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Background: Epidemiological studies demonstrate that foetal growth restriction and low birth weight affect long-term health. Derangements in tissue-specific epigenetic programming of foetal and placental tissues are a suggested underlying mechanism of which DNA methylation is best understood. DNA methylation has been mostly investigated in DNA from white blood cells. To improve baseline understanding of tissue-specific DNA methylation, we examined variation in DNA methylation profiles of the imprinted foetal growth genes IGF2 and H19 in three different tissues from the same newborn obtained at the same time., Findings: We obtained DNA from umbilical cord blood mononuclear cells (MNC; CD34+ and CD34-, n = 6), foetal side of the placenta (n = 5) and umbilical cord Wharton jelly (n = 5). DNA methylation of the IGF2 differentially methylated region (DMR) and H19 DMR was measured using quantitative mass spectrometry. Analysis of variance testing showed no statistical difference between total mean methylation of CD34+ and CD34- MNC. Further comparisons were made with the pooled total MNC fraction. Mean IGF2 DMR methylation of Wharton jelly was 1.3 times higher (P = 0.001) than mean methylation of the pooled MNC. Placental mean methylation was 0.8 times lower (P <0.001) and Wharton jelly 0.9 times lower (P <0.001) than the pooled MNC of H19 DMR., Conclusion: The total MNC fraction is a rather homogeneous cell population for methylation studies of imprinted genes in umbilical cord blood white blood cells, but may not always reflect the methylation levels of IGF2 and H19 in other organs.

Study Question: Is it possible to evaluate first trimester brain ventricle development in human pregnancies using an innovative virtual reality (VR) application and to analyze the relation of the embryonic volume (EV) and brain ventricle fluid volume (BVFV) with gestational age (GA), crown-rump length (CRL) and the Carnegie stage?, Summary Answer: Volumetry and staging of the human embryo using a VR application make it possible to obtain unique information about in-vivo embryonic normal and abnormal development and about the sizes of the ventricles and body., What Is Known Already: Human brain development is complex and has a rapidly changing anatomy during the first trimester of pregnancy. New insights will enable early detection of cerebral pathology., Study Design, Size, Duration: In a prospective cohort study, we weekly performed three-dimensional (3D) ultrasound examinations in 112 uncomplicated pregnancies between 6 + 0 and 12 + 6 weeks GA., Materials, Setting, Methods: The examinations resulted in 696 3D ultrasound scans that were transferred to the I-Space VR system and analyzed using V-Scope volume rendering software. V-Scope is used to create a 'hologram' of the ultrasound image and allows depth perception and interaction with the rendered objects. The CRL measurements were performed with a tracing tool, and the volume measurements were automatically performed with a segmentation algorithm. The embryos were staged according to the internal and external characteristics of the Carnegie staging system. All longitudinal outcomes were analyzed using repeated measures ANOVA., Main Results and the Role of Chance: CRL could be measured in 91% of the datasets and ranged from 2.5 to 79.0 mm. EV could be measured in 66% of the datasets and ranged from 2.4 to 23 812.0 mm&sup3;, whereas the BVFV could be measured in 38% of the datasets and ranged from 10.4 to 226.3 mm&sup3;. Finally, in 74% of the datasets, the embryos were staged according to the Carnegie criteria, starting as early as stage 12. Reference charts of volumes versus GA, CRL and stage were constructed. There was no significant relationship between the CRL or EV and the birthweight., Limitations, Reasons for Cautions: The low success rate is a limitation of this study that can be explained mainly by non-targeted scanning of the embryonic head., Wider Implications of the Findings: The I-Space VR system and the V-Scope software enable automatic EV and BVFV measurements and 3D observations of embryonic development in the first trimester. This allows in-vivo staging of human embryos based on both internal and external morphological characteristics., Study Funding, Competing Interests: None.

Two pregnancy cohorts were used to investigate the association between single-nucleotide polymorphisms (SNPs) in genes within the insulin-like growth factor (IGF)-axis and antenatal and postnatal growth from birth to adolescence. Longitudinal analyses were conducted in the Raine pregnancy cohort (n = 1162) using repeated measures of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) from 18 to 38 weeks gestation and eight measures of postnatal height and weight (1-17 years). Replications of significant associations up to birth were undertaken in the Generation R Study (n = 2642). Of the SNPs within the IGF-axis genes, 40% (n = 58) were associated with measures of antenatal growth (P ⩽ 0.05). The majority of these SNPs were in receptors; IGF-1R (23%; n = 34) and IGF-2R (13%; n = 9). Fifteen SNPs were associated with antenatal growth (either AC or HC or FL) in Raine (P ⩽ 0.005): five of which remained significant after adjusting for multiple testing. Four of these replicated in Generation R. Associations were identified between 38% (n = 55) of the IGF-axis SNPs and postnatal height and weight; 21% in IGF-1R (n = 31) and 9% in IGF-2R (n = 13). Twenty-six SNPs were significantly associated with both antenatal and postnatal growth; 17 with discordant effects and nine with concordant effects. Genetic variants in the IGF-axis appear to play a significant role in antenatal and postnatal growth. Further replication and new analytic methods are required in order to better understand this key metabolic pathway integrating biologic knowledge about the interaction between IGF-axis components.

Introduction: Studies on the association of preeclampsia (PE) with thrombophilias (TRPH) are conflicting. Clinical heterogeneity of PE may be one of the explanations., Objectives: The present study addresses the question whether different phenotypes of PE are associated with subtypes of TRPH., Methods: In this retrospective cohort study between 1985 until 2010 women with PE were offered postpartum screening for the following TRPH: anti-phospholipid antibodies (APA), APC-resistance, protein C deficiency and protein S deficiency (PSD), hyperhomocysteinemia (HCY), factor V Leiden and Prothrombin gene mutation., Results: 890 Women with PE were screened for TRPH. 49% Also had HELLP, 60% had IUGR, 71% delivered before the 34th week. One or more TRPH factors were present in 31% of the women. Severe PE was associated with PSD (p=0.01). IUGR (p<0.01) was associated with APA (p<0.01) and PSD (P=0.03). Early onset PE was associated with APA (P, 0.01). More than 10% of placental infarction was associated with APA (p<0.01). Placental weight below the 5th percentile was associated with HCY (p=0.03). Other phenotypes of PE and TRPH were not associated., Conclusion: Severe and early onset PE, especially if complicated by IUGR, are associated with APA and PSD. Other phenotypes of PE, especially HELLP syndrome, were not associated with TRPH. We advise to screen for APA and PSD after severe and early onset PE, especially if complicated by IUGR. We do not recommend screening for TRPH in other phenotypes of PE., (Copyright © 2013. Published by Elsevier B.V.)

Background: Preeclampsia (PE), foetal growth restriction (FGR) and preterm birth (PTB) are associated with an increased risk on the development of cardiovascular disease in offspring. Abnormal programming of the embryonic and extra-embryonic vasculature may be involved. The umbilical cord could be a good model for studying foetal vascular development., Objectives: We examined the morphology of the umbilical cord vasculature in complicated (PE, FGR, PTB) and uncomplicated pregnancies., Methods: In a case-control study, we included 105 patients consisting of PE (n=31), FGR (n=26), PTB (n=24) and controls (n=24). Macroscopic measurements were performed and tissue samples were formalin-fixed within 1 hour after birth, for microscopic analysis of digitised paraffin sections., Results: The macroscopic evaluation showed shorter umbilical cords in PE than in controls. Microscopic measurements revealed a smaller total cord area in all complicated pregnancies compared to controls. The artery wall area was smaller in PE and IUGR, and a smaller vein wall area was present in PE only, compared to controls. The percentage of elastic fibres in the vein was lower in PE and IUGR than in controls (Table 1)., Conclusion: Our study demonstrates umbilical cord vascular abnormalities in PE, FGR and PTB, suggesting early vascular damage. Future studies should focus on similar structural changes in foetal vasculature and associations with cardiovascular disease in later life., (Copyright © 2013. Published by Elsevier B.V.)

Introduction: Circulating angiogenic factors are potential markers for preeclampsia, but heterogeneous studies have failed to identify precise predictive/diagnostic properties. The Global CoLaboratory is investigating how to merge published data of angiogenic factors for meta-analysis on an individual sample basis., Objective: To amalgamate pregnancy angiogenic factor studies, investigate diagnostic and predictive properties of these markers in preeclampsia and placenta-related pregnancy complications, and to test if measures from disparate platforms can be standardised. This is the first report using PlGF measures to diagnose preeclampsia., Methods: Data were derived from 15 cohorts, within and outside the CoLaboratory network. Women were classified as either case (confirmed diagnosis of preeclampsia at sampling) or non-case (no preeclampsia at sampling). Individual PlGF measurements from four different analytical platforms were used, along with transformations of the data (e.g. log-transformations, transformations to a baseline platform). Transformed measurements were standardised both for specific platforms and globally, stratifying on gestational age. Different statistical techniques were compared., Results: The database currently contains 1442 cases and 11,512 non-cases, which were used to define an algorithm to merge PlGF measurements from different platforms. Non-case distributions were used to standardise case results. Diagnostic PlGF measurements in relation to preeclampsia will be presented and confirm feasibility., Conclusions: Future studies can extend this approach to other angiogenic factors, prediction as well as diagnosis and to other placenta-related disorders., (Copyright © 2013. Published by Elsevier B.V.)

