Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants

doi:10.1016/j.ajog.2009.06.025

American Journal of Obstetrics and Gynecology

Volume 201, Issue 6, December 2009, Pages 587.e1-587.e8

Presented, in part, at the 35th Annual Meeting of the Fetal and Neonatal Physiologic Society, Maastricht, The Netherlands, June 22-25, 2008; the Annual Congress of the European Academy of Paediatrics, Barcelona, Spain, Oct. 7-10, 2006; and the Annual Meeting of the Pediatric Academic Societies, San Francisco, CA, April 29-May 2, 2006.

https://doi.org/10.1016/j.ajog.2009.06.025 Get rights and content

Objective

The objective of the study was to study the effects of histologic chorioamnionitis (HC) with or without fetal involvement and antenatal steroid (AS) exposure on neonatal outcome in a prospective cohort of preterm infants.

Study Design

The clinical characteristics and placental histology were prospectively collected in 301 infants born at a gestational age 32.0 weeks or less in the Erasmus University Medical Center.

Results

In univariable analyses, HC without fetal involvement (n = 53) was associated with decreased severe respiratory distress syndrome (RDS) (11% vs 28%; P < .05), whereas HC with fetal involvement infants (n = 68) had more necrotizing enterocolitis (9% vs 2%; P < .05), intraventricular hemorrhage (IVH) (25% vs 12%; P < .05), and neonatal mortality (19% vs 9%; P < .05). In HC without fetal involvement infants, AS reduced the incidences of RDS (43% vs 85%; P < .05) and IVH (5% vs 39%; P < .01). In multivariable analyses, HC without fetal involvement was associated with decreased severe RDS (odds ratio, 0.22; 95% confidence interval, 0.05–0.93; P < .05) and increased early-onset sepsis (odds ratio, 2.22; 95% confidence interval, 1.02–4.83; P < .05).

Conclusion

In a prospective cohort of preterm infants, multivariable analyses reveal only a modest association between histologic chorioamnionitis and neonatal outcome.

Section snippets

Design

This was a prospective, observational, nontherapeutic study with the aim to examine the association of histologic chorioamnionitis in early preterm delivery with neonatal outcome. Pregnant women, who delivered between May 2001–February 2003 in the Erasmus University Medical Center–Sophia Children's Hospital in Rotterdam, The Netherlands, at a gestational age of 32.0 weeks or less, were eligible for the study. Routine health care workers (residents, research-nursing staff, and neonatologists)

Maternal and delivery characteristics

Three hundred one preterm infants were included in the study. Histologic chorioamnionitis was present in 121 of these (40.2%), 68 (56.2%) of whom had signs of fetal involvement. Of the latter, all but 4 had inflammatory signs of both the fetal and maternal compartment. Maternal and delivery characteristics for the groups are shown in Table 1.

Both chorioamnionitis groups had lower gestational age and significantly higher rates of clinical chorioamnionitis and preterm premature rupture of

Comment

In this prospective cohort of preterm infants, chorioamnionitis with fetal involvement was associated with increased incidences of IVH, NEC, and neonatal mortality in univariable analyses. However, none of these associations remained after multivariable adjustment. Conversely, chorioamnionitis without fetal involvement was independently associated with a lower severe RDS risk, whereas the effect of chorioamnionitis with fetal involvement on the incidence of severe RDS was gestational-age

Acknowledgments

We thank F. Jonkers, P. van Felius, and E. Oschatz-Overbosch for their help in data collection and database design.

