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Introduction Maternal elevated plasma total homocysteine (tHcy) is involved in the origin of several placenta-related pregnancy complications. The first trimester is the most sensitive period for placentation influenced by maternal and paternal health. The aim is to study associations between periconceptional parental tHcy levels and utero-placental growth trajectories in the first trimester of pregnancy. Methods Pregnant women and their partners were enrolled before 10 weeks of gestation in the Virtual Placenta study as subcohort of the Rotterdam periconception cohort (Predict study). A total of 190 women with a singleton pregnancy, of which 109 conceived naturally and 81 after IVF/ICSI treatment, were included. We measured serial utero-placental vascular volumes (uPVV) and placental volumes (PV) at 7, 9 and 11 weeks of gestation. First-trimester trajectories of PV were also measured in 662 pregnancies from the total Predict study. Results Comparing all participants of the virtual placenta study, no association between maternal tHcy and uPVV was observed. However, in IVF/ICSI pregnancies sub-analyses showed significantly negative associations between maternal tHcy in the 3rd and 4th quartile and uPVV trajectories (beta: −0.38 (95%CI -0.74 to −0.02) and beta: −0.42 (95% CI -0.78 to −0.05), respectively) with the 1st quartile as reference. Analysis in the total Predict cohort showed similar negative associations for the total study population. Discussion Periconceptional high maternal tHcy levels are associated with smaller placental growth trajectories depicted as PV and uPVV in the first trimester of pregnancy. The stronger negative associations with uPVV in IVF/ICSI pregnancies underline the need for further investigation.

Introduction: Impaired placental development is a major cause of fetal growth restriction (FGR) and early detection will therefore improve antenatal care and birth outcomes. Here we aim to investigate serial first-trimester ultrasound markers of utero-placental (vascular) development in association with embryonic and fetal growth. Methods: In a prospective cohort, we periconceptionally included 214 pregnant women. Three-dimensional power Doppler ultrasonography at 7, 9 and 11 weeks gestational age (GA) was used to measure placental volumes (PV) and basal plate surface area by Virtual Organ Computer-aided AnaLysis™, and utero-placental vascular volume (uPVV), crown-rump length (CRL) and embryonic volume (EV) by a V-scope volume rendering application. Estimated fetal weight (EFW) was measured by ultrasound at 22 and 32 weeks GA and birth weight percentile (BW) was recorded. Linear mixed models and regression analyses were applied and appropriately adjusted. All analyses were stratified for fetal sex. Results: PV trajectories were positively associated with CRL (βadj = 0.416, 95%CI:0.255; 0.576, p < 0.001), EV (βadj = 0.220, 95%CI:0.058; 0.381, p = 0.008) and EFW (βadj = 0.182, 95%CI:0.012; 0.352, p = 0.037). uPVV trajectories were positively associated with CRL (βadj = 0.203, 95%CI 0.021; 0.384, p = 0.029). In girls, PV trajectories were positively associated with CRL (p < 0.001), EV (p = 0.018), EFW (p = 0.026), and uPVV trajectories were positively associated with BW (p = 0.040). In boys, positive associations were shown between PV trajectories and CRL (p = 0.002), and between uPVV trajectories and CRL (p = 0.046). Discussion: First-trimester utero-placental (vascular) development is associated with embryonic and fetal growth, with fetal sex specific modifications. This underlines the opportunity to monitor first-trimester placental development and supports the associations with embryonic and fetal growth.

Research question: Does first-trimester maternal renin–angiotensin–aldosterone system (RAAS) activity determine early and late fetal growth and birthweight? Design: A total of 201 ongoing pregnancies, of which 104 were conceived naturally, seven following single intrauterine insemination (IUI), eight after IUI with ovulation induction and 82 after IVF or intracytoplasmic sperm injection treatment were selected from the Rotterdam Periconceptional Cohort. Renin, prorenin and aldosterone concentrations were determined in blood plasma at 9 and 11 weeks of gestational age. Serial crown–rump length and embryonic volume at 7, 9 and 11 weeks of gestational age were measured using virtual reality software to assess early fetal growth. Estimated fetal weight at 22 and 32 weeks of gestational age and birthweight were measured to assess late fetal growth trajectories. Pregnancy outcomes, small for gestational age (SGA) (z-scores –0.28, 95% CI –0.55 to –0.01, P=0.03), and an increased risk of SGA (1 corpus luteum versus pregnancies with 1 corpus luteum (betaz-scores –0.17, 95% CI –0.32 to –0.01, P=0.04). Conclusion: This study shows that excessive first-trimester prorenin release, resulting in angiotensin up-regulation, can explain why pregnancies with >1 corpus luteum are at risk for offspring with decreased birthweight and SGA. Simultaneously, high concentrations of aldosterone, independent of renin, seem to have a beneficial influence.

Research question: What is the association between the degree of a state of maternal vulnerability, determined by suboptimal periconceptional social, lifestyle and medical exposures and embryonic growth? Design: In total, 555 pregnancies, comprising 324 naturally conceived pregnancies and 231 pregnancies conceived after IVF and intracytoplasmic sperm injection (ICSI) were included from the Rotterdam Periconceptional Cohort (Predict Study) between November 2010 and August 2018. Data on periconceptional social, lifestyle and medical exposures, i.e. vulnerability markers, were collected through self-administered questionnaires. To estimate embryonic growth, crown–rump length (CRL) and embryonic volume measurements were taken at 7, 9 and 11 weeks of gestation using three-dimensional ultrasound scans and virtual reality techniques. Results: Exposure to two or more vulnerability markers was negatively associated with embryonic growth in naturally conceived pregnancies. The CRL and embryonic volume trajectories of embryos of women exposed to two vulnerability markers were reduced compared with those of women exposed to zero or one vulnerability marker (√CRL: β = –0.29 mm, 95% CI –0.56 to –0.02; 3√EV: β = –0.14 cm3, 95% CI –0.27 to –0.01). These associations were not found in pregnancies conceived after IVF or ICSI. Conclusions: This study showed that a higher degree of the periconceptional state of maternal vulnerability is associated with reduced embryonic growth (CRL and embryonic volume) in naturally conceived pregnancies.

Preconception folic acid supplement use is a well-known method of primary prevention of neural tube defects (NTDs). Obese women are at a higher risk for having a child with a NTD. As different international recommendations on folic acid supplement use for obese women before and during pregnancy exist, this narrative review provides an overview of epidemiology of folate deficiency in obese (pre)pregnant women, elaborates on potential mechanisms underlying folate deficiency, and discusses considerations for the usage of higher doses of folic acid supplements. Women with obesity more often suffer from an absolute folate deficiency, as they are less compliant to periconceptional folic acid supplement use recommendations. In addition, their dietary folate intake is limited due to an unbalanced diet (relative malnutrition). The association of obesity and NTDs also seems to be independent of folate intake, with studies suggesting an increased need of folate (relative deficiency) due to derangements involved in other pathways. The relative folate deficiency, as a result of an increased metabolic need for folate in obese women, can be due to: (1) low-grade chronic inflammation (2) insulin resistance, (3) inositol, and (4) dysbiotic gut microbiome, which plays a role in folate production and uptake. In all these pathways, the folate-dependent one-carbon metabolism is involved. In conclusion, scientific evidence of the involvement of several folate-related pathways implies to increase the recommended folic acid supplementation in obese women. However, the physiological uptake of synthetic folic acid is limited and side-effects of unmetabolized folic acid in mothers and offspring, in particular variations in epigenetic (re)programming with long-term health effects, cannot be excluded. Therefore, we emphasize on the urgent need for further research and preconception personalized counseling on folate status, lifestyle, and medical conditions.

