. Limits of agreement ± 2 standard deviations (SD) for the mean differences in renal measurements were derived. Intraobserver ICCs ranged from 0.93 (left and right renal width and right renal thickness) to 0.99 (left renal length), and interobserver ICCs ranged from 0.64 (right renal thickness) to 0.90 (right renal length). Limits of agreement in the Bland and Altman plots ranged from -8.0 to 9.2% (intraobserver left renal width) to the widest limit from -18.0 to 19.2% (interobserver left renal length). Overall, this study demonstrated the good reproducibility and agreement of most renal dimensions in children measured by ultrasound (US). Based on these results, we conclude that US is an appropriate measure to assess renal dimensions in both clinical and epidemiological studies.

An association study of 45 folate-related genes in spina bifida: Involvement of Cubilin (CUBN) and tRNA Aspartic Acid Methyltransferase 1 (TRDMT1) (Article)

2009-03-01T00:00:00Z

BACKGROUND: Spina bifida is a class of neural tube defects, which are congenital malformations of the central nervous system with a prevalence of 0.5 to 12 per 1000 births globally. In this article we attempt to identify genes related to folate and its metabolic pathways that are involved in the etiology of spina bifida. METHODS: We selected 50 folate metabolism-related genes and genotyped polymorphisms in those genes. Eighty-seven polymorphisms in 45 genes passed quality controls. Associations with spina bifida were investigated in 180 patients and 190 controls. For those polymorphisms that were nominally associated with spina bifida risk, the relation with serum and red blood cell folate, vitamin B12, and homocysteine was evaluated in controls. RESULTS: A polymorphism in CUBN was significantly associated with decreased spina bifida risk, after correction for multiple testing, and was related to increased vitamin B12 (p = 0.039) and red blood cell folate (p = 0.001). The CUBN gene encodes the intrinsic factor-cobalamin receptor (or cubilin), a peripheral membrane protein that acts as a receptor for intrinsic factor-vitamin B12 complexes. Vitamin B12 is an important cofactor in the folate metabolism, and low B12 status in mothers has been linked to neural tube defects in children. Other interesting findings include nominally significant associations with polymorphisms in TRDMT1, ALDH1L1, SARDH, and SLCA19A1 (RFC1). CONCLUSION: Our study indicates interesting new candidate genes and functional pathways for further study and confirms earlier findings. None of the genes CUBN, TRDMT1, ALDH1L1, or SARDH have been investigated previously for association with spina bifida.

The maternal Mediterranean dietary pattern is associated with a reduced risk of spina bifida in the offspring (Article)

2009-02-01T00:00:00Z

Objective: The objective of this study was to test the hypothesis whether a maternal dietary pattern is associated with the risk of spina bifida (SB) in the offspring. Design: Case-control study. Setting: Eight clinic sites in the Netherlands, 1999-2001. Sample: A total of 50 mothers of children with SB and 81 control mothers. Methods: Maternal food intakes were obtained by food frequency questionnaires at the standardised study moment of 14 months after the birth of the index child. Principal component factor analysis (PCA) and reduced rank regression (RRR) were used to identify dietary patterns. Main outcome measures: Maternal biomarkers were used as response measures in the RRR analysis and composed of serum and red blood cell (RBC) folate, serum vitamin B12 and total plasma homocysteine. The strength of the use of the dietary pattern in association with SB risk was estimated by odds ratios and 95% CI with the highest quartiles of the dietary pattern as reference. Results: A predominantly Mediterranean dietary pattern was identified by both PCA and RRR. Those dietary patterns were highly correlated (r = 0.51, P < 0.001) and characterised by joint intakes of fruit, vegetables, vegetable oil, alcohol, fish, legumes and cereals and low intakes of potatoes and sweets. We observed a significantly increased risk of SB offspring in mothers with a weak use of the Mediterranean dietary pattern, OR 2.7 (95% CI 1.2-6.1) and OR 3.5 (95% CI 1.5-7.9). The Mediterranean dietary pattern was correlated with higher levels of serum and RBC folate, serum vitamin B12 and lower plasma homocysteine. Conclusion: The Mediterranean dietary pattern seems to be associated with reduction in the risk of offspring being affected by SB.

High maternal vitamin E intake by diet or supplements is associated with congenital heart defects in the offspring (Article)

2009-02-01T00:00:00Z

Objective: To study associations between maternal dietary and supplement intake of antioxidants vitamin E, retinol and congenital heart defects (CHDs). Design: Case-control study. Setting: Erasmus MC, University Medical Center Rotterdam, the Netherlands. Population: Participants were 276 case mothers of a child with CHD and 324 control mothers with their children. Methods: Food frequency questionnaires covering the intake of the previous 4 weeks were filled out at 16 months after the index pregnancy. Data were compared between cases and controls using the Mann-Whitney U test. Risk estimates for the association between CHD and dietary intake of vitamin E and retinol were estimated in a multivariable logistic regression model. Main outcome measures: Medians (5-95th percentile) and odds ratios with 95% CI. Results: Dietary vitamin E intake was higher in case mothers than in controls, 13.3 (8.1-20.4) and 12.6 (8.5-19.8) mg/day (P = 0.05). CHD risk increased with rising dietary vitamin E intakes (P-trend = 0.01). Periconception use of vitamin E supplements in addition to a high dietary vitamin E intake above 14.9 mg/day up to nine-fold increased CHD risk. Retinol intakes were not significantly different between the groups and not associated with CHD risk. Conclusions: High maternal vitamin E by diet and supplements is associated with an increased risk of CHD offspring.

Tracking and Determinants of Kidney Size From Fetal Life Until the Age of 2 Years: The Generation R Study (Article)

2009-02-01T00:00:00Z

Background: An adverse fetal environment may lead to smaller kidneys and subsequently kidney disease and hypertension in adulthood. The aims of this study are to examine whether kidney size tracks from fetal life to childhood and whether maternal and fetal characteristics are associated with kidney size at the age of 2 years. Study Design: Prospective cohort study from fetal life onward. Setting & Participants: The study was conducted in a group of 688 infants in Rotterdam, The Netherlands. Entry criteria were singleton, noncomplicated pregnancies, and Dutch ethnicity. Predictors: The maternal characteristics age, height, and prepregnancy weight were measured in early pregnancy. Fetal growth, head circumference, abdominal circumference, femur length and estimated fetal weight, and placental characteristics were assessed in the second and third trimesters. Outcomes & Measurements: Kidney size, defined as length, width, depth, and volume, was measured in the third trimester of pregnancy and at postnatal ages 6 and 24 months. Results: Overall median gestational age was 40.3 weeks (95% range, 36.0 to 42.3 weeks), and mean birth weight was 3,536 ± 524 (SD) g. Children tended to remain in the lowest and highest quartiles of kidney volume from the third trimester to the age of 2 years (odds ratio, 2.05; 95% confidence interval, 1.38 to 3.06; odds ratio, 3.29; 95% confidence interval, 2.22 to 4.87, respectively). Maternal height and prepregnancy weight were associated positively with kidney volume at the age of 2 years. Third-trimester fetal head circumference, abdominal circumference, and estimated weight and postnatal length were associated positively with kidney volume at the age of 2 years. Preferential fetal blood flow to the brain was associated with smaller kidneys. Limitations: Kidney measurements successfully performed in only 86% of children. Conclusions: Small kidney size in fetal life tends to persist in early childhood. Maternal anthropometrics and fetal biometrics and blood flow patterns are associated with kidney size in childhood. Follow-up studies are needed to examine whether these variations in kidney size are related to kidney function and blood pressure in later life.

Fetal growth influences lymphocyte subset counts at birth: The generation R study (Article)

2009-02-01T00:00:00Z

Background: Preterm born and low-birth-weight infants are at risk for severe infections in infancy. It has been suggested that these infants have an immature immune system. Objective:To assess the associations of gestational age, birth weight and fetal growth with absolute lymphocyte subset counts at birth. Methods: This study was conducted in 571 infants participating in the Generation R Study, a population-based prospective cohort study from fetal life onwards. Gestational age and birth weight were obtained from midwives and hospital registries. Fetal growth was defined as increase in weight between late pregnancy and birth. Lymphocytes and T lymphocyte subset counts in cord blood were determined by 6-color flow cytometry. Multivariate linear regression models with adjustment for gender, maternal education, smoking, alcohol use, fever and mode of delivery were applied. Results: Per week increase of gestational age, T, B and NK lymphocyte counts increased with 3, 5 and 6%, respectively (p < 0.05). Helper, cytotoxic and naive T lymphocyte counts increased with 3, 4 and 5%, respectively (p < 0.05), but memory T lymphocyte counts did not. Increased birth weight and fetal growth were significantly associated with higher B lymphocyte counts, independent of gestational age, but not with the other lymphocyte subset counts. Conclusions: Lymphocyte subset counts increase with prolonged gestation, suggesting an ongoing development of the immune system. Birth weight and fetal growth seem to influence only B lymphocyte counts. Copyright

Folic acid is positively associated with uteroplacental vascular resistance: The Generation R Study (Article)

2009-01-01T00:00:00Z

Background and aims: Periconception folic acid supplementation may influence early placentation processes and thereby the occurrence of hypertensive pregnancy disorders. For this reason we examined the associations between periconception folic acid supplementation and uteroplacental vascular resistance, blood pressure, and the risks of gestational hypertension and preeclampsia, in 5993 pregnant women, participating in a population-based cohort study. Methods and results: Folic acid supplementation was assessed by questionnaire. Mean pulsatility index (PI) and resistance index (RI) of the uterine (UtA) and umbilical arteries (UmA) were measured by Doppler ultrasound in mid- and late pregnancy. Systolic and diastolic blood pressures (SBP, DBP) were measured in early, mid- and late pregnancy. Compared to women who did not use folic acid, preconception folic acid users had a slightly lower UtA-RI in mid-pregnancy [β -0.02, 95% confidence interval (CI) -0.03, -0.01] and late pregnancy [β -0.02, 95% CI -0.03, -0.001], a lower UtA-PI in mid-pregnancy [β -0.06, 95% CI -0.1, -0.03] and late pregnancy [β -0.03, 95% CI -0.05, -0.01], as well as tendencies towards a lower UmA-PI in mid-pregnancy [β -0.02, 95% CI -0.04, -0.001] and late pregnancy [β -0.01, 95% CI -0.02, 0.01]. Additionally, these women had slightly higher SBP and DBP throughout pregnancy. Neither the patterns of blood-pressure change during pregnancy, nor the risk of gestational hypertension and preeclampsia differed between the folic acid categories. Conclusion: Periconception folic acid supplementation is associated with lower uteroplacental vascular resistance and higher blood pressures during pregnancy. The effects are small and within physiologic ranges and seem not associated with the risk of hypertensive pregnancy disorders.

The preconception Mediterranean dietary pattern in couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment increases the chance of pregnancy (Article)

2009-01-01T00:00:00Z

Objective: To investigate associations between preconception dietary patterns and IVF/intracytoplasmic sperm injection (ICSI) outcomes validated by biomarkers of the homocysteine pathway. Design: Observational prospective study. Setting: A tertiary referral fertility clinic at the Erasmus University Medical Centre, Rotterdam, The Netherlands. Patient(s): One hundred sixty-one couples undergoing IVF/ICSI treatment. Intervention(s): No interventions other than the Dutch governmental recommendation of folic acid. Main Outcome Measure(s): Dietary patterns, blood and follicular fluid concentrations of folate, vitamin B12, vitamin B6, homocysteine, and fertilization rate, embryo quality, and pregnancy. Result(s): In women, two dietary patterns were identified. The "health conscious-low processed" dietary pattern (variation explained 12.1%) was characterized by high intakes of fruits, vegetables, fish, and whole grains and low intakes of snacks, meats, and mayonnaise, and positively correlated with red blood cell folate (β = 0.07). The "Mediterranean" dietary pattern (variation explained 9.1%), that is, high intakes of vegetable oils, vegetables, fish, and legumes and low intakes of snacks, was positively correlated with red blood cell folate (β = 0.13), and vitamin B6 in blood (β = 0.09) and follicular fluid (β = 0.18). High adherence by the couple to the "Mediterranean" diet increased the probability of pregnancy, odds ratio 1.4 (95% confidence interval 1.0-1.9). Conclusion(s): A preconception "Mediterranean" diet by couples undergoing IVF/ICSI treatment contributes to the success of achieving pregnancy. © 2010 American Society for Reproductive Medicine.

Early pregnancy volume measurements: Validation of ultrasound techniques and new perspectives (Article)

2009-01-01T00:00:00Z

Objective: To investigate accuracy and reliability of four different ultrasound-related volume-measuring methods. Design: Observational study. Setting: Both in vitro and in vivo. Population or Sample: Ten phantoms for in vitro measurements and 28 pregnancies with gestational ages ranging from 6 to 11 weeks for in vivo measurements were included. Methods: Three-dimensional (3D) ultrasound images of phantoms (with known variable contents) and yolk sacs were used to calculate volumes using four different methods: Virtual Organ Computed-Aided AnaLysis (VOCAL), inversion mode, Sono Automatic Volume Calculation (SonoAVC) and V-Scope. V-Scope is a newly developed 3D volume visualisation application using a Barco I-Space virtual reality system. Intra- and interobserver agreement was established by calculating intraclass correlation coefficients (ICC). Main outcome measure: Evaluation of accuracy and reliability by comparing the different techniques with true volumes (in vitro) and with each other (in vitro and in vivo). Results: In the in vitro study, volume measurements by VOCAL, inversion mode and V-Scope proved to be accurate. SonoAVC measurements resulted in a substantial systematic underestimation. Correlation coefficients of measured versus true volumes were excellent in all four techniques. For all techniques, an intra- and interobserver agreement of at least 0.91 was found. Yolk sac measurements by the different techniques proved to be highly correlated (ICCs > 0.91). Conclusions: We demonstrated that VOCAL, inversion mode and V-Scope can all be used to measure volumes of hypoechoic structures. The newly introduced V-Scope application proved to be accurate and reliable.

Human fetal amino acid metabolism at term gestation (Article)

2009-01-01T00:00:00Z

Background: Knowledge on human fetal amino acid (AA) metabolism, largely lacking thus far, is pivotal in improving nutritional strategies for prematurely born infants. Phenylalanine kinetics is of special interest as is debate as to whether neonates will adequately hydroxylate phenylalanine to the semiessential AA tyrosine. Objective: Our aim was to quantify human fetal phenylalanine and tyrosine metabolism. Design: Eight fasted, healthy, pregnant women undergoing elective cesarean delivery at term received primed continuous stable-isotope infusions of [1-13C]phenylalanine and [ring-D4]tyrosine starting before surgery. Umbilical blood flow was measured by ultrasound. Maternal and umbilical cord blood was collected and analyzed by gas chromatography-mass spectrometry for phenylalanine and tyrosine enrichments and concentrations. Data are expressed as medians (25th-75th percentile). Results: Women were in a catabolic state for which net fetal AA uptake was responsible for ≥25%. Maternal and fetal hydroxylation rates were 2.6 (2.2-2.9) and 7.5 (6.2-15.5) μmol phenylalanine/(kg·h), respectively. Fetal protein synthesis rates were higher than breakdown rates: 92 (84-116) and 73 (68-87) μmol phenylalanine/(kg·h), respectively, which indicated an anabolic state. The median metabolized fraction of available phenylalanine and tyrosine in the fetus was <20% for both AAs. Conclusions: At term gestation, fetuses still show considerable net AA uptake and AA accretion [converted to tissue ≈12 g/(kg·d)]. The low metabolic uptake (AA usage) implies a very large nutritional reserve capacity of nutrients delivered through the umbilical cord. Fetuses at term are quite capable of hydroxylating phenylalanine to tyrosine.