Objectives: To investigate the determinants of the intention of preconception care use of women in a multi-ethnic urban population., Methods: The ASE-model-a health behaviour model-was used as an explanatory framework. A representative sample was taken from the municipal population registers of two districts in Rotterdam, the Netherlands, 2009-2010. 3,225 women (aged 15-60 years) received a questionnaire, which was returned by 631: 133 Dutch, 157 Turkish and Moroccan, and 341 Surinamese and Antillean. Descriptive, univariate and multivariate analyses were performed., Results: The multiple logistic analyses showed that intention to attend preconception care was significantly higher in women with a Turkish and Moroccan background (β 1.02, P = 0.006), a higher maternal age (β 0.04, P = 0.008) and a positive attitude (β 0.50, P < 0.001). Having no relationship (β -1.16, P = 0.004), multiparity with previous adverse perinatal outcome (β -1.32, P = 0.001), a high educational level (β -1.23, P = 0.03), having paid work (β -0.72, P = 0.01) and experienced barriers level (β -0.15, P = 0.003) were associated with less intention to use preconception care., Conclusions: Modifiable determinants as attitude and barriers can be addressed to enhance preconception care attendance.

Introduction: Evidence indicates a gender specific interaction between the mother, placenta and fetus in which maternal adaptation to pregnancy and outcome partly depends on fetal gender., Objectives: This study assesses fetal gender specific differences in placental biomarkers and uteroplacental vascular resistance. Methods Within the Generation R Study, in 1st and 2nd trimester (median 13.3 and 20.4 wks) blood samples were drawn to assess soluble fms-like tyrosine kinase (s-Flt1), placental growth factor (PLGF) and plasminogen activator inhibitor 2 (PAI-2). Uteroplacental resistance was assessed by mean pulsatility index (PI) of the uterine and umbilical arteries in the 2nd trimester. Mann-Whitney U and Student's t-test were performed to assess associations of gender on the above mentioned factors., Results: In total 8631 women were included (4274 female and 4357 male fetuses). From these women, 172 had a pregnancy complicated by pre-eclampsia (1.9%). Fetal sex related differences in placental biomarkers, being most pronounced in non pre-eclamptic pregnancies (Table 1). Differences were also observed between early (<34wks) and late onset pre-eclamptic women (>34wks)., Conclusion: This study shows that maternal adaptation to pregnancy varies by fetal gender, suggesting gender specific differences in placentation and placental function. The differences between pre-eclamptic and non pre-eclamptic women, and among pre-eclamptic women, suggest that different mechanisms apply to pre-eclamptic pregnancies., (Copyright © 2013. Published by Elsevier B.V.)

Objective: To identify periconceptional maternal dietary patterns associated with crown-rump length (CRL), estimated fetal weight (EFW) and birthweight., Design: Population-based prospective birth cohort study., Setting: Rotterdam, the Netherlands., Participants: For this study, 847 pregnant Dutch women were eligible. Women were included between 2001 and 2005., Methods: Information on nutritional intake was collected by a semiquantitative food frequency questionnaire. For extracting dietary patterns, principal component factor analysis was used. Fetal growth was assessed using ultrasound measurements. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used., Main Outcome Measures: Crown-to-rump length, estimated fetal weight in second and third trimester and birthweight., Results: An 'energy-rich dietary pattern' was identified, characterised by high intakes of bread, margarine and nuts. A significant association was shown between a high adherence to this dietary pattern (difference, mm: 2.15, 95% confidence interval 0.79-3.50) and CRL (linear trend analyses P = 0.015). No association was revealed between increasing adherence to this dietary pattern and EFW in second or third trimester, or birthweight., Conclusion: This study suggests that increasing adherence to an energy-rich dietary pattern is associated with increased CRL in the first trimester., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Objective: To investigate adverse perinatal outcomes and gestational weight gain trajectories in women with lifetime (current/past) eating disorders (ED: anorexia nervosa [AN] and bulimia nervosa [BN])., Design: A longitudinal population-based birth cohort., Setting: Rotterdam, the Netherlands., Sample: Women who enrolled prenatally, had complete information on exposure (lifetime ED), and gave birth to a live singleton (n = 5256). Four groups of exposed women: lifetime AN (n = 129), lifetime BN (n = 209), lifetime AN + BN (n = 100), other lifetime psychiatric disorder (n = 1002) were compared with unexposed women (n = 3816)., Methods: Perinatal outcomes and gestational weight gain were obtained from obstetric and midwifery records, self-report and objective measurements. Exposed women were compared with unexposed women within the cohort using linear, logistic regression and mixed models., Main Outcome Measures: Any pregnancy, delivery and postnatal complications. Birthweight adjusted for gestational age, prematurity (born <37 weeks), small-for-gestational age; maternal weight gain during pregnancy., Results: Maternal AN was positively associated with suspected fetal distress. No differences were found in mean birthweight, prevalence of a small-for-gestational-age, or premature birth. Relative to unexposed women, women with AN had, on average, a lower body weight but a higher rate of weight gain subsequently; whereas women with BN had a higher body weight but a lower rate of weight gain., Conclusions: Maternal lifetime ED is associated with few adverse perinatal outcomes in this sample. Differential gestational weight gain patterns in women with AN and BN are consistent with possible biological compensatory mechanisms aimed at protecting the fetus., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Maternal smoking during pregnancy and a low socioeconomic status (SES) lead to increased risks of adverse pregnancy outcome. Maternal education is often used as proxy for SES. We explored the programming of the insulin pathway genes IGF2 DMR (insulin growth factor 2 differentially methylated region), IGF2R (insulin growth factor 2 receptor) and INSIGF [the overlapping region of IGF2 and insulin (INS)] in the child through any periconception maternal smoking and education level. In 120 children at 17 months of age, methylation of DNA derived from white blood cells was measured. Periconception smoking and low education were independently associated with INSIGF methylation and showed a relative increase in methylation of +1.3%; P = 0.043 and +1.6%; P = 0.021. Smoking and low education showed an additive effect on INSIGF methylation (+2.8%; P = 0.011). There were no associations with IGF2 DMR and IGF2R methylation. Our data suggest that periconception maternal smoking and low education are associated with epigenetic marks on INSIGF in the very young child, this warrants further study in additional populations.

Introduction: The objective of this study was to evaluate whether differences existed in the adherence to the Dutch national guidelines regarding basic antenatal care by Dutch midwives for low-risk women of different ethnic groups., Methods: This was an observational study using data from electronic antenatal charts of 7 midwife practices (23 midwives), participating in the Generation R Study. The Generation R Study is a multiethnic, population-based, prospective, cohort study that is investigating the growth, development, and health of urban children from fetal life until young adulthood. The study is conducted in Rotterdam, The Netherlands. The antenatal charts of 2093 low-risk pregnant women with an expected birthing date in 2002 through 2004 were used to determine the mean quality of antenatal care scores for 7 ethnic groups. These scores reflected the degree of adherence to the guidelines regarding 10 tests and examinations., Results: Few differences between ethnic groups were found in adherence to the guidelines that addressed the obstetric-technical quality of antenatal care. This finding applied more to nulliparous than to multiparous women. Adherence to guidelines was not always better in the antenatal care provided to native Dutch multiparous women when compared to other ethnic groups. Midwives adhered well to the guidelines regarding most tests. For all women, irrespective of ethnic background, hemoglobin was not measured as often as recommended, and this was especially the case for Moroccan, Surinamese-Creole, and Dutch-Antillean multiparous women., Discussion: The poorer adherence regarding screening for hemoglobin needs further investigation, as women with African or Mediterranean heritage are more at risk for hemoglobinopathies. However, in general, midwives adhered well to the clinical guidelines regarding most tests irrespective of the ethnic background of the pregnant women. When differences were present, these were not systematically less favorable for non-Dutch pregnant women., (© 2012 by the American College of Nurse-Midwives.)