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Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies affecting very low birth weight (VLBW) infants with an incidence of 6–15 %. Early recognition is crucial. Mortality is high and variable (30–50 %). Those requiring surgical intervention have a higher mortality rate than those who receive medical treatment.
1) To assess the prevalence of surgical NEC and associated risk factors 2) To compare outcomes based on the type of treatment required 3) To estimate the mortality associated with NEC and surgical NEC.
A multicentre retrospective cohort study was designed (level II), including VLBW infants born between 2011 and 2020 in Centers of the Neocosur Network. A multivariate logistic regression analysis was performed to evaluate risk factors associated with the need for surgery.
NEC was diagnosed in 1679 (10.4 %) of 16,131 births in this period. The prevalence of surgery was 25 % (95 % CI 23–27 %). In multivariable analysis, variables associated with an increased risk of surgery requirement were birth weight <750 g (aOR 1.73–95%CI 1.2–2.5) and receiving antenatal antibiotics (aOR 1.54–95%CI 1.09–2.74). Those requiring surgery had significantly higher morbidity and mortality than the ones receiving medical treatment.
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The histologic fetal inflammatory response and neonatal outcomes: systematic review and meta-analysis
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This study aimed to investigate the prognostic role of concomitant histological fetal inflammatory response with chorioamnionitis on neonatal outcomes through a systematic review and meta-analysis of existing literature.
The primary search was conducted on October 17, 2021, and it was updated on May 26, 2023, across 4 separate databases (MEDLINE, the Cochrane Central Register of Controlled Trials, Embase, and Scopus) without using any filters.
Observational studies reporting obstetrical and neonatal outcomes of infant-mother dyads with histological chorioamnionitis and histological fetal inflammatory response vs infant-mother dyads with histological chorioamnionitis alone were eligible. Studies that enrolled only preterm neonates, studies on neonates born before 37 weeks of gestation, or studies on neonates with very low birthweight (birthweight <1500 g) were included. The protocol was registered with the International Prospective Register of Systematic Reviews (registration number: CRD42021283448).
The records were selected by title, abstract, and full text, and disagreements were resolved by consensus. Random-effect model-based pooled odds ratios with corresponding 95% confidence intervals were calculated for dichotomous outcomes.
Overall, 50 studies were identified. A quantitative analysis of 14 outcomes was performed. Subgroup analysis using the mean gestational age of the studies was performed, and a cutoff of 28 weeks of gestation was implemented. Among neonates with lower gestational ages, early-onset sepsis (pooled odds ratio, 2.23; 95% confidence interval, 1.76–2.84) and bronchopulmonary dysplasia (pooled odds ratio, 1.30; 95% confidence interval, 1.02–1.66) were associated with histological fetal inflammatory response. Our analysis showed that preterm neonates with a concomitant histological fetal inflammatory response are more likely to develop intraventricular hemorrhage (pooled odds ratio, 1.54; 95% confidence interval, 1.18–2.02) and retinopathy of prematurity (pooled odds ratio, 1.37; 95% confidence interval, 1.03–1.82). The odds of clinical chorioamnionitis were almost 3-fold higher among infant-mother dyads with histological fetal inflammatory response than among infant-mother dyads with histological chorioamnionitis alone (pooled odds ratio, 2.99; 95% confidence interval, 1.96–4.55).
This study investigated multiple neonatal outcomes and found association in the case of 4 major morbidities: early-onset sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and retinopathy of prematurity.
Amniotic fluid interleukin 6 and interleukin 8 are superior predictors of fetal lung injury compared with maternal or fetal plasma cytokines or placental histopathology in a nonhuman primate model
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Intra-amniotic infection or inflammation is common in early preterm birth and associated with substantial neonatal lung morbidity owing to fetal exposure to proinflammatory cytokines and infectious organisms. Amniotic fluid interleukin 8, a proinflammatory cytokine, was previously correlated with the development of neonatal bronchopulmonary dysplasia, but whether amniotic fluid cytokines or placental pathology more accurately predicts neonatal lung pathology and morbidity is unknown. We have used a pregnant nonhuman primate model of group B Streptococcus infection to study the pathogenesis of intra-amniotic infection, bacterial invasion of the amniotic cavity and fetus, and microbial-host interactions. In this nonhuman primate model, we have studied the pathogenesis of group B Streptococcus strains with differing potential for virulence, which has resulted in a spectrum of intra-amniotic infection and fetal lung injury that affords the opportunity to study the inflammatory predictors of fetal lung pathology and injury.
This study aimed to determine whether fetal lung injury is best predicted by placental histopathology or the cytokine response in amniotic fluid or maternal plasma.
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The principal findings in our study are as follows: (1) adverse pregnancy outcomes occurred more frequently in animals receiving hyperhemolytic group B Streptococcus (80% with preterm labor, 80% with fetal inflammatory response syndrome) than in animals receiving weakly hemolytic group B Streptococcus (40% with preterm labor, 20% with fetal inflammatory response syndrome) and in controls (0% preterm labor, 0% fetal inflammatory response syndrome); (2) despite differences in the rate of adverse pregnancy outcomes and fetal inflammatory response syndrome, fetal lung injury scores were similar between animals receiving the weakly hemolytic group B Streptococcus strains and animals receiving the hyperhemolytic group B Streptococcus strains; (3) fetal lung injury score was significantly correlated with peak amniotic fluid cytokines interleukin 6 and interleukin 8 but not tumor necrosis factor alpha or interleukin 1 beta; and (4) fetal lung scores were poorly correlated with maternal and fetal plasma cytokine levels and placental pathology.
Amniotic fluid interleukin 6 and interleukin 8 levels were superior predictors of fetal lung injury than placental histopathology or maternal plasma cytokines. This evidence supports a role for amniocentesis in the prediction of neonatal lung morbidity owing to intra-amniotic infection, which cannot be provided by cytokine analysis of maternal plasma or placental histopathology.