Background Pregnancies with > 1 corpus luteum (CL) display a hyperdynamic circulation and an increased risk of small-for-gestational age deliveries. Among the factors released by the CL is prorenin, the inactive precursor of renin. Since the renin-angiotensin-aldosterone system (RAAS) is involved in early hemodynamic pregnancy adaptation, we linked both CL number and first-trimester concentrations of prorenin (as an indicator of RAAS activity) and the aldosterone/renin ratio (as an indicator of angiotensin-independent aldosterone effectiveness) to non-invasive markers of utero-placental (vascular) development, measured longitudinally from the first trimester onwards. Methods A total of 201 women, who conceived naturally or after in-vitro fertilization treatment (with 0 (n = 8), 1 (n = 143), or > 1 (n = 51) CL), were selected from the Rotterdam Periconceptional Cohort. Maternal RAAS components were determined at 11 weeks gestation. Placental volume and utero-placental vascular volume were measured from transvaginal 3D ultrasound scans at 7, 9 and 11 weeks gestation, pulsatility and resistance indices of the uterine arteries were assessed by pulsed wave Doppler ultrasounds at 7, 9, 11, 13, 22 and 32 weeks gestation. At birth placental weight was obtained using standardized procedures. Results Pregnancies without a CL show lower uterine artery indices throughout gestation than 1 CL and > 1 CL pregnancies, while parameters of placental development are comparable among the CL groups. After adjustment for patient- and treatment-related factors, first-trimester prorenin concentrations are positively associated with uterine artery pulsatility and resistance indices (β 0.06, 95% CI 0.01;0.12, p = 0.04 and β 0.10, 95% CI 0.01;0.20, p = 0.04, respectively), while high prorenin concentrations are negatively associated with first-trimester utero-placental vascular volume (β -0.23, 95% CI -0.44;-0.02, p = 0.04) and placental weight (β -93.8, 95%CI -160.3;-27.4, p = 0.006). In contrast, the aldosterone/renin ratio is positively associated with first-trimester placental volume (β 0.12, 95% CI 0.01;0.24, p = 0.04). Conclusions The absence of a CL, resulting in low prorenin concentrations, associates with low uterine artery pulsatility and resistance, while high prorenin concentrations associate with a low utero-placental vascular volume and weight. These data support a scenario in which excess prorenin, by upregulating angiotensin II, increases uterine resistance, thereby preventing normal placental (vascular) development, and increasing the risk of small-for-gestational age deliveries. Simultaneously, high aldosterone concentrations, by ensuring volume expansion, exert the opposite.

Objective: Women with obesity have an increased risk of pregnancy complications. Although complications generally present in the second and third trimester of pregnancy, most of them develop in the periconception period. Moreover, fetal sex also impacts pregnancy course and outcome. Therefore, our aim is to study (sex-specific) associations between periconceptional maternal body mass index (BMI) and embryonic growth and morphological development. Methods: A total of 884 women with singleton pregnancies were selected from the Rotterdam Periconception Cohort, comprising 15 women with underweight, 483 with normal weight, 231 with overweight and 155 with obesity. Longitudinal three-dimensional ultrasound examinations were performed at 7, 9, and 11 weeks of gestation for offline measurements of crown-rump length (CRL), embryonic volume (EV), and Carnegie stages. Analyses were adjusted for maternal age, parity, ethnicity, education, and periconceptional lifestyle. Results: A negative trend was observed for embryos of women with obesity (βEV −0.03, p = 0.086), whereas embryonic growth and developmental trajectories in women with overweight were comparable to those with normal weight. Maternal underweight was associated with faster morphological development (βCarnegie 0.78, p = 0.004). After stratification for fetal sex, it was demonstrated that female embryos of underweight women grow and morphologically develop faster than those of normal weight women (βEV 0.13, p = 0.008; βCarnegie 1.39, p < 0.001), whereas female embryos of women with obesity grow slower (βEV −0.05, p = 0.027). Conclusion: We found that periconceptional maternal underweight is associated with faster embryonic growth, especially in females. In contrast, female embryos of women with obesity grow slower than female embryos of women with normal weight. This may be the result of altered female adaptation to the postnatal environment. Future research should focus on strategies for optimizing preconceptional maternal weight, to reduce BMI-related pregnancy complications and improve the health of future generations.

The maternal environment during the periconceptional period influences foetal growth and development, in part, via epigenetic mechanisms moderated by one-carbon metabolic pathways. During embryonic development, one-carbon metabolism is involved in brain development and neural programming. Derangements in one-carbon metabolism increase (i) the short-term risk of embryonic neural tube-related defects and (ii) long-term childhood behaviour, cognition, and autism spectrum disorders. Here we investigate the association between maternal one-carbon metabolism and foetal and neonatal brain growth and development. Database searching resulted in 26 articles eligible for inclusion. Maternal vitamin B6, vitamin B12, homocysteine, and choline were not associated with foetal and/or neonatal head growth. First-trimester maternal plasma folate within the normal range (>17 nmol/L) associated with increased foetal head size and head growth, and high erythrocyte folate (1538–1813 nmol/L) with increased cerebellar growth, whereas folate deficiency (

Background Overweight and obesity affect millions of people globally, which has also serious implications for reproduction. For example, treatment outcomes after in vitro fertilisation (IVF) are worse in women with a high body mass index (BMI). However, the impact of maternal BMI on embryo quality is inconclusive. Our main aim is to study associations between preconceptional maternal BMI and morphokinetic parameters of preimplantation embryos and predicted implantation potential. In addition, associations with clinical IVF outcomes are investigated. Methods From a tertiary hospital, 268 women undergoing IVF or IVF with intracytoplasmic sperm injection (ICSI) were included; 143 normal weight, 79 overweight and 46 obese women. The embryos of these women were cultured in the EmbryoScope, a time-lapse incubator. The morphokinetic parameters of preimplantation embryos and predicted implantation potential, assessed by the KIDScore algorithm were longitudinally evaluated as primary and secondary outcomes, respectively. The tertiary outcomes included clinical outcomes, i.e., fertilization, implantation and live birth rate. Results After adjustment for patient- and treatment-related factors, we demonstrated in 938 embryos that maternal BMI is negatively associated with the moment of pronuclear appearance (βtPNa -0.070 h (95%CI -0.139, -0.001), p = 0.048), pronuclear fading (βtPNf -0.091 h (95%CI -0.180, -0.003), p = 0.043 and the first cell cleavage (βt2 -0.111 h (95%CI -0.205, -0.016), p = 0.022). Maternal BMI was not significantly associated with the KIDScore and tertiary clinical treatment outcomes. In embryos from couples with female or combined factor subfertility, the impact of maternal BMI was even larger (βtPNf -0.170 h (95%CI -0.293, -0.047), p = 0.007; βt2 -0.199 h (95%CI -0.330, -0.067), p = 0.003). Additionally, a detrimental impact of BMI per point increase was observed on the KIDScore (β -0.073 (se 0.028), p = 0.010). Conclusions Higher maternal BMI is associated with faster early preimplantation development. In couples with female or combined factor subfertility, a higher BMI is associated with a lower implantation potential as predicted by the KIDScore. Likely due to power issues, we did not observe an impact on clinical treatment outcomes. However, an effect of faster preimplantation development on post-implantation development is conceivable, especially since the impact of maternal BMI on pregnancy outcomes has been widely demonstrated.

Background Maternal overweight has a substantial impact on reproductive, maternal, pregnancy, and neonatal outcomes with long-term and transgenerational health consequences. Interventions that aim to optimize periconception maternal lifestyle can improve maternal and fetal health during pregnancy and throughout the life course. However, it remains difficult to change and adopt adequate lifestyle behaviors. We hypothesize that additional psychological therapy targeting cognitive and affective factors substantially contribute to the effectiveness of these interventions. Objective The proposed study aims to examine the feasibility and effectiveness of a blended personalized periconception lifestyle care intervention with additional psychological therapy aimed at women with a BMI≥25 and who are contemplating pregnancy or are already pregnant (≤12 weeks) in reducing inadequate lifestyle behaviors and improving early and late pregnancy outcome. Methods The eHealth and Face-to-face Counseling (eFUSE) study follows a single-center two-arm randomized controlled trial design at the Erasmus MC, University Medical Center, with a multicenter regional referral. The female patients with overweight (BMI≥25), together with their male partner, will be stratified by pregnancy status (preconception vs pregnant) and randomized to receive either the blended personalized periconception lifestyle care intervention with additional psychological therapy (n=313) or usual care (n=313). The primary outcome is a change in the lifestyle risk score (between baseline and 24 weeks) between the randomization arms (difference in differences). Secondary outcomes include measurements defined as most relevant by the International Consortium for Health Outcomes Measurement, including behavioral determinants, patient satisfaction, provider feasibility, and maternal pregnancy and neonatal complications. Results The study will be open for recruitment from Fall 2021 onward. Data collection is expected to be completed by the beginning of 2023, and the results are expected to be published by Fall 2023. Conclusions This study will evaluate the feasibility and effectiveness of a blended periconception lifestyle intervention with additional psychological therapy, aimed at women with a BMI≥25. Positive results of this innovative care approach will be used for implementation in routine medical care of all women with overweight, with the ultimate aim to improve clinical outcomes of these high-risk pregnancies. Trial Registration Netherlands Trial Register NL9264; https://www.trialregister.nl/trial/9264 International Registered Report Identifier (IRRID) PRR1-10.2196/28600

Polycystic ovary syndrome (PCOS) is an endocrine condition associated with reproductive and psychiatric disorders, and with obesity. Eating disorders, such as bulimia and recurrent dieting, are also linked to PCOS. They can lead to the epigenetic dysregulation of the hypothalamic–pituitary–gonadal (HPG) axis, thereby impacting on ovarian folliculogenesis. We postulate that PCOS is induced by psychological distress and episodes of overeating and/or dieting during puberty and adolescence, when body dissatisfaction and emotional distress are often present. We propose that upregulated activation of the central HPG axis during this period can be epigenetically altered by psychological stressors and by bulimia/recurrent dieting, which are common during adolescence and which can lead to PCOS. This hypothesis is based on events that occur during a largely neglected stage of female reproductive development. To date, most research into the origins of PCOS has focused on the prenatal induction of this disorder, particularly in utero androgenization and the role of anti-Müllerian hormone. Establishing causality in our peripubertal model requires prospective cohort studies from infancy. Mechanistic studies should consider the role of the gut microbiota in addition to the epigenetic regulation of (neuro) hormones. Finally, clinicians should consider the importance of underlying chronic psychological distress and eating disorders in PCOS.