Objective: Nitrous oxide (N(2) O) is routinely used as an analgesic in obstetrics during labour. Epidemiological studies have linked chronic occupational exposure to N(2) O to specific health problems, including reproductive risks. Occupational exposure limits (OELs) allow the use of N(2) O once appropriate preventive and safety measures have been taken. We assessed the effectiveness of a scavenger system (Anevac P-system®, Medicvent Heinen & Löwestein Benelux, Barneveld, the Netherlands) applied in N(2) O administration during labour in a midwifery-led birthing centre in the Netherlands., Methods: After informed consent, non-pregnant midwives were trained to administer N(2) O. N(2) O was delivered as a 50 : 50 mixture with oxygen and was self administered by the patient. The scavenging device, containing a double mask and a chin mask, was connected to the local evacuation system vented outside the building. Data on the 8-h time-weighted average (8-h TWA) as well as the 15-min TWA (15-min TWA) were obtained., Results: Thirteen patients were included. Six patients were included in the first study period. In this period the 8-h TWA was not exceeded, however, in all patients, the 15-min TWA occasionally exceeded the OELs. After four additional measures, seven patients were included. After implementation of these measures, the 8-h TWA and 15-min TWA never exceeded the OELs. System leakage was not observed during both study periods., Conclusion: The Anevac P-scavenging system during N(2) O analgesia in labour prevents exceeding OELs in professional workers. The scavenging system appeared acceptable and effective, and can be considered in hospital settings that use N(2) O as analgesic during labour., (© 2012 The Authors. Acta Anaesthesiologica Scandinavica © 2012 The Acta Anaesthesiologica Scandinavica Foundation.)

Background: Subfertility and poor nutrition are increasing problems in Western countries. Moreover, nutrition affects fertility in both women and men. In this study, we investigate the association between adherence to general dietary recommendations in couples undergoing IVF/ICSI treatment and the chance of ongoing pregnancy., Methods: Between October 2007 and October 2010, couples planning pregnancy visiting the outpatient clinic of the Department of Obstetrics and Gynaecology of the Erasmus Medical Centre in Rotterdam, the Netherlands were offered preconception counselling. Self-administered questionnaires on general characteristics and diet were completed and checked during the visit. Six questions, based on dietary recommendations of the Netherlands Nutrition Centre, covered the intake of six main food groups (fruits, vegetables, meat, fish, whole wheat products and fats). Using the questionnaire results, we calculated the Preconception Dietary Risk score (PDR), providing an estimate of nutritional habits. Dietary quality increases with an increasing PDR score. We define ongoing pregnancy as an intrauterine pregnancy with positive heart action confirmed by ultrasound. For this analysis we selected all couples (n=199) who underwent a first IVF/ICSI treatment within 6 months after preconception counselling. We applied adjusted logistic regression analysis on the outcomes of interest using SPSS., Results: After adjustment for age of the woman, smoking of the woman, PDR of the partner, BMI of the couple and treatment indication we show an association between the PDR of the woman and the chance of ongoing pregnancy after IVF/ICSI treatment (odds ratio 1.65, confidence interval: 1.08-2.52; P=0.02]. Thus, a one-point increase in the PDR score associates with a 65% increased chance of ongoing pregnancy., Conclusions: Our results show that increasing adherence to Dutch dietary recommendations in women undergoing IVF/ICSI treatment increases the chance of ongoing pregnancy. These data warrant further confirmation in couples achieving a spontaneous pregnancy and in randomized controlled trials.

The aim of the study was to investigate whether first trimester chorionic villous vascularisation is different in women who smoked cigarettes before and during pregnancy in comparison with women who did not smoke. Placentas of smoking (>10 cigarettes/day, n = 13) and non-smoking women (n = 13), scheduled for a legal termination of a viable first trimester pregnancy for social indications, were retrieved. Placental tissues of 3-5 mm³ were whole mount CD31 immunofluorescence stained. Images of the CD31 immunofluorescence and contour of the villi were captured using an Optical Projection Tomography scanner. An immersive BARCO virtual reality system was used to create an enlarged interactive 3-dimensional hologram of the reconstructed images. Automatic volume measurements were performed using a flexible and robust segmentation algorithm that is based on a region-growing approach in combination with a neighbourhood variation threshold. The villous volume, vascular volume and vascular density were measured for the total chorionic villous tree as well as for its central and peripheral parts. No differences in maternal age and gestational age were found between non-smoking and smoking women. No differences were found in the total, central and peripheral villous tree volume and vascular volume. The central (13.4% vs. 9.5%, p=0.03) and peripheral (8.4% vs. 6.4%, p=0.02) villous tree vascular densities were increased in the smoking women as compared with the non-smoking women. In conclusion, chorionic villous vascularisation is already altered in first trimester of pregnancy in women who smoked cigarettes before and during pregnancy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Virtual reality is a novel method of visualizing ultrasound data with the perception of depth and offers possibilities for measuring non-planar structures. The levator ani hiatus has both convex and concave aspects. The aim of this study was to compare levator ani hiatus volume measurements obtained with conventional three-dimensional (3D) ultrasound and with a virtual reality measurement technique and to establish their reliability and agreement., Methods: 100 symptomatic patients visiting a tertiary pelvic floor clinic with a normal intact levator ani muscle diagnosed on translabial ultrasound were selected. Datasets were analyzed using a rendered volume with a slice thickness of 1.5 cm at the level of minimal hiatal dimensions during contraction. The levator area (in cm(2)) was measured and multiplied by 1.5 to get the levator ani hiatus volume in conventional 3D ultrasound (in cm(3)). Levator ani hiatus volume measurements were then measured semi-automatically in virtual reality (cm(3) ) using a segmentation algorithm. An intra- and interobserver analysis of reliability and agreement was performed in 20 randomly chosen patients., Results: The mean difference between levator ani hiatus volume measurements performed using conventional 3D ultrasound and virtual reality was 0.10 (95% CI, - 0.15 to 0.35) cm(3). The intraclass correlation coefficient (ICC) comparing conventional 3D ultrasound with virtual reality measurements was > 0.96. Intra- and interobserver ICCs for conventional 3D ultrasound measurements were > 0.94 and for virtual reality measurements were > 0.97, indicating good reliability for both., Conclusion: Levator ani hiatus volume measurements performed using virtual reality were reliable and the results were similar to those obtained with conventional 3D ultrasonography., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Introduction: The prevalence of overweight and obesity among women of reproductive age is increasing. Maternal obesity seems to be associated with short-term and long-term adverse outcomes. Excessive gestational weight gain might also influence the risk of adverse pregnancy outcomes. Not much is known about risk factors of maternal obesity and excessive gestational weight gain. Also, little is known about critical periods of gestational weight gain in relation to adverse pregnancy outcomes., Objectives: We aimed to determine risk factors and maternal, fetal and childhood consequences of maternal obesity and excessive gestational weight gain. Furthermore, we examined the associations of trimester-specific weight gain with the risk of adverse pregnancy outcomes., Methods: The study was embedded in a population-based prospective cohort study among 6959 mothers and their children. Maternal anthropometrics were measured in each trimester of pregnancy. Information about maternal weight just before pregnancy, maximum weight during pregnancy and potential socio-demographic and lifestyle related determinants was obtained from questionnaire. Information about gestational hypertensive disorders and birth outcomes was obtained from medical records. Multivariate linear and logistic regression analyses were used., Results: Maternal lower educational level, lower household income, multiparity, and FTO risk allel were associated with an increased risk of maternal obesity, whereas maternal European ethnicity, nulliparity, higher total energy intake, and smoking during pregnancy were associated with an increased risk of excessive gestational weight gain (all p-values <0.05). As compared to normal weight, maternal obesity was associated with increased risks of gestational hypertension (OR 6.31 (95% CI 4.30,9.26)), preeclampsia (OR (3.61 (95% CI 2.04,6.39)), gestational diabetes (OR 6.28 (95%CI 3.01,13.06)), caesarean delivery (OR 1.91 (95% CI 1.46,2.50)), delivering large size for gestational age infants (OR 2.97 (95% CI 2.16,4.08)), and childhood obesity (OR 5.02 (95% CI:2.97,8.45)). Weaker associations of excessive gestational weight gain with these outcomes were observed, with the strongest effects for first trimester weight gain. Weight gain in first and third trimester was associated with the risk of gestational hypertension (OR 1.24 (95% CI 1.12,1.39) and OR 1.27 (95% CI 1.06,1.51) per standard deviation of change in gestational weight gain per week, respectively), whereas weight gain in third trimester was associated with the risk of preeclampsia (OR 1.35 (95% CI 1.08,1.69), per standard deviation of change in gestational weight gain per week)., Conclusion: Our study shows that maternal obesity and excessive weight gain during pregnancy are associated with socio-demographic, lifestyle, and genetic factors and with increased risks of adverse maternal, fetal and childhood health outcomes. As compared to prepregnancy overweight and obesity, excessive gestational weight gain has a limited influence on adverse pregnancy outcomes., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Women with a pregnancy complicated by preeclampsia, intra-uterine growth restriction and/or gestational diabetes are at increased risk of future cardiovascular and metabolic disease. Lifestyle intervention may help these women to effectively lower these risks., Objectives: To test if offering lifestyle intervention after a complicated pregnancy significantly improves saturated fat-intake and exercise (primary objectives) and/or smoking habits (secondary objective)., Methods: The Pro-Active study (Postpartum Rotterdam Appraisal of Cardiovascular health and Tailored Intervention) is a feasibility study to develop and evaluate a postpartum lifestyle intervention program. In a prospective case-control setting we tested the effect of the lifestyle intervention. Women were included between April 2007 and August 2009. They were eligible if ⩾18 years old at time of inclusion, being able to understand and speak the Dutch language and not having pre-existing conditions that could interfere with the lifestyle intervention. Cases were offered lifestyle intervention by a trained counsellor between 6 and 10 months postpartum. During 3 private sessions, mainly exercise and fat-intake and to some extend smoking habits were discussed and aims were made to improve lifestyle. Controls did not receive these sessions, but were not restricted to improve lifestyle on their own. Lifestyle habits were scored at 6 and 13 months postpartum. For saturated fat-intake we used the Maastricht Fatlist. For exercise we used the International Physical Activity Questionnaire (IPAQ). For smoking habits we used a short version of the questionnaire of STIVORO (the Dutch anti-smoking association). We also performed a formative evaluation of the intervention program., Results: During our study 1121 women gave birth after a complicated pregnancy. 490 Women were eligible for the study of which 240 women (49%) gave informed consent to participate. 56 Women (23%) were lost-to-follow-up, leaving 186 women for the analysis. Between 6 and 13 months postpartum saturated fat-intake was significantly reduced by 3.6g/day (95%>CI 1.8-5.4) in cases compared to controls. Exercise was improved in cases compared to controls, but it did not reach significance (277 MET's (-2699-3254)). Although smoking decreased from 14.5% to 10.4% in cases, it was not significant and comparable to the decrease in controls (15.0% to 8.4%). The formative evaluation showed that the most important motivator to improve lifestyle was the increased risk of future cardiovascular and metabolic disease (70%) and the increased risk for recurrence in a next pregnancy (57%). Main barriers were an already busy life (40%), distance (35%) and duration (38%) of travelling to the hospital and to early postpartum to pay attention to lifestyle (26%)., Conclusion: Lifestyle intervention after complicated pregnancy may be effective in improving saturated fat-intake. Other interventions, specially aimed at postpartum women, are needed to improve exercise and smoking habits. More research is needed to develop lifestyle intervention program specifically aimed at these women. New possibilities of multimedia are promising., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Blood pressure levels during pregnancy are important risk factors for gestational hypertensive disorders. Non-pregnant women from ethnic minority groups are found to have higher blood pressure levels compared to white women. Little is known about variation in blood pressure development during pregnancy across different ethnic groups., Objectives: To investigate ethnic differences in blood pressure levels in each trimester of pregnancy and the risk of gestational hypertensive disorders and the degree to which such differences can be explained by education and lifestyle related factors., Methods: The study included 6215 women participating in a population-based prospective cohort study from early pregnancy onwards in Rotterdam, The Netherlands. Ethnicity was assessed at enrolment. Blood pressure was measured in each trimester. Information about gestational hypertensive disorders was available from medical records. Lifestyle factors included smoking, alcohol, caffeine intake, folic acid supplementation, sodium and energy intake, body mass index and maternal stress. Associations and explanatory pathways were investigated using linear and logistic regression analysis., Results: Dutch pregnant women had higher systolic blood pressure levels as compared to women in other ethnic groups in each trimester of pregnancy. Compared to Dutch women, Turkish and Moroccan women had lower diastolic blood pressure levels in each trimester. These differences remained after adjusting for education and lifestyle factors. Turkish and Moroccan women had a lower risk of gestational hypertension as compared to Dutch women (OR 0.32; 95% CI: 0.18, 0.58 and OR 0.28; 95% CI: 0.14, 0.58) and Cape Verdean women had an elevated risk of preeclampsia (OR 2.22; 95% CI: 1.22, 4.07). Differences could not be explained by education or lifestyle., Conclusion: Substantial ethnic differences were observed in blood pressure levels in each trimester of pregnancy and risk of gestational hypertensive disorders. A wide range of potential explanatory variables could not explain these differences., (Copyright © 2012. Published by Elsevier B.V.)