Review of the role of the plasminogen activator system and vascular endothelial growth factor in subfertility (Article)

2008-12-01T00:00:00Z

Objective: To assess the importance of the plasminogen activator (PA) system and vascular endothelial growth factor (VEGF) in subfertility. Design: Review. Setting: Two university IVF centers. Intervention(s): Systematic literature search (MEDLINE, Science Direct, and bibliographies of published works). Result(s): The PA system in the male is involved in the passage of spermatozoa precursor cells over the blood-testis barrier, the epididymal maturation of spermatozoa, the modifications of the sperm surface for capacitation, the acrosome reaction and zona pellucida attachment, and finally the facilitation of spermatozoa to move into the fallopian tubes. In the female, the PA system plays a role during ovulation in the release of the oocyte from the follicle, the facilitation of oocyte movement into the fallopian tubes, and the extracellular matrix degradation important for angiogenesis in the ovary. The function of VEGF during fertilization is largely unknown. It has been suggested that VEGF is important for the fluid and proteins in semen and fluid secretion in the female genital tract, thereby influencing sperm motility and survival. The latter could be due to an effect of VEGF on testicular microvasculature, through which an adequate microenvironment for spermatogenesis is provided. In the female, VEGF is involved in the regulation of the cyclic ovarian angiogenesis, the development and/or selection of follicles, the accumulation of follicular fluid, and corpus luteum angiogenesis. Conclusion(s): The role of the PA system and VEGF in reproduction most likely is of great interest. However, much of the data are derived from experimental animal studies. So far, information on the importance of these systems in humans is scarcely investigated. Therefore, further research is required to elucidate the role of the PA system and VEGF in the pathogenesis and prevention of male and female subfertility. Eventually, this will contribute to the improvement of the diagnosis of subfertility and may possibly lead to targeted therapeutic management of subfertility.

The generation R study: Design and cohort update until the age of 4 years (Article)

2008-12-01T00:00:00Z

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health from fetal life until young adulthood. The study focuses on four primary areas of research: (1) growth and physical development; (2) behavioural and cognitive development; (3) diseases in childhood; and (4) health and healthcare for pregnant women and children. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Of all eligible children at birth, 61% participate in the study. In addition, more detailed assessments are conducted in a subgroup of 1,232 pregnant women and their children. Data collection in the prenatal phase and postnatal phase until the age of 4 years includes questionnaires, detailed physical and ultrasound examinations, behavioural observations and biological samples. This paper gives an update of the study design and cohort profile until the children's age of 4 years. Eventually, results forthcoming from the Generation R Study have to contribute to the development of strategies for optimizing health and healthcare for pregnant women and children.

Demographic, emotional and social determinants of cannabis use in early pregnancy: The Generation R study (Article)

2008-12-01T00:00:00Z

Aims: To ascertain demographic, emotional and social determinants of cannabis use in early pregnancy. Design: This study was embedded in the Generation R study, a multiethnic population-based cohort of parents and their children, followed from pregnancy to childhood. Setting: Rotterdam, The Netherlands. Participants: Mothers enrolled in pregnancy who answered questions about their own and their partners substance use before and during pregnancy (n = 7610). Measurements: Using self-report questionnaires, information was collected on maternal demographics, psychopathology, delinquency, childhood trauma, social stress, family functioning, and parental alcohol, tobacco and substance use. Multinomial logistic regression analysis was used, with non-using women as reference. Findings: 246 (3.2%) women used cannabis before pregnancy and 220 (2.9%) women used cannabis both before and during pregnancy. The strongest determinant for maternal cannabis use during pregnancy was cannabis use by the biological father of the child (OR = 38.56; 95%CI = 26.14-58.88). Maternal cannabis use during pregnancy was also independently associated with being single (OR = 4.25; 95%CI = 2.33-7.75) or having a partner without being married (OR = 2.75; 95%CI = 1.56-4.85), childhood trauma (OR = 1.39; 95%CI = 1.22-1.57) and delinquency (OR = 3.37; 95%CI = 1.90-5.98), but not with maternal age, ethnicity, psychopathology, family functioning and perceived stress. Being religious was protective (Islam: OR = 0.25; 95%CI = 0.09-0.65) for maternal cannabis use during pregnancy. Additionally, lower educational level determined continued cannabis use in ever-users (OR = 3.22; 95%CI = 1.54-6.74). Conclusions: Our results showed that multiple demographic, emotional and social characteristics were associated with maternal cannabis use. These characteristics should be considered when investigating offspring exposed to cannabis in utero, as they may play an important role in mother-child interaction and child development.

Reliability of three-dimensional sonographic measurements in early pregnancy using virtual reality (Article)

2008-12-01T00:00:00Z

Objective: To establish the reliability of three-dimensional (3D) ultrasound measurements in early pregnancy using a virtual reality system (the Barco I-Space). Methods: The study included 28 pregnancies with gestational ages ranging from 6 to 14 (median, 10) weeks. 3D volumes were acquired and offline measurements were made, where possible, of the yolk sac diameter, crown-rump length, biparietal diameter, head circumference and abdominal circumference, using specialized 3D imaging software (4DView). The datasets were then transferred to the Barco I-Space, a virtual reality system that allows the observer to perceive depth and interact with volume-rendered (ultrasound) data. The 3D rendered volumes were measured using a virtual pointer, controlled by a wireless joystick. For intraobserver variability, 3D and virtual reality volumes were measured twice by one operator. For interobserver variability, another operator performed the same measurements once. All measurements were repeated three times and their mean values were used for comparisons. Results: All intraclass correlation coefficients (ICCs) comparing 4DView measurements with I-Space measurements were >0.97. Intra- and interobserver ICCs for the 4DView measurements were >0.96 and for the I-Space ones were >0.98, representing good agreement. Conclusions: The application of virtual reality is a novel method of visualizing 3D ultrasound data and perception of the depth in the I-Space offers possibilities for measuring non-planar structures. We have demonstrated that early pregnancy measurements in the I-Space are reliable. New areas of embryonic and fetal biometry can now be explored using this technique, which we tentatively name 'virtual embryoscopy'. Copyright

Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip (Article)

2008-11-01T00:00:00Z

Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 × 10-11) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2α and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2α in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

Homocysteine metabolism in the pre-ovulatory follicle during ovarian stimulation (Article)

2008-11-01T00:00:00Z

BACKGROUND: Ovarian stimulation gives rise to supraphysiological estradiol levels, which may affect oocyte quality. This study aims to investigate whether ovarian stimulation deranges the homocysteine pathway thereby affecting the pre-ovulatory follicle. METHODS: Blood samples were collected on cycle day 2 and the day of hCG administration in 181 women undergoing ovarian stimulation for IVF. In each subject, the diameter of the two leading follicles was measured and the corresponding follicular fluids were collected. In blood and follicular fluid samples, total homocysteine (tHcy), folate, cobalamin and pyridoxal'5-phosphate (PLP) were determined. According to the blood folate levels, women were classified as either folic acid supplemented (n = 113) or non-supplemented (n = 32). RESULTS: Ovarian stimulation resulted in a significant decrease in blood tHcy and cobalamin levels (both P ≤ 0.001). The blood concentrations of tHcy, folate, cobalamin and PLP were significantly correlated with the corresponding follicular fluid concentrations (all P ≤ 0.001). Follicular fluid tHcy concentrations were inversely correlated with follicular diameter (P ≤ 0.05). In folic acid supplemented women, follicular fluid folate was inversely correlated with follicular diameter (P ≤ 0.05). CONCLUSIONS: Ovarian stimulation deranges blood and follicular fluid biomarkers of the homocysteine pathway. High ovarian follicular fluid tHcy and folate levels may have detrimental effects on follicular development.

Maternal intake of fat, riboflavin and nicotinamide and the risk of having offspring with congenital heart defects (Article)

2008-10-01T00:00:00Z

Background: With the exception of studies on folic acid, little evidence is available concerning other nutrients in the pathogenesis of congenital heart defects (CHDs). Fatty acids play a central role in embryonic development, and the B-vitamins riboflavin and nicotinamide are co-enzymes in lipid metabolism. Aim of the study: To investigate associations between the maternal dietary intake of fats, riboflavin and nicotinamide, and CHD risk in the offspring. Methods: A case-control family study was conducted in 276 mothers of a child with a CHD comprising of 190 outflow tract defects (OTD) and 86 non-outflow tract defects (non-OTD) and 324 control mothers of a non-malformed child. Mothers filled out general and food frequency questionnaires at 16 months after the index-pregnancy, as a proxy of the habitual food intake in the preconception period. Nutrient intakes (medians) were compared between cases and controls by Mann-Whitney U test. Odds ratios (OR) for the association between CHDs and nutrient intakes were estimated in a logistic regression model. Results: Case mothers, in particular mothers of a child with OTD, had higher dietary intakes of saturated fat, 30.9 vs. 29.8 g/d; P < 0.05. Dietary intakes of riboflavin and nicotinamide were lower in mothers of a child with an OTD than in controls (1.32 vs. 1.41 mg/d; P < 0.05 and 14.6 vs. 15.1 mg/d; P < 0.05, respectively). Energy, unsaturated fat, cholesterol and folate intakes were comparable between the groups. Low dietary intakes of both riboflavin (<1.20 mg/d) and nicotinamide (<13.5 mg/d) increased more than two-fold the risk of a child with an OTD, especially in mothers who did not use vitamin supplements in the periconceptional period (OR 2.4, 95%CI 1.4-4.0). Increasing intakes of nicotinamide (OR 0.8, 95%CI 0.7-1.001, per unit standard deviation increase) decreased CHD risk independent of dietary folate intake. Conclusions: A maternal diet high in saturated fats and low in riboflavin and nicotinamide seems to contribute to CHD risk, in particular OTDs.

Determinants of folic acid use in early pregnancy in a multi-ethnic urban population in The Netherlands: The Generation R study (Article)

2008-10-01T00:00:00Z

Objective: Recommendations on folic acid use to prevent neural tube defects have been launched in several countries. Adequate folic acid use seems to be low. This study assesses the prevalence of folic acid use and identifies its determinants. Methods: The study was embedded in the Generation R Study Rotterdam, the Netherlands, a population-based prospective cohort study between 2002 and 2006. Complete information of 6940 women was available. Information on folic acid use and potential determinants was obtained by questionnaires and physical examination. Results: Of all women 37% adequately used folic acid during the preconception period. Most important risk factors for inadequate use were unplanned pregnancy (OR 9.5, CI 7.2-12.4, p < 0.001), low educational level (OR 2.5, CI 1.8-3.6, p < 0.001) and non-western ethnicity, (OR 3.5, CI 2.9-4.3, p < 0.001). After stratification for ethnicity, unplanned pregnancy remained the most important risk factor for inadequate use. Other risk factors for inadequate use were younger age, single marital status, smoking, multiparity (all p < 0.001) and alcohol use (p < 0.05). In contrast, previous spontaneous abortion decreased the risk of inadequate folic acid use (p < 0.001). Conclusion: Adequate preconception folic acid supplementation is still too low. Implementation of preconception programs and other public health strategies are strongly needed.

Severe, very early onset preeclampsia: Subsequent pregnancies and future parental cardiovascular health (Article)

2008-10-01T00:00:00Z

Objective: To study subsequent pregnancy outcome in women with severe, very early onset preeclampsia (onset before 24 weeks' gestation) and to analyze cardiovascular risk profiles of these women and their partners. Study design: Twenty women with preeclampsia with an onset before 24 weeks' gestation, admitted between 1 January 1993 and 31 December 2002 at a tertiary university referral center, were enrolled in the study. Data on subsequent pregnancies were obtained from medical records. Their cardiovascular risk profiles and those of their partners (n = 15) were compared with those of 20 control women after uncomplicated pregnancies only, matched for age and parity, and those of their partners (n = 13). Body weight, height, waist and hip circumference, blood pressure and intima media thickness (IMT) of the common carotid artery were measured. Fasted blood samples were drawn for detection of metabolic cardiovascular risk factors. Results: Of the 20 case women 17 women had 24 subsequent pregnancies, of which 12 (50%) were complicated by preeclampsia. Severe preeclampsia developed in five (21%) pregnancies. No perinatal deaths occurred. Case women had significantly more often chronic hypertension as compared to controls (55% vs. 10%, P = 0.002). IMT of the common carotid artery was increased in a subset of case women using antihypertensive medication (P = 0.03). Case women showed increased microalbuminuria (P < 0.05). No differences were found in cardiovascular risk profiles between partners of cases and controls. Conclusions: Women with severe, very early onset preeclampsia have an increased risk of preeclampsia in future pregnancies, yet neonatal outcome is, in general, favourable. Regarding cardiovascular health, women after severe, very early onset preeclampsia exhibit more risk factors compared to controls whereas men who fathered these pregnancies do not.

Blood pressure estimation in the human fetal descending aorta (Article)

2008-10-01T00:00:00Z

Objectives: The objectives of this study were to estimate fetal blood pressure non-invasively from two-dimensional color Doppler-derived aortic blood flow and diameter waveforms, and to compare the results with invasively derived human fetal blood pressures available from the literature. Methods: Aortic pressures were calculated from digitally recorded color Doppler cineloops of the fetal descending aorta by applying the Womersley model in combination with the two-element Windkessel model, assuming constant pulse wave velocity during the second half of pregnancy. The results were compared with invasively derived human fetal blood pressures obtained from the literature. Results: In 21 normal pregnancies the estimated mean aortic pressure regression line increased linearly from 28 mmHg at 20 weeks of gestation to 45 mmHg at 40 weeks of gestation. The pulse pressure based on the regression line increased linearly from 21 mmHg at 20 weeks of gestation to 29 mmHg at 40 weeks of gestation. The aortic compliance exhibited a log linear relationship with the gestational age and a statistically significant eightfold increase was observed between 20 and 40 weeks. The aortic downstream peripheral resistance exhibited an exponentially decaying relationship across the same gestational age range. Non-invasively derived aortic systolic and diastolic aortic pressures were comparable with previously reported invasively derived systolic and diastolic umbilical arterial pressures; however, the mean pressures differed significantly from those reported in the umbilical artery in a separate study. The aortic systolic pressures calculated in this study were significantly higher than invasively derived left ventricular systolic pressures that have been previously reported in the literature. Conclusions: This study demonstrates the feasibility of estimating arterial blood pressure in the human fetus. The method described is of potential use in assessing fetal blood pressure non-invasively, particularly for studying relative changes with time. Copyright

Genome-wide pathway analysis of folate-responsive genes to unravel the pathogenesis of orofacial clefting in man (Article)

2008-09-01T00:00:00Z

BACKGROUND: A cleft of the lip with or without the palate (CLP) is a frequent congenital malformation with a heterogeneous etiology, for which folic acid supplementation has a protective effect. To gain more insight into the molecular pathways affected by natural folate, we examined gene expression profiles of cultured B-lymphoblasts from CLP patients before and after the addition of 5-methyltetrahydrofolate (5-mTHF) to the cultures. METHODS: Immortalized B-lymphoblasts from five children with CLP were cultured in folate-deficient medium for 5 days. 5-mTHF was added to a concentration of 30 nM. Gene expression patterns were then evaluated before and after supplementation using Human Genome U133 Plus 2.0 arrays. Data analysis was performed with Omniviz and the GEPAS analysis suite. Differential genes were categorized into biological pathways with Ingenuity Pathway systems. Differential expression was validated by quantitative RT-PCR. RESULTS: Using supervised clustering, with a false discovery rate <1%, we identified 144 and 409 significantly up-regulated and down-regulated probesets, respectively, after 5-mTHF addition. The regulated genes were involved in a variety of biological pathways, including one carbon pool and cell cycle regulation, biosynthesis of amino acids and DNA/RNA nucleotides, protein processing, apoptosis, and DNA repair. CONCLUSIONS: The large variety of the identified folate responsive pathways fits with the modifying role of folate via the methylation pathway. From the present data we may conclude that folate deficiency deranges normal cell development, which might contribute to the development of CLP. The role of these folate responsive genes in CLP development is intriguing and needs further investigation.