Research question: Is there an association between the use of sympathomimetics for asthmatic disease and semen quality in humans? Design: Between 2007 and 2012 a prospective cohort study was conducted among couples visiting the preconception counselling clinic at a tertiary hospital in the Netherlands. The study included 882 men of subfertile couples and information on medication use was obtained from self-administered questionnaires. Moreover, data on semen parameters were retrieved from medical records. Results: The study population of men revealed a mean (± SD) age of 34 ± 4 years with a mean body mass index (BMI) of 26.1 ± 2.3 kg/m2, and sympathomimetic use was reported by 3.6%. The use of sympathomimetics was positively associated with a 10% higher sperm motility (beta 10.265; 95% confidence interval [CI] 3.258–17.272) after adjustment for smoking, alcohol use, age, geographic background, BMI, folic acid supplement use, the four astronomical seasons and asthma/bronchitis. Subgroup analysis between men with total motile sperm count (TMSC) < or ≥10 million showed that this association remained (P ≤ 0.001) after adjustment for these confounders. After adjustment for confounders the sperm concentration was also positively associated with the use of sympathomimetics, but only in men with TMSC ≥10 million (beta 0.300; 95% CI 0.032–0.568). Conclusions: These preliminary data show the potential benefits of the use of sympathomimetics to improve sperm motility in men of subfertile couples, which needs further investigation.

Background: In patients with azoospermia, pregnancy can be achieved after surgical techniques using sperm retrieved from the testis or epididymis, which can impact on DNA integrity and epigenetics. DNA of the fetus and placenta is equally derived from both parents; however, genes important for placental development are expressed from the paternal alleles. Therefore, the origin of sperm may affect fetal and placental development. Objectives: To investigate whether first-trimester trajectories of embryonic and placental development of pregnancies conceived after intracytoplasmic sperm injection (ICSI) with testicular sperm extraction (TESE) or microsurgical epididymal sperm aspiration (MESA), are different from pregnancies after ICSI with ejaculated sperm or natural conceptions. Materials and methods: A total of 147 singleton ICSI pregnancies, including pregnancies conceived after TESE (n = 23), MESA (n = 25) and ejaculated sperm (n = 99), and 380 naturally conceived and 140 after IVF treatment without ICSI were selected from the prospective Rotterdam periconception cohort. Crown-rump length (CRL), embryonic volume (EV), Carnegie stages, and placental volume (PV) at 7, 9, and 11 weeks of gestation were measured using 3D ultrasound and virtual reality technology. Results: Linear mixed model analysis showed no differences in trajectories of CRL, EV, and Carnegie stages between pregnancies conceived after ICSI with testicular, epididymal, and ejaculated sperm. A significantly positive association was demonstrated for PV between pregnancies conceived after TESE-ICSI (adjusted beta: 0.28(95%CI: 0.05-0.50)) versus ICSI with ejaculated sperm. Retransformation to original values showed that the PV of pregnancies after TESE-ICSI is 14.6% (95%CI: 1.4%-25.5%) larger at 11 weeks of gestation compared to ICSI pregnancies conceived with ejaculated sperm. Discussion and Conclusion: Here we demonstrate that the first-trimester growth trajectory of the placenta is increased in pregnancies conceived after TESE-ICSI compared to those conceived after ICSI with ejaculated sperm. Findings are discussed in the light of known differences in sperm DNA integrity, epigenetics, and placental gene expression.

Epigenetic programming is essential for lineage differentiation, embryogenesis and placentation in early pregnancy. In epigenetic association studies, DNA methylation is often examined in DNA derived from white blood cells, although its validity to other tissues of interest remains questionable. Therefore, we investigated the tissue specificity of epigenome-wide DNA methylation in newborn and placental tissues. Umbilical cord white blood cells (UC-WBC, n = 25), umbilical cord blood mononuclear cells (UC-MNC, n = 10), human umbilical vein endothelial cells (HUVEC, n = 25) and placental tissue (n = 25) were obtained from 36 uncomplicated pregnancies. Genome-wide DNA methylation was measured by the Illumina HumanMethylation450K BeadChip. Using UC-WBC as a reference tissue, we identified 3595 HUVEC tissue-specific differentially methylated regions (tDMRs) and 11,938 placental tDMRs. Functional enrichment analysis showed that HUVEC and placental tDMRs were involved in embryogenesis, vascular development and regulation of gene expression. No tDMRs were identified in UC-MNC. In conclusion, the extensive amount of genome-wide HUVEC and placental tDMRs underlines the relevance of tissue-specific approaches in future epigenetic association studies, or the use of validated representative tissues for a certain disease of interest, if available. To this purpose, we herewith provide a relevant dataset of paired, tissue-specific, genome-wide methylation measurements in newborn tissues.

Background Approximately 1 in 7 couples experience subfertility, many of whom have lifestyles that negatively affect fertility, such as poor nutrition, low physical activity, obesity, smoking, or alcohol consumption. Reducing lifestyle risk factors prior to pregnancy or assisted reproductive technology treatment contributes to the improvement of reproductive health, but cost-implications are unknown. Objective The goal of this study was to evaluate reproductive, maternal pregnancy, and birth outcomes, as well as the costs of pre-conception lifestyle intervention programs in subfertile couples and obese women undergoing assisted reproductive technology. Methods Using a hypothetical model based on quantitative parameters from published literature and expert opinion, we evaluated the following lifestyle intervention programs: (1) Smarter Pregnancy, an online tool; (2) LIFEstyle, which provides outpatient support for obese women; (3) concurrent use of both Smarter Pregnancy and LIFEstyle for obese women; (4) smoking cessation in men; and (5) a mindfulness mental health support program using group therapy sessions. The model population was based on data from the Netherlands. Results All model-based analyses of the lifestyle interventions showed a reduction in the number of in vitro fertilization, intracytoplasmic sperm injection, or intrauterine insemination treatments required to achieve pregnancy and successful birth for couples in the Netherlands. Smarter Pregnancy was modeled to have the largest increase in spontaneous pregnancy rate (13.0%) and the largest absolute reduction in potential assisted reproductive technology treatments. Among obese subfertile women, LIFEstyle was modeled to show a reduction in the occurrence of gestational diabetes, maternal hypertensive pregnancy complications, and preterm births by 4.4%, 3.8%, and 3.0%, respectively, per couple. Modeled cost savings per couple per year were €41 (US $48.66), €360 (US $427.23), €513 (US $608.80), €586 (US $695.43), and €1163 (US $1380.18) for smoking cessation, mindfulness, Smarter Pregnancy, combined Smarter Pregnancy AND LIFEstyle, and LIFEstyle interventions, respectively. Conclusions Although we modeled the potential impact on reproductive outcomes and costs of fertility treatment rather than collecting real-world data, our model suggests that of the lifestyle interventions for encouraging healthier behaviors, all are likely to be cost effective and appear to have positive effects on reproductive, maternal pregnancy, and birth outcomes. Further real-world data are required to determine the cost-effectiveness of pre-conception lifestyle interventions, including mobile apps and web-based tools that help improve lifestyle, and their effects on reproductive health. We believe that further implementation of the lifestyle app Smarter Pregnancy designed for subfertile couples seeking assistance to become pregnant is likely to be cost-effective and would allow reproductive health outcomes to be collected.