Introduction: Women with a pregnancy complicated by preeclampsia, intra-uterine growth restriction and/or gestational diabetes are at increased risk of future cardiovascular and metabolic disease. Lifestyle intervention may help these women to effectively lower these risks., Objectives: To test if offering lifestyle intervention after a complicated pregnancy significantly reduces weight (primary objective) and/or other cardiovascular and metabolic risk factors (secondary objective)., Methods: The Pro-Active study (Postpartum Rotterdam Appraisal of Cardiovascular health and Tailored Intervention) is a feasibility study to develop and evaluate a postpartum lifestyle intervention program. In a prospective case-control setting we tested the effect of the lifestyle intervention. Women were included between April 2007 and August 2009. They were eligible if ⩾18 years old at time of inclusion, being able to understand and speak the Dutch language and not having pre-existing conditions that could interfere with the lifestyle intervention. Cases were offered lifestyle intervention by a trained counsellor between 6 and 10 months postpartum. During 3 private sessions, mainly exercise and fat-intake and to some extend smoking habits were discussed and aims were made to improve lifestyle. Controls did not receive these sessions, but were not restricted to improve lifestyle on their own. Anthropometric and laboratory measurements were taken at 6 and 10 months postpartum and again at 13 months postpartum to test for durability of the effects., Results: During our study 1121 women gave birth after a complicated pregnancy. Four hundred and ninety Women were eligible for the study of which 240 women (49%) gave informed consent to participate. 56 Women (23%) were lost-to-follow-up, leaving 186 women for the analysis. Between 6 and 13 months postpartum weight was significantly reduced in cases compared to controls by 2.1kg (95%>CI 0.4-3.7), resulting in a 0.7kg/m(2) (0.1-1.3) lower BMI. Also systolic blood pressure (5.0mmHg(0.3-9.7)), waist circumference (4.6cm(2.6-6.6)) and waist-to-hip ratio (0.03(0.01-0.04)) were significantly improved in cases compared to controls. Heart rate, hip circumference and total cholesterol were significantly improved within cases, but not compared to controls. Diastolic blood pressure and fasting glucose were not improved., Conclusion: Lifestyle intervention after complicated pregnancy may be effective in lowering weight and improving other cardiovascular and metabolic risk factors. It suggests that now is prudent and justified to start a large-scale randomised controlled trial to validate our results., (Copyright © 2012. Published by Elsevier B.V.)