Histological chorioamnionitis and its impact on respiratory outcome in very-low-birth-weight preterm infants
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The role of intrauterine infection in the development of neonatal pulmonary disease is unclear and the impact of histological chorioamnionitis (HCAM) on respiratory outcomes in preterm infants remains controversial. The aim of this study was to explore the association between HCAM and neonatal respiratory outcomes in very-low-birth-weight (VLBW) preterm infants and evaluate the stepwise difference in the stage and severity of HCAM among neonatal respiratory outcomes.
We retrospectively enrolled 129 VLBW preterm infants with placenta histopathology examinations in this study. HCAM was subdivided into 3 stages (early, intermediate, and advanced) according to the progression of the maternal inflammatory response. The perinatal characteristics, placental histopathology, and neonatal morbidities, including respiratory outcomes (respiratory distress syndrome (RDS), Wilson-Mikity syndrome (WMS) and bronchopulmonary dysplasia (BPD)), were collected for comparison.
A total of 52.7% (68/129) of the infants had HCAM, including 23 early (stage 1), 30 intermediate (stage 2), and 15 advanced (stage 3) stage. There was no significant difference in the gestational age, birth body weight or mortality rate between the HCAM and non-HCAM groups. Mothers with HCAM had a significantly lower incidence of pre-eclampsia but a higher rate of premature rupture of membrane. They also had higher WBC counts and C-reactive protein levels before delivery. Neonates with HCAM had a lower incidence of RDS but were at a higher risk for developing WMS and BPD. After multivariate analysis adjustment, HCAM was still negatively associated with RDS (aOR = .069, p < .001) but without correlation with BPD. However, neonates with intermediate to advanced-stage HCAM had a higher risk of developing WMS and increased home oxygen usage rate compared to those with early-stage HCAM.
HCAM has a protective effect from RDS in preterm neonates. Additionally, VLBW neonates with intermediate to advanced-stage HCAM are at risk for WMS.
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Preterm prelabour rupture of membranes occurs in over one third of pregnant women with a cervical cerclage in situ. In the setting of preterm prelabour rupture of membranes, clinicians are faced with the difficult decision of the optimal timing for removing the cerclage. We compared the maternal and neonatal outcomes following immediate removal or retention of the cervical cerclage.
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43 women with cerclage retained for over 24 h following preterm prelabour rupture of membranes were compared to 25 women in whom the cerclage was removed. The latency between preterm prelabour rupture of membranes and delivery was on average 70.4 h longer in women who had their cerclage retained compared to the removed group (p = 0.009). Rates of chorioamnionitis, maternal blood results, neonatal birthweight and Apgar scores did not differ significantly between the two groups, however a trend towards higher rates of chorioamnionitis (60 % vs 45 %) were seen in the retained group.
Cervical cerclage retention in women following preterm prelabour rupture of membranes was associated with a longer latency period to delivery and was not significantly associated with any adverse obstetric, maternal or neonatal outcomes. Therefore, in women at risk of spontaneous preterm birth, cerclage retention may be beneficial, however these women and their babies should be monitored closely for any signs of infection. Further prospective randomised controlled studies assessing these outcomes as well as longer-term outcomes in these women and their children are needed.
Management of clinical chorioamnionitis: an evidence-based approach
2020, American Journal of Obstetrics and Gynecology
This review aimed to examine the existing evidence about interventions proposed for the treatment of clinical chorioamnionitis, with the goal of developing an evidence-based contemporary approach for the management of this condition. Most trials that assessed the use of antibiotics in clinical chorioamnionitis included patients with a gestational age of ≥34 weeks and in labor. The first-line antimicrobial regimen for the treatment of clinical chorioamnionitis is ampicillin combined with gentamicin, which should be initiated during the intrapartum period. In the event of a cesarean delivery, patients should receive clindamycin at the time of umbilical cord clamping. The administration of additional antibiotic therapy does not appear to be necessary after vaginal or cesarean delivery. However, if postdelivery antibiotics are prescribed, there is support for the administration of an additional dose. Patients can receive antipyretic agents, mainly acetaminophen, even though there is no clear evidence of their benefits. Current evidence suggests that the administration of antenatal corticosteroids for fetal lung maturation and of magnesium sulfate for fetal neuroprotection to patients with clinical chorioamnionitis between 24 0/7 and 33 6/7 weeks of gestation, and possibly between 23 0/7 and 23 6/7 weeks of gestation, has an overall beneficial effect on the infant. However, delivery should not be delayed to complete the full course of corticosteroids and magnesium sulfate. Once the diagnosis of clinical chorioamnionitis has been established, delivery should be considered, regardless of the gestational age. Vaginal delivery is the safer option and cesarean delivery should be reserved for standard obstetrical indications. The time interval between the diagnosis of clinical chorioamnionitis and delivery is not related to most adverse maternal and neonatal outcomes. Patients may require a higher dose of oxytocin to achieve adequate uterine activity or greater uterine activity to effect a given change in cervical dilation. The benefit of using continuous electronic fetal heart rate monitoring in these patients is unclear. We identified the following promising interventions for the management of clinical chorioamnionitis: (1) an antibiotic regimen including ceftriaxone, clarithromycin, and metronidazole that provides coverage against the most commonly identified microorganisms in patients with clinical chorioamnionitis; (2) vaginal cleansing with antiseptic solutions before cesarean delivery with the aim of decreasing the risk of endometritis and, possibly, postoperative wound infection; and (3) antenatal administration of N-acetylcysteine, an antioxidant and antiinflammatory agent, to reduce neonatal morbidity and mortality. Well-powered randomized controlled trials are needed to assess these interventions in patients with clinical chorioamnionitis.