A variant of the IGF-I gene is associated with blood pressure but not with left heart dimensions at the age of 2 years: The Generation R Study (Article)

2008-09-01T00:00:00Z

Background and objective: A common variant of the IGF-I gene has been shown to be associated with cardiovascular disease in adulthood. The objective of this study was to examine whether this variant of the IGF-I gene is associated with blood pressure and left heart dimensions in early childhood. Research design and methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life onwards. IGF-I promoter region was genotyped in DNA obtained from cord blood. Blood pressure (systolic and diastolic) and echocardiography (left ventricular mass, left atrial diameter and aortic root diameter) measurements were performed at the age of 2 years. Analyses were performed in 538 subjects. Results: Eight alleles of the IGF-I promoter region were identified. In total, 43% of the subjects were homozygous for the 192 bp allele (wild type), 46% were heterozygous and 11% were non-carriers. Significantly lower systolic and diastolic blood pressures were found in non-carrier subjects (difference compared with homozygous subjects: - 4.4 (95% confidence interval (CI) - 7.8 to - 1.1) mmHg and - 3.5 (95% CI: - 6.9 to - 0.1) mm respectively). No significant differences were found for left heart dimensions at the age of 2 years. No association was found when we used a previously proposed alternative classification of the IGF-I gene. Conclusion: The variant type of the IGF-I promoter region is associated with lower blood pressure but not with left heart dimensions at the age of 2 years. Follow-up studies are needed to examine whether these differences persist in later life.

Evaluation of volume vascularization index and flow index: A phantom study (Article)

2008-09-01T00:00:00Z

Objectives Three-dimensional (3D) power Doppler ultrasonography provides indices to quantify moving blood within a volume of interest (e.g. ovary, endometrium, tumor or placenta). The purpose of this study was to determine the influence of ultrasound instrument settings on vascularization index (VI) and flow index (FI) at different flow velocities, using a specially built flow phantom with a small tube diameter. Methods Blood-mimicking fluid was pumped at 10-100 mL/h through a plastic tube with a diameter of 0.65 mm within a virtual spherical volume (content 137.12 cm3) of a Voluson 730 Expert 3D power Doppler ultrasound instrument. VI and FI were determined at different pulse repetition frequency (PRF) settings, with minimal and maximal wall motion filter (WMF) settings. The measured VI was compared with the actual VI. Results The ability to measure VI and FI at different flow velocities was highly dependent on the PRF and WMF settings. In our experimental set-up, using a PRF of 0.3 kHz, flow velocities of about 2 cm/s and higher could be registered. Measured VI was overestimated up to 44 times relative to actual VI. Conclusions Our main finding in a laboratory set-up was a considerable overestimation of moving blood volume using 3D power Doppler ultrasound in a single small tube. The degree of overestimation depends on the spatial resolution and on the settings of the ultrasound instrument. When small vessels are involved in a clinical setting, interpretation of VI should take this overestimation of moving blood volume into account. Copyright

Maternal global methylation status and risk of congenital heart diseases (Article)

2008-08-01T00:00:00Z

OBJECTIVE: To investigate whether the association between the maternal methylation status as reflected by low S-adenosylmethionine and high S-adenosylhomocysteine, is detrimental for cardiogenesis and congenital heart disease (CHD) in the offspring. METHODS: As part of a case-control study in the western part of the Netherlands, we evaluated 231 mothers of children with CHD and 315 control mothers of nonmalformed children. The total case group was analyzed and stratified into isolated (n=180) and nonisolated CHDs (n=51). The latter subgroup was further subdivided into Nonsyndromic (n=20), Down Syndrome (n=19), and Other Syndromes (n=12). A multivariable general linear model was used to test for differences between the case groups and controls. All analyses were adjusted for current B vitamin supplement use. RESULTS: Plasma total homocysteine was significantly different between the total case group (median, range 10.3, 4.0-43.8, P=.026) and the nonisolated cases (11.1, 5.5-43.8, P=.006) compared with the controls (10.0, 5.3-42.0). The subgroup of Down Syndrome presented significantly higher total homocysteine and S-adenosylhomocysteine levels and a lower S-adenosylmethionine/S-adenosylhomocysteine ratio than controls. CONCLUSION: Maternal hyperhomocysteinemia, and not hypomethylation, is a risk factor for having a child with CHD. Maternal hypomethylation, however, seems to be associated with offspring having CHD and Down syndrome.

Cleft palate cells can regenerate a palatal mucosa in vitro (Article)

2008-08-01T00:00:00Z

Cleft palate repair leaves full-thickness mucosal defects on the palate. Healing might be improved by implantation of a mucosal substitute. However, the genetic and phenotypic deviations of cleft palate cells may hamper tissue engineering. The aim of this study was to construct mucosal substitutes from cleft palate cells, and to compare these with substitutes from normal palatal cells, and with native palatal mucosa. Biopsies from the palatal mucosa of eight children with cleft palate and eight age-matched control individuals were taken. Three biopsies of both groups were processed for (immuno)histochemistry; 5 were used to culture mucosal substitutes. Histology showed that the substitutes from cleft-palate and non-cleft-palate cells were comparable, but the number of cell layers was less than in native palatal mucosa. All epithelial layers in native palatal mucosa and mucosal substitutes expressed the cytokeratins 5, 10, and 16, and the proliferation marker Ki67. Heparan sulphate and decorin were present in the basal membrane and the underlying connective tissue, respectively. We conclude that mucosal cells from children with cleft palate can regenerate an oral mucosa in vitro.

Maternal smoking in prenatal and early postnatal life and the risk of respiratory tract infections in infancy. the Generation R study (Article)

2008-08-01T00:00:00Z

Objective: To assess the associations of maternal smoking during pregnancy and in the postnatal period with respiratory tract infections in young infants. Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onwards. All data were assessed by questionnaires. Maternal smoking was assessed in pregnancy (no, stopped when pregnancy was known, continued during pregnancy) and at 6 months postnatally. Doctor-attended respiratory tract infections were recorded at the age of 6 months. The present analyses were based on 3,418 subjects. Results: Continued maternal smoking during pregnancy was not associated with respiratory tract infections in young infants. Maternal smoking in the postnatal period showed a tendency for an increased risk of lower respiratory tract infections in infants (adjusted odds ratio (aOR) 1.61 (95% confidence interval: 0.99, 2.63)). Dose-response effects for maternal smoking during pregnancy or in the postnatal period on the risk of respiratory tract infections were not observed. In infants of mothers who smoked neither during pregnancy nor in the postnatal period, environmental smoking during pregnancy and in the postnatal period together was associated with upper respiratory tract infections (aOR 1.58 (95% CI: 1.07, 2.35)). Conclusions: No effect of maternal smoking during pregnancy with respiratory tract infections was observed. Weak evidence for the association between maternal smoking in the postnatal period and lower respiratory tract infections were found. Exposure to non-maternal environmental smoking during pregnancy and in the postnatal period together increases the risk of upper respiratory tract infections in young infants.

The incidence of neonatal herpes in The Netherlands (Article)

2008-08-01T00:00:00Z

Background: In The Netherlands the incidence of neonatal herpes was 2.0-2.9 per 100,000 live births during the period 1981-1998. The low incidence warranted a rather conservative prevention policy. Objectives: To monitor for potential changes in the incidence of neonatal herpes in The Netherlands between 1999 and 2005, which may affect the prevention policy. Study design: Questionnaires were sent to all virological laboratories, the gynaecological and paediatric departments of every university hospital and half the number of the general hospitals in The Netherlands. The questionnaires pertained to the incidence of proven cases of neonatal herpes, the numbers of caesarean sections performed for the prevention of neonatal herpes and the numbers of pregnant women with genital herpes. Results: In the period 1999-2005 33 cases of neonatal herpes were reported, yielding an incidence of 3.2 cases per 100,000 live births per year. The estimated annual numbers of pregnant women with genital herpes ranged from 200 to 240. Approximately 9 caesarean sections were performed annually to prevent neonatal herpes. Conclusions: In The Netherlands neonatal herpes is still a rare condition. From the findings of this study it is concluded that it is not necessary to revise the Dutch guidelines for the prevention of neonatal herpes simplex infection.

Smoking during pregnancy in ethnic populations: The Generation R study (Article)

2008-08-01T00:00:00Z

Patterns and correlates of maternal smoking could differ according to ethnic background, and these differences might have consequences for intervention strategies. In the Generation R study, we examined patterns of smoking during pregnancy and the associations of socioeconomic (educational level), demographic (maternal age, marital status, generational status, parity) and lifestyle (alcohol consumption, partner smoking) correlates with smoking during pregnancy in 5,748 women of Dutch, Turkish, Moroccan, Surinamese-Hindustani, Surinamese-Creole, Capeverdean and Antillean ethnic background. Smoking rates before pregnancy were highest in the Turkish group (43.7%) and lowest in the Moroccan group (7.0%). Compared with Dutch women (24.1%), Turkish and Moroccan women were less likely to quit smoking before pregnancy (17.0% and 5.9%, respectively; p<.001). Turkish and Moroccan women (72.0% and 70.6%, respectively) were more likely to continue smoking during pregnancy compared to Dutch women (58.6%, p<.001). Lower education was associated with smoking during pregnancy only in the Dutch group. No significant association of education with smoking was seen in the non-Dutch groups. Second-generation (i.e., foreign-born) Turkish and Capeverdean women were more likely to smoke during pregnancy compared with first-generation women. Partner smoking was associated with smoking during pregnancy in all ethnic groups except for Surinamese-Creole and Antillean. Maternal alcohol consumption was associated with smoking during pregnancy in all ethnic groups except for Capeverdean. Smoking rates and correlates of smoking during pregnancy varied by ethnic background. These observations should be considered when designing maternal smoking prevention and intervention strategies.

Haplotype-specific expression of the human PDGFRA gene correlates with the risk of glioblastomas (Article)

2008-07-15T00:00:00Z

Aberrant expression of the platelet-derived growth factor α-receptor (PDGFRA) gene has been associated with various diseases, including neural tube defects and gliomas. We have previously identified 5 distinct haplotypes for the PDGFRA promoter region, designated H1, H2α, H2β H2γ and H2δ. Of these haplotypes H1 and H2α are the most common, whereby H1 drives low and H2α high transcriptional activity in transient transfection assays. Here we have investigated the role of these PDGFRA promoter haplotypes in gliomagenesis at both the genetic and cellular level. In a case-control study on 71 glioblastoma patients, we observed a clear underrepresentation of H1 alleles, with pH1 = 0.141 in patients and pH1 = 0.211 in a combined Western European control group (n = 998, p < 0.05). Furthermore, in 3 out of 4 available H1/H2α heterozygous human glioblastoma cell lines, H1-derived mRNA levels were more than 10-fold lower than from H2α, resulting at least in part from haplotype-specific epigenetic differences such as DNA methylation and historic acetylation. Together, these results indicate that PDGFRA promoter haplotypes may predispose to gliomas. We propose a model in which PDGFRA is upregulated in a haplotype-specific manner during neural stem cell differentiation, which affects the pool size of cells that can later undergo gliomagenesis.

Embryonic staging using a 3D virtual reality system (Article)

2008-07-01T00:00:00Z

BACKGROUND: The aim of this study was to demonstrate that Carnegie Stages could be assigned to embryos visualized with a 3D virtual reality system. METHODS: We analysed 48 3D ultrasound scans of 19 IVF/ICSI pregnancies at 7-10 weeks' gestation. These datasets were visualized as 3D 'holograms' in the BARCO I-Space virtual reality system. Embryos were staged according to external morphological features (i.e. mainly limb development). After staging, the crown rump length (CRL) was measured. Stage and CRL were compared with gestational age based on the date of oocyte retrieval and with the classical data on embryology from the Carnegie Collection. RESULTS: Embryonic staging was relatively easy because the I-Space allows depth perception, which helps in the estimation of size and position. The presumed stages corresponded well with the measured CRL. However, in 28 out of 48 cases, the stages seemed to have been reached earlier than previously described for the Carnegie Collection. CONCLUSIONS: The I-Space, tentatively named Virtual Embryoscopy, is a promising non-invasive tool for early pregnancy evaluation. Combining embryonic growth with embryonic development opens a new area to study the relationship between embryonic growth, development and morphology, as well as second and third trimester pregnancy complications.

Tracking and determinants of subcutaneous fat mass in early childhood: The Generation R Study (Article)

2008-07-01T00:00:00Z

Objectives: To examine the development and tracking of subcutaneous fat mass in the first 2 years of life and to examine which parental, fetal and postnatal characteristics are associated with subcutaneous fat mass. Design: This study was embedded in the Generation R Study, a prospective cohort study from early fetal life onward. Subcutaneous fat mass was measured by skinfold thickness (biceps, triceps, suprailiacal, subscapular) at the ages of 1.5, 6 and 24 months in 1012 children. Information about parental, fetal and postnatal growth characteristics was collected by physical and fetal ultrasound examinations and questionnaires. Results: Normal values of subcutaneous fat mass are presented. Total subcutaneous fat mass was higher in girls than in boys at the age of 24 months (P=0.01). Subjects in the lowest and highest quartiles at the age of 6 months tended to keep their position in the same quartile at the age of 24 months (odds ratios 1.86 (95% confidence interval (CI) 1.3, 2.7)) and 1.84 (95% CI: 1.3, 2.6), respectively). Maternal height and weight, paternal weight, fetal weight at 30 weeks, birth weight and weight at the age of 6 weeks were each inversely associated with subcutaneous fat mass at the age of 24 months after adjustment for current weight at 24 months. Conclusion: This study shows for the first time that subcutaneous fat mass tends to track in the first 2 years of life. Furthermore, the results suggest that an adverse fetal environment and growth are associated with increased subcutaneous fat mass at the age of 24 months. Further studies are needed to examine whether these associations persist in later life.

