Design and overview of the Origins of Alzheimer's Disease Across the Life course (ORACLE) study.

Brain development and deterioration across the lifespan are integral to the etiology of late-life neurodegenerative disease. Factors that influence the health of the adult brain remain to be elucidated and include risk factors, protective factors, and factors related to cognitive and brain reserve. To address this knowledge gap we designed a life-course study on brain health, which received funding through the EU ERC Programme under the name Origins of Alzheimer's Disease Across the Life course (ORACLE) Study. The ORACLE Study is embedded within Generation R, a prospective population-based cohort study of children and their parents, and links this with the Rotterdam Study, a population-based study in middle-aged and elderly persons. The studies are based in Rotterdam, the Netherlands. Generation R focuses on child health from fetal life until adolescence with repeated in-person examinations, but has also included data collection on the children's parents. The ORACLE Study aims to extend the parental data collection in nearly 2000 parents with extensive measures on brain health, including neuroimaging, cognitive testing and motor testing. Additionally, questionnaires on migraine, depressive symptoms, sleep, and neurological family history were completed. These data allow for the investigation of longitudinal influences on adult brain health as well as intergenerational designs involving children and parents. As a secondary focus, the sampling is enriched by mothers (n = 356) that suffered from hypertensive disorders during pregnancy in order to study brain health in this high-risk population. This article provides an overview of the rationale and the design of the ORACLE Study.

Hypertensive Disorders of Pregnancy and Cognitive Impairment: A Prospective Cohort Study.

OBJECTIVE: To determine the association between hypertensive disorders of pregnancy (HDP) and cognitive impairment 15 years after pregnancy, we measured cognitive performance in 115 women with a history of HDP and in 481 women with a previous normotensive pregnancy. METHODS: This was a nested cohort study embedded in a population-based prospective cohort from early pregnancy onwards. Cognitive function was assessed with cognitive tests 15 years after the index pregnancy (median 14.7 years, 90% range [13.9-16.1]). Cognitive performance was measured in different cognitive domains: executive function, processing speed, verbal memory, motor function, and visuospatial ability. A global cognition factor (g-factor) was derived from principal component analysis. RESULTS: Of the women with HDP, 80 (69.6%) had gestational hypertension (GH) and 35 (30.4%) had preeclampsia. Women with HDP had a lower g-factor than women with a previous normotensive pregnancy (mean -0.22, 90% range [-2.06-1.29]). HDP was negatively associated with the 15-word learning test: immediate recall (-0.25, 95% CI [-0.44 to -0.06]) and delayed recall (-0.30, 95% CI [-0.50 to -0.10]). Women with GH perform significantly worse on their 15-word learning test than women with a previous normotensive pregnancy. CONCLUSION: A history of HDP is independently associated with poorer working memory and verbal learning 15 years after pregnancy. This association is mainly driven by women with GH. Clinicians and women who experienced HDP should be aware of this risk.

Caries experience among children born after a complicated pregnancy.

OBJECTIVES: Behavioural and lifestyle factors, as oral hygiene and diet, are well-established risk factors in the pathogenesis of dental caries, though displaying large differences in susceptibility across individuals. Since enamel formation already starts in utero, pregnancy course and outcome may eventually play a role in enamel strength and caries susceptibility. Therefore, we studied the association between history of pregnancy complications and the caries experience in their six-year-old children. The pregnancy complications included small for gestational age (SGA), spontaneous preterm birth (sPTB), gestational hypertension (GH), pre-eclampsia (PE), individually, and a combination of those, designated as placental syndrome. METHODS: This study was embedded in Generation R, a prospective longitudinal Dutch multiethnic pregnancy cohort study. Information about pregnancy complications was obtained from questionnaires completed by midwives and obstetricians with cross-validation in medical records. These included SGA, sPTB, GH and PE. Caries experience was assessed with the decayed, missing and filled teeth (dmft) index at a mean age of six years. The association between dental caries experience and a history of pregnancy complications was studied by using hurdle negative binomial (HNB) models. RESULTS: We were able to assess the dmft index in 5323 six-year-old children (mean age 6.2 years, SD 0.5). We did not find an association between the different pregnancy complications and dental caries experience in childhood, whether for SGA, sPTB, GH, PE, or for the combined outcome placental syndrome (HNB estimates: OR 1.02, 95%CI 0.87 - 1.19; RR 0.90, 95%CI 0.78 - 1.04). Further adjustment of the models with different confounders did not alter the outcome. CONCLUSIONS: Although it is expected that prenatal stress can be a risk factor for caries development later in life, our findings do not support this hypothesis. Therefore, we believe disparities in caries experience between children are probably not explained by early life events during a critical intrauterine period of development.

