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

Maternal cardiovascular adaptation to twin pregnancy: A population-based prospective cohort study

Background: In women with singleton pregnancies, maternal adaptation is considered a stress test for later life cardiovascular disease. The aim of this study was to assess maternal adaptation in women with twin pregnancies compared to women carrying singletons during and after pregnancy. Methods: This was a population based prospective cohort study of 91 women with twin pregnancies and 8107 women carrying singletons. The association of twin pregnancy and maternal adaptation was examined using regression analyses. In pregnancy, we measured soluble fms-like tyrosine kinase-1 (sFLT-1), placental growth (PGF) factor, systolic (SBP) and diastolic blood pressure (DBP), and the occurrence of pre-eclampsia (PE). After pregnancy, measurements were obtained on SBP and DBP, cardiac function, retinal calibres, intima media thickness and distensibility of the common carotid artery. Results: sFLT-1 and PGF concentrations were higher in early (13.4 weeks) and mid-pregnancy (20.4 weeks) in women with twin pregnancies compared to women with singleton pregnancies. Women with twin pregnancies had a different DBP pattern in pregnancy. Women with twin pregnancies were more likely to have PE (odds ratio 3.63; 95% CI [1.76 to 7.48]). Six and ten years after pregnancy, no differences in maternal adaptation were observed. Conclusions: Women with twin pregnancies show an altered adaptation during pregnancy compared to women with singleton pregnancies. This is associated with a substantially increased incidence of PE, but does not lead to persistent altered maternal adaptation years after pregnancy

Fetal sex and maternal pregnancy outcomes: a systematic review and meta-analysis

BACKGROUND: Since the placenta also has a sex, fetal sex-specific differences in the occurrence of placenta-mediated complications could exist. OBJECTIVE: To determine the association of fetal sex with multiple maternal pregnancy complications. SEARCH STRATEGY: Six electronic databases Ovid MEDLINE, EMBASE, Cochrane Central, Web-of-Science, PubMed, and Google Scholar were systematically searched to identify eligible studies. Reference lists of the included studies and contact with experts were also used for identification of studies. SELECTION CRITERIA: Observational studies that assessed fetal sex and the presence of maternal pregnancy complications within singleton pregnancies. DATA COLLECTION AND ANALYSES: Data were extracted by 2 independent reviewers using a predesigned data collection form. MAIN RESULTS: From 6522 original references, 74 studies were selected, including over 12,5 million women. Male fetal sex was associated with term pre-eclampsia (pooled OR 1.07 [95%CI 1.06 to 1.09]) and gestational diabetes (pooled OR 1.04 [1.02 to 1.07]). All other pregnancy complications (i.e., gestational hypertension, total pre-eclampsia, eclampsia, placental abruption, and post-partum hemorrhage) tended to be associated with male fetal sex, except for preterm pre-eclampsia, which was more associated with female fetal sex. Overall quality of the included studies was good. Between-study heterogeneity was high due to differences in study population and outcome definition. CONCLUSION: This meta-analysis suggests that the occurrence of pregnancy complications differ according to fetal sex with a higher cardiovascular an