The outcome of gastroschisis after a prenatal diagnosis or a diagnosis only at birth. Recommendations for prenatal surveillance (Article)

2008-07-01T00:00:00Z

Objectives: To establish in infants with gastroschisis whether outcome is different when comparing a prenatal diagnosis with a diagnosis only at birth with the intention to develop a prenatal surveillance protocol. Intestinal atresia established after birth and preterm versus term delivery were studied as risk factors. Study design: All 24 fetuses and 9 infants diagnosed with gastroschisis and referred to our tertiary center between January 1991 and June 2003 were studied retrospectively. Results: The infants of the prenatal subset delivered at our tertiary center and 18 survived. There were two pregnancy terminations, three intrauterine deaths at 19, 33 and 36 weeks respectively and one neonatal death. All nine infants in the postnatal subset survived. Eight were out born and one was delivered at our tertiary center. Prenatal bowel dilatation did not correlate with outcome. Between the prenatal and postnatal subset no significant difference in outcome of live-born infants was established. For four infants with intestinal atresia a significant difference was demonstrated for induction of preterm labour (P < 0.05), duration of parenteral nutrition (P < 0.01), number of additional surgical procedures (P < 0.001) and length of hospital stay (P < 0.01). The fifteen infants born prior to 37 weeks of gestation spent a significantly longer period in hospital compared to those delivered at term. When the cases with bowel atresia were excluded this difference was no longer present. Five of the 33 cases were diagnosed with associated anomalies which mainly involved the urinary tract. Conclusion: Neonatal outcome of live born infants following a prenatal diagnosis of gastroschisis is not different from a diagnosis at birth. The presence of intestinal atresia is the most important prognostic factor for morbidity. The supplemental value of prenatal diagnosis to the outcome of infants with gastroschisis may be in the prevention of unnecessary intrauterine death and detection of intestinal complications. A proposed surveillance protocol for fetuses with gastroschisis focused on intrauterine signs of pending distress such as a dilated stomach, intra abdominal bowel dilatation with peristalsis, notches in the umbilical artery Doppler signal, development of polyhydramnios and an abnormal CTG registration may improve outcome.

Preconception folic acid treatment affects the microenvironment of the maturing oocyte in humans (Article)

2008-06-01T00:00:00Z

Objective: To investigate the influence of folic acid supplementation on the follicular fluid concentrations of folate and total homocysteine and their relationship to the diameter of the follicle. Design: Observational study. Setting: Tertiary referral fertility clinic at the Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Patient(s): Thirty-seven women undergoing IVF or intracytoplasmic sperm injection treatment. Intervention(s): No interventions other than routine stimulation treatment and the recommendation of folic acid supplementation. Main Outcome Measure(s): Concentrations of folate and total homocysteine in monofollicular and pooled follicular fluid and the diameter of the follicle. Result(s): Folic acid supplementation significantly increased folate and decreased total homocysteine concentrations in pooled follicular fluid. In monofollicular fluid, folate concentrations only were significantly increased in supplemented women. The total homocysteine concentration appeared to be significantly correlated with the diameter of the follicle (r = 0.27). Samples from single follicles were less prone to artifacts in the measurements of the folate and total homocysteine concentration. Conclusion(s): Preconception folic acid supplementation significantly alters both folate and total homocysteine concentrations in follicular fluid. The correlation between the diameter of the follicle and total homocysteine concentration in follicular fluid warrants further investigation.

Eight-fold increased risk for congenital heart defects in children carrying the nicotinamide N-methyltransferase polymorphism and exposed to medicines and low nicotinamide (Article)

2008-06-01T00:00:00Z

Aims: Congenital heart defects (CHDs) have a multifactorial origin, in which subtle genetic factors and peri-conception exposures interact. We hypothesize that derangements in the homocysteine and detoxification pathways, due to a polymorphism in the nicotinamide N-methyltransferase (NNMT) gene, low maternal dietary nicotinamide intake, and medicine use in the peri-conception period, affect CHD risk. Methods and results: In 292 case and 316 control families, maternal peri-conception medicine use and low dietary intake of nicotinamide (≤13.8 mg/day) were independently associated with CHD risk [odds ratio (95% confidence interval) 1.6 (1.1-2.3) and 1.5 (1.03-2.3), respectively]. No significant association was found for the NNMT AG/AA genotype in mothers [0.9 (0.7-1.3)], fathers [1.1 (0.8-1.6)], or children [1.1 (0.8-1.6)]. However, the combination of peri-conception medicine use, low dietary nicotinamide intake, and the NNMT AG/AA genotype in mothers or children showed risk of 2.7 (1.02-8.1) and 8.8 (2.4-32.5), respectively. Conclusion: Children carrying the NNMT A allele face additional CHD risk in combination with peri-conception exposure to medicines and/or a low dietary nicotinamide intake. These findings provide a first set of data against which future studies with larger sample sizes can be compared with.

Polymorphisms in genes related to folate and cobalamin metabolism and the associations with complex birth defects (Article)

2008-06-01T00:00:00Z

Objective: To investigate the associations between biomarkers and genetic variants involved in homocysteine metabolism and the risk of complex birth defects. Methods: Total homocysteine (tHcy), folate, cobalamin, apo-transcobalamin (apo-TC) and apo-haptocorrin (apo-HC) were measured in the amniotic fluid of 82 women who were pregnant with a child having a complex birth defect, such as neural tube defect, cleft lip and/or palate, heart defect or omphalocele, and in 110 women pregnant with a non-malformed child. The determined genotypes of the child comprised of 5, 10-methylenetetrahydrofolate reductase (MTHFR 677C>T, 1298A>C), methionine synthase (MTR 2756A>G), methionine synthase reductase (MTRR 66A>G) and transcobalamin (TCN2 776C>G). Univariate and multivariate logistic regression analyses were performed. Results: Significantly lower cobalamin and higher apo-TC, apo-HC, tHcy and folate concentrations were determined in amniotic fluids of cases compared with controls (p ≤ 0.001). Logistic regression analysis revealed that after adjustment for maternal age, children carrying the MTHFR 677T allele showed a four-fold increased risk of having a complex birth defect, OR (95% CI) = 4.0 (1.1-15.4). Other genotypes did not show significant associations. Conclusion: The MTHFR 677C>T polymorphism in conjunction with reduced folate- and/or cobalamin status may increase the risk of complex birth defects. Copyright

Two MTHFR polymorphisms, maternal B-vitamin intake, and CHDs (Article)

2008-06-01T00:00:00Z

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms are associated with complex congenital malformations. Whether these polymorphisms are associated with CHDs is not clear. We studied both MTHFR polymorphisms, folate and vitamin B2 by maternal food intake and supplements, and CHD risk. METHODS: A case-control family study was conducted in a European population in the Netherlands including 230 case and 251 control children with both parents. Approximately 17 months after the index pregnancy, mothers filled out standardized questionnaires on periconception use of folic acid supplements and a validated food frequency questionnaire on current dietary folate and vitamin B2 intake. All subjects were genotyped for the MTHFR C677T and A1298C polymorphisms. Data were analyzed by logistic regression analysis and ORs and 95% CIs were calculated. For the interaction analysis the dominant model was used. RESULTS: The risk estimates for the MTHFR 677 CT genotypes were 1.4 (0.9-2.0) in mothers, 1.1 (0.8-1.6) in fathers, and 1.2 (0.8-1.7) in children, and for the MTHFR 677 TT genotypes 0.9 (0.6-1.2), 1.4 (1.0-1.9), and 1.0 (0.7-1.3), respectively. The MTHFR 1298 CC genotype in fathers and the MTHFR 1298 AC genotype in children significantly reduced CHD risk, 0.6 (0.5-0.9) and 0.6 (0.4-0.9), respectively. Of interest is the significant interaction (p = .008) towards a nearly twofold increased risk in mothers carrying the MTHFR 1298 C allele and using a periconception folic acid supplement. CONCLUSIONS: The MTHFR C677T and A1298C polymorphisms are not strong risk factors for CHDs.

Risk of complications during pregnancy in women with congenital aortic stenosis (Article)

2008-05-23T00:00:00Z

Background: Pregnancy in women with congenital aortic stenosis (AS) is associated with increased cardiac complications. Data on non-cardiac complications are limited, and this information is crucial for prenatal counselling and perinatal care. The aim of this study was to present the maternal and perinatal outcome of pregnancy in women with congenital AS. Methods: By review of the Dutch CONCOR national registry and a local Belgian tertiary care centre database, 35 women with congenital AS with a history of completed pregnancy before aortic valve replacement were enrolled in this study. Medical history and maternal and perinatal outcome were determined. Results: Thirty-five women had 58 pregnancies resulting in 53 successful pregnancies, three miscarriages, and two abortions. The most serious cardiac complications were heart failure (n = 2, 3.8%) and atrial arrhythmia (n = 3, 5.7%). Although cardiac complications were present (9.4%), obstetric (22.6%) and perinatal (24.5%) complications were observed more often. A total of six pregnancies (11.3%) were complicated by hypertension-related disorders, including one case of eclampsia. Furthermore, 7 premature births (13.2%) and 7 small-for-gestational-age births (13.2%) were encountered. Pregnancy in women with severe AS was characterized by an increased incidence of heart failure and premature labour, and shorter pregnancy duration. Older women (> 30 years) were at increased risk of perinatal events (odds ratio 4.38, 95% confidence interval 1.02 to 18.81). Conclusions: Pregnancy is generally well tolerated in women with congenital AS. Importantly, an excess of obstetric and perinatal complications was found, requiring more meticulous attention.

The transient increase of oxidative stress during normal pregnancy is higher and persists after delivery in women with pre-eclampsia (Article)

2008-05-01T00:00:00Z

Objectives: Glutathione, an intracellular tripeptide, functions in the protection of cells against free radicals and toxins of endogenous and exogenous origin. To maintain the intracellular redox status in presence of reactive oxygen species, glutathione (GSH) and other thiols are oxidized. The oxidative status of thiols is reflected by the free-to-oxidized ratio and is a real-time measure for oxidative stress. Previously, we have reported abnormal ratios for the thiols cysteine (Cys), homocysteine (Hcy) and cysteinylglycine (CysGly) in women with pre-eclampsia. The aims of this study were to confirm our previous findings in a different case-control cohort and more importantly to determine whether these differences persist postpartum. Study design: At onset of disease and at 6-8 weeks postpartum we analyzed whole blood of 41 women with pre-eclampsia and of 31 women with normotensive pregnancies for the free-to-oxidized ratio of thiols by the assessment of free and oxidized thiol levels using high performance liquid chromatography. Differences between values were determined using either the paired t-test (antepartum versus postpartum) or the t-test (pre-eclampsia versus normotensive pregnancy). Results: Antepartum levels of free GSH as well as the free-to-oxidized ratios of Hcy were lower in pre-eclampsia and normotensive pregnancy when compared with corresponding postpartum values (P < 0.0001 and P < 0.01, respectively). Moreover, the free-to-oxidized ratio for Hcy was significantly lowered in pre-eclamptic compared with normotensive women, during as well as after pregnancy (both P ≤ 0.01). Conclusion: The data suggest that pregnancy is a state of higher oxidative stress when compared to the postpartum period. In women with pre-eclampsia, oxidative stress is higher and persists in the postpartum period.

Genetic and lifestyle factors related to the periconception vitamin B12 status and congenital heart defects: A Dutch case-control study (Article)

2008-05-01T00:00:00Z

Maternal hyperhomocysteinemia is associated with congenital heart defects (CHDs) in the offspring. A low periconception vitamin B12 status is determined by genetic and lifestyle factors and causes hyperhomocysteinemia. We investigated methionine synthase reductase (MTRR) and transcobalamin II (TC) genes and maternal intake and serum concentrations of vitamin B12 in association with CHD risk. Seventeen months after the index-pregnancy, we studied 230 children with a CHD and 251 non-malformed children and their parents. Data were collected on current and periconception maternal vitamin supplement use and maternal dietary vitamin B12 intake of the month before the study moment. Blood samples were taken for the determination of MTRR A66G and TC C776G genotypes in families and maternal serum vitamin B12 concentrations. Transmission disequilibrium tests and univariate and multivariate analyses were applied. Allele transmissions were not significantly distorted. The MTRR and TC genotypes did not significantly affect CHD risk. Neither polymorphisms in mothers and/or children revealed significant interactions nor in combination with low vitamin B12 intake. Low maternal serum vitamin B12 combined with the maternal or child's MTRR 66 GG genotype resulted in odds ratios of 1.4 (95% confidence interval 0.6-3.5) and 1.3 (0.5-3.4), respectively. The TC 776 GG genotype in mothers and children revealed risk estimates of 2.2 (0.7-7.1) and 1.9 (0.5-7.4), respectively. In conclusion, MTRR 66 GG and TC 776 GG genotypes in mothers and children may contribute to the risk of CHDs, particularly when the maternal vitamin B12 status is low. The future enlargement of our sample size might demonstrate significant associations.

Substandard care in maternal mortality due to hypertensive disease in pregnancy in the Netherlands (Article)

2008-05-01T00:00:00Z

Objectives: To review the standard of care in cases of maternal mortality due to hypertensive diseases in pregnancy and to make recommendations for its improvement. Design: Care given to women with hypertensive disease in pregnancy was audited and substandard care factors identified. Setting: Confidential enquiry by the Dutch Maternal Mortality Committee (MMC) from the Netherlands Society of Obstetrics and Gynaecology. Population: All maternal deaths reported to the MMC due to hypertensive disease in pregnancy in the Netherlands during the years 2000-04. Methods: Assessment for substandard care factors using a checklist based on the Dutch guideline of 'Hypertensive Disorders in Pregnancy'. Main outcome measures: Substandard care in cases of maternal mortality due to hypertensive diseases in pregnancy. Results: A total of 27 cases of maternal death due to hypertensive disease in pregnancy were reported to the committee in the study period. In 26 cases (96%), substandard care factors were present, of which in 17 cases (63%), these were for more than five different items. In community midwifery care, the most frequent substandard care factor was no testing for proteinuria when clearly indicated (41%). In hospital care, the most frequent substandard care was related to insufficient diagnostic testing when indicated (41%), insufficient management of hypertension by obstetricians (85%), no use or inadequate use of magnesium sulphate (67%), inadequate stabilisation before transport to tertiary care centres and/or delivery (52%) and failure to consider timely delivery (44%). Conclusions: Education of pregnant women concerning danger signs of hypertensive disease should be improved. Training of midwives and obstetricians should be improved in the following areas: performing basic diagnostic tests, adequate management of hypertension and eclampsia, with more attention to treatment of systolic blood pressure. This training should be guided by clear local protocols. Delivery should not be delayed in serious cases of hypertensive disease in pregnancy, not only after 32-34 weeks but also in early-onset pre-eclampsia as maternal risks often outweigh possible fetal benefits of temporising management.

Impaired maternal cognitive functioning after pregnancies complicated by severe pre-eclampsia: A pilot case-control study (Article)

2008-04-10T00:00:00Z

Background. Pre-eclampsia is the most significant cause of neurological symptoms in pregnancy. Neurological symptoms may persist even after pregnancy. Somatic symptoms of pre-eclampsia, such as hypertension and proteinuria, generally disappear after delivery. However, formerly pre-eclamptic women more often complain of cognitive disturbances compared to women after uncomplicated pregnancies. Methods. Three to eight months postpartum, a neuropsychological test battery was performed in 10 former severely pre-eclamptic women (according to the guidelines of the American College Obstetricians and Gynecologists) and 10 women after uncomplicated normotensive pregnancies. The control group was matched for age, educational level and mode of anesthesia. All women delivered by cesarean section either under general or regional anesthesia. Tests were performed for premorbid intelligence, short- and long-term memory, attention, concentration, executive functions, visual and spatial abilities. Anxiety and depression levels were measured. Results. The formerly pre-eclamptic women had significantly lower scores on most indices of the auditory-verbal memory test. Formerly pre-eclamptic patients learned considerably fewer words than controls and recalled less after interference. Both case and control group did not differ in age, parity or level of education. There were no differences in the level of intellectual functioning and language tests, such as naming and word fluency. No persistent differences were observed in tests for attention/concentration and executive functioning. There were no significant differences on depression and anxiety scales. Conclusions. Maternal memory seems to be impaired after pregnancies complicated by severe pre-eclampsia. This effect cannot be attributed to depression and/or anxiety or method of anesthesia.