Gestational lipid profile as an early marker of metabolic syndrome in later life: a population-based prospective cohort study.

BACKGROUND: In pregnancy lipid levels increase with gestation resembling an atherogenic lipid profile. Currently it is unclear whether gestational lipid levels are associated with an adverse cardiovascular risk profile later in life. The aim of this study is to assess the association between gestational lipid levels and lipid levels and prevalence of the metabolic syndrome (MS) six years after pregnancy. METHODS: In plasma of 3510 women from the Generation R Study; a prospective population-based cohort, we measured lipid levels (total cholesterol, triglycerides and high-density lipoprotein cholesterol [HDL-c]), and low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated in early pregnancy (median 13.2 weeks, 90% range [10.5 to 17.1]) and six years after pregnancy (median 6.5 years, 90% range [6.2 to 7.8]). MS was assessed six years after pregnancy according to the NCEP/ATP3 criteria. We also examined the influence of pregnancy complications on these associations. RESULTS: Gestational lipid levels were positively associated with corresponding lipid levels six years after pregnancy, independent of pregnancy complications. Six years after pregnancy the prevalence of MS was 10.0%; the prevalence was higher for women with a previous placental syndrome (13.5%). Gestational triglycerides and remnant cholesterol in the highest quartile and HDL-c in the lowest quartile were associated with the highest risk for future MS, independent of smoking and body mass index. CONCLUSIONS: Gestational lipid levels provide an insight in the future cardiovascular risk profile of women in later life. Monitoring and lifestyle intervention could be indicated in women with an unfavorable gestational lipid profile to optimize timely cardiovascular risk prevention.

Maternal lipid profile in early pregnancy is associated with foetal growth and the risk of a child born large-for-gestational age: a population-based prospective cohort study : Maternal lipid profile in early pregnancy and foetal growth.

BACKGROUND: Lipids such as cholesterol and triglycerides play an important role in both maternal and foetal energy metabolism. Little is known about maternal lipid levels in pregnancy and their effect on foetal growth. The aim of this study was to assess maternal lipid levels, foetal growth and the risk of small-for-gestational age (SGA) and large-for-gestational age (LGA). METHODS: We included 5702 women from the Generation R Study, a prospective population-based cohort. Maternal lipid levels (total cholesterol, triglycerides and high-density lipoprotein cholesterol [HDL-c]) were measured in early pregnancy (median 13.4 weeks, 90% range [10.5 to 17.2]). Low-density lipoprotein cholesterol (LDL-c), remnant cholesterol and non-HDL-c were calculated. Foetal growth was measured repeatedly by ultrasound. Information on birth anthropometrics was retrieved from medical records. A birth weight below the 10th percentile was defined as SGA and above the 90th percentile as LGA. RESULTS: Maternal triglyceride and remnant cholesterol levels were associated with increased foetal head circumference and abdominal circumference growth rates. Triglycerides and remnant cholesterol were positively associated with the risk of LGA (odds ratio [OR] 1.11, 95% confidence interval [CI] [1.01 to 1.22] and OR 1.11, 95% CI [1.01 to 1.23], respectively). These associations were independent of maternal pre-pregnancy body mass index, but not maternal glucose levels. We observed no association between maternal lipids in early pregnancy and SGA. CONCLUSIONS: Our study suggests a novel association of early pregnancy triglyceride and remnant cholesterol levels with foetal growth, patterns of foetal growth and the risk of LGA. Future studies are warranted to explore clinical implication possibilities.

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 and metabolic load for the mother in the presence of a male fetus. FUNDING: None.

Validation of a Semi-Quantitative Food-Frequency Questionnaire for Dutch Pregnant Women from the General Population Using the Method or Triads.

