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.

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.

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.

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 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.

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.

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

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.

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.

Helicobacter pylori colonization and pregnancies complicated by preeclampsia, spontaneous prematurity, and small for gestational age birth.

BACKGROUND: Preeclampsia (PE), small for gestational age (SGA), and spontaneous preterm birth (PTB) each may be complications of impaired placental function in pregnancy. Although their exact pathogenesis is still unknown, certain infectious agents seem to play a role. Helicobacter pylori (H. pylori) colonization has been associated with increased risk for PE. Our aim was to assess the association between H. pylori colonization and PE, SGA, and PTB. MATERIAL AND METHODS: We measured IgG anti-H. pylori and CagA antibodies in serum of pregnant women (median 20.5 weeks, range 16.5-29.4) who participated in a population-based prospective cohort study. Delivery and medical records were assessed. Information on demographics, education, and maternal risk factors was collected by questionnaire. We used multivariate logistic regression analyses to assess associations between H. pylori colonization and PE, SGA, and PTB. RESULTS: In total, 6348 pregnant women were assessed. H. pylori positivity was found in 2915 (46%) women, of whom 1023 (35%) also were CagA-positive. Pregnancy was complicated by PE, SGA, or PTB in 927 (15%) women. H. pylori colonization was associated with PE (aOR 1.51; 95%CI 1.03-2.25). Differentiation according to CagA status revealed the same risk. H. pylori was positively related with SGA, mainly explained by CagA-positive strains (aOR 1.34; 1.04-1.71). No association was observed between H. pylori and PTB. CONCLUSIONS: Our data suggest that H. pylori colonization may be a risk factor for PE and SGA. If these associations are confirmed by future studies and shown to be causal, H. pylori eradication may reduce related perinatal morbidity and mortality.

Maternal and Neonatal Markers of the Homocysteine Pathway and Fetal Growth: The Generation R Study.

BACKGROUND: Suboptimal dietary intake during pregnancy may have long-term health implications in children. These effects may be mediated by fetal growth. We investigated the associations of early pregnancy and umbilical cord total homocysteine (tHcy), folate, and total and active vitamin B12 concentrations with fetal growth parameters repeatedly measured in pregnancy and at birth. METHODS: This study was performed in 5890 pregnant women, participating in a population-based prospective cohort study. Blood samples were obtained from women in early pregnancy and from the umbilical vein at delivery. Fetal size parameters were repeatedly measured by ultrasound. Information about birth anthropometrics was retrieved from medical records. RESULTS: High early pregnancy maternal tHcy (≥8.31 µmol/L), as compared with low maternal homocysteine (≤5.80 µmol/L), and low early pregnancy maternal folate (≤9.10 nmol/L), as compared with high maternal folate (≥25.81 nmol/L) concentrations, were associated with reduced weight growth patterns throughout pregnancy, resulting in birthweight differences of -102.3 g (95% CI -139.6, -65.0) and -113.0 g (95% CI -159.6, -66.3), respectively. Low umbilical cord folate concentrations (≤15.20 nmol/L) as compared with high umbilical cord folate concentrations (≥28.41 nmol/L) were also associated with a lower birthweight and birth length (P < 0.001). Interestingly, compared with higher umbilical cord vitamin B12 , lower vitamin B12 concentrations were associated with a higher weight, length, and head circumference at birth (P < 0.01). CONCLUSION: Early pregnancy maternal and umbilical cord markers of the homocysteine pathway are significantly associated with fetal growth patterns. These differences arise from mid-pregnancy onwards.

Reference ranges and determinants of total hCG levels during pregnancy: the Generation R Study.

Human chorionic gonadotropin (hCG) is a pregnancy hormone secreted by the placental synctiotrophoblast cell layer that has been linked to fetal growth and various placental, uterine and fetal functions. In order to investigate the effects of hCG on clinical endpoints, knowledge on reference range (RR) methodology and determinants of gestational hCG levels is crucial. Moreover, a better understanding of gestational hCG physiology can improve current screening programs and future clinical management. Serum total hCG levels were determined in 8195 women participating in the Generation R Study. Gestational age specific RRs using 'ultrasound derived gestational age' (US RRs) were calculated and compared with 'last menstrual period derived gestational age' (LMP RRs) and a model-based RR. We also investigated which pregnancy characteristics were associated with hCG levels. Compared to the US RRs, the LMP RRs were lower, most notably for the median and lower limit levels. No considerable differences were found between RRs calculated in the general population or in uncomplicated pregnancies only. Maternal smoking, BMI, parity, ethnicity, fetal gender, placental weight and hyperemesis gravidarum symptoms were associated with total hCG. We provide gestational RRs for total hCG and show that total hCG values and RR cut-offs during pregnancy vary depending on pregnancy dating methodology. This is likely due to the influence of hCG on embryonic growth, suggesting that ultrasound based pregnancy dating might be less reliable in women with high/low hCG levels. Furthermore, we identify different pregnancy characteristics that influence total hCG levels considerably and should therefore be accounted for in clinical studies.

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.

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.

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.

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.

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.

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.