Maternal TLR4 and NOD2 gene variants, pro-inflammatory phenotype and susceptibility to early-onset preeclampsia and HELLP syndrome (Article)

2008-04-02T00:00:00Z

Background: Altered maternal inflammatory responses play a role in the development of preeclampsia and the hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. We examined whether allelic variants of the innate immune receptors toli-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain (NOD2), that impair the inflammatory response to endotexin are related to preeclampsia and HELLP syndrome. Methods and Finding: We determined five common mutations in TLR4 (D299G and T399I and NOD2 (R70W, G908R and L1007fs) in 340 primiparous women with a history of early-onset preeclampsia, of whom 177 women developed HELLP syndrome and in 113 women with a history of only uneventful pregnancies as controls. In addition, we assessed plasma levels of pro-inflammatory biomarkers C-reactive protein, interleukin-6 soluble intercellular adhesion molecule-1, fibrinogen and von Willebrand factor in a subset of 214 women included at least six months after delivery. After adjustment for maternal age and chronic hypertension, attenuating allelic variants of TLR4 were more common in women with a history of early onset preeclampsia than in controls (OR 2.9 [95% CI 1.2-6.7]). Highest frequencies for TLR4 variants were observed in women who developed HELLP syndrome (adjusted OR 4.1 [9.5% CI 1.7-9.8]). In addition, high levels of interleukin-6 and fibrinogen were associated with a history of early-onset preeclampsia. Combined positivity for any of the TLR4 and NOD2 allelic variants and high levels of interleukin-6 was 6.9-fold more common in women with a history of early-onset preeclampsia (95% CI 2.1-23.2) compared to controls. Conclusions: We observed an association of common TLR4 and NOD2 gene variants, and pro-inflammatory phenotype with a history of early-onset preeclampsia and HELLP syndrome. These suggest involvement of the maternal innate immune system in severe hypertensive disorders of pregnancy.

Fetal/neonatal allo-immune thrombocytopenia (FNAIT): Past, present, and future (Article)

2008-04-01T00:00:00Z

We reviewed the English, American, and German literature for articles describing the prevalence, clinical presentation, outcome, therapeutic options, and screening possibilities for fetal/neonatal allo-immune thrombocytopenia (FNAIT), published between January 1950 and March 2007. The reported prevalence of FNAIT in human platelet antigen (HPA)-1a-negative women varies between 1/600 to 1/5000 live births among various populations. The typical picture is that of a neonate presenting with purpura minutes to hours after birth, born to a healthy mother with no history of infection or abnormal bleeding, after an uneventful pregnancy with a normal maternal platelet count. Thrombocytopenia in FNAIT can be severe, with intracranial hemorrhage occurring in 10% to 30% of severe FNAIT cases. Several types of neonatal treatment have been proposed, of which transfusion of HPA-compatible platelets is most effective. Antenatal management of FNAIT consists of weekly maternal intravenous immunoglobulin (IVIG) infusions, with or without oral steroid therapy. Serial fetal platelet transfusions can be provided in cases of failure of IVIG therapy, but the multiple cordocenteses that would be required to administer the platelets entail substantial risk. The possibilities for antenatal screening of first pregnancies are limited. Postnatal screening does not prevent neonatal morbidity and mortality. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians LEARNING OBJECTIVES: After completion of this article, the reader should be able to summarize the many and varied causes of neonatal thrombocytopenia, explain that fetal/neonatal allo-immune thrombocytopenia (FNAIT) is a rare but devastating cause with potential high risk of recurrence, and recall the treatment options for FNAIT as well as their potential side effects.

Shared constitutional risks for maternal vascular-related pregnancy complications and future cardiovascular disease (Article)

2008-04-01T00:00:00Z

Maternal predisposition to vascular and metabolic disease may underlie both vascular-related pregnancy complications, such as preeclampsia and intrauterine growth restriction, as well as future maternal cardiovascular disease. We aimed to substantiate this hypothesis with biochemical and anthropometric evidence by conducting an intergenerational case-control study in a Dutch isolated population including 106 women after preeclampsia or intrauterine growth restriction (median follow-up: 7.1 years) and their fathers (n=43) and mothers (n=64), as well as 106 control subjects after uncomplicated pregnancies with their fathers (n=51) and mothers (n=68). Cardiovascular risk profiles were assessed, including fasting glucose, lipids, anthropometrics, blood pressure, intima-media thickness, and metabolic syndrome. We found significantly higher fasting glucose levels, larger waist circumferences, and a 5-fold increased prevalence of hypertension in women with a history of preeclampsia as compared with control subjects (P<0.001). Likewise, their parents had higher glucose levels than control parents (P<0.05). Their mothers had larger waist circumferences and higher blood pressures (P<0.05). Also, women after pregnancies complicated by intrauterine growth restriction had higher glucose levels and increased prevalence of hypertension (P<0.01). Their fathers showed higher glucose levels as well (P<0.05). Mean carotid intima-media thickness was increased in a subset of women after preeclampsia diagnosed with chronic hypertension as compared with those without hypertension (P<0.01). Metabolic syndrome was more prevalent both in women with a history of preeclampsia and their mothers (P<0.05). We demonstrated intergenerational similarities in cardiovascular risk profiles between women after preeclampsia or intrauterine growth restriction and their parents. These findings suggest shared constitutional risks for vascular-related pregnancy complications and future cardiovascular disease.

Intra- and interobserver reproducibility study of early fetal growth parameters (Article)

2008-04-01T00:00:00Z

Objective: To assess the intra- and interobserver reproducibility of fetal biometry measurements by transabdominal ultrasound in early pregnancy. Methods: The study consisted of 21 singleton pregnancies with a gestational age between 9 and 14 weeks. Intraclass correlation coefficients (ICCs) and coefficients of variation (CVs) were calculated. Bland and Altaian plots were computed to analyze agreement for measurements between and among observers. Limits of agreement ±2 SD for the differences in fetal biometry measurements in proportions of the mean of the measurements were derived. Results: High intra- and interobserver ICCs were found, ranging from 0.998, crown-rump length (CRL) to 0.982, femur length (FL) and CVs ranging from 1.4% (CRL) to 5.9% (FL). Limits of agreement in the Bland and Altman plots ranged from -2.7 to 2.3% (CRL) difference from the mean to -13 to 23% (FL) difference. Agreement for fetal biometry increased with fetal size. Conclusions: This study demonstrated good reproducibility of most measurements of fetal biometry in early pregnancy by abdominal ultrasound. CRL and biparietal diameter (BPD) showed high reproducibility and agreement, and head circumference (HC) to a lesser extend, from 9 weeks of gestational age onwards, abdominal circumference (AC) is only reliable from circa 11 weeks onwards. FL has a poor reproducibility before 14 weeks of gestational age. Copyright

New charts for ultrasound dating of pregnancy and assessment of fetal growth: Longitudinal data from a population-based cohort study (Article)

2008-04-01T00:00:00Z

Objectives: Correct assessment of gestational age and fetal growth is essential for optimal obstetric management. The objectives of this study were, first, to develop charts for ultrasound dating of pregnancy based on crown-rump length and biparietal diameter and, second, to derive reference curves for normal fetal growth based on biparietal diameter, head circumference, transverse cerebellar diameter, abdominal circumference and femur length from 10 weeks of gestational age onwards. Methods: A total of 8313 pregnant women were included for analysis in this population-based prospective cohort study. All women had repeated ultrasound assessments to examine fetal growth. Results: Charts for ultrasound dating of pregnancy, based on crown-rump length and biparietal diameter, were derived. Internal validation with the actual date of delivery showed that ultrasound imaging provided reliable gestational age estimates. Up to 92% of deliveries took place within 37-42 weeks of gestation if gestational age was derived from ultrasound data, compared with 87% based on a reliable last menstrual period. The earlier the ultrasound assessment the more accurate the prediction of date of delivery. After 24 weeks of gestation a reliable last menstrual period provided better estimates of gestational age. Reference curves for normal fetal growth from 10 weeks of gestational age onwards were derived. Conclusions: Charts for ultrasound dating of pregnancy and reference curves for fetal biometry are presented. The results indicate that, up to 24 weeks of pregnancy, dating by ultrasound examination provides a better prediction of the date of delivery than does last menstrual period. The earlier the ultrasound assessment in pregnancy, preferably between 10 and 12 weeks, the better the estimate of gestational age. Copyright

Perinatal stress influences lymphocyte subset counts in neonates. The generation R study (Article)

2008-03-01T00:00:00Z

In the general population, it is unknown whether stress-related perinatal factors influence lymphocyte subset counts in neonates. The aim of this study was to assess the associations of perinatal factors related to stress and hypoxia (mode of delivery, Apgar scores, and umbilical cord blood pH) with absolute lymphocyte subset counts (T, B, NK, helper T, cytotoxic T, naïve, memory T) in cord blood of 571 neonates. This study was embedded in a population-based prospective cohort study from fetal life onwards. All models were adjusted for gestational age, birth weight, gender, maternal fever, and each of the other perinatal stress-relating factors. Our results showed that increasing stress-related mode of delivery was positively associated with NK and memory T-lymphocyte subset counts (all p < 0.01). Effects of Apgar scores on lymphocyte subsets were explained by umbilical cord blood pH. Lower umbilical cord blood pH was associated with higher B, NK, and memory T-lymphocyte counts (all p < 0.05). Effects of mode of delivery and umbilical cord blood pH on other lymphocyte subsets were not observed. We conclude that, in the general population, lymphocyte subset counts in neonates increase with increasing stress- and hypoxia-related perinatal factors.

Active and passive maternal smoking during pregnancy and the risks of low birthweight and preterm birth: The generation R study (Article)

2008-03-01T00:00:00Z

The objective of this study was to examine the associations between active and passive smoking in different periods of pregnancy and changing smoking habits during pregnancy, with low birthweight and preterm birth. The study was embedded in the Generation R Study, a population-based prospective cohort study from early fetal life onwards in Rotterdam, The Netherlands. Active and passive smoking were assessed by questionnaires in early, mid- and late pregnancy. Analyses were based on 7098 pregnant women and their children. Active smoking until pregnancy was ascertained and was not associated with low birthweight and preterm birth. Continued active smoking after pregnancy was also recorded and was associated with low birthweight (adjusted odds ratio 1.75 [95% CI 1.20, 2.56]) and preterm birth (adjusted odds ratio 1.36 [95% CI 1.04, 1.78]). The strongest associations were found for active maternal smoking in late pregnancy. Passive maternal smoking in late pregnancy was associated with continuously measured birthweight (P for trend <0.001). For all active smoking categories in early pregnancy, quitting smoking was associated with a higher birthweight than continuing to smoke. Tendencies towards smaller non-significant beneficial effects on mean birthweight were found for reducing the number of cigarettes without quitting completely. This study shows that active and passive smoking in late pregnancy are associated with adverse effects on weight and gestational age at birth. Smoking in early pregnancy only, seems not to affect fetal growth adversely. Health care strategies for pregnant women should be aimed at quitting smoking completely rather than reducing the number of cigarettes.

Variation in the IGF1 gene and growth in foetal life and infancy. The Generation R Study (Article)

2008-03-01T00:00:00Z

Objective: The objective of this study was to examine whether variants of the IGF1 gene are associated with growth patterns from foetal life until infancy. Study design and measurements: This study was embedded in the Generation R Study, a population-based prospective cohort study of foetal life. Foetal growth (head circumference, abdominal circumference, femur length, estimated foetal weight) was assessed by ultrasound in early, mid- and late pregnancy. Growth in infancy was assessed at birth (weight) and at the ages of 6 weeks, 6 months and 14 months (head circumference, length, weight). The IGF1 promoter region genotype was determined in 738 children. Results: Eight alleles of the IGF1 promoter region were identified. In total, 43% of the subjects were homozygous for the most common 192-bp allele (wild-type), 45% were heterozygous, and 12% were noncarriers of the 192-bp allele. No differences were found in birthweight between the three groups. However, noncarriers had a lower estimated foetal weight in mid-pregnancy (P = 0.040), followed by an increased growth rate until 6 months (P < 0.005) in comparison to the 192-bp homozygotes. A similar difference in growth rate was found for length (P < 0.001). Conclusions: Variants of the IGF1 promoter region are not associated with birthweight. However, noncarriers of the 192-bp allele tend to have a smaller foetal size, followed by an increased growth rate from mid-pregnancy to early infancy. Studies in larger cohorts are necessary to replicate our findings and to examine whether these effects persist throughout childhood.

The I105V polymorphism in glutathione S-transferase P1, parental smoking and the risk for nonsyndromic cleft lip with or without cleft palate (Article)

2008-03-01T00:00:00Z

Genetic variations in the detoxification enzyme glutathione S-transferase P1 (GSTP1) may modify the teratogenicity of lifestyles, such as smoking. We investigated the role of the I105V polymorphism in GSTP1, parental periconception smoking, and their interaction with nonsyndromic cleft lip with or without cleft palate (CL/P) risk in the offspring. The GSTP1 I105V polymorphisms were determined in Dutch non-consanguineous Caucasians comprising of 155 CL/P triads (mother, father, child) and 195 control triads. The analyses were also carried out on complete triads only (n = 69 CL/P and n=95 controls). Transmission disequilibrium testing and logistic regression analyses were performed. Neither maternal nor paternal smoking increased CL/P risk; odds ratios (OR): 1.2, 95 confidence intervals (CI) = 0.7-2.0 and OR: 1.0, 95% CI = 0.6-1.6, respectively. Carriership of the polymorphic Val105 allele in mothers may increase CL/P risk, OR: 1.5, 95% CI = 0.96-2.5. Children homozygous for the Val105 allele may show an increased risk of CL/P, OR: 2.2, 95% CI = 0.8-6.4. Maternal smoking tended to increase CL/P risk in mothers and children carrying Val105 alleles, OR = 1.9, 95% CI = 0.9-4.0 and OR = 2.2, 95% CI = 0.98-4.9, respectively. The highest risk for CL/P in children carrying Val105 alleles with a smoking father was 1.7, 95% CI = 0.8-3.5. The GSTP1 I105V polymorphism in mothers and/or children either alone or in combination with maternal smoking may contribute to CL/P risk. Although of borderline significance, these results may underline the importance of smoking cessation in the periconception period for the prevention of CL/P in future generations.

Foetal growth determines cerebral ventricular volume in infants. The Generation R Study (Article)

2008-02-15T00:00:00Z

The cerebral ventricular system is a marker of brain development and a predictor of neurodevelopmental outcome. In premature or dysmature neonates, neuroanatomical structures including the ventricular system appear to be altered. The present study aims to provide information on the association between foetal growth and neonatal cerebral ventricular size in the normal population. Within the Generation R Study, a population-based cohort study, we used three-dimensional cranial ultrasound to determine lateral ventricular volume in 778 term infants aged 4-12 weeks. Foetal growth characteristics were repeatedly measured in early, mid- and late pregnancy and analysed in relation to ventricular volume divided by head circumference. Results revealed positive associations between foetal head circumference in late pregnancy and log-transformed ventricular volume (β = 0.077, 95% confidence interval (0.017; 0.136), equivalent to a 7.7% increase in ventricular volume per standard deviation of head circumference). Similarly, in a per week-longer gestational duration, ventricular volume in infancy was 6.0% larger. Multilevel modelling demonstrated that reduced growth of foetal head circumference and biparietal diameter during pregnancy were associated with decreased ventricular volume in infancy. In conclusion, foetal maturation is positively associated to cerebral ventricular size in term infants. Larger ventricular size in term infants needs to be distinguished from ventricular enlargement due to intraventricular haemorrhage or white matter damage in premature or dysmature infants. Moreover, the naturally occurring enlargement of ventricles during infancy should be considered in interpreting reports on increased ventricular volumes in several neuropsychiatric disorders.