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. ispartof: Birth Defects Research vol:112 issue:9 pages:645-651 ispartof: location:United States status: published

Scope The effectiveness of maternal folate in reducing the risk of congenital malformations during pregnancy is well established. However, the role of the paternal folate status is scarcely investigated. The aim of this study is to investigate the evidence of associations between the paternal folate status and sperm quality, sperm epigenome, and pregnancy outcomes. Methods and results Databases are searched up to December 2017 resulting in 3682 articles, of which 23 are retrieved for full‐text assessment. Four out of thirteen human and two out of four animal studies show positive associations between folate concentrations and sperm parameters. An additional meta‐analysis of four randomized controlled trials in subfertile men shows that the sperm concentration increases (3.54 95% confidence interval (CI) [−1.40 to 8.48]) after 3–6 months of 5 mg folic acid use per day compared to controls. Moreover, two out of two animal and one out of three human studies show significant alterations in the overall methylation of the sperm epigenome. One animal and one human study show associations between low folate intake and an increased risk of congenital malformations. Conclusions This systematic review and meta‐analysis shows evidence of associations between paternal folate status and sperm quality, fertility, congenital malformations, and placental weight., The aim of this study is to investigate and provide an overview of the evidence of associations between the periconceptional paternal folate status and folic acid supplement use and sperm quality, sperm epigenome, and pregnancy outcomes in both human and animal studies. It is concluded that more research is necessary into the periconceptional roles of paternal micronutrients.

Background During the turbulent postpartum period, there is an urgent need by parents for support and information regarding the care for their infant. In the Netherlands, professional support is provided during the first 8 days postpartum and for a maximum of 8 hours a day. This care is delivered by maternity care assistants (MCAs). Despite the availability of this extensive care, a majority of women prefer to make use of a lesser amount of postpartum care. After this period, access to care is less obvious. Where parents are automatically offered care in the first 8 days after birth, they must request care in the period thereafter. To compensate for a possible gap in information transfer, electronic health (eHealth) can be a valuable, easily accessible addition to regular care. Objective We explored the needs and preferred content by new parents and health care professionals of a web-based platform dedicated to the postpartum period and identified barriers and facilitators for using such a platform. Methods We conducted 3 semistructured focus groups among (1) parents of newborns, (2) MCAs, and (3) clinicians and administrators in maternity care. A topic list based on a framework designed for innovation processes was used. Thematic content analysis was applied. Results In the focus group for parents, 5 mothers and 1 male partner participated. A total of 6 MCAs participated in the second focus group. A total of 5 clinicians and 2 administrators—a member of a stakeholder party and a manager of a maternity care organization—participated in the third focus group. All user groups underlined that a platform focusing on the postpartum period was missing in current care, especially by parents experiencing a gap following the intensive care ending after the first week of childbirth. Parents indicated that they would perceive a postpartum platform as a proper source of reliable information on topics regarding breastfeeding, growth, and developmental milestones, but also as a tool to support them in seeking care with appropriate professionals. They also emphasized the need to receive personalized information and the opportunity to ask questions via the platform. MCAs acknowledged added value of providing additional information on topics that they address during the early postpartum period. MCAs as well as clinicians and administrators would guide parents to such a platform for additional support. All user groups experienced disadvantages of using an authentication procedure and filling out extra questionnaires to receive tailored information. Conclusions Our research shows that parents of newborns, MCAs, and clinicians and administrators foresee the additional value of a web-based postpartum platform for at least the whole postpartum period. The platform should be easily accessible and personalized. Content on the platform should contain information regarding breastfeeding, growth, and developmental milestones. A chat function with professionals could be considered as an option.

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&rsquo, 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.

Inadequate nutrition and lifestyle behaviors, particularly during the periconception period, are associated with a negative impact on embryonic and subsequent fetal development. We investigated the associations between parental nutritional and lifestyle factors and pre-implantation embryo development. A total of 113 women and 41 partners, with a corresponding 490 embryos, who underwent intracytoplasmic sperm injection (ICSI) treatment subscribed to the mHealth coaching platform “Smarter Pregnancy.” At baseline, nutrition and lifestyle behaviors (intake of fruits, vegetables, folic acid, and smoking and alcohol use) were identified and risk scores were calculated. A lower risk score represents healthier behavior. As outcome measure, a time-lapse morphokinetic selection algorithm (KIDScore) was used to rank pre-implantation embryo quality on a scale from 1 (poor) to 5 (good) after being cultured in the Embryoscope™ time-lapse incubator until embryonic day 3. To study the association between the nutritional and lifestyle risk scores and the KIDScore in men and women, we used a proportional odds model. In women, the dietary risk score (DRS), a combination of the risk score of fruits, vegetables, and folic acid, was negatively associated with the KIDScore (OR 0.86 (95% CI 0.76 to 0.98), p = 0.02). This could mainly be attributed to an inadequate vegetable intake (OR 0.76 (95% CI 0.59 to 0.96), p = 0.02). In men, smoking was negatively associated with the KIDscore (OR 0.53 (95% CI 0.33 to 0.85), p

Given all its systemic adaptive requirements, pregnancy shares several features with physical exercise. In this pilot study, we aimed to assess the physiological response to submaximal cardiopulmonary exercise testing (CPET) in early pregnancy. In 20 healthy, pregnant women (, The response to a cardiopulmonary exercise test is already altered in the first trimester of pregnancy. Pregnant women show a slower hemodynamic recovery and an excessive ventilatory response to submaximal exercise.

Background There is a need for non-invasive prenatal markers of the brain to assess fetuses at risk for poor postnatal neurodevelopmental outcome. Periconceptional maternal conditions and pregnancy complications impact prenatal brain development. Aims To investigate associations between growth trajectories of fetal brain structures and neurodevelopmental outcome in children in the early life course. Study design Periconceptional prospective observational cohort. Subjects Singleton pregnancies were included in the Rotterdam periconception cohort. Two- and three-dimensional ultrasound scans at 22, 26 and 32 weeks gestational age were analysed. Outcome measures Head circumference (HC), cerebellum, corpus callosum (CC), Sylvian fissure, insula and parieto-occipital fissure (POF) were measured. Neurodevelopment was evaluated using the Age-and-Stages-questionnaire-3 (ASQ-3) and the Child-Behaviour-Checklist (CBCL) at 2 years of age. Linear mixed models, used to estimate the prenatal brain growth trajectories, and linear regression models, used to evaluate the associations between prenatal brain structures and neurodevelopmental outcomes, were applied in the total study population, and in subgroups: fetal growth restriction (FGR), preterm birth (PTB), fetal congenital heart disease (CHD), and uncomplicated controls. Results Consent for participation was received from parents on behalf of their child 138/203 (68%). ASQ-3 was completed in 128/203 children (63%) and CBCL in 93/203 children (46%). Significant smaller subject-specific growth trajectories (growth rate of CC, HC, left insula, left POF and right POF and the baseline size of CC, HC, left POF and right POF) were found in the FGR subgroup, compared to the other subgroups (all p-values

Background: Neighbourhood deprivation is a risk factor for impaired health and adverse pregnancy outcomes. We investigated whether living in a deprived neighbourhood is associated with embryonic growth. Methods: From the Predict cohort, we studied 566 women who underwent repeated first trimester ultrasound examinations. Crown rump length (CRL, n = 1707) and embryonic volume (EV, n = 1462) were measured using three-dimensional techniques. Neighbourhood deprivation was assessed using the neighbourhood status scores (NSS) of the Dutch Social Cultural Planning office. A high NSS represents a non-deprived neighbourhood. Associations between the NSS and embryonic growth were investigated using linear mixed models. Adjustment was performed for individual-level factors: maternal age, geographic origin, educational level, BMI, folic acid supplement use, fruit and vegetable intake, alcohol use and smoking habits. Results: The NSS was negatively associated with embryonic growth: a higher score (a less deprived neighbourhood) was associated with a smaller CRL and EV, adjusted &beta, &minus, 0.025 (95% CI &minus, 0.046, &minus, 0.003) and adjusted &beta, 0.015 (95% CI &minus, 0.026, &minus, 0.003). At 11 weeks of pregnancy, we observed a 0.55 cm3 smaller EV (7.65 cm3 vs. 7.10 cm3) and 1.08 mm smaller CRL (43.14 mm vs. 42.06 mm) in the highest compared to the lowest category. Conclusion: In deprived neighbourhoods, embryos are larger than in non-deprived neighbourhoods.