OBJECTIVE: We aimed to validate a food-frequency questionnaire (FFQ) for Dutch pregnant women, against three 24 h-recalls and blood concentrations of B-vitamins and fatty acids, using the method of triads. METHODS: We included 83 pregnant women from the general population of Rotterdam, the Netherlands, at a median gestational age of 15.6 weeks. Participants completed three non-consecutive 24 h-recalls, and subsequently filled out the 293-item FFQ. Participants provided blood samples from which we analyzed serum folate and vitamin B12, as well as red blood cell folate, linoleic acid, and total saturated, monounsaturated, and polyunsaturated fatty acids. RESULTS: Estimated energy intake did not differ between the FFQ and 24 h-recalls. Deattenuated Pearson's correlation coefficients, between energy-adjusted nutrient intake estimates from the FFQ and the 24 h-recalls, ranged from 0.41 (fat) to 0.88 (fiber) for macronutrients, and were around 0.6 for most micronutrients, except for vitamin E (0.27). Using the triad method, we obtained validity coefficients of 0.86 (95% Confidence Interval (CI) 0.36, 1.00) for serum folate, 0.86 (95% CI 0.18, 1.00) for red blood cell folate, and 1.00 (95% CI 0.42, 1.00) for vitamin B12. Validity coefficients for serum fatty acids ranged from 0.22 to 0.67. CONCLUSION: This FFQ is a reliable tool for estimating intake of energy, macronutrients, folate and vitamin B12 among women in mid-pregnancy.

Preconception telomere length as a novel maternal biomarker to assess the risk of spina bifida in the offspring.

BACKGROUND: Periconception interactions between maternal conditions and environmental and genetic factors are involved in the pathogenesis and prevention of neural tube defects (NTD), such as spina bifida. These factors have in common that they can impair the oxidative pathway, resulting in excessive (chronic) oxidative stress and inflammation. METHODS: Review of the literature concerning underlying mechanisms and biomarkers of aging particularly during reproduction. A number of molecular markers for biological aging have been identified, including telomere length (TL). Excessive telomere shortening is an index of senescence, causes genomic instability and is associated with a higher risk of age-related diseases. Furthermore, TL shortening is associated with the similar environmental and lifestyle exposures associated with NTD risk. RESULTS: Embryonic mice deficient in the telomerase gene show shorter TL and failure of closure of the neural tube as the main defect, suggesting that this developmental process is among the most sensitive to telomere loss and chromosomal instability. CONCLUSIONS: From this background, we hypothesize that preconceptional long term exposure to harmful environmental and lifestyle risk factors accelerates a woman's aging process, which can be measured by TL, and thereby her underlying risk of NTD offspring. Alternatively, it might be that women with an increased NTD risk already exhibit a more advanced biological age before the onset of pregnancy compared to women of identical calendar age.

Early Pregnancy Cardiovascular Health and Subclinical Atherosclerosis.

Background Assessing and optimizing cardiovascular health (CVH) early in life, such as in pregnancy, could lead to a longer lifetime spent in better CVH and reduce the risk of cardiovascular disease. This might especially benefit women with a hypertensive disorder of pregnancy (HDP) who are more likely to develop atherosclerosis and cardiovascular disease. We hypothesized that CVH in pregnancy is related to later life CVH and carotid intima-media thickness (CIMT), and that these associations differ between women with a normotensive pregnancy and women with an HDP. Methods and Results This study was conducted within the prospective population-based Generation R Study. CVH in pregnancy was based on 5 metrics (blood pressure, total-cholesterol, glucose, smoking, and body mass index). Postpartum CVH additionally included physical activity and diet scores, according to the American Heart Association classification. Postpartum CVH and CIMT were measured 10 years after pregnancy. Results were analyzed for women with a normotensive pregnancy and those with an HDP. Women with a normotensive pregnancy (n=1786) and women with an HDP (n=138) were evaluated from early pregnancy until 10 years postpartum. Better CVH in early pregnancy was associated with a smaller CIMT and better postpartum CVH in all women, especially in those with an HDP (CIMT: -9.82 µm [95% CI: -17.98, -1.67]). Conclusions Already in pregnancy, better CVH is associated with a smaller CIMT and better CVH 10 years postpartum, especially in women with an HDP. As pregnancy is an incentive for women to improve lifestyle, assessing CVH in pregnancy might help improve postpartum CVH and reduce cardiovascular disease risk.

Deceleration of fetal growth rate as alternative predictor for childhood outcomes: a birth cohort study.