Background and Aims: Maternal hyperglycaemia and hyperhomocysteinaemia are risk factors for congenital heart disease (CHD). These metabolic derangements and deranged lipid levels are associated with adult cardiovascular disease. We examined whether maternal lipid levels are associated with the risk of CHD offspring., Methods and Results: From 2003 onwards, a case-control study was conducted. Participants were mothers of children with (n = 261) and without (n = 325) CHD. At around 16 months after the index-pregnancy, maternal lipid levels were determined. Maternal characteristics and lipid levels were compared by Student's t-test. In a multivariable logistic regression model, risk estimates were calculated for associations between CHD and lipid levels. Adjustments were made for maternal age, diabetes, ethnicity, body mass index (BMI), parity, periconception folic acid use and total homocysteine levels. Outcome measures are presented in (geometric) means (p5-p95) and odds ratios (ORs) with 95% confidence intervals (CIs). Case mothers showed higher cholesterol (4.9 vs. 4.7 mmol l(-1), P < 0.05), low-density lipoprotein (LDL)-cholesterol (3.2 vs. 3.0 mmol l(-1), P < 0.05), apolipoprotein B (84.0 vs. 80.0 mg dl(-1), P < 0.01) and homocysteine (10.8 vs. 10.2 μmol l(-1), P < 0.05) than controls. LDL-cholesterol above 3.3 mmol l(-1) (OR 1.6 (95%CI, 1.1-2.3)) and apolipoprotein B above 85.0 mg dl(-1) were associated with an almost twofold increased CHD risk (OR 1.8 (95%CI, 1.2-2.6)). This was supported by elevated CHD risks per unit standard deviation increase in cholesterol (OR 1.2 (95% CI 1.03-1.5)), LDL-cholesterol (OR 1.3 (95%CI, 1.1-1.6) and apolipoprotein B (OR 1.3 (95% CI 1.1-1.6)). Apolipoprotein B was most strongly associated with CHD risk., Conclusion: A mildly deranged maternal lipid profile is associated with an increased risk of CHD offspring., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: To investigate associations between early pregnancy homocysteine, folate and vitamin B12 concentrations and placental weight, birthweight and adverse pregnancy outcomes., Design: Population-based birth cohort study., Setting: Rotterdam, the Netherlands., Population: Cohort of 5805 pregnant women., Methods: To analyse homocysteine, folate and vitamin B12 concentrations, blood was drawn in early pregnancy. These concentrations were divided into quintiles. Information on birth outcomes was retrieved from medical records. Multivariate regression analyses were used., Main Outcome Measures: Placental weight, birthweight, small for gestational age at birth (SGA) (<5th centile), prematurity and pre-eclampsia., Results: High homocysteine concentrations (highest quintile) were associated with lower placental weight (difference 30 g; P < 0.001) and birthweight (difference 110 g; P < 0.001), and increased risk of SGA [odds ratio (OR) 1.7; P = 0.006] compared with lowest quintile (reference). Low folate concentrations (lowest quintile) were associated with lower placental weight (difference 26 g; P = 0.001) and birthweight (difference 125 g; P < 0.001), and increased risks of SGA (OR 1.9; P = 0.002), prematurity (OR 2.2; P = 0.002) and pre-eclampsia (OR 2.1; P = 0.04) compared with highest quintile (reference). The risk of developing SGA and pre-eclampsia was substantially higher in women who had higher homocysteine and lower folate concentrations. No associations were found with vitamin B12., Conclusions: Higher homocysteine and lower folate concentrations in early pregnancy are associated with lower placental weight and birthweight, and higher risk of adverse pregnancy outcomes. These findings suggest that high homocysteine and low folate concentrations in early pregnancy may adversely influence placentation and subsequently affect the success of pregnancy and birth outcomes., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

Objective: To study regional differences in maternal mortality in the Netherlands., Design: Confidential inquiry into the causes of maternal mortality., Setting: Nationwide., Population: A total of 3 108 235 live births and 337 maternal deaths., Methods: Data analysis of all maternal deaths in the period 1993-2008., Main Outcome Measure: Maternal mortality., Results: The overall national maternal mortality ratio was 10.8 per 100 000 live births. In the 12 provinces of the Netherlands, the maternal mortality ratio ranged from 6.2 in Noord Brabant to 16.3 per 100 000 live births in Zeeland. In the four largest cities, maternal mortality varied from 9.3 in Amsterdam to 21.0 in Rotterdam. At a national level, the most frequent direct cause was pre-eclampsia. Increased risks for maternal mortality were found for women living in deprived neighbourhoods (RR 1.41), women from non-Western origin (RR 1.59), and women who were 35 years or older (RR 1.61)., Conclusion: There are significant variations in maternal mortality ratios in the Netherlands between cities, provinces, and neighbourhoods. In addition, higher maternal mortality was observed in women of non-Western origin and in women who were 35 years of age or older., (© 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.)

In most Western countries, information on prenatal screening for Down syndrome is provided in the first-trimester of pregnancy. The purpose of this study was to examine whether this information should additionally be provided before pregnancy to improve the informed decision-making process. In an empirical study, we obtained data from pregnant women with respect to their preferences regarding information on prenatal screening preconceptionally. Questionnaire data (n = 510) showed that 55.7% of responding women considered participating in prenatal screening for Down syndrome before pregnancy. 28.0% of women possessed information on prenatal screening preconceptionally. 84.6% preferred not to receive information preconceptionally in retrospect. In an ethical analysis, we elaborated on these preferences by weighing pros and cons. We considered two arguments against the provision of information on prenatal screening preconceptionally: women's preference to receive information in a step-by-step manner, and the risk of providing a directive message. We identified three reasons supporting its provision preconceptionally: the likelihood of making an informed decision could, firstly, be increased by "unchaining" the initial information from possible subsequent decisions, and, secondly, by providing women sufficient time to deliberate. Thirdly, the probability of equal access to prenatal screening may increase. To conclude with, we propose to incorporate an information offer on prenatal screening for Down syndrome in preconception care consultations. By offering information, instead of providing information, prospective parents are enabled to either accept or decline the information, which respects both their right to know and their right not-to-know., (Copyright © 2012 Wiley Periodicals, Inc.)

Fat mass and obesity-associated (FTO) gene variants are associated with childhood and adult obesity; however, the influence of FTO polymorphisms on foetal growth is unknown. Associations between the FTO variant rs9939609 and the foetal growth trajectories, maternal pregnancy weight gain, anthropometric measures at birth and body mass index (BMI) at age 14 years were assessed in 1079 singleton-birth Australian Caucasians. Analyses were repeated in 3512 singleton-birth Dutch Caucasians. The rs9939609 obesity-risk AA genotype was associated with symmetrical intrauterine growth restriction; an effect reversed in mothers who smoked during pregnancy. The effect increased over time and was modified by maternal smoking for head circumference (P = 0.007), abdominal circumference (P = 0.007), femur length (P = 0.02) and estimated foetal weight (P = 0.001). The modification of the association between the AA genotype and birth anthropometrics by maternal smoking was consistent across birth weight (P = 0.01) and birth length (P = 0.04) and neonatal day 2 anthropometry. Consistent associations were replicated in the Generation R cohort. Maternal pregnancy weight gain matched the pattern of birth weight and was independent of placental weight. In adolescents, the AA genotype was associated with increased BMI-adjusted-for-age in males (P = 0.00009), but no effect was detected in females. A variant in the FTO gene influences foetal growth trajectories in the third trimester, early postnatal growth and adiposity in adolescence. Maternal smoking during pregnancy reversed the direction of association of rs9939609 on foetal growth, which was probably mediated by maternal energy intake. The detection of genetic variants associated with foetal growth has the potential to identify novel molecular mechanisms underlying growth and targeted early life intervention.

Objective: To determine the incidence of maternal deaths attributable to vascular dissection and rupture in the Netherlands, and to assess clinical features, risk factors and the frequency of substandard care in the cases identified., Design: Confidential enquiry into the causes of maternal deaths., Setting: Nationwide in the Netherlands., Population: A total of 3,108,235 live births., Methods: Data analysis of all cases of maternal death from vascular dissection and rupture in the period 1993-2008. A literature review was also performed., Main Outcome Measures: Incidence, clinical features, risk factors and frequency of substandard care., Results: A total of 23 maternal deaths attributable to vascular dissection and rupture were reported. In most cases the location was aortic (n=13), followed by coronary (n=4) and splenic (n=3) arteries. Clinical features were various, but most women presented with sudden unexplainable pain. Risk factors were present in 14 cases (61%), with hypertension being most frequently reported in ten cases (43%). Substandard care was determined to have been received in 13 cases (56%), inadequate assessment of complaints and a delay in diagnosis being the most frequent problems identified., Conclusions: Vascular dissection and rupture in pregnancy, although rare, carry a high risk of maternal and fetal morbidity and mortality. Because of the rarity of this condition and its variety in presentation, diagnosis is easily missed. A high index of suspicion when a woman presents with suggestive complaints, leading to an early diagnosis, may improve the prognosis for the woman and her child., (© 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.)

Objective: To determine the content of decision-relevant knowledge needed for informed decision-making about (non-) participation in prenatal screening for Down's syndrome (DS), in order to develop a knowledge questionnaire for routine application in large-scale programme evaluations., Methods: A generic list of content domains for knowledge about screening was extracted from the literature. Items reflecting specific knowledge domains were constructed. An expert group of professionals and pregnant women expressed whether domains and items represented decision-relevant information., Results: All presented domains were scored as (very) important. Options when receiving an 'increased probability for DS' test result, the meaning of this result, the aim of the screening, and voluntary nature of the test were scored as most important. The condition being screened for, prevalence, and the screening procedure were scored as relatively less important, with a high amount of expert consensus., Conclusion: A knowledge measure for prenatal screening for DS was developed, based on domains and items acquired by expert consensus., Practice Implications: This measure of decision-relevant knowledge can be used in routine, large-scale evaluations of the procedure for offering information about prenatal screening for DS., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Reproductive health has improved little in the last few decades. The Netherlands, particularly in large cities, has relatively high perinatal death rates compared with other European countries. Lack of improvement in reproductive outcomes despite improved quality of and better access to prenatal care strongly suggests that prenatal care alone is insufficient. We discuss how preconception care offers new strategies for improving reproductive health, how it usefully connects the life course of the affected individual and many health-care disciplines, and the benefits of combining a top-down policy structure and bottom-up organisation around caregivers. Given the likely benefits and cost savings calculated for The Netherlands, we conclude that failing to facilitate preconception care would reflect a breakdown of both professional and governmental responsibilities.