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: Reprints not available from the authors.

: This study was supported in part by the Revolving Fund, Erasmus University Medical Center, Rotterdam, The Netherlands. J.V.B. is supported by a Profileringsfonds Grant from the Maastricht University Medical Center.

: The first 2 authors contributed equally to the study and article.

: Cite this article as: Been JV, Rours IGIJG, Kornelisse RF, et al. Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants. Am J Obstet Gynecol 2009;201:587.e1-8.

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ResearchObstetricsHistologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants

Objective

Study Design

Results

Conclusion

Section snippets

Design

Maternal and delivery characteristics

Comment

Acknowledgments

A fetal response to chorioamnionitis is associated with early survival after preterm birth

Am J Obstet Gynecol

Early neonatal brain injury in histologic chorioamnionitis

J Pediatr

Neonatal morbidity and placental pathology

Indian J Pediatr

Chorioamnionitis and early lung inflammation in infants in whom bronchopulmonary dysplasia develops

Pediatrics

Are histopathologic chorioamnionitis and funisitis associated with metabolic acidosis in the preterm fetus?

Am J Obstet Gynecol

Lung and brain damage in preterm newbornsAre they related? How? Why?

Biol Neonate

Maternal, placental and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks' gestation

Am J Perinatol

Histologic chorioamnionitis and severity of illness in very low birth weight newborns

Pediatr Crit Care Med

Histologic chorioamnionitis and respiratory outcome in preterm infants

Arch Dis Child Fetal Neonatal Ed

Outcome of neonates less than 30 weeks gestation with histologic chorioamnionitis

Am J Perinatol

Maternal versus fetal inflammation and respiratory distress syndrome: a 10 year hospital cohort study

Arch Dis Child Fetal Neonatal Ed

Influence of chorioamnionitis on survival and morbidity in singletons live-bron at < 32 weeks gestation

Acta Obstet Gynecol Scand

The Alabama Preterm Birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants

Am J Obstet Gynecol

Re-evaluation of chorioamnionitis and funisitis with a special reference to subacute chorioamnionitis

Hum Pathol

Cord immunoproteins as predictors of respiratory outcome in preterm infants

Am J Obstet Gynecol

Inflammatory brain damage in preterm newborns—dry numbers, wet lab, and causal inferences

Early Hum Dev

Decreased expression of angiogenic factors in placentas with chorioamnionitis after preterm birth

Pediatr Res

Positive screening for autism in ex-preterm infants: prevalence and risk factors

Pediatrics

Research
Obstetrics
Histologic chorioamnionitis, fetal involvement, and antenatal steroids: effects on neonatal outcome in preterm infants