Fetal sex dependency in pregnancy; fetal and maternal outcomes : The Generation R Study

The aim of this thesis was to evaluate fetal sex specific differences on placental, fetal and maternal level and to assess different definitions on fetal growth restriction and their associations with childhood outcomes.
All studies described in this thesis were embedded in The Generation R Study, a prospective cohort study from early pregnancy onwards in Rotterdam, The Netherlands. The first and second aim of this thesis concerned fetal growth restriction (FGR) and its association with childhood outcomes and the search for a biomarker to retrospectively assess FGR. We showed that FGR, just as neonates born small for gestational age (SGA), is associated with accelerated growth at the age of two years and altered cardiovascular outcomes at six years. This study emphasizes that despite birth weight, a deviating growth curve is associated with adverse health in childhood and therefore possibly adulthood. Moreover we showed that lower umbilical cord levels of placental growth factor (PlGF) are associated with lower birth weight, different fetal growth patterns and a deviating growth curve. Therefore, PlGF might be a promising biomarker to determine deviations in fetal growth and FGR retrospectively enabling follow-up of these neonates in the postnatal period.
The third aim of this thesis was to evaluate fetal sex specific differences on a placental, fetal and maternal level. Fetal sex specific differences were found on all these three levels. Within the placental biomarker production fetal sex specific differences exist, in which women carrying a female fetus have higher serum levels of PlGF, s-Flt1 and PAI-2 in the first trimester of pregnancy. However, in pregnancies complicated with pre-eclampsia, spontaneous preterm birth or SGA these fetal sex specific differences are not observed. This suggests that other mechanisms causing these complications may dominate the effect of fetal sex. Moreover sex specific difference were observed in fetal growth. Already in the first trimester of pregnancy male crown-rump-length (CRL) is larger as compared with female CRL. In the second and third trimester of pregnancy head and abdominal circumference are larger in male fetuses, while femur length is larger in female fetuses. Also different growth patterns were observed. Interestingly, these different growth patterns persist postnatally. On the level of maternal vascular adaptation to pregnancy, differential blood pressure patterns are observed between pregnancies with a male or female fetus. In pregnancies with a male fetus, the uterine artery pulsatility index and the occurrence of notching was higher as compared with pregnancies with a female fetus.
Eventually, the results will contribute to the development of strategies for optimizing health and healthcare for both pregnant women and their children. Since currently fetal sex is not taken into account in research, we recommend that all studies regarding maternal adaptation to pregnancy, placental biology, fetal growth, pregnancy complications and pharmacological therapies should stratify for fetal sex.