BACKGROUND: Small for gestational age (SGA) is frequently used to define fetal growth restriction (FGR). However, FGR describes a slowdown in fetal growth and is not synonymous with SGA, which may introduce misclassification. We investigated the effect of both on delivery and childhood outcomes. METHODS: From a prospective population-based cohort study we included 7959 live singleton births with data available on second trimester estimated fetal weight (EFW) and birth weight. We used a decrease in growth of > 40 percentiles between second trimester EFW and birthweight to define a deceleration in growth. SGA was defined as birthweight

Is maternal lipid profile in early pregnancy associated with pregnancy complications and blood pressure in pregnancy and long term postpartum?

BACKGROUND: An atherogenic lipid profile is a risk factor for the initiation and progression of atherosclerosis. This ultimately leads to cardiovascular disease. Women with a history of hypertensive disorders of pregnancy are at increased risk of sustained hypertension and cardiovascular disease later in life. Currently it is unclear whether dyslipidemia during pregnancy contributes to these risks. OBJECTIVE: The objective of the study was to determine the associations between early pregnancy maternal lipid profile, hypertensive disorders of pregnancy, and blood pressure during and years after pregnancy. STUDY DESIGN: We included 5690 women from the Generation R Study, an ongoing population-based prospective birth cohort. Two hundred eighteen women (3.8%) developed gestational hypertension and 139 (2.4%) preeclampsia. A maternal lipid profile consisting of total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, remnant cholesterol, and non-high-density lipoprotein cholesterol was determined in early pregnancy (median, 13.4 weeks of gestation). Systolic and diastolic blood pressures were measured in early, mid-, and late pregnancy and 6 and 9 years after pregnancy. RESULTS: Triglycerides and remnant cholesterol in early pregnancy were positively associated with preeclampsia. Maternal lipid levels in early pregnancy were not associated with gestational hypertension. Total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and especially triglycerides and remnant cholesterol were positively associated with blood pressure in pregnancy and 6 and 9 years after pregnancy. Triglycerides and remnant cholesterol are positively associated with sustained hypertension 6 and 9 years after pregnancy. CONCLUSION: An atherogenic lipid profile in early pregnancy reflecting impaired triglyceride-rich lipoprotein metabolism is independently associated with preeclampsia and blood pressure throughout pregnancy but also with sustained hypertension long term postpartum. Lipid levels in early pregnancy may help to identify women at risk for future hypertension and perhaps also women at risk for future cardiovascular disease.

Placental Growth Factor as an Indicator of Maternal Cardiovascular Risk After Pregnancy.

BACKGROUND: Angiogenic placental growth factor (PlGF) concentrations rise during pregnancy, peaking at the end of midpregnancy. Low PlGF concentrations during pregnancy are associated with pregnancy complications with recognized later-life cardiovascular risk. We hypothesized that low PlGF concentrations, especially in midpregnancy, identify not only a subset of women at risk for pregnancy complications but also women with greater cardiovascular risk factor burden after pregnancy regardless of pregnancy outcome. METHODS: In a population-based prospective cohort study of 5475 women, we computed gestational age-adjusted multiples of the medians of early pregnancy and midpregnancy PlGF concentrations. Information on pregnancy complications (preeclampsia, small for gestational age, and spontaneous preterm birth) was obtained from hospital registries. Six years after pregnancy, we measured maternal systolic and diastolic blood pressures, cardiac structure (aortic root diameter, left atrial diameter, left ventricular mass, and fractional shortening), carotid-femoral pulse wave velocity, and central retinal arteriolar and venular calibers. Blood pressure was also measured 9 years after pregnancy. RESULTS: Women were on average 29.8 (SD, 5.2) years of age in pregnancy, were mostly European (55.2%), and 14.8% developed a pregnancy complication. Quartile analysis showed that especially women with midpregnancy PlGF in the lowest quartile (the low-PlGF subset) had a larger aortic root diameter (0.40 mm [95% CI, 0.08-0.73]), left atrial diameter (0.34 mm [95% CI, -0.09 to 0.78]), left ventricular mass (4.6 g [95% CI, 1.1-8.1]), and systolic blood pressure (2.3 mm Hg [95% CI, 0.93-3.6]) 6 years after pregnancy than women with the highest PlGF. Linear regression analysis showed that higher midpregnancy PlGF concentrations were associated with a smaller aortic root diameter (-0.24 mm [95% CI, -0.39 to -0.10]), smaller left atrial diameter (-0.75 mm [95% CI, -0.95 to -0.56]), lower left ventricular mass (-3.9 g [95% CI, -5.5 to -2.3]), and lower systolic blood pressure (-1.1 mm Hg [95% CI, -1.7 to -0.46]). These differences persisted after the exclusion of women with complicated pregnancies. CONCLUSIONS: Women with low PlGF in midpregnancy have a greater aortic root diameter, left atrial diameter, and left ventricular mass and higher systolic blood pressure 6 and 9 years after pregnancy compared to women with higher PlGF, including women with uncomplicated pregnancies. The pathophysiological implications of lower PlGF concentrations in midpregnancy might provide insight into the identification of pathways contributing to greater cardiovascular risk factor burden.

