Nienke Bergen

Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: The generation R study

Please cite this paper as: Bergen N, Jaddoe V, Timmermans S, Hofman A, Lindemans J, Russcher H, Raat H, Steegers‐Theunissen R, Steegers E. Homocysteine and folate concentrations in early pregnancy and the risk of adverse pregnancy outcomes: the Generation R Study. BJOG 2012;119:739–751.

Placental Vascularization in Early Onset Small for Gestational Age and Preeclampsia

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.

Early pregnancy maternal and fetal angiogenic factors and fetal and childhood growth: the Generation R Study

STUDY QUESTION What are the effects of maternal and fetal soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF) concentrations on fetal and childhood growth patterns? SUMMARY ANSWER An angiogenic profile that is characterized by both low early pregnancy maternal sFlt-1 and PlGF concentrations and higher sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio in umbilical cord blood is associated with a reduced fetal and childhood growth. WHAT IS KNOWN ALREADY An imbalance in maternal and fetal sFlt-1 and PlGF concentrations has been suggested to affect pregnancy outcomes. However, their effects on longitudinal fetal and childhood growth remain largely unknown. STUDY DESIGN, SIZE, DURATION This study was performed in 5980 mothers and 4108 of their children, participating in the Generation R Study; a population-based prospective cohort study from fetal life onwards in Rotterdam, the Netherlands (2001-2005). PARTICIPANTS/MATERIALS, SETTING, METHODS Blood samples were obtained from mothers in early and mid-pregnancy and from the umbilical vein at delivery. Fetal and childhood growth characteristics (weight and length) were measured repeatedly by ultrasound and physical examinations until the age of 6 years. We assessed the associations of maternal and fetal angiogenic factors with fetal and childhood growth using repeated measurement regression models. Logistic regression models were used to determine associations between angiogenic factors and small for gestational age at birth (SGA). MAIN RESULTS AND THE ROLE OF CHANCE Compared with early pregnancy maternal sFlt-1 concentrations in the lowest quintile, early pregnancy maternal sFlt-1 concentrations in the highest quintile were associated with a higher fetal weight growth resulting in a higher birthweight (difference in birthweight 0.33 standard deviation score (SDS); 95% Confidence Interval (CI) 0.25-0.41), a lower risk of SGA (Odds Ratio (OR) 0.36; 95% CI 0.27-0.48) and a subsequent higher weight growth until the age of 6 years. Early pregnancy maternal PlGF concentrations in the lowest quintile were associated with a reduced weight growth pattern resulting in a smaller birthweight (difference in birthweight -0.34 SDS; 95% CI -0.44, -0.25), an increased risk of SGA (OR 3.48; 95% CI 2.39-5.08) and a lower weight growth throughout childhood. An early pregnancy maternal sFlt-1:PlGF ratio in the highest quintile was associated with a higher fetal weight growth pattern from 30 weeks onwards, resulting in a higher weight at birth (difference in birthweight 0.09 SDS; P-value <0.05), which remained present until the age of 2 years. Newborns with higher umbilical cord sFlt-1 concentrations, lower PlGF concentrations or a higher sFlt-1:PlGF ratio showed a lower fetal and childhood weight growth from 30 weeks gestation onwards until the age of 6 years (P-value <0.05). Similar patterns were observed in relation to fetal and childhood length growth. LIMITATIONS, REASONS FOR CAUTION The study is an observational study. Therefore, no causal relationships can be established. WIDER IMPLICATIONS OF THE FINDINGS Both a maternal and fetal angiogenic imbalance may affect fetal and childhood growth. Changes in angiogenic profiles may be involved in the pathways linking fetal growth restriction with the long-term risk of vascular disease in adulthood. STUDY FUNDING/COMPETING INTERESTS The first phase of the Generation R Study is made possible by financial support from The Erasmus Medical Centre, Rotterdam, the Erasmus University Rotterdam, and the Netherlands Organization for Health Research and Development (ZonMw 21000074). V.W.V.J. received additional grants from the Netherlands Organization for Health Research and Development (ZonMw VIDI). M.I.B.-B. is financially supported by the Bo Hjelt foundation (grant 2009). The authors have no competing interests.

Associations of Maternal and Paternal Blood Pressure Patterns and Hypertensive Disorders during Pregnancy with Childhood Blood Pressure

Background Hypertensive disorders in pregnancy may affect the cardiovascular risk of offspring. We examined the associations of maternal blood pressure throughout pregnancy and hypertensive disorders in pregnancy with childhood blood pressure of offspring. Specific focus was on the comparison with paternal blood pressure effects, the identification of critical periods, and the role of birth outcomes and childhood body mass index in the observed associations. Methods and Results This study was embedded in a population‐based prospective cohort study among 5310 mothers and fathers and their children. We measured maternal blood pressure in each trimester of pregnancy and paternal blood pressure once. Information about hypertensive disorders in pregnancy was obtained from medical records. We measured childhood blood pressure at the median age of 6.0 years (95% range 5.7–8.0 years). Both maternal and paternal blood pressure were positively associated with childhood blood pressure (all P<0.05), with similar effect estimates. Conditional regression analyses showed that early, mid‐, and late‐pregnancy maternal blood pressure levels were all independent and positively associated with childhood blood pressure, with the strongest effect estimates for early pregnancy. Compared with children of mothers without hypertensive disorders in pregnancy, children of mothers with hypertensive disorders in pregnancy had higher diastolic blood pressure by a standard deviation score of 0.13 (95% CI 0.05–0.21). The observed associations were not materially affected by birth outcomes and childhood body mass index. Conclusions Both maternal and paternal blood pressure affects childhood blood pressure, independent of fetal and childhood growth measures, with the strongest effect of maternal blood pressure in early pregnancy.

Maternal lipid profile 6 years after a gestational hypertensive disorder

BACKGROUND Gestational hypertensive disorders (GHDs), including gestational hypertension and preeclampsia, are associated with an increased risk of cardiovascular disease in later life, possibly through an atherogenic lipid profile. OBJECTIVE The objective of this study is to assess if women with a previous GHD have a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy. METHODS In a population-based prospective cohort study, we included 4933 women during pregnancy, including 302 women with a GHD. Six years after pregnancy, we determined maternal lipid profile (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipoprotein[a], and apolipoprotein B) and glucose levels. RESULTS Women with a previous GHD had a more atherogenic lipid profile 6 years after pregnancy compared to women with a previous normotensive pregnancy. These atherogenic lipid profiles were a result of higher levels of triglycerides, low-density lipoprotein cholesterol, and apolipoprotein B and lower levels of high-density lipoprotein cholesterol. Differences in lipid profile between women with a previous GHD and women with a previous normotensive pregnancy were attenuated after adjustment for prepregnancy body mass index. Between women from both groups, no differences were observed in total cholesterol, lipoprotein[a], and glucose levels. CONCLUSION Women with a previous GHD show a more atherogenic lipid profile 6 years after pregnancy than women with a previous normotensive pregnancy. The increased risk of cardiovascular disease after a GHD might result from an atherogenic lipid profile after pregnancy, primarily driven by prepregnancy body mass index.