Fetal hemodynamic adaptive changes related to intrauterine growth the generation R study (Article)

2008-02-05T00:00:00Z

Background-It has been suggested that an adverse fetal environment increases susceptibility to hypertension and cardiovascular disease in adult life. This increased risk may result from suboptimal development of the heart and main arteries in utero and from adaptive cardiovascular changes in conditions of reduced fetal growth. The aim of the present study was to evaluate whether reduced fetal growth is associated with fetal circulatory changes and cardiac dysfunction. Methods and Results-This study was embedded in a population-based, prospective cohort study starting in early fetal life. Fetal growth characteristics and fetal circulation variables were assessed with ultrasound and Doppler examinations in 1215 healthy women. The fetal circulation was examined in relation to estimated fetal weight. Higher placental resistance indices were strongly associated with decreased fetal growth. Cerebral resistance showed a gradual decline with reduced fetal growth. Cardiac output, peak systolic velocity of the outflow tracts, and cardiac compliance showed a gradual reduction with diminished fetal growth, whereas intraventricular pressure gradually increased. Conclusions-Decreased fetal growth is associated with adaptive fetal cardiovascular changes. Cardiac remodeling and cardiac output changes are consistent with a gradual increase in afterload and compromised arterial compliance in conditions of decreased fetal growth. These changes have already begun to occur before the stage of clinically apparent fetal growth restriction and may contribute to the increased risk of cardiovascular disease in later life. (Circulation. 2008;117:649-659.).

Symptomatic pelvic organ prolapse and possible risk factors in a general population (Article)

2008-02-01T00:00:00Z

Objective: We sought to examine the prevalence of pelvic organ prolapse (POP) symptoms and risk factors in a general white population. Study Design: This was a cross-sectional study. All female residents aged 45-85 years in a small Dutch city received validated questionnaires. Women were classified as symptomatic if they reported feeling and/or seeing vaginal bulge. Results: Response rate was 62.7% (1869/2979). Prevalence of POP was 11.4%. Multivariate analysis revealed POP symptoms during pregnancy, a maternal history of POP, and heavy physical work, with a total population-attributable risk of 46%. Conclusion: There is high prevalence of symptomatic POP in a general white population of which independent risk factors are POP symptoms during pregnancy, a maternal history of POP, and heavy physical work. Clinicians should focus on risk factors in counseling of (pregnant) women to inform women to be aware of further exposures for themselves and their daughters.

A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: A case-control study (Article)

2008-02-01T00:00:00Z

Context: Polycystic ovary syndrome (PCOS) is associated with a higher frequency of cardiovascular risk factors. Apolipoprotein (apo) A-I and apoB are potent markers for cardiovascular risk. Data on apo levels in women with PCOS are scarce and contradictory. Objective: Our objective was to identify changes in lipid metabolism in women with PCOS, and the relative impact of obesity, insulin resistance, and hyperandrogenism on lipid parameters. Design: This was a case-control study. Setting: The study was performed at a single referral center. Subjects: PCOS was diagnosed according to the 2003 Rotterdam criteria. Healthy mothers with regular menstrual cycles served as controls. Main Outcome Parameters: Fasting insulin, triglycerides (TGs), cholesterol, high-density lipoprotein (HDL)-cholesterol, apoA-I, and apoB were determined. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedewald formula. Results: We included 557 women with PCOS and 295 controls. After correction for age and body mass index, PCOS women had higher median levels of insulin (10.1 vs. 6.9 mU/liter), TGs (95 vs. 81 mg/dl), cholesterol (196 vs. 178 mg/dl), and LDL-cholesterol (125 vs. 106 mg/dl) in combination with lower levels of HDL-cholesterol (46 vs. 55 mg/dl) and apoA-I (118 vs. 146 mg/dl) compared with controls (all P values ≤ 0.01). apoB levels were similar in cases and controls. Free androgen index, body mass index, SHBG, and estradiol were independent predictors of apoA-I levels inwomenwith PCOS. Conclusions: PCOS is associated with a more pronounced atherogenic lipid profile. Furthermore, obesity and hyperandrogenism contribute to an adverse lipid profile. Finally, PCOS seems to constitute an additional risk factor for an atherogenic lipid profile. Copyright

Low folate in seminal plasma is associated with increased sperm DNA damage (Article)

2008-01-01T00:00:00Z

Objective: To determine associations between vitamin B status, homocysteine (tHcy), semen parameters, and sperm DNA damage. Design: Observational study. Setting: A tertiary referral fertility clinic. Patient(s): Two hundred fifty-one men of couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment, with subgroups of fertile (n = 70) and subfertile men (n = 63) defined according to semen concentration and proven fertility. Intervention(s): None. Main Outcome Measure(s): The DNA fragmentation index (DFI) as marker of sperm DNA damage determined using the sperm chromatin structure assay (SCSA), and semen parameters assessed according to World Health Organization criteria; tHcy, folate, cobalamin, and pyridoxine concentrations determined in seminal plasma and blood. Result(s): In the total group of fertile and subfertile men, all biomarkers in blood were statistically significantly correlated with those in seminal plasma. No correlation was found between the biomarkers in blood and the semen parameters. In seminal plasma, both tHcy and cobalamin positively correlated with sperm count. Folate, cobalamin, and pyridoxine were inversely correlated with ejaculate volume. In fertile men, seminal plasma folate showed an inverse correlation with the DNA fragmentation index. Conclusion(s): Low concentrations of folate in seminal plasma may be detrimental for sperm DNA stability.

Maternal anthropometrics in pregnancy are associated with left ventricular mass in infancy. The generation R study (Article)

2008-01-01T00:00:00Z

Pregnancy and early life factors may permanently affect left ventricular growth and development in the offspring. The aim of this study was to examine the associations of maternal anthropometrics during pregnancy with left ventricular mass (LVM) in infancy. This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life onwards. Maternal anthropometrics were obtained in early (gestational age <18 wk), mid- (gestational age 18-25 wk), and late (gestational age >25 wk) pregnancy. Echocardiographic follow-up measurements were performed in 791 infants aged 6 wk and 6 mo. We found no associations of maternal height, weight, or body mass index (BMI) measured in early, mid-, and late pregnancy with longitudinally measured left ventricular mass (LVM) from 6 wk to 6 mo. Maternal weight gain until late pregnancy was associated with an increased growth of LVM from 6 wk to 6 mo [difference 0.46 g per week for the highest tertile of weight gain compared with the lowest tertile (p value <0.05)]. We concluded that maternal weight gain until late pregnancy is associated with larger LVM at the age of 6 mo, suggesting that maternal health status during pregnancy may have permanent consequences for LVM in their children. Further studies are needed to identify the underlying causal mechanisms and the long-term consequences.

The Generation R Study Biobank: A resource for epidemiological studies in children and their parents (Article)

2007-12-01T00:00:00Z

The Generation R Study is a population-based prospective cohort study from fetal life until young adulthood. The study is designed to identify early environmental and genetic causes of normal and abnormal growth, development and health from fetal life until young adulthood. In total, 9,778 mothers were enrolled in the study. Prenatal and postnatal data collection is conducted by physical examinations, questionnaires, interviews, ultrasound examinations and biological samples. Major efforts have been conducted for collecting biological specimens including DNA, blood for phenotypes and urine samples. In this paper, the collection, processing and storage of these biological specimens are described. Together with detailed phenotype measurements, these biological specimens form a unique resource for epidemiological studies focused on environmental exposures, genetic determinants and their interactions in relation to growth, health and development from fetal life onwards.

Insulin gene variable number of tandem repeats is not associated with weight from fetal life until infancy: The Generation R Study (Article)

2007-12-01T00:00:00Z

Objective: The aim of this study was to examine whether the insulin gene variable number of tandem repeats (INS VNTR) is associated with growth patterns in fetal life and infancy. Design and methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from fetal life until young adulthood. Fetal growth was assessed by ultrasounds in early, mid-, and late pregnancy. Anthropometry in infancy was assessed at birth and at the ages of 6 weeks, 6 months, and 14 months. DNA for genotyping of the INS VNTR promoter region was available in 859 children. Results: The genotype distribution was I/1 50.8%, I/III40.0%, and III/ III9.2%. III/III individuals had a shorter gestational age (P<0.005 versus I/I) and a lower birth weight (P<0.05 versus I/I). There were no differences in birth weight after adjusting for gestational age. Class III homozygotes had a smaller abdominal circumference/head circumference (HC) ratio (P<0.005 versus I/I) in mid-pregnancy, but not in late pregnancy. Also, III/III subjects had a relative decrease in HC (SDS) from mid-pregnancy to the age of 14 months (P<0.05 versus I/I). No other differences in pre- and postnatal growth characteristics and patterns were found. Conclusions: Class III homozygotes were born at an earlier gestational age. No association was found between INS VNTR and birth weight adjusted for gestational age. Our data suggest that the III/III genotype may be associated with asymmetrical growth in mid-pregnancy, but not in late pregnancy.

Explaining differences in birthweight between ethnic populations. The Generation R Study (Article)

2007-12-01T00:00:00Z

Objective: To examine whether differences in birthweight of various ethnic groups residing in the Netherlands can be explained by determinants of birthweight. Design: Population-based birth cohort study. Setting: Data of pregnant women and their partners in Rotterdam, the Netherlands. Population: We examined data of 6044 pregnant women with a Dutch, Moroccan, Turkish, Capeverdean, Antillean, Surinamese-Creole, Surinamese-Hindustani and Surinamese-other ethnic background. Methods: Regression analyses were used to assess the impact of biomedical, socio-demographic and lifestyle-related determinants on birthweight differences. Main outcome measure: Birthweight was established immediately after delivery in grams. Results: Compared with mean birthweight of offspring of Dutch women (3485 g, SD 555), the mean birthweight was lower in all non-Dutch populations, except in Moroccans. Differences ranged from an 88-g lower birthweight in offspring of the Turkish women to a 424-g lower birthweight in offspring of Surinamese-Hindustani women. Differences in gestational age, maternal and paternal height largely explained the lower birthweight in the Turkish, Antillean, Surinamese-Creole and Surinamese-other populations. Differences in birthweight between the Dutch and the Capeverdean and Surinamese-Hindustani populations could only partly be explained by the studied determinants. Conclusions: These results confirm significant differences in birthweight between ethnic populations that can only partly be understood from established determinants of birthweight. The part that is understood points to the importance of determinants that cannot easily be modified, such as parental height. Further study is necessary to obtain a fuller understanding.

Complex congenital malformations and the impact of the plasminogen activator system and β-hCG in amniotic fluid (Article)

2007-11-01T00:00:00Z

Objective: The plasminogen activator system and β-hCG may affect neural crest cells and angiogenesis, and thereby embryogenesis. Therefore, we investigated these parameters in amniotic fluids of pregnancies with a complex congenital malformation. Study design: In a case-control study amniotic fluid samples were collected from 62 pregnancies with a complex congenital malformation and from 110 healthy control pregnancies at an obstetric department of a large university hospital in the Netherlands. We determined concentrations of tissue-type plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitors (PAI-1, PAI-2), tPA∼PAI-1 and uPA∼PAI-1 complexes, and β-hCG with enzyme-linked immunosorbent assays. Mann-Whitney U-tests and analysis of covariance, adjusting for gestational and maternal age, were performed for data comparisons. Results: Compared with controls, cases demonstrated significantly lower adjusted geometric mean levels of uPA (24%), tPA (≥19%) and tPA∼PAI-1 (35%). Cases showed significantly higher adjusted mean levels of β-hCG (≥48%) and PAI-2 (10 ng/mL) than controls. Mean PAI-1 and uPA∼PAI-1 levels were comparable between both groups. Conclusions: Disturbances in the plasminogen activator system and β-hCG levels are suggested to be involved in the pathogenesis of complex congenital malformations by affecting neural crest cell migration and angiogenesis.

Relationship between haemoglobin change and estimated blood loss after delivery [6] (Article)

2007-11-01T00:00:00Z

The effect of maternal ketanserin treatment on foetal 5-HT receptor function in umbilical cord artery of pre-eclamptic patients (Article)

2007-11-01T00:00:00Z

Background: Maternal treatment with the 5-HT2Areceptor antagonist ketanserin (KT) in pre-eclamptic patients is associated with a high placental transmission of KT, resulting in pharmacologically active levels of KT in the umbilical cord artery (UCA) and the neonate. Prolonged exposure to a 5-HT receptor antagonist may influence the functionality of foetal 5-HT receptors and compromise foetal development. Objective: To study whether exposure to KT influences the characteristics of foetal 5-HT receptors, functional studies were performed on 5-HT2Aand 5-HT1B/1Dreceptors in UCA from pre-eclamptic patients treated with KT. Methods: UCAs were obtained, immediately after delivery, from pre-eclamptic patients (n = 7), treated antenatally with intravenous KT. Pre-eclamptic patients (n = 13), not treated with KT (non-KT), were included as a control group. Segments of UCA were prepared and mounted in tissue baths and isometric force changes were determined. Cumulative concentration response curves to 5-HT and to the 5-HT1B/1Dreceptor agonist sumatriptan were constructed in the absence or presence of the 5-HT2Areceptor antagonist KT or the 5-HT1B/1Dreceptor antagonist GR125743, respectively. Results: All UCA segments showed contractile responses to both 5-HT and sumatriptan, and the concentration response curves showed a rightward shift with increasing concentrations of KT and GR125743, respectively, indicating the presence of functional 5-HT2Aand 5-HT1B/1Dreceptors in the foetal tissue. No significant differences were found in maximum response (Emax)(expressed in percent of response on 100 mM KCl) or potency (pEC50) of 5-HT in both groups (Emax= 141 ± 7.7%, pEC50= 7.67 ± 0.26 in KT-treated group and Emax= 162 ± 12.6%, pEC50= 7.69 ± 0.14 in non-KT treated group, respectively). No significant differences were found in the potency of the antagonist KT in both study groups (pKb= 7.65 ± 0.31 in KT group and 7.46 ± 0.17 in non-KT group, respectively). Similarly, with sumatriptan, no significant differences were found between KT-treated patients and non-KT treated patients (Emax= 142 ± 16.2 and 140 ± 14.7%, respectively, pEC50= 6.17 ± 0.37 and 6.41 ± 0.28 respectively, pKbof GR125743 = 7.83 ± 0.48 and 8.43 ± 0.29, respectively). Conclusion: Foetal exposure to KT in pre-eclamptic patients does not seem to influence the functional characteristics of 5-HT2Aand 5-HT1B/1Dreceptors in the UCA. Copyright

Ethnic differences in determinants of participation and non-participation in prenatal screening for Down syndrome: A theoretical framework (Article)

2007-10-01T00:00:00Z

Objective: To develop a theoretical framework for analysing ethnic differences in determinants of participation and non-participation in prenatal screening for Down syndrome. Methods: We applied Weinstein's Precaution Adoption Process (PAP) Model to the decision of whether or not to participate in prenatal screening for Down syndrome. The prenatal screening stage model was specified by reviewing the empirical literature and by data from seven focus group interviews with Dutch, Turkish and Surinamese pregnant women in the Netherlands. Results: We identified 11 empirical studies on ethnic differences in determinants of participation and nonparticipation in prenatal screening for Down syndrome. The focus group interviews showed that almost all stages and determinants in the stage model were relevant in women's decision-making process. However, there were ethnic variations in the relevance of determinants, such as beliefs about personal consequences of having a child with Down syndrome or cultural and religious norms. Discussion: The prenatal screening stage model can be applied as a framework to describe the decision-making process of pregnant women from different ethnic backgrounds. It provides scope for developing culturally sensitive, tailored methods to guide pregnant women towards informed decision-making on participation or non-participation in prenatal screening for Down syndrome. Copyright

Moderate Alcohol Consumption During Pregnancy and the Risk of Low Birth Weight and Preterm Birth. The Generation R Study (Article)

2007-10-01T00:00:00Z

Purpose: To examine the associations of alcohol consumption in different periods of pregnancy with the risks of low birth weight and preterm birth. Methods: This study was based on 7141 subjects participating in a population-based prospective cohort study from early pregnancy. Alcohol consumption was assessed in early, mid, and late pregnancy. Birth outcomes were birth weight in grams, low birth weight (<2500 g), small size for gestational age at birth (< -2 standard deviation scores) and preterm birth (gestational age <37 weeks). Results: Overall, alcohol consumption during pregnancy was not associated with adverse birth outcomes. However, dose-response analyses showed tendencies toward adverse effects of average consumption of 1 or more alcoholic drinks per day in early pregnancy on birth weight (difference -129 g [95% confidence interval (CI): -271, 12]), low birth weight (adjusted odds ratio [aOR] 4.81 [95% CI: 1.10, 21.08]), small size for gestational age at birth (aOR 1.45 [95% CI: 0.33, 6.44]) and preterm birth (aOR 2.51 [95% CI: 0.92, 6.81]). Similar effects were found in late pregnancy. Conclusion: Average consumption of one or more but not less than one alcoholic drink per day in early or late pregnancy seems to be associated with adverse birth outcomes in the offspring.