IntroductionThe importance of cardiovascular health in relation to pregnancy outcome is increasingly acknowledged. Women who develop certain pregnancy complications, in particular preeclampsia, are at higher risk for future cardiovascular disease. Independent of its outcome, pregnancy requires a substantial adaptive response of the maternal cardiovascular system. In the Hemodynamic Adaptation to Pregnancy and Placenta-related Outcome (HAPPO) study, we aim to examine longitudinal maternal haemodynamic adaptation to pregnancy from the preconception period onwards. We hypothesise that women who will develop adverse pregnancy outcomes have impaired cardiovascular health before conception, leading to haemodynamic maladaptation to pregnancy and diminished uteroplacental vascular development.Methods and analysisIn this prospective cohort study embedded in the Rotterdam periconception cohort, 200 women with a history of placenta-related pregnancy complications (high-risk group) and 100 women with an uncomplicated obstetric history (low-risk group) will be included. At five moments (preconception, first, second and third trimester and postdelivery), women will undergo an extensive examination of the macrocirculatory and microcirculatory system and uteroplacental vascular development. The main outcome measures are differences in maternal haemodynamic adaptation to pregnancy between women with and without placenta-related pregnancy complications. In a multivariate linear mixed model, the relationship between maternal haemodynamic adaptive parameters, (utero)placental vascularisation indices and clinical outcomes (occurrence of pregnancy complications, embryonic and fetal growth trajectories, miscarriage rate, gestational age at delivery, birth weight) will be studied. Subgroup analysis will be performed to study baseline and trajectory differences between high-risk and low-risk women, independent of subsequent pregnancy outcome.Ethics and disseminationThis study protocol was approved by the Medical Ethics Committee of the Erasmus MC, Rotterdam, the Netherlands (MEC 2018–150). Results will be disseminated to the medical community by publications in peer-reviewed journals and presentations at scientific congresses. Also, patient associations will be informed and the public will be informed by dissemination through (social) media.Trial registration numberNL7394 (www.trialregister.nl)

Purpose: The objective of present study is to determine serum levels and placental distribution of two interacting proteins calcyclin and heat shock protein 90 in preeclampsia. Experimental design: Maternal serum levels of calcyclin and heat shock protein 90 are compared throughout pregnancy from the first trimester till term among women with preeclampsia (n = 43) and age-matched normotensive pregnant controls (n = 46). A serum-based 2D LC-MS assay using Parallel Reaction Monitoring is applied to quantify both calcyclin and heat shock protein 90. Results: Serum levels of calcyclin are significantly lower in patients with preeclampsia in the second trimester of pregnancy as compared to controls (p

BackgroundIn 2011, we launched the Smarter Pregnancy mobile health (mHealth) coaching program, which has shown to effectively improve inadequate nutrition and lifestyle behaviors in women before and during pregnancy. It is known that in deprived neighborhoods, risk factors for adverse pregnancy outcomes like inadequate nutrition and lifestyle behaviors accumulate. However, it has not yet been investigated whether the Smarter Pregnancy program is equally effective in women living in deprived neighborhoods. ObjectiveThis paper aimed to study the associations between neighborhood deprivation and improvement of inadequate nutrition and lifestyle behaviors of women who were either contemplating pregnancy or already pregnant and subscribed to the Smarter Pregnancy program. MethodsWe performed an additional analysis on data from women who used the Smarter Pregnancy program from 2011 to 2016. The program comprised 24 weeks of coaching on 5 nutrition and lifestyle behaviors, of which adequate intakes or lifestyle behaviors were defined as an intake of 200 grams or above of vegetables, 2 pieces of fruit, daily folic acid supplement use of 400 µg per day, and no smoking or alcohol consumption. Neighborhood deprivation was determined according to the status scores of the Netherlands Institute for Social Research. Logistic regression analyses and generalized estimating equation models were used to assess the associations between the neighborhood status score (NSS) and the improvement of inadequate nutrition and lifestyle behaviors, taking into account the behaviors at baseline. We adjusted the analyses for maternal age, body mass index, geographic origin, pregnancy status, and participation as a couple. ResultsOf the 2554 women included, 521 participated with their male partner. Overall, daily vegetable intake was most frequently inadequate at the start of the program (77.72, 1985/2554). Women with a higher NSS (ie, nondeprived neighborhood) smoked less often (adjusted odds ratio [OR] 0.85; 95% CI 0.77-0.93), consumed alcohol more often (adjusted OR 1.14, 95% CI 1.04-1.24), and were less likely to complete the 24 weeks of coaching (OR 0.91, 95% CI 0.88-0.95) compared with women who lived in a neighborhood with a low NSS (ie, deprived). In the total group, the relative improvement of inadequate nutrition and lifestyle behaviors after 24 weeks of coaching was between 26% and 64%. NSS was negatively associated with this improvement, indicating that women with a higher NSS were less likely to improve inadequate nutrition and lifestyle behaviors, especially vegetable intake (adjusted OR 0.89, 95% CI 0.82-0.97). ConclusionsThe Smarter Pregnancy mHealth coaching program empowers women to improve inadequate nutrition and lifestyle behaviors. Unexpectedly, the program seemed more effective in women living in deprived neighborhoods. It is important to unravel differences in needs and behaviors of specific target groups to further tailor the mHealth program on the basis of demographic characteristics like neighborhood deprivation.

Polycystic ovary syndrome (PCOS) is generally considered a complex disorder caused by interactions between genetic and environmental factors. In a sub-cohort of women with PCOS visiting the preconception outpatient clinic of a tertiary hospital with follow-up in a periconception cohort, we identified specific dietary patterns and adherence in patients with PCOS with and without hyperandrogenism and the chance of ongoing pregnancy. Food frequency questionnaires were available from 55 patients diagnosed with PCOS during follow-up in routine clinical practice, including 25 with hyperandrogenism and 30 without hyperandrogenism. Strong adherence to the healthy dietary pattern was inversely associated with the hyperandrogenic PCOS phenotype (Adjusted OR 0.27; 95% CI 0.07 to 0.99). In women with PCOS overall, a strong adherence to the healthy dietary pattern showed a three-fold higher chance of ongoing pregnancy (adjusted OR 3.38; 95% CI 1.01 to 11.36) and an association with anti-Müllerian hormone concentration (β -0.569 μg/L; 95% CI -0.97 to -0.17). The effect of this dietary pattern on the chance of ongoing pregnancy and AMH suggests causality, which needs further investigation in prospective studies in the general population.

IntroductionThe pathophysiology of preeclampsia is largely unknown. Serum placental induced growth factor (PlGF) levels are decreased during second trimester pregnancy. Aberrant DNA methylation is suggested to be involved in the etiology of preeclampsia (PE). We hypothesize that DNA methylation is altered in PE placentas determined the methylation index by measuring placental S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels. In addition, we assessed global DNA methylation status by long-interspersed nuclear element-1 (LINE-1) and DNA methylation status of the PlGF gene.MethodsPlacental tissue of 11 early onset PE (EOPE), 11 late onset PE (LOPE) and 60 controls consisting of 25 uncomplicated controls 20 fetal growth restriction (FGR) and 15 preterm births (PTB) controls was collected from a nested case-control study of The Rotterdam Periconceptional Cohort. RNA and DNA was isolated from placental tissue and DNA was treated with sodium bisulfite. SAM and SAH levels were measured by LC-ESI-MS/MS. Methylation of LINE-1 and PlGF genes was analyzed by Sequenom Epityper and. mRNA expression of PlGF was assessed with qPCR. Differences were assessed by analysis of covariance (ANCOVA) corrected for gestational age and birth weight.ResultsPlacental SAM levels were significantly lower in placental tissue of EOPE pregnancies compared to PTB controls (mean difference -240 ± 71.4 nmol/g protein, P = 0.01). PlGF DNA methylation was decreased in placental tissue of EOPE cases versus LOPE (mean difference -17.4 ± 5.1%, P = 0.01), uncomplicated controls (mean difference -23.4 ± 5.4%%, P DiscussionThe hypomethylation state of the placenta in EOPE, which is reflected by lower SAM and PlGF DNA hypomethylation underlines the possible role of placental DNA hypomethylation in the pathophysiology of EOPE, which needs further investigation.

Objective: To investigate the influence of MTHFR c.677C>T genotype on LINE-1 methylation in lateral and medial tissues from cleft lip (CL). Methods: Forty-five consecutive non-syndromic cleft lip with or without cleft palate (nsCL/P) cases were included in the study. Genomic DNA was extracted from tissues at both sides of cleft lip, and LINE-1 methylation was detected by bisulfite conversion and pyrosequencing. MTHFR c.677C>T genotyping was carried out using the TaqMan genotyping assay. Results: LINE-1 methylation level was significantly higher on medial side of cleft lip compared with lateral side (p = 0.001). This difference was not significantly influenced by the case's sex or cleft type. However, MTHFR c.677C>T genotyping revealed that the difference in LINE-1 methylation across cleft lip was restricted to carriers of C allele of MTHFR c.677C>T and was not apparent in TT homozygous cases (p = 0.027). Conclusion: This integrated analysis supports the previous finding of differences in DNA methylation across the two sides of cleft lip and further suggests a possible role of MTHFR c.677C>T genotype in establishing this difference.