Background: There are physiological reasons for the effects of positioning on hemodynamic variables and cardiac dimensions related to altered intra-abdominal and intra-thoracic pressures. This problem is especially evident in pregnant women due to the additional aorto-caval compression by the enlarged uterus. The purpose of this study was to investigate the effect of postural changes on cardiac dimensions and function during mid and late pregnancy using cardiovascular magnetic resonance (CMR)., Methods: Healthy non-pregnant women, pregnant women at 20th week of gestation and at 32nd week of gestation without history of cardiac disease were recruited to the study and underwent CMR in supine and left lateral positions. Cardiac hemodynamic parameters and dimensions were measured and compared between both positions., Results: Five non-pregnant women, 6 healthy pregnant women at mid pregnancy and 8 healthy pregnant women at late pregnancy were enrolled in the study. In the group of non-pregnant women left ventricular (LV) cardiac output (CO) significantly decreased by 9% (p=0.043) and right ventricular (RV) end-diastolic volume (EDV) significantly increased by 5% (p=0.043) from the supine to the left lateral position. During mid pregnancy LV ejection fraction (EF), stroke volume (SV), left atrium lateral diameter and left atrial supero-inferior diameter increased significantly from the supine position to the left lateral position: 8%, 27%, 5% and 11%, respectively (p<0.05). RV EDV, SV and right atrium supero-inferior diameter significantly increased from the supine to the left lateral position: 25%, 31% and 13% (p<0.05), respectively. During late pregnancy a significant increment of LV EF, EDV, SV and CO was observed in the left lateral position: 11%, 21%, 35% and 24% (p<0.05), respectively. Left atrial diameters were significantly larger in the left lateral position compared to the supine position (p<0.05). RV CO was significantly increased in the left lateral position compared to the supine position (p<0.05)., Conclusions: During pregnancy positional changes affect significantly cardiac hemodynamic parameters and dimensions. Pregnant women who need serial studies by CMR should be imaged in a consistent position. From as early as 20 weeks the left lateral position should be preferred on the supine position because it positively affects venous return, SV and CO.

Background: Chromosome segregation errors during human oocyte meiosis are associated with low fertility in humans and the incidence of these errors increases with advancing maternal age. Studies of mitosis and meiosis suggest that defective remodeling of chromatin plays a causative role in aneuploidy. We analyzed the histone deacetylation pattern during the final stages of human oocyte maturation to investigate whether defective epigenetic regulation of chromatin remodeling in human oocytes is related to maternal age and leads to segregation errors., Methods: Human surplus oocytes of different meiotic maturation stages [germinal vesicle (GV), metaphase (M)I and MII] were collected from standard IVF/ICSI treatments. Oocytes were analyzed for acetylation of different lysines of histone 4 (H4K5, H4K8, H4K12 and H4K16) and for α-tubulin., Results: Human GV oocytes had an intense staining of the chromatin for all four histone 4 lysine acetylations. MI and MII stage oocytes showed either normal deacetylation or various amounts of defective histone deacetylation. Residual H4K12 acetylation was more frequently found in oocytes obtained from older women, with a significant correlation between defective deacetylation and maternal age (r = 0.185, P = 0.007). Eighty-eight percent of the oocytes with residual acetylation had misaligned chromosomes, whereas only 33% of the oocytes that showed correct deacetylated chromatin had misaligned chromosomes (P < 0.001)., Conclusions: We conclude that defective deacetylation during human female meiosis increases with maternal age and is correlated with misaligned chromosomes. As chromosome misalignment predisposes to segregation errors, our data imply that defective regulation of histone deacetylation could be an important factor in age-related aneuploidy.

Objective: To examine the association between maternal age and birth outcomes, and to investigate the role of sociodemographic and lifestyle-related determinants., Design: Population-based prospective cohort study from early pregnancy onwards., Setting: Rotterdam, the Netherlands., Population: A cohort of 8568 mothers and their children., Methods: Maternal age was assessed at enrolment. Information about sociodemographic (height, weight, educational level, ethnicity, parity) and lifestyle-related determinants (alcohol consumption, smoking habits, folic acid supplement use, caffeine intake, daily energy intake) and birth outcomes was obtained from questionnaires and hospital records. Multivariate linear and logistic regression analyses were used., Main Outcomes Measures: Birthweight, preterm delivery, small-for-gestational-age, and large-for-gestational-age., Results: As compared with mothers aged 30-34.9 years, no differences in risk of preterm delivery were found. Mothers younger than 20 years had the highest risk of delivering small-for-gestational-age babies(OR 1.6, 95% CI: 1.1-2.5); however, this increased risk disappeared after adjustment for sociodemographic and lifestyle-related determinants. Mothers older than 40 years had the highest risk of delivering large-for-gestational-age babies (OR 1.3, 95% CI: 0.8-2.4). The associations of maternal age with the risks of delivering large-for-gestational-age babies could not be explained by sociodemographic and lifestyle-related determinants., Conclusions: As compared with mothers aged 30-34.9 years, younger mothers have an increased risk of small-for-gestational-age babies, whereas older mothers have an increased risk of large-for-gestational-age babies. Sociodemographic and lifestyle-related determinants cannot fully explain these differences., (© 2011 The Authors Journal compilation © RCOG 2011 BJOG An International Journal of Obstetrics and Gynaecology.)

Objective: To investigate the influence of maternal working conditions on fertility and pregnancy outcomes., Methods: 8880 women were enrolled in a large prospective birth cohort during early (76%), mid (21%) or late pregnancy (3%) (61% participation). Complete questionnaire information was available for 6302 women (71% response). Outcomes were prolonged time to pregnancy (TTP) (> 6 months), preterm birth (< 37 weeks) and decreased birth weight (< 3000 g). Self-reported exposure to chemical agents was based on a limited list of chemicals. Physical load questions concerned manual materials handling, prolonged sitting and long periods of standing. A job-exposure matrix (JEM) linked reported job title to workplace chemical exposure within jobs according to expert judgement. Associations between maternal occupational exposure and fertility and pregnancy outcomes, adjusted for age, education, minority, parity, smoking and alcohol use, were studied using logistic regression analysis., Results: Women in jobs with regular handling of loads ≥ 5 kg had better fertility and pregnancy outcomes. No self-reported exposure to chemicals was associated with any outcomes and self-assessments had very low reliability compared with JEM-based assessments. JEM-based maternal occupational exposure to phthalates was associated with prolonged TTP (OR 2.16, 95% CI 1.02 to 4.57) and exposure to pesticides was associated with decreased birth weight (OR 2.42, 95% CI 1.10 to 5.34). The population attributable fractions were small at 0.7% for phthalates and 0.7% for pesticides., Conclusion: This birth cohort study presents evidence of health-based selection into the workforce and adverse effects of maternal occupational exposure to phthalates and pesticides on fertility and pregnancy outcomes.

Because of changes in the society, couples in Western countries are increasingly delaying reproduction. This is accompanied by unhealthy lifestyles that may be detrimental not only to general health but also to reproductive capacity. It is well known that maternal age has detrimental effects on fertility; the paternal influence on this outcome is largely unknown. This study aims to investigate associations between a paternal age below 60 years, lifestyles, and sperm quality. In a periconceptional prospective cohort study we included 227 men undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Age at sperm collection, lifestyles, cause of subfertility, ethnicity, sperm DNA fragmentation index (DFI; as marker of sperm DNA damage), and sperm parameters were determined. Linear regression analyses showed a positive association between a rising age from 26 to 59 years and DFI (P ≤ .01) and an inverse association with ejaculate volume (P ≤ .05). Inverse associations were determined between DFI and all conventional sperm parameters (all P ≤ .01). There were no associations between smoking, alcohol use, body mass index, and DFI and sperm parameters. Dutch men compared to migrants, however, showed a higher DFI (P ≤ .05) independent of lifestyles. We conclude that the trend of delaying fatherhood in men undergoing IVF or ICSI treatment is detrimental to sperm quality.