Fetal kidney volume and its association with growth and blood flow in fetal life: The Generation R Study (Article)

2007-09-01T00:00:00Z

An adverse fetal environment may lead to smaller kidneys and subsequent hypertension with renal disease in adult life. The aim of our study was to examine whether maternal characteristics, fetal growth, fetal blood flow redistribution, or inadequate placental perfusion in different periods of fetal life affect kidney volume in late fetal life. We also determined if fetal kidney volume was linked to the amount of amniotic fluid. In a population-based prospective study from early fetal life, fetal growth characteristics and fetal blood flow parameters were assessed by ultrasound and Doppler examinations in 1215 women in mid- and late-pregnancy. Kidney volume was measured in late pregnancy. Maternal height and pre-pregnancy weight were associated with kidney volume. After adjustment for the same characteristics in late pregnancy, fetal growth and blood flow in mid-pregnancy were not associated with kidney volume in late pregnancy. In late pregnancy, however, all fetal growth parameters were positively linked with kidney volume. The largest effect on kidney volume was found for abdominal circumference. Signs of fetal blood flow redistribution and increased placental resistance were associated with decreased kidney volume in late pregnancy. Amniotic fluid volume was positively associated with kidney volume. Our study shows that maternal anthropometrics, fetal growth, fetal blood flow redistribution, and raised placental resistance all correlate with kidney volume.

STOX1 gene in pre-eclampsia and intrauterine growth restriction (Article)

2007-09-01T00:00:00Z

The STOX1 gene, identified as a candidate gene for pre-eclampsia in Dutch women, is placentally expressed and subject to imprinting with preferential transmission of the maternal allele. In our study, STOX1-Y153H frequencies were similar in 157 women with pre-eclampsia (65%) and in 157 controls (64%) from the general Dutch population. In an isolated Dutch population, a distortion could not be demonstrated in the transmission of STOX1-Y153H variation from heterozygous mothers to offspring in 50 and 56 families with pregnancies complicated by pre-eclampsia or intrauterine growth restriction, respectively. Our findings do not confirm previous suggestions that STOX1 plays a major role in Dutch women with pre-eclampsia.

Maternal western dietary patterns and the risk of developing a cleft lip with or without a cleft palate (Article)

2007-08-01T00:00:00Z

OBJECTIVE: To identify maternal dietary patterns in association with a cleft lip or cleft palate or both in the offspring. METHODS: In a case-control study of 203 mothers of a child with a cleft lip or cleft palate and 178 mothers with nonmalformed offspring, maternal nutritional intakes were assessed 14 months after the birth of the index child to estimate the preconception intake. We measured serum and red blood cell folate, serum vitamin B12, whole blood vitamin B6, and total plasma homocysteine as biomarkers. Dietary patterns were analyzed by factor analysis. Univariate and multivariate analyses were performed and odds ratios with 95% confidence intervals calculated. RESULTS: Two major dietary patterns were identified. The Western dietary pattern, eg, high in meat, pizza, legumes, and potatoes, and low in fruits, was associated with a higher risk of a cleft lip or cleft palate (odds ratio 1.9; 95% confidence interval 1.2-3.1). This risk remained significant after adjustment for potential confounders of maternal education and smoking at the time of the study, and periconception use of folic acid or multivitamins. This dietary pattern was associated with lower red blood cell folate (P=.02), vitamin B6 (P=.001), vitamin B12 (P=.02), and higher homocysteine (P=.05) concentrations. The use of the Prudent pattern, eg, high intakes of fish, garlic, nuts, vegetables, increased vitamin B12 (P<.001) and serum folate (P=.05) levels, was not associated with cleft lip or cleft palate risk compared with the Western diet. CONCLUSION: The use of the maternal Western diet increases the risk of offspring with a cleft lip or cleft palate approximately two fold. Therefore, dietary and lifestyle profiles should be included in preconception screening programs. LEVEL OF EVIDENCE: II.

Esophageal atresia and tracheoesophageal fistula in children of women exposed to diethylstilbestrol in utero (Article)

2007-07-01T00:00:00Z

Objective: This study was undertaken to study the possible risk to mothers exposed in utero to diethylstilbestrol for offspring with esophageal atresia/tracheoesophageal fistula. Study Design: Information on the mothers' in utero exposure to diethylstilbestrol was obtained from 3 sources: questionnaires completed by members of the parents' association of children with esophageal atresia/tracheoesophageal fistula; records of patients with esophageal atresia/tracheoesophageal fistula from a hospital database; and files from the Northern Netherlands EUROCAT birth defects registry. Results: Three of 124 (2.4%) mothers from the parents' association and 6 of 192 (3.1%) mothers from the hospital cases reported in utero exposure to diethylstilbestrol. For 8848 children registered by EUROCAT, 33 (0.37%) mothers reported in utero exposure to diethylstilbestrol. Of 117 infants with esophageal atresia/tracheoesophageal fistula, 4 (3.4%) had a mother with in utero exposure to diethylstilbestrol; this association was statistically significant (P = .001). Conclusion: We report a possible transgenerational effect of diethylstilbestrol exposure in the cause of some cases of esophageal atresia/tracheoesophageal fistula.

Seminal plasma cobalamin significantly correlates with sperm concentration in men undergoing IVF or ICSI procedures (Article)

2007-07-01T00:00:00Z

Mild hyperhomocysteinemia is caused by B vitamin deficiencies. We hypothesize that these biochemical derangements detrimentally affect spermatogenesis. Therefore, the aim of this study was to investigate the folate, cobalamin, pyridoxine, and homocysteine concentrations in blood and seminal plasma and the associations between these biomarkers and semen parameters in men participating in an in vitro fertilization or intracytoplasmic sperm injection program. From 73 men (median age [range]: 37 years [28-53]), blood and semen samples were obtained for the determination of serum and red blood cell (RBC) folate, serum total cobalamin, whole-blood pyridoxal-5′-phosphate, plasma total homocysteine (tHcy), and serum total testosterone. Semen analysis included sperm concentration, motility, and morphology according to World Health Organization criteria. The B vitamins and tHcy concentrations were significantly correlated in blood but not in seminal plasma. The serum and RBC folate concentrations were significantly correlated also with the total folate concentration in seminal plasma (r = .44; P < .001 and r = .39; P < .001, respectively). Likewise, the total cobalamin concentration in serum and seminal plasma was significantly correlated (r = .55; P = .001). Of interest is that the total cobalamin concentration in seminal plasma was significantly correlated with the sperm concentration (r= .42; P< .001). This is in contrast to the absence of significant associations between the other vitamins and tHcy in blood and seminal plasma and any of the semen parameters. These findings suggest that folate and cobalamin are transferred from the blood to the male reproductive organs and emphasize the role of cobalamin in spermatogenesis in human. Copyright

Matrix Metalloproteinase-9 Gene -1562C/T Polymorphism Mitigates Preeclampsia (Article)

2007-07-01T00:00:00Z

Although the aetiology of preeclampsia is unknown, there is substantial evidence that it finds its roots in abnormal placentation. Prerequisites for successful placentation include trophoblast invasion, degradation and remodelling of the uterine decidual extracellular matrix, and apoptosis without thrombosis. We tested this hypothesis by analysing the effect of functional polymorphisms in the genes coding for MMP9, MMP3 and annexin A5 on the risk of preeclampsia using a case-control design. In 163 women with preeclampsia and 163 controls we studied the association with polymorphisms in the MMP9 (-1562 C/T), MMP3 (-1612 5A/6A) and annexin A5 (-1 C/T) genes using logistic regression analysis. A lower prevalence of the rare T allele of the MMP9 (-1562 C/T) polymorphism in women with preeclampsia was found (odds ratio 0.48, 95% confidence interval 0.25-0.90). The distribution of the MMP3 (-1612 5A/6A) and annexin A5 (-1 C/T) gene polymorphisms were similar in cases and controls. Our results suggest that the MMP9-1562T allele is associated with a reduced risk of preeclampsia and therefore may protect against maladaptation of the spiral arteries and decreased decidual degradation. The elevated MMP9 concentrations reported to be associated with the -1562T allele might be essential for the development of an adequate maternal-fetal interface early in pregnancy by facilitating trophoblast apoptosis and degradation.

Application of the Magnitude-Squared Coherence Function Between Uterine and Umbilical Flow Velocity Waveforms for Predicting Placental Dysfunction: A Preliminary Study (Article)

2007-07-01T00:00:00Z

To examine whether the magnitude-squared coherence between uterine and umbilical blood flow velocity waveforms can, in conjunction with estimated fetal weight, uterine and umbilical pulsatility indices, fetal and maternal heart rates, diastolic notching and the amniotic fluid index, create a sensitive and specific model for the prediction of placental dysfunction. Binary logistic prediction models are created for preeclampsia, pregnancy induced hypertension and intrauterine growth restriction in a study group of 284 unselected midtrimester pregnancies. In each study group, the median value of derived parameters were compared with the uncomplicated pregnancy control group. The magnitude-squared coherence function between the uterine and umbilical flow velocity waveforms was found to be a statistically significant predictor of preeclampsia during the midtrimester of pregnancy. The magnitude-squared coherence did not improve the prediction of intrauterine growth restriction or pregnancy induced hypertension. The inclusion of magnitude-squared coherence as one of the prediction parameters may improve the early identification of pregnancies subsequently complicated by preeclampsia. (E-mail: p.struijk@erasmusmc.nl).

New insights into fatigue and health-related quality of life after delivery (Article)

2007-05-07T00:00:00Z

Background. A delivery has a major impact on the health-related quality of life (HRQoL) of the new mother, especially on fatigue. A common complication during delivery that might have a relationship with maternal morbidity is blood loss. The objectives were to investigate fatigue and HRQoL in women after vaginal delivery (VD), elective caesarean section (CS) and emergency CS, and its relationship with postpartum hemoglobin (Hb) levels during the first 6 weeks postpartum. Methods. Some 141 patients (71 after VD, 36 after elective CS and 34 after emergency CS) completed the HRQoL questionnaires MFI and EQ-5D between 12 and 24 h after VD and 24-48 h after CS (t=0). At 1, 3 and 6 weeks postpartum these questionnaires were repeated, together with the SF36. Results. Patients after VD had higher mean physical HRQoL scores than after CS. The average period to reach full physical recovery was 3 weeks after VD, 6 weeks after elective CS, and >6 weeks after emergency CS. Mean mental HRQoL scores of the study groups were similar or even better compared to reference values. The significant correlation between Hb level and mean physical HRQoL scores found at t=0 had disappeared at 1 week postpartum. Conclusions. Results of this study provided insights into the natural course of fatigue and HRQoL postpartum. Important differences in fatigue and HRQoL scores were observed between the 3 modes of delivery. These HRQoL measures can be used in future clinical trials to assess the effects of interventions postpartum.

Susceptibility to pre-eclampsia is associated with multiple genetic polymorphisms in maternal biotransformation enzymes (Article)

2007-05-01T00:00:00Z

Background/Aims: Probably no single gene is responsible for pre-eclampsia, but the disease merely is the result of polymorphisms in several genes in association with environmental factors. We therefore studied the simultaneous occurrence of several genetic polymorphisms in biotransformation enzymes in women who had developed pre- eclampsia, either with or without the HELLP syndrome, in comparison with healthy controls. Methods: The results of two previous studies on genetic polymorphisms in glutathione S-transferases P1, M1 and T1, epoxide hydrolase (EPHX) and cytochrome P4501A1 (CYP1A1) in 167 women with a history of pre-eclampsia and in 110 controls were combined. χ2analyses were used for statistical evaluation of the number of polymorphisms between cases and controls. Results: There was a significant association with the number of genetic polymorphisms in biotransformation enzymes, pointing at an increased toxification or decreased detoxification, in women with a history of pre-eclampsia, as compared to healthy controls (p < 0.001). Conclusion: Women withthe simultaneous occurrence of two or more genetic polymorphisms in the above-mentioned biotransformation enzymes, most probably resulting in a disturbed detoxification capacity, may be at increased risk for pre-eclampsia. Copyright

Maternal smoking and fetal growth characteristics in different periods of pregnancy: The Generation R Study (Article)

2007-05-01T00:00:00Z

The authors examined the associations of maternal smoking in pregnancy with various fetal growth characteristics among 7,098 pregnant women participating in the Generation R Study (2002-2006), a population-based prospective cohort study of pregnant women and their children in Rotterdam, the Netherlands. Maternal smoking was assessed by questionnaires administered in early, mid-, and late pregnancy. Fetal growth characteristics evaluated included head circumference, abdominal circumference, and femur length measured repeatedly in mid- and late pregnancy. Maternal smoking during pregnancy was associated with reduced growth in head circumference (-0.56 mm/week; 95% confidence interval (CI): -0.73, -0.40), abdominal circumference (-0.58 mm/week; 95% CI: -0.81, -0.34), and femur length (-0.19 mm/week; 95% CI: -0.23, -0.14). This reduced growth resulted in a smaller femur length from midpregnancy (gestational age 18-24 weeks) onwards and smaller head and abdominal circumferences from late pregnancy (gestational age ≥25 weeks) onwards. Analyses using standard deviation scores for the growth characteristics demonstrated the largest effect estimates for femur length. The authors concluded that maternal smoking during pregnancy is associated with reduced growth in fetal head circumference, abdominal circumference, and femur length. The larger effect on femur length suggests that smoking during pregnancy affects primarily peripheral tissues. Copyright

Validation of the assessment of folate and vitamin B12 intake in women of reproductive age: The method of triads (Article)

2007-05-01T00:00:00Z

Objective: To validate the folate and vitamin B12intakes estimated by a food-frequency questionnaire (FFQ) designed to be used in a case-control study on the association between maternal dietary intake and the risk of having a child with a congenital heart defect. Design and subjects: The FFQ was filled out by 53 women of reproductive age. Immediately thereafter, blood samples were taken to determine serum folate, red blood cell (RBC) folate and serum vitamin B12concentrations. Subsequently, three dietary 24-h recalls (24HR) were completed during a period of three successive weeks and used as a reference method. The recalls comprised two weekdays and one weekend day. Using the method of triads, validity coefficients were calculated by comparing nutrient intakes derived from the FFQ and 24HR with the corresponding nutritional biomarkers in blood. The validity coefficient is the correlation between the dietary intake reported by the FFQ and the unknown 'true' dietary intake. Results: The comparison of B-vitaminin takes reported by the FFQ and the mean of the 24HR revealed deattenuated correlation coefficients of 0.98 for folate and 0.66 for vitamin B12. The correlation coefficients between the B-vitamin intakes estimated by the FFQ and concentrations of serum folate, RBC folate and serum vitamin B12were 0.20, 0.28 and 0.21, respectively. The validity coefficients for serum folate, RBC folate and serum vitamin B12were 0.94, 0.75 and 1.00, respectively. The estimated folate and vitamin B12intakes were comparable with the results of the most recent Dutch food consumption survey. Conclusions: The adapted FFQ is a reliable tool to estimate the dietary intake of energy, macronutrients, folate and vitamin B12in women of reproductive age. Therefore, this FFQ is suitable for the investigation of nutrient-disease associations in future.