OBJECTIVE: To compare vitamin D status in women with PCOS versus fertile women and subsequently evaluate the association between vitamin D status and metabolic disturbances in PCOS women.METHODS: We conducted a cross-sectional comparison study of 639 women with PCOS and 449 fertile women. Serum 25-hydroxyvitamin D (25(OH)D) was stratified into a severe deficient (< 25 nmol/l), insufficient (25-50 nmol/l), moderate (50-75 nmol/l) and adequate (> 75 nmol/l) status. The main outcome measures were the difference in vitamin D status between PCOS and fertile women, and the association between serum 25(OH)D and metabolic disturbances in PCOS women only.RESULTS: Serum 25(OH)D was significantly lower in PCOS women compared to fertile controls (mean 25(OH)D of 49.0 nmol/l versus 64.5 nmol/l). An adjusted significant difference was seen between serum 25(OH)D and homeostasis model assessment (HOMA-IR) (β = 0.76; 95% CI: 0.63-0.91; p < 0.01), HDL-cholesterol (β = 0.20; 95% CI: 0.05-0.60, p < 0.01) and apolipoprotein A1 (β = 26.2; 95% CI: 7.5-45.0, p < 0.01) between the highest vitamin D group compared to the lowest vitamin D group.CONCLUSIONS: This study demonstrates that women with PCOS have a significantly lower serum 25(OH)D compared to fertile controls. A compromised vitamin D status in PCOS women is associated with a higher HOMA-IR and an unfavourable lipid profile. Large randomized controlled trials are necessary to explore the causality of this linkage.

Background Maternal nutrition during pregnancy has been related to intrauterine brain development and neurodevelopmental disabilities in adult life. We aim to investigate associations between periconceptional maternal dietary patterns and prenatal cerebellar growth from the first trimester onwards. Materials and methods 126 women with singleton non-malformed pregnancies were enrolled before 8 weeks of gestation in the Rotterdam periconceptional cohort between 2013 and 2015. Periconceptional maternal dietary patterns were extracted from food frequency questionnaires and associated with blood biomarkers and micronutrient intakes. Serial two-dimensional and three-dimensional ultrasound scans were performed at 9, 11, 22, 26 and 32 weeks of gestation for transcerebellar diameter (TCD) measurement. Linear mixed models were estimated to investigate associations between periconceptional maternal dietary patterns and longitudinal TCD measurements as a function of gestational age. Results We performed a median of 4 scans per pregnancy, resulting in 570 total datasets. The success rate of TCD measurements was 87% (range 65–100%), depending on gestational age. The Mediterranean, Western, egg-rich and dairy-rich dietary patterns were extracted, explaining 37.2% of the overall variance of food intake in this population. The dairy-rich dietary pattern was positively associated with cerebellar growth trajectories (β = 0.02 (95% CI: 0.01; 0.03) pmm, p = 0.01). Maternal strong adherence to this dietary pattern increased TCD measurements by 0.8 standard deviation scores (SDs) compared to weak adherence, reflected in increased TCD estimates of 0.44 mm at 9 weeks (+6.8%), 0.88 mm at 22 weeks (+3.6%), and 1.17 mm at 32 weeks (+2.8%). No significant associations were detected for the Mediterranean, Western and egg-rich dietary patterns. Conclusions This study shows a positive association between periconceptional maternal adherence to a dairy-rich dietary pattern and human prenatal TCD measurements as a proxy of cerebellar growth. Next step is the investigation of the impact on neurodevelopmental outcomes in the offspring.

BACKGROUND AND PURPOSE: Most ultrasound markers for monitoring brain growth can only be used in either the prenatal or the postnatal period. We investigated whether corpus callosum length and corpus callosum–fastigium length could be used as markers for both prenatal and postnatal brain growth. MATERIALS AND METHODS: A 3D ultrasound study embedded in the prospective Rotterdam Periconception Cohort was performed at 22, 26 and 32 weeks' gestational age in fetuses with fetal growth restriction, congenital heart defects, and controls. Postnatally, cranial ultrasound was performed at 42 weeks' postmenstrual age. First, reliability was evaluated. Second, associations between prenatal and postnatal corpus callosum and corpus callosum–fastigium length were investigated. Third, we created reference curves and compared corpus callosum and corpus callosum–fastigium length growth trajectories of controls with growth trajectories of fetuses with fetal growth retardation and congenital heart defects. RESULTS: We included 199 fetuses; 22 with fetal growth retardation, 20 with congenital heart defects, and 157 controls. Reliability of both measurements was excellent (intraclass correlation coefficient ≥ 0.97). Corpus callosum growth trajectories were significantly decreased in fetuses with fetal growth restriction and congenital heart defects (β = −2.295; 95% CI, −3.320–1.270; P < .01; β = −1.267; 95% CI, −0.972–0.562; P < .01, respectively) compared with growth trajectories of controls. Corpus callosum–fastigium growth trajectories were decreased in fetuses with fetal growth restriction (β = −1.295; 95% CI, −2.595–0.003; P = .05). CONCLUSIONS: Corpus callosum and corpus callosum–fastigium length may serve as reliable markers for monitoring brain growth from the prenatal into the postnatal period. The clinical applicability of these markers was established by the significantly different corpus callosum and corpus callosum–fastigium growth trajectories in fetuses at risk for abnormal brain growth compared with those of controls.

UNLABELLED: We aimed to study the association between use of antihistamines in early pregnancy and congenital heart defects (CHD) in the offspring.DESIGN: Two case-control studies.SETTING: HAVEN study, Erasmus MC, University Medical Centre, Rotterdam, and Eurocat Northern Netherlands (NNL), University Medical Center Groningen, Groningen, the Netherlands. We studied 361 children with CHD and 410 controls without congenital malformations from the HAVEN study and replicated the analyses in 445 children with CHD and 530 controls from the Eurocat NNL registry. Information about antihistamine use in early pregnancy and potential confounders was obtained from questionnaires postpartum. We calculated the association between antihistamines and CHD risk by multivariable logistic regression analysis.MAIN OUTCOME MEASURES: Odds ratios (OR) with 95% confidence intervals (CI). In the HAVEN study, 25 of 771 mothers used antihistamines that were associated with an increased CHD risk (OR 3.0, 95% CI 1.2-7.3), particularly atrioventricular septal defects (AVSD) (OR 5.1, 95 % CI 1.3-20.5) and perimembranous ventricular septal defects (pVSD) (OR 5.1, 95% CI 1.8-14.4). Mothers with severe nausea who did not use antihistamines had a reduced risk (OR 0.7, 95% CI 0.5-0.98), whereas nauseous mothers using antihistamines showed an almost fivefold increased risk of pVSD (OR 4.8, 95% CI 1.1-21.8). The association between antihistamines and AVSD was confirmed in the Eurocat cohort (OR 3.5, 95% CI 1.4-8.7), but we could not replicate the association with overall CHD risk. We found a positive association between antihistamine use in early pregnancy and CHD risk, particularly AVSD, which seemed to be independent of nausea/vomiting.

Objective To study associations between periconceptional dietary patterns and semen quality parameters. Design Prospective periconception cohort study. Setting Tertiary hospital. Patient(s) One hundred and twenty-nine male partners of pregnant women who participated in the Rotterdam Periconception Cohort (Predict study). Intervention(s) None. Main Outcome Measure(s) Semen quality parameters—ejaculate volume, sperm concentration, total sperm count, progressive motility, immotile sperm, and total motile sperm count (TMSC). Result(s) Men included in our study were on average 35 (±6 standard deviation) years old and had a body mass index of 26.4 ± 4 kg/m 2 . Two dietary patterns were identified using principle component analysis, which were labeled as "healthy" and "unhealthy." An increase of one factor score (stated as β) represented an increase of 1 standard deviation. Sperm concentration (β = 0.278; 95% CI, 0.112–0.444), total sperm count (β = 1.369; 95% CI, 0.244–2.495), progressive motility (β = 4.305; 95% CI, 0.675–7.936), and TMSC (β = 0.319; 95% CI, 0.113–0.526) were all positively associated with a strong adherence to the healthy dietary pattern. Subgroup analysis showed that these associations were mainly present in men with a TMSC Conclusion(s) The positive associations between strong adherence to a healthy dietary pattern and semen parameters in men with poor semen quality support the importance of preconceptional tailored nutritional counseling and coaching of couples who are trying to conceive.