Cardiovascular Risk Factors Track From Mother to Child.

Background Cardiovascular risk factors can track from mother to child by several pathways: pregnancy complications, genetic inheritance, and shared environmental risk factors after pregnancy. The degree of tracking, and to which extent this is influenced by these pathways, is unknown. We hypothesized that cardiovascular risk factors track from mother to child regardless of pregnancy complications and environmental risk factors. We determined the degree of tracking between maternal and offspring micro- and macrovascular cardiovascular risk factors after pregnancy and the extent to which this is influenced by pregnancy complications and shared environmental risk factors. Methods and Results We included 5624 mother-offspring pairs from The Generation R Study, an ongoing prospective, population-based birth cohort. Information on pregnancy complications (preeclampsia, small for gestational age, and preterm birth) was obtained through hospital charts. Mother-offspring associations were assessed 6 years after pregnancy (central retinal arteriolar and venular calibers, body mass index, blood pressure, left atrial diameter, aortic root diameter, left ventricular mass, fractional shortening, and pulse wave velocity) and 9 years after pregnancy (body mass index and blood pressure). We observed that worse cardiovascular parameters in mothers were associated with worse cardiovascular parameters in their offspring 6 and 9 years after pregnancy ( P<0.001). Results were similar when mother-offspring pairs with a previous pregnancy complication were excluded. Conclusions Six and 9 years after pregnancy, an adverse cardiovascular profile in mothers is strongly associated with an adverse cardiovascular profile in their offspring. Results were not attenuated by environmental exposures or a previous pregnancy complication. This supports the hypothesis that cardiovascular risk factors (micro- and macrovascular) track from mother to child, regardless of the course of pregnancy.

Hypertensive disorders of pregnancy and subsequent maternal cardiovascular health.

To examine associations between hypertensive pregnancy disorders and maternal cardiovascular disease (CVD) in later life. We examined the associations between blood pressure (BP) in pregnancy, gestational hypertension (GH) and preeclampsia (PE) with cardiovascular measurements 6 years after index pregnancy among 4912 women participating in the Generation R Study, the Netherlands. BP, left ventricular mass (LV mass), aortic root diameter (AOD), left atrial diameter, fractional shortening, and carotid-femoral pulse wave velocity (PWV). Early pregnancy systolic and diastolic BP were associated with more adverse maternal cardiovascular measurements and a higher incidence of chronic hypertension 6 years after pregnancy. GH was associated with a higher BP, a higher PWV, a larger AOD and an increased LV mass 6 years after index pregnancy. Compared to previous normotensive pregnancies these women had a sixfold increased risk to develop chronic hypertension after pregnancy (OR 6.6, 95% CI 4.6-9.5). Compared to women with a normotensive pregnancy, women with PE had a higher BP and a higher risk of chronic hypertension (OR 4.5, 95% CI 2.6-7.8) at follow-up. After adjustment for BMI at follow-up in all the analyses on GH, PE and cardiovascular measurements, effect estimates attenuated up to 65%, but remained significant. Both GH and PE are associated with markers of adverse maternal cardiovascular health after pregnancy with an increased risk of chronic hypertension. Women with GH and PE may be offered long-term cardiovascular follow-up incorporated in CVD risk management guidelines.

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.

Fetal Growth and Placental Growth Factor Umbilical Cord Blood Levels.