Relationship between haemoglobin change and estimated blood loss after delivery [13] (Article)

2007-05-01T00:00:00Z

Hyperhomocysteinemia and MTHFR polymorphisms in association with orofacial clefts and congenital heart defects: A meta-analysis (Article)

2007-05-01T00:00:00Z

Several studies have reported an association between hyperhomocysteinemia, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms and cleft lip with or without cleft palate (CLP), and congenital heart defects (CHDs). However, findings have been inconsistent. A meta-analysis was performed of published studies until September 2006 investigating these associations in both mothers and children. Homocysteine data were provided in two CLP and three CHD studies, and MTHFR polymorphisms were reported in ten CLP and eight CHD studies. Data were analyzed using the random effects model in the Cochrane Review Manager. The pooled odds ratio (OR) of maternal hyperhomocysteinemia was 2.3 (95% CI 0.4-11.9) for CLP, and 4.4 (2.6-7.3) for CHDs. The MTHFR C677T polymorphism and CLP showed pooled ORs of 1.2 (0.9-1.5) in mothers and 1.0 (0.9-1.2) in children, whereas these estimates for the A1298C polymorphism were 1.0 (0.7-1.2) in mothers and 0.9 (0.6-1.2) in children. The MTHFR C677T polymorphism in CHD studies demonstrated a pooled OR of 1.0 (0.8-1.3) for mothers and 1.1 (0.9-1.5) for children. Two studies investigating the maternal A1298C polymorphism in CHDs demonstrated a pooled OR of 1.2 (0.8-1.8). Only one CHD study reported an OR of 1.3 (0.8-2.1) for this polymorphism in children. In conclusion, this meta-analysis demonstrates that maternal hyperhomocysteinemia is a risk factor for CHDs. The MTHFR polymorphisms C677T and A1298C in both mothers and children are not independently associated with CLP or CHDs. Future studies should be performed to investigate the interactions between maternal hyperhomocysteinemia, B-vitamin intake, related polymorphisms and the risk of CLP and CHDs.

Hemolysis, elevated liver enzymes and low platelets during pregnancy due to Vitamin B12 and folate deficiencies (Article)

2007-04-01T00:00:00Z

Possible role of the plasminogen activation system in human subfertility (Article)

2007-03-01T00:00:00Z

Objective: To correlate components of the plasminogen activator (PA) system with fertility outcome parameters in participants in an IVF/intracytoplasmic sperm injection (ICSI) procedure. Design: Case-control study. Setting: Outpatient clinic for IVF/ICSI treatment at the Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. Patient(s): One hundred and fifty-six couples undergoing an IVF/ICSI procedure. Intervention(s): None. Main Outcome Measure(s): Urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), and t-PA-PAI-1 complex concentrations in the ejaculate, spermatozoa, and follicular fluid (FF). Result(s): Concentrations of t-PA were higher in spermatozoa of the male factor subfertility group (geometrical mean, 77.1 pg/million spermatozoa; 25th-75th percentiles, 31.8-211.2), compared to fertile men (geometrical mean, 1.91; 25th-75th percentiles, 0.74-5.79) and idiopathic subfertile men (geometrical mean, 3.14; 25th-75th percentiles, 0.97-9.97). Furthermore, the concentration of t-PA in spermatozoa was significantly associated with pregnancy (odds ratio [OR], 0.995). Likewise, a trend was shown for higher t-PA concentrations in the FF of women with fallopian-tube pathology (geometrical mean, 18.5 pg t-PA/mg protein; 25th-75th percentiles, 11.4-25.7) or endometriosis (geometrical mean, 18.8; 25th-75th percentiles, 11.4-27.1), compared to fertile women (geometrical mean, 14.3; 25th-75th percentiles, 10.3-17.6) and idiopathic subfertile women (geometrical mean, 13.9; 25th-75th percentiles, 9.5-17.8). Also, t-PA in FF is associated with the proportion of cleaved embryos (regression coefficient, 0.16). The concentrations of u-PA, PAI-1, and t-PA-PAI-1 complex were comparable between diagnostic subgroups in both men and women. Conclusion(s): The t-PA concentrations in spermatozoa and FF tend to be higher in human subfertility, and seem to be associated with some fertility outcome parameters.

The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility (Article)

2007-03-01T00:00:00Z

Current treatments of subfertile couples are usually empiric, as the true cause of subfertility often remains unknown. Therefore, we outline the role of nutritional and biochemical factors in reproduction and subfertility. A literature search was performed using MEDLINE, Science Direct and bibliographies of published work with both positive and negative results. The studies showed that folate has a role in spermatogenesis. In female reproduction, folate is also important for oocyte quality and maturation, implantation, placentation, fetal growth and organ development. Zinc has also been implicated in testicular development, sperm maturation and testosterone synthesis. In females, zinc plays a role in sexual development, ovulation and the menstrual cycle. Both folate and zinc have antioxidant properties that counteract reactive oxygen species (ROS). Thiols, such as glutathione, balance the levels of ROS produced by spermatozoa and influence DNA compaction and the stability and motility of spermatozoa. Oocyte maturation, ovulation, luteolysis and follicle atresia are also affected by ROS. After fertilization, glutathione is important for sperm nucleus decondensation and pronucleus formation. Folate, zinc, ROS and thiols affect apoptosis, which is important for sperm release, regulation of follicle atresia, degeneration of the corpus luteum and endometrial shedding. Therefore, the concentrations of these nutrients may have substantial effects on reproduction. In conclusion, nutritional and biochemical factors affect biological processes in male and female reproduction. Further research should identify pathways that may lead to improvements in care and treatment of subfertility.

Exposure of neural crest cells to elevated glucose leads to congenital heart defects, an effect that can be prevented by N-acetylcysteine (Article)

2007-03-01T00:00:00Z

BACKGROUND: Diabetes mellitus during pregnancy increases the risk for congenital heart disease in the offspring. The majority of the cardiovascular malformations occur in the outflow tract and pharyngeal arch arteries, where neural crest cells are essential for normal development. We studied the effects of specific exposure of neural crest cells to elevated glucose on heart development. Antioxidants reduce the damaging effect of glucose on neural crest cells in vitro; therefore, we investigated the effect of supplementing N-acetylcysteine in vivo. METHODS: Cardiac neural crest of HH 8-12 chicken embryos was directly exposed by a single injection in the neural tube with 30 mM D-glucose (or 30 mM L-glucose as a control). To examine the effect of a reduction in oxidative stress, we added 2 mM N-acetylcysteine to the injected D-glucose. RESULTS: Exposure of neural crest cells to elevated D-glucose-induced congenital heart malformations in 82% of the embryos. In the embryos injected with L-glucose, only 9% developed a heart malformation. As expected, all malformations were located in the outflow tract and pharyngeal arch arteries. The frequency of heart malformations decreased from 82% to 27% when 2 mM N-acetylcysteine was added to the injected D-glucose. CONCLUSIONS: These data are the first to confirm that the vulnerability of neural crest cells to elevated glucose induces congenital heart malformations. The fact that N-acetylcysteine limits the teratogenicity of glucose implies that its damaging effect is mediated by an increase of oxidative stress in the neural crest cells.

Specific peptides identified by mass spectrometry in placental tissue from pregnancies complicated by early onset preeclampsia attained by laser capture dissection (Article)

2007-03-01T00:00:00Z

Preeclampsia is a common pregnancy-specific syndrome that is diagnosed by the appearance of both increased blood pressure and proteinuria. Preeclampsia is associated with significant fetal and maternal morbidity and mortality. Although the etiology of preeclampsia is unknown, it is evident that abnormal placentation and trophoblast metabolism plays an important role. We therefore analyzed, identified, and verified specific proteins of villous trophoblast and villous stroma in small numbers of microdissected cells (approximately 125 cells) from seven placentas of women with pregnancies complicated by preeclampsia (cases) and seven uncomplicated pregnancies (controls). Tryptic peptide profiling by MALDI-TOF MS was used for comparison and identification of significantly expressed peptides. The data were analyzed by ClinProTools (Bruker Daltonics) and by principal component analysis. Subsequently, a subset of placental tissues were homogenized and separated on a NanoLC system to obtain sequencing information (MS/MS spectra). We identified specific peptide patterns in the different cell types: villous stroma and trophoblast cells and differences in these cells of placentas from women with pregnancies complicated by early compared to late onset preeclampsia (<34 and > 34 wk gestation, respectively) and controls. Principal component analysis revealed significant differences between the groups. The comparison with placental tissue after preterm delivery with unknown cause revealed that placental peptide patterns in early onset preeclampsia could not be explained by preterm delivery per se. Subsequently, specific, discriminating proteins for early onset preeclampsia compared to controls were identified including calcyclin, surfeit locus protein, and choriomammotropin A precursor. The expression of calcyclin was verified in early onset preeclamptic placental sections by immunohistochemistry. These data suggest that in early onset preeclampsia trophoblastic choriomammotropin regulation is abnormal, possibly through abnormal calcyclin expression and regulation.

Maternal deaths after elective cesarean section for breech presentation in the Netherlands (Article)

2007-02-20T00:00:00Z

Background and methods. The cesarean section rate for term singleton breech babies in the Netherlands rose from 57 to 81% after the Term Breech Trial in 2000. The Dutch Maternal Mortality Committee registered and evaluated maternal mortality due to elective cesarean section for breech. Results. Four maternal deaths after elective cesarean section for breech presentation, from 2000 to 2002 inclusive, were registered, 7% of total direct maternal mortality in that period. Two women died due to massive pulmonary embolism, both were obese, and thromboprophylaxis was not adjusted to their weight. The other two women died from sepsis, one had not receive perioperative prophylactic antibiotics. The case fatality rate for elective cesarean section for breech presentation was 0.47/1,000 operations. No death after emergency cesarean section for breech presentation was registered at the committee. Conclusions. Elective cesarean section does not guarantee the improved outcome of the child, but may increase risks for the mother, compared to vaginal delivery.

Effects of maternal smoking in pregnancy on prenatal brain development. The generation R study (Article)

2007-02-01T00:00:00Z

Nicotine, as has been shown in animal studies, is a neuroteratogen, even in concentrations that do not cause growth retardation. In humans, there is only indirect evidence for negative influences of nicotine on brain development from studies on the association between maternal smoking in pregnancy and behavioural and cognitive development in the offspring. We investigated the associations of maternal smoking in pregnancy with foetal head growth characteristics in 7042 pregnant women. This study was embedded in the Generation R Study, a population-based prospective cohort study from foetal life until adulthood. Maternal smoking was assessed by questionnaires in early, mid- and late pregnancy. Head circumference, biparietal diameter, transcerebellar diameter and atrial width of lateral ventricles were repeatedly measured by ultrasound. When mothers continued to smoke during pregnancy, foetal head circumference showed a growth reduction of 0.13 mm [95% confidence interval (CI): -0.18, -0.09] per week compared to foetuses of mothers who never smoked during pregnancy. Biparietal diameter of foetuses with smoking mothers grew 0.04 mm (95% CI: -0.05, -0.02) less per week than that of foetuses of nonsmoking mothers. Atrial width of lateral ventricle was 0.12 mm (95% CI: -0.22, -0.02) smaller and transcerebellar diameter was 0.08 mm (95% CI: -0.15, -0.00) smaller if mothers smoked, but growth per week of these characteristics was not affected by maternal smoking in pregnancy. In conclusion, continuing to smoke during pregnancy leads to reduced growth of the foetal head. Further research should focus on the causal pathway from prenatal cigarette exposure via brain development to behavioural and cognitive functions.

Nicardipine in pre-eclamptic patients: Placental transfer and disposition in breast milk (Article)

2007-02-01T00:00:00Z

To assess the safety risks to the fetus and neonate caused by maternal use of nicardipine in pre-eclamptic patients, we evaluated the placental transfer and the transfer to breast milk after maternal intravenous administration of nicardipine. In ten pre-eclamptic subjects, nicardipine concentrations of maternal blood (P) and both arterial and venous umbilical cord blood samples (Uarterialand Uvenous) were assessed, and the U/P ratio was calculated as an indication of placental transfer. We found a median transfer of 0.15 (Uarterial/P, range 0.05-0.22) and 0.17 (Uvenous/P, range 0.023-0.22). The highest umbilical cord concentration found after maternal dosage of 4.5 mg/hour was 18 ng/ml, which can be considered as subtherapeutic. Therefore, adverse fetal reactions caused by a direct pharmacological effect of nicardipine are unlikely to occur. Nicardipine levels were determined in 34 breast milk samples of seven women, and were found to be undetectable in 82% of the samples. In six breast milk samples of four different women, nicardipine levels (ranging from 5.1 to 18.5 ng/ml) were detectable during maternal nicardipine dosages ranging from 1 to 6.5 mg/hour. The maximum possible exposure of a neonate to nicardipine was calculated to be less than 300 ng/day, which is an insignificant fraction of therapeutic dosages used in neonates. In conclusion, the exposure of a fetus and neonate to nicardipine through placental transfer and disposition in breast milk expression is low.

Increased expression of vascular endothelial growth factor in cardiac structures of fetus with hydrops as compared to nonhydropic controls (Article)

2005-12-01T00:00:00Z

Objective: The hypothesis that severe fetal hydrops is caused by an excess of vascular endothelial growth factor (VEGF), mainly produced in the fetal heart, is tested. Methods: Immunohistochemical VEGF-stained post-mortem biopsies from the right ventricle and right atrium of 8 hydropic fetuses were compared to those of 8 nonhydropic fetuses. The endocardium, myocardium, epicardium, endothelium, and vascular smooth muscle cells were scored on intensity of VEGF-staining. The Mann-Witney test was used to test for significancy (p < 0.05) of the differences in staining. Increased vascularization as a result of VEGF was measured in both groups by standard randomization count. Results: The endocardium, epicardium and endothelium of the coronary vessels showed significantly (p < 0.05) more intense VEGF-staining in the hydrops group than in the control group. The atria showed more intense staining than the ventricles in both groups. The hydropic fetuses showed a significantly increased number of coronary vessels in the myocardium. These vessels contained more blood cells than the coronary vessels in nonhydropic fetuses. Conclusion: The fetal heart appears to be a major source of excess VEGF in fetal hydrops. Copyright