Background and Aims: Periconception folic acid supplementation may influence early placentation processes and thereby the occurrence of hypertensive pregnancy disorders. For this reason we examined the associations between periconception folic acid supplementation and uteroplacental vascular resistance, blood pressure, and the risks of gestational hypertension and preeclampsia, in 5993 pregnant women, participating in a population-based cohort study., Methods and Results: Folic acid supplementation was assessed by questionnaire. Mean pulsatility index (PI) and resistance index (RI) of the uterine (UtA) and umbilical arteries (UmA) were measured by Doppler ultrasound in mid- and late pregnancy. Systolic and diastolic blood pressures (SBP, DBP) were measured in early, mid- and late pregnancy. Compared to women who did not use folic acid, preconception folic acid users had a slightly lower UtA-RI in mid-pregnancy [β -0.02, 95% confidence interval (CI) -0.03, -0.01] and late pregnancy [β -0.02, 95% CI -0.03, -0.001], a lower UtA-PI in mid-pregnancy [β -0.06, 95% CI -0.1, -0.03] and late pregnancy [β -0.03, 95% CI -0.05, -0.01], as well as tendencies towards a lower UmA-PI in mid-pregnancy [β -0.02, 95% CI -0.04, -0.001] and late pregnancy [β -0.01, 95% CI -0.02, 0.01]. Additionally, these women had slightly higher SBP and DBP throughout pregnancy. Neither the patterns of blood-pressure change during pregnancy, nor the risk of gestational hypertension and preeclampsia differed between the folic acid categories., Conclusion: Periconception folic acid supplementation is associated with lower uteroplacental vascular resistance and higher blood pressures during pregnancy. The effects are small and within physiologic ranges and seem not associated with the risk of hypertensive pregnancy disorders., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Background: Because breastfeeding is the best method of infant feeding, groups at risk of low breastfeeding rates should be identified. Therefore, this study compared breastfeeding patterns of ethnic minority groups in The Netherlands with those of native mothers and established how they were influenced by generational status and socio-demographic determinants of breastfeeding., Methods: We used data on 2914 Dutch, 366 Mediterranean first-generation, 143 Mediterranean second-generation, 285 Caribbean first-generation and 140 Caribbean second-generation mothers. Information on starting breastfeeding and breastfeeding at 2 and 6 months after birth were obtained from questionnaires during the first year after birth., Results: Overall, 90.6% of women started breastfeeding after delivery. This percentage was lowest among the native Dutch (89.1%) and highest among the Mediterranean second-generation women (98.6%; p<0.001). At 6 months postpartum, 30.6% of mothers were still breastfeeding, ranging from 19.3% in the Caribbean second-generation mothers to 42.6% in first-generation Mediterranean mothers. After adjustment for covariates, more non-native mothers started breastfeeding than native Dutch mothers. While Mediterranean first-generation mothers had higher breastfeeding rates at 6 months (OR: 2.71, 95% CI: 2.09 to 3.51), there were no differences in Mediterranean second-generation and Caribbean mothers compared to native Dutch mothers., Conclusion: More non-native mothers started breastfeeding than native mothers, but relative fewer continued. Although both native Dutch and non-native mothers had low continuation rates, ethnic minorities may face other difficulties in continuing breastfeeding than native women.

Objective:   To examine whether specific pregnancy and delivery complications are risk factors for postpartum depression., Design:   A prospective longitudinal study., Setting:  Rotterdam, the Netherlands., Population:  A cohort of 4941 pregnant women who enrolled in the Generation R Study., Methods:   Information on perinatal complications was obtained from the midwife and hospital registries or by questionnaire. Logistic regression analyses were used to calculate the risk of postpartum depression for the separate perinatal complications., Main Outcome Measures: Postpartum psychiatric symptoms were assessed 2 months after delivery using the Edinburgh postnatal depression scale., Results:  Several perinatal complications were significantly associated with postpartum depression, namely: pre-eclampsia (adjusted OR, aOR 2.58, 95% CI 1.30-5.14), hospitalization during pregnancy (aOR 2.25, 95% CI 1.19-4.26), emergency caesarean section (aOR 1.53, 95% CI 1.02-2.31), suspicion of fetal distress (aOR 1.56, 95% CI 1.08-2.27), a medically indicated delivery provided by an obstetrician (aOR 2.43, 95% CI 1.56-3.78), and hospital admission of the baby (aOR 1.45, 95% CI 1.10-1.92). Unplanned pregnancy, thrombosis, meconium-stained amniotic fluid, and Apgar score were not associated with postpartum depression after adjustment for confounding factors, such as pre-existing psychopathological symptoms and sociodemographic characteristics. The risk of postpartum depression increased with the number of perinatal complications women experienced (P < 0.001)., Conclusions:  We showed that several pregnancy and delivery complications present a risk for women's mental health in the postpartum period. Obstetricians, midwives, general practitioners, and staff at baby well clinics should be aware that women who experienced perinatal complications-especially those with a number of perinatal complications-are at risk for developing postpartum depression.

Background: For normal fetal growth and development a well-developed chorionic villous vascularization is essential., Aim: The aim of this study is to investigate whether idiopathic second trimester fetal loss is associated with an underdeveloped chorionic villous vascularization., Methods: 38 placentas after late miscarriage, classified as idiopathic fetal loss (IFL, n=16) or as fetal loss due to intrauterine infection (IUI, n=22) were collected. After CD34 immunohistochemical staining the villous stromal area, number of villous vessels, vascular area and vascular area density (central, peripheral and total) were measured in randomly selected immature intermediate villi., Results: The mean gestational age was 19+4 weeks for the IFL group and 20+6 weeks for the IUI group. After controlling for gestational age, we found no differences in fetal weight, placental weight, villous stromal area, number of vessels and central vascular features. The mean peripheral vascular area and peripheral vascular area density were, after adjusting for gestational age, reduced in the IFL group., Conclusion: Idiopathic second trimester fetal loss is associated with a reduced peripheral chorionic villous vascularization. We hypothesize that in these cases, placentation is already disturbed in first trimester of pregnancy, leading to a reduced materno-fetal interface in second trimester, thus to early postplacental fetal hypoxia and fetal death., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Objective: To assess causes, trends and substandard care factors in maternal mortality in the Netherlands. Design Confidential enquiry into the causes of maternal mortality., Setting: Nationwide in the Netherlands., Population: 2,557,208 live births., Methods: Data analysis of all maternal deaths in the period 1993-2005., Main Outcome Measures: Maternal mortality., Results: The overall maternal mortality ratio was 12.1 per 100 000 live births, which was a statistically significant rise compared with the maternal mortality ratio of 9.7 in the period 1983-1992 (OR 1.2, 95% CI 1.0-1.5). The most frequent direct causes were (pre-)eclampsia, thromboembolism, sudden death in pregnancy, sepsis, obstetric haemorrhage and amniotic fluid embolism. The number of indirect deaths also increased, mainly caused by an increase in cardiovascular disorders (OR 2.5, 95% CI 1.4-4.6). Women younger than 20 years and older than 45 years, those with high parity or from nonwestern immigrant populations were at higher risk. Most substandard care was found in women with pre-eclampsia (91%) and in immigrant populations (62%)., Conclusions: Maternal mortality in the Netherlands has increased since 1983-1992. Pre-eclampsia remains the number one cause. Groups at higher risk for complications during pregnancy should be better identified early in pregnancy or before conception, in order to receive preconception advice and more frequent antenatal visits. There is an urgent need for the better education of women and professionals concerning the danger signs, and for the training of professionals in order to improve maternal health care.

Background/objectives: Riboflavin is a cofactor for the 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme involved in the homocysteine pathway. The aim of this study was to investigate the effects of maternal riboflavin intake and two MTHFR polymorphisms (677C>T; Ala222Val and 1298A>C; Glu429Ala substitutions) on the biomarkers of the homocysteine pathway, and investigate the risk of having offspring with an orofacial cleft (OFC)., Subjects/methods: In a case-control study design, dietary riboflavin intake and the MTHFR 677C>T and 1298A>C polymorphisms were evaluated in 123 OFC and 108 control mothers by using food frequency questionnaires and blood samples. Homocysteine (tHcy), folate and vitamin B12 concentrations in blood were analyzed in 70 cases and 68 controls. Linear and logistic regression analyses were applied., Results: At 14 months postpartum riboflavin intake and MTHFR 677C>T and 1298A>C genotypes were not significantly different between cases and controls. The 677TT genotype showed lower folate concentrations compared to C-allele carriers with a mean difference of 2.8 nmol/l in serum and 174 nmol/l in red blood cell (both P's=0.01). Every mg per day increase of dietary riboflavin intake was positively associated with increase in vitamin B12 concentration by 52.1% (P<0.01). This effect was most pronounced in MTHFR 677TT homozygotes (205.1%, P=0.03). The riboflavin-adjusted MTHFR 677TT and 1298CC genotypes showed a trend toward an increasing risk for OFC, adjusted odds ratio 1.7 (confidence interval (95% CI), 0.7-4.5) and 1.6 (95% CI, 0.7-4.2), respectively., Conclusions: Maternal riboflavin intake is significantly associated with biomarkers of the homocysteine pathway, with the strongest effects in MTHFR 677TT homozygotes. The maternal risk of having OFC offspring, however, is not associated with dietary riboflavin intake.