OBJECTIVE: We assessed whether umbilical cord blood placental growth factor (PlGF) levels at delivery are associated with fetal growth. METHODS: From a prospective population-based cohort study we included 3,461 live singleton births. Fetal growth was assessed by birth weight, fetal growth pattern, and fetal growth restriction (FGR; decrease in growth between the second trimester and birth of ≥40 percentiles). In all analyses the highest PlGF multiple of the median (MoM) quintile was used as the reference category. RESULTS: Umbilical cord PlGF was neither correlated with maternal second-trimester PlGF (p = 0.08) nor placental weight (p = 0.18), suggesting that PlGF from umbilical cord blood was of fetal origin. Lower PlGF MoM quintiles were associated with a lower birth weight (lowest quintile -0.60 standard deviation [95% confidence interval -0.71 to -0.48, p for trend <0.001]) and a different fetal growth pattern (p < 0.001). Finally, lower PlGF MoM quintiles were associated with FGR (lowest quintile odds ratio 2.00 [95% confidence interval 1.25 to 3.21, p for trend <0.001]). CONCLUSION: Lower umbilical cord PlGF levels are associated with lower birth weight, deviating fetal growth patterns, and a higher odds of FGR. Hence, cord blood PlGF might be a promising biomarker to determine deviations in fetal growth and FGR retrospectively, enabling follow-up of these neonates.

Gestational hypertensive disorders and retinal microvasculature: the Generation R Study.

BACKGROUND: Changes in the microvasculature associated with pre-eclampsia and gestational hypertension have been proposed as a potential pathway in the development of cardiovascular disease. We examined whether gestational hypertensive disorders, such as pre-eclampsia and gestational hypertension, are related to the maternal retinal microvasculature status after pregnancy. METHODS: This study is part of an ongoing population-based prospective cohort study. During pregnancy and 6.2 years after the index pregnancy (90% range 5.7-7.4 years), we examined 3391 women with available information on pre-eclampsia, gestational hypertension, and retinal vascular calibers. Retinal arteriolar and venular calibers were measured in the left eye from digitized retinal photographs. RESULTS: Women with pre-eclampsia had smaller retinal arteriolar calibers 6 years after pregnancy than women with a normotensive pregnancy (adjusted difference: -0.40 standard deviation score [SDS]; 95% confidence interval [CI]: -0.62, -0.19). For women with previous gestational hypertension, similar trends were observed (-0.20 SDS; 95% CI: -0.34, -0.05). With respect to retinal venular calibers, we did not observe consistent trends for women with previous pre-eclampsia. However, in women with previous gestational hypertension, we observed larger venular calibers (0.22 SDS; 95% CI: 0.07-0.36) than in women with a previous normotensive pregnancy. The association of gestational hypertensive disorders with retinal vessel calibers was mediated through mean arterial pressure at the time of retinal imaging. CONCLUSIONS: Compared to women with a previous normotensive pregnancy, women with pre-eclampsia and gestational hypertension show an altered status of the microvasculature 6 years after the index pregnancy. This is reflected by smaller retinal arteriolar calibers and wider retinal venular calibers. These microvascular changes may possibly contribute to the development of cardiovascular disease in later life.

Fetal sex-specific differences in gestational age at delivery in pre-eclampsia: a meta-analysis.

Background: : Pre-eclampsia (PE) is a major pregnancy disorder complicating up to 8% of pregnancies. Increasing evidence indicates a sex-specific interplay between the mother, placenta and fetus. This may lead to different adaptive mechanisms during pregnancy. Methods: We performed an individual participant data meta-analysis to determine associations of fetal sex and PE, with specific focus on gestational age at delivery in PE. This was done on 219 575 independent live-born singleton pregnancies, with a gestational age at birth between 22.0 and 43.0 weeks of gestation, from 11 studies participating in a worldwide consortium of international research groups focusing on pregnancy. Results: Of the women, 9033 (4.1%) experienced PE in their pregnancy and 48.8% of the fetuses were female versus 51.2% male. No differences in the female/male distribution were observed with respect to term PE (delivered ≥ 37 weeks). Preterm PE (delivered < 37 weeks) was slightly more prevalent among pregnancies with a female fetus than in pregnancies with a male fetus [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.02-1.21]. Very preterm PE (delivered < 34 weeks) was even more prevalent among pregnancies with a female fetus as compared with pregnancies with a male fetus (OR 1.36, 95% CI 1.17-1.59). Conclusions: Sexual dimorphic differences in the occurrence of PE exist, with preterm PE being more prevalent among pregnancies with a female fetus as compared with pregnancies with a male fetus and with no differences with respect to term PE.