BackgroundNonsyndromic cleft lip with or without cleft palate (nsCL±P) and nonsyndromic cleft palate (nsCP) are caused by a combination of genetic and environmental risk factors. We investigated gene-environment and gene-gene joint effects in a large multicenter study of case-parent triads.MethodsThe nsCL±P or nsCP triads were recruited in 11 European countries between 2001 and 2005. We collected DNA samples from infants and from their mothers and fathers, and mothers completed a questionnaire on exposures, including smoking and folic acid supplement use during pregnancy. We used log-linear regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between nsCL±P or nsCP and variants in MTHFR, MTHFD1, TGFA, SATB2, and MSX1, stratifying by environmental or genetic factors.ResultsWe obtained genotype and exposure data for 728 nsCL±P triads and 292 nsCP triads. In male infants, there was no association between the mother's homozygous MSX1 p(CA)∗4/∗4 genotype and nsCL±P (RR, 0.98; 95% CI, 0.63–1.54), but this maternal genotype resulted in a doubling of risk for female infants (RR, 2.21; 95% CI, 1.13–4.34). There was evidence suggestive of gene-gene joint-effects between MTHFR-TGFA for nsCP but not for nsCL±P.ConclusionAlthough we chose the genes and their variants and putative joint effects based on associations previously reported in the literature, we replicated few associations. These results do not provide evidence supporting associations between these genes and oral clefts in European populations, although gene-environment and gene-gene interactions could play a role in oral cleft etiology.

Pregnancies complicated by preeclampsia (PE) are characterised by an enhanced maternal and fetal inflammatory response with increased numbers of leukocytes in maternal peripheral blood. The impact of PE on newborn umbilical cord blood cell (UCBC) populations however, has been scarcely studied. We hypothesise that PE deranges fetal haematopoiesis and subsequently UCBC populations. Therefore, the objective of this study was to investigate newborn umbilical cord blood cell populations in early- (EOPE) and late-onset PE (LOPE). A secondary cohort analysis in The Rotterdam Periconceptional Cohort was conducted comprising 23 PE cases, including 11 EOPE and 12 LOPE, and 195 controls, including 153 uncomplicated and 23 fetal growth restriction- and 19 preterm birth complicated controls. UCBC counts and differentials were quantified by flow cytometry and analysed as main outcome measures. Multivariable regression analysis revealed associations of EOPE with decreased leucocyte- (monocytes, neutrophils, eosinophils, immature granulocytes) and thrombocyte counts and increased NRBC counts (all p < 0.05). EOPE remained associated with neutrophil- (beta-0.92, 95%CI -1.27,-0.57, p < 0.001) and NRBC counts (beta 1.11, 95%CI 0.27,1.95, p = 0.010) after adjustment for gestational age and birth weight. LOPE did not reveal any significant association. We conclude that derangements of fetal haematopoiesis, in particular of neutrophil- and NRBC counts, are associated with EOPE only, with a potential impact for future health of the offspring. This heterogeneity in UCBC should be considered as confounder in epigenetic association studies examining EOPE. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

STUDY QUESTION: Can growth trajectories of the human embryonic head be created using 3D ultrasound (3D-US) and virtual reality (VR) technology, and be associated with second trimester fetal head size and periconceptional maternal conditions? SUMMARY ANSWER: Serial first trimester head circumference (HC) and head volume (HV) measurements were used to create reliable growth trajectories of the embryonic head, which were significantly associated with fetal head size and periconceptional maternal smoking, age and ITALIC! in vitro fertilization (IVF)/intra-cytoplasmic sperm injection (ICSI) treatment. WHAT IS KNOWN ALREADY: Fetal growth is influenced by periconceptional maternal conditions. STUDY DESIGN, SIZE, DURATION: We selected 149 singleton pregnancies with a live born non-malformed fetus from the Rotterdam periconception cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Bi-parietal diameter and occipital frontal diameter to calculate HC, HV and crown-rump length (CRL) were measured weekly between 9 + 0 and 12 + 6 weeks gestational age (GA) using 3D-US and VR. Fetal HC was obtained from second trimester structural anomaly scans. Growth trajectories of the embryonic head were created with general additive models and linear mixed models were used to estimate associations with maternal periconceptional conditions as a function of GA and CRL, respectively. MAIN RESULTS: A total of 303 3D-US images of 149 pregnancies were eligible for embryonic head measurements (intra-class correlation coefficients >0.99). Associations were found between embryonic HC and fetal HC ( ITALIC! ρ = 0.617, ITALIC! P < 0.001) and between embryonic HV and fetal HC ( ITALIC! ρ = 0.660, ITALIC! P < 0.001) in ITALIC! Z-scores. Maternal periconceptional smoking was associated with decreased, and maternal age and IVF/ICSI treatment with increased growth trajectories of the embryonic head measured by HC and HV (All ITALIC! P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The consequences of the small effect sizes for neurodevelopmental outcome need further investigation. As the study population consists largely of tertiary hospital patients, external validity should be studied in the general population. WIDER IMPLICATIONS OF THE FINDINGS: Assessment of growth trajectories of the embryonic head may be of benefit in future early antenatal care. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Department of Obstetrics and Gynaecology, Erasmus MC University Medical Centre and Sophia Foundation for Medical Research, Rotterdam, The Netherlands (SSWO grant number 644). No competing interests are declared.

Developmental adaptations due to early nutritional exposures may have permanent health consequences. Studies of diet and fetal size have mainly focused on individual nutrients despite evidence that the pattern of food consumption may be of significance. Hence, we evaluated the associations of dietary habits in early pregnancy (gestational age 12 concentrations and showed an inverse relationship with homocysteine and high-sensitivity C-reactive protein plasma concentrations (P <0·05). Important fetal size and placental parameters were associated with the degree of adherence to the diet, revealing a 72 g lower birth weight (95 % CI − 110·8, − 33·3) and a 15 g lower placental weight (95 % CI − 29·8, − 0·2) for women with low adherence to the diet. To conclude, low adherence to a Mediterranean diet in early pregnancy seems associated with decreased intra-uterine size with a lower placental and a lower birth weight.

Background: Folate is a methyl donor. Availability of folate affects DNA methylation profiles and thereby gene expression profiles. We investigated the effects of low-dose folic acid use (0.4 mg/d) on the ovarian response to mild and conventional ovarian stimulation in women. Methods: In a randomized trial among subfertile women, 24 and 26 subjects received conventional and mild ovarian stimulation, respectively. Blood samples were taken during the early follicular phase of the cycle prior to treatment and on the day of human chorionic gonadotropin administration for determination of serum total homocysteine, anti-Müllerian hormone (AMH), estradiol, and folate. Folic acid use was validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian response was assessed using linear regression analysis. Results: Folic acid use modified the ovarian response to ovarian stimulation treatment. The estradiol response was higher in nonfolic acid users receiving conventional treatment [βinteraction = 0.52 (0.07–0.97); P = 0.03], and this effect was independent of serum AMH levels and the preovulatory follicle count. In the conventional treatment, the mean follicle number was also greater in nonusers compared with the users group (14.1 vs. 8.9, P = 0.03). Conclusion: Low-dose folic acid use attenuates follicular and endocrine responses to conventional stimulation, independent of AMH and follicle count. The nature of this observation suggests that the effect of folic acid is most prominent during early follicle development, affecting immature follicles. Deleterious effects of folate deficiency, like DNA hypomethylation and oxidative stress, can help to explain our observations.

Udgivelsesdato: 2008-Nov Previously we have shown that nonsyndromic cleft lip with or without cleft palate (NSCL/P) is strongly associated with SNPs in IRF6 (interferon regulatory factor 6). Here, we use multispecies sequence comparisons to identify a common SNP (rs642961, G>A) in a newly identified IRF6 enhancer. The A allele is significantly overtransmitted (P = 1 x 10(-11)) in families with NSCL/P, in particular those with cleft lip but not cleft palate. Further, there is a dosage effect of the A allele, with a relative risk for cleft lip of 1.68 for the AG genotype and 2.40 for the AA genotype. EMSA and ChIP assays demonstrate that the risk allele disrupts the binding site of transcription factor AP-2alpha and expression analysis in the mouse localizes the enhancer activity to craniofacial and limb structures. Our findings place IRF6 and AP-2alpha in the same developmental pathway and identify a high-frequency variant in a regulatory element contributing substantially to a common, complex disorder.

Objective: To investigate the influence of folic acid supplementation on the follicular fluid concentrations of folate and total homocysteine and their relationship to the diameter of the follicle.Design: Observational study.Setting: Tertiary referral fertility clinic at the Erasmus MC, University Medical Center, Rotterdam, The Netherlands.Patient(s): Thirty-seven women undergoing IVF or intracytoplasmic sperm injection treatment.Intervention(s): No interventions other than routine stimulation treatment and the recommendation of folic acid supplementation.Main Outcome Measure(s): Concentrations of folate and total homocysteine in monofollicular and pooled follicular fluid and the diameter of the follicle.Result(s): Folic acid supplementation significantly increased folate and decreased total homocysteine concentrations in pooled follicular fluid. In monofollicular fluid, folate concentrations only were significantly increased in supplemented women. The total homocysteine concentration appeared to be significantly correlated with the diameter of the follicle (r = 0.27). Samples from single follicles were less prone to artifacts in the measurements of the folate and total homocysteine concentration.Conclusion(s): Preconception folic acid supplementation significantly alters both folate and total homocysteine concentrations in follicular fluid. The correlation between the diameter of the follicle and total homocysteine concentration in follicular fluid warrants further investigation.