Aim: Validation of a self-administered Internet questionnaire for preconception risk assessment., Methods: Women with an appointment at the outpatient clinics for preconception care or fertility at the Erasmus Medical Center Rotterdam were requested to fill out the online questionnaire prior to attendance. Subsequently, the items of the questionnaire were verified by history taking during the first or next appointment. Agreement between the 2 screening methods (Internet vs. history taking) was calculated using Kappa statistic., Results: Most lifestyle variables, including smoking, alcohol, and dietary items, showed a good to high level of agreement when compared to the interview. Most medical history and obstetric history items also showed a good to high level of agreement. The use of over-the-counter drugs revealed a poor level of agreement (Kappa = 0.21). The items pertaining to women's family history showed a reasonable level of agreement; however, the partner's family history was unreliable and should be checked at the interview., Conclusion: The online questionnaire www.zwangerwijzer.nl is a useful tool for the identification of a number of potential risk factors in the preconception care setting and was found to be a an efficient and clear screening instrument by the majority of women. However, additional history taking by trained professionals is necessary to verify several items and to further explore identified risk factors for an adverse pregnancy outcome., (Copyright 2009 S. Karger AG, Basel.)

Current methods for pregnancy diagnostics are based on immunodetection of pregnancy-specific proteins and in a forensic context suffer from sensitivity and specificity issues. Here, we applied reverse transcriptase polymerase chain reaction (RT-PCR) technology to 11 genes previously reported with placental mRNA circulating in maternal blood. We found two genes, hPL and betahCG, with pregnancy-specific expression in whole blood samples. RT-PCR detection of hPL was positive in all samples tested throughout the pregnancy, whereas betahCG was detectable until half of the second trimester but not at later gestation ages. For hPL, in vitro stability of the transcript was demonstrated until 2 months of age, and the hPL-specific RT-PCR assay applied was highly sensitive with reliable detection from down to 0.25 cm(2) dried bloodstain. We therefore suggest hPL-specific RT-PCR as a new molecular tool for forensic pregnancy diagnostics from dried blood stains. Moreover, our results indicate that the time-wise reverse expression of hPL and betahCG during pregnancy may allow an RT-PCR-based estimation of the gestational age from blood stains, adding to the value of forensic pregnancy diagnosis for crime scene investigations.

Hematopoietic stem cells (HSCs) are responsible for the life-long production of the blood system and are pivotal cells in hematologic transplantation therapies. During mouse and human development, the first HSCs are produced in the aorta-gonad-mesonephros region. Subsequent to this emergence, HSCs are found in other anatomical sites of the mouse conceptus. While the mouse placenta contains abundant HSCs at midgestation, little is known concerning whether HSCs or hematopoietic progenitors are present and supported in the human placenta during development. In this study we show, over a range of developmental times including term, that the human placenta contains hematopoietic progenitors and HSCs. Moreover, stromal cell lines generated from human placenta at several developmental time points are pericyte-like cells and support human hematopoiesis. Immunostaining of placenta sections during development localizes hematopoietic cells in close contact with pericytes/perivascular cells. Thus, the human placenta is a potent hematopoietic niche throughout development.

BACKGROUND This study investigates whether dietary patterns, substantiated by biomarkers, are associated with semen quality. METHODS In 161 men of subfertile couples undergoing in vitro fertilization treatment in a tertiary referral clinic in Rotterdam, the Netherlands, we assessed nutrient intakes and performed principal component factor analysis to identify dietary patterns. Total homocysteine (tHcy), folate, vitamin B12 and B6 were measured in blood and seminal plasma. Semen quality was assessed by sperm volume, concentration, motility, morphology and DNA fragmentation index (DFI). Linear regression models analyzed associations between dietary patterns, biomarkers and sperm parameters, adjusted for age, body mass index (BMI), smoking, vitamins and varicocele. RESULTS The 'Health Conscious' dietary pattern shows high intakes of fruits, vegetables, fish and whole grains. The 'Traditional Dutch' dietary pattern is characterized by high intakes of meat, potatoes and whole grains and low intakes of beverages and sweets. The 'Health Conscious' diet was inversely correlated with tHcy in blood (beta = -0.07, P = 0.02) and seminal plasma (beta = -1.34, P = 0.02) and positively with vitamin B6 in blood (beta = 0.217, P = 0.01). An inverse association was demonstrated between the 'Health Conscious' diet and DFI (beta = -2.81, P = 0.05). The 'Traditional Dutch' diet was positively correlated with red blood cell folate (beta = 0.06, P = 0.04) and sperm concentration (beta = 13.25, P = 0.01). CONCLUSIONS The 'Health Conscious' and 'Traditional Dutch' dietary pattern seem to be associated with semen quality in men of subfertile couples.

First trimester human villous vascularization is mainly studied by conventional two-dimensional (2D) microscopy. With this (2D) technique it is not possible to observe the spatial arrangement of the haemangioblastic cords and vessels, transition of cords into vessels and the transition of vasculogenesis to angiogenesis. The Confocal Laser Scanning Microscopy (CLSM) allows for a three-dimensional (3D) reconstruction of images of early pregnancy villous vascularization. These 3D reconstructions, however, are normally analyzed on a 2D medium, lacking depth perception. We performed a descriptive morphologic study, using an immersive Virtual Reality system to utilize the full third dimension completely. This innovative 3D technique visualizes 3D datasets as enlarged 3D holograms and provided detailed insight in the spatial arrangement of first trimester villous vascularization, the beginning of lumen formation within various junctions of haemangioblastic cords between 5 and 7 weeks gestational age and in the gradual transition of vasculogenesis to angiogenesis. This innovative immersive Virtual Reality system enables new perspectives for vascular research and will be implemented for future investigation.

Background: Although a low socioeconomic status has consistently been associated with an increased risk of preterm birth, little is known about the pathways through which socioeconomic disadvantage influences preterm birth., Aim: To examine mechanisms that might underlie the association between the educational level of pregnant women as an indicator of socioeconomic status, and preterm birth., Methods: The study was nested in a population-based cohort study in the Netherlands. Information was available for 3830 pregnant women of Dutch origin., Findings: The lowest-educated pregnant women had a statistically significant higher risk of preterm birth (odds ratio (OR) = 1.89 (95% CI 1.28 to 2.80)) than the highest educated women. This increased OR was reduced by up to 22% after separate adjustment for age, height, preeclampsia, intrauterine growth restriction, financial concerns, long-lasting difficulties, psychopathology, smoking habits, alcohol consumption, and body mass index (BMI) of the pregnant women. Joint adjustment for these variables resulted in a reduction of 89% of the increased risk of preterm birth among low-educated pregnant women (fully adjusted OR = 1.10 (95% CI 0.66 to 1.84))., Conclusions: Pregnant women with a low educational level have a nearly twofold higher risk of preterm birth than women with a high educational level. This elevated risk could largely be explained by pregnancy characteristics, indicators of psychosocial well-being, and lifestyle habits. Apparently, educational inequalities in preterm birth go together with an accumulation of multiple adverse circumstances among women with a low education. A number of explanatory mechanisms unravelled in the present study seem to be modifiable by intervention programmes.

Objective: To analyse the association between neighbourhood, ethnicity and adverse perinatal outcome in pregnant women from the 4 largest cities (Amsterdam, Rotterdam, The Hague and Utrecht; G4) and elsewhere in The Netherlands., Design: Descriptive, retrospective., Method: The perinatal outcome of 877,816 single pregnancies during the years 2002-2006, derived from The Netherlands Perinatal Registry, was analysed for the ethnicity (Western or non-Western) and the neighbourhood (deprived or not) of the pregnant women in the G4 and elsewhere in The Netherlands. Adverse perinatal outcome was defined as perinatal mortality, congenital abnormalities, intra-uterine growth restriction, preterm birth, Apgar score after 5 minutes < 7 and/or admission to a neonatal intensive-care unit., Results: The overall perinatal mortality rate was higher in the G4 than elsewhere in The Netherlands (11.1 per thousand versus 9.3 per thousand; p < 0.001; 95% confidence interval of the difference: 1.2-2.4 per thousand). The same was true for the sum of adverse perinatal outcomes (154.9 per thousand versus 138.9 per thousand). In the G4 the perinatal mortality among non-Western women was higher than among Western women (13.2 per thousand versus 9.5 per thousand). Residing in Dutch deprived neighbourhoods was associated with a higher perinatal mortality than outside deprived neighbourhoods (13.5 per thousand versus 9.3 per thousand). The relative risks of living in deprived neighbourhoods for adverse pregnancy outcomes are higher among Western than among non-Western women., Conclusion: Pregnant women in the G4 have an increased risk ofadverse perinatal outcomes. The risks of residing in a deprived neighbourhood are even higher, especially among Western women. The findings are important for new strategies to improve perinatal outcomes.