Context: Polycystic ovary syndrome (PCOS) is associated with a higher frequency of cardiovascular risk factors. Apolipoprotein (apo) A-I and apoB are potent markers for cardiovascular risk. Data on apo levels in women with PCOS are scarce and contradictory. Objective: Our objective was to identify changes in lipid metabolism in women with PCOS, and the relative impact of obesity, insulin resistance, and hyperandrogenism on lipid parameters. Design: This was a case-control study. Setting: The study was performed at a single referral center. Subjects: PCOS was diagnosed according to the 2003 Rotterdam criteria. Healthy mothers with regular menstrual cycles served as controls. Main Outcome Parameters: Fasting insulin, triglycerides (TGs), cholesterol, high-density lipoprotein (HDL)-cholesterol, apoA-I, and apoB were determined. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedewald formula. Results: We included 557 women with PCOS and 295 controls. After correction for age and body mass index, PCOS women had higher median levels of insulin (10.1 vs. 6.9 mU/liter), TGs (95 vs. 81 mg/dl), cholesterol (196 vs. 178 mg/dl), and LDL-cholesterol (125 vs. 106 mg/dl) in combination with lower levels of HDL-cholesterol (46 vs. 55 mg/dl) and apoA-I (118 vs. 146 mg/dl) compared with controls (all P values ≤ 0.01). apoB levels were similar in cases and controls. Free androgen index, body mass index, SHBG, and estradiol were independent predictors of apoA-I levels in women with PCOS. Conclusions: PCOS is associated with a more pronounced atherogenic lipid profile. Furthermore, obesity and hyperandrogenism contribute to an adverse lipid profile. Finally, PCOS seems to constitute an additional risk factor for an atherogenic lipid profile.

Background Deleterious effects of prenatal tobacco smoking on fetal growth and newborn weight are well-established. One of the proposed mechanisms underlying this relationship is alterations in epigenetic programming. We selected 506 newborns from a population-based prospective birth cohort in the Netherlands. Prenatal parental tobacco smoking was assessed using self-reporting questionnaires. Information on birth outcomes was obtained from medical records. The deoxyribonucleic acid (DNA) methylation of the growth genes IGF2DMR and H19 was measured in newborn umbilical cord white blood cells. Associations were assessed between parental tobacco smoking and DNA methylation using linear mixed models and adjusted for potential confounders. Results The DNA methylation levels of IGF2DMR and H19 in the non-smoking group were median (90 % range), 54.0 % (44.6–62.0), and 30.0 % (25.5–34.0), in the first trimester only smoking group 52.2 % (44.5–61.1) and 30.8 % (27.1–34.1), and in the continued smoking group 51.6 % (43.9–61.3) and 30.2 % (23.7–34.8), respectively. Continued prenatal maternal smoking was inversely associated with IGF2DMR methylation (β = −1.03, 95 % CI −1.76; −0.30) in a dose-dependent manner (P-trend = 0.030). This association seemed to be slightly more profound among newborn girls (β = −1.38, 95 % CI −2.63; −0.14) than boys (β = −0.72, 95 % CI −1.68; 0.24). H19 methylation was also inversely associated continued smoking

Phenotype of the neural tube defect mouse model bent tail is not sensitive to maternal folinic acid, myo-inositol, or zinc supplementation.Franke B, Klootwijk R, Lemmers B, de Kovel CG, Steegers-Theunissen RP, Mariman EC.Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands. b.franke@antrg.umcn.nlBACKGROUND: Bent tail is a mouse model for X-linked neural tube defects (NTDs) that is characterized by the presence of exencephaly, a delayed posterior neuropore closure, and a tail phenotype. In addition, Bent tail shows laterality defects and increased prenatal mortality. The congenital malformations of this mouse are caused by a submicroscopic deletion that completely encompasses the gene coding for the zinc finger transcription factor Zic3. In this study we investigated the sensitivity of the phenotype of Bent tail to the nutrients folinic acid, myo-inositol, and zinc. These nutrients are thought to be involved in the etiology of NTDs, in combination with a genetic predisposition. METHODS: The most penetrant phenotype of the Bent tail mouse, the tail malformation, was used as a marker for the nutrient sensitivity of the neural phenotype. The size of the litters and the survival of the offspring, subdivided according to genotype, were analyzed as markers for the nutrient sensitivity of other phenotypic features of Bent tail. RESULTS: In confirmation of earlier studies, we observed the prenatal loss of a number of homozygous females and hemizygous males, as well as the effect of genotype on the tail phenotype of Bent tail. However, periconceptional supplementation of the maternal diet with folinic acid, myo-inositol, or zinc produced no significant effects on either the tail phenotype of the offspring or the size and genotypic composition of the litters. CONCLUSIONS: Bent tail appears to be a folinic acid-, myo-inositol-, and zinc-insensitive mouse model for NTDs. Copyright 2003 Wiley-Liss, Inc

We aimed to investigate whether periconceptional maternal folate status affects human embryonic cerebellar size and growth trajectories. In a prospective periconceptional cohort participants filled out questionnaires and received weekly transvaginal 3D-ultrasounds between 7+0 and 12+6 weeks gestational age (GA). Viable non-malformed singleton pregnancies were selected for cerebellar measurements; transcerebellar diameter, (TCD), left and right cerebellar diameters (LCD, RCD). Linear mixed models were performed to estimate associations between questionnaire data on the timing of maternal folic acid supplement initiation and longitudinal cerebellar measurements as a function of crown-rump length (CRL) and GA. Maternal red blood cell folate concentrations were analysed before 8 weeks GA to validate the associations. A total of 263 serial high quality three-dimensional ultrasound scans of 135 pregnancies were studied. Preconceptional compared to postconceptional initiation of folic acid use was associated with slightly larger cerebellar diameters per millimetre increase of CRL (TCD: β = 0.260mm, 95%CI = 0.023-0.491, p

Background/Aims: Elevated plasma total homocysteine (tHcy) concentrations are a risk factor for neural tube defects and vascular diseases. Supplementation with folic acid decreases tHcy. We investigated whether supplementation with 500 µg folic acid every other day is as effective in lowering tHcy as 250 µg folic acid each day. Methods: In a 4-week intervention study, 22 healthy young women (18–40 years old) took either 500 µg folic acid every other day (500-µg/2d group) or 250 µg folic acid each day (250-µg/d group). Fasting blood was collected on days 0 and 28. Results: Plasma folate concentrations increased by 11.4 nmol/l (6.8–15.9) in the 250-µg/d group and by 9.1 nmol/l (95% Cl 1.9–16.3) in the 500-µg/2d group. These increases were not significantly different from each other. THcy concentrations decreased by 1.52 µmol/l (95% Cl –2.09 to –0.95; p < 0.001) in the 250-µg/d group and by 0.88 µmol/l (–1.53 to –0.23; p < 0.05) in the 500-µg/2d group. The difference in decrease between the 250-µg/d group and the 500-µg/2d group was 0.64 µmol/l (p = 0.11). Conclusion: Although not conclusive, this study suggests that supplying subjects with folic acid each day decreases tHcy more effectively than a double dose every other day.

Attention deficit/hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder. In addition, early life environmental factors contribute to the occurrence of ADHD. Recently, DNA methylation has emerged as a mechanism potentially mediating genetic and environmental effects. Here, we investigated whether newborn DNA methylation patterns of selected candidate genes involved in psychiatric disorders or fetal growth are associated with ADHD symptoms in childhood. Participants were 426 children from a large population based cohort of Dutch national origin. Behavioral data were obtained at age 6 years with the Child Behavior Checklist. For the current study, 11 regions at 7 different genes were selected. DNA methylation levels of cord blood DNA were measured for the 11 regions combined and for each region separately. We examined the association between DNA methylation levels at different regions and ADHD symptoms with linear mixed models. DNA methylation levels were negatively associated with ADHD symptom score in the overall analysis of all 11 regions. This association was largely explained by associations of DRD4 and 5-HTT regions. Other candidate genes showed no association between DNA methylation levels and ADHD symptom score. Associations between DNA methylation levels and ADHD symptom score were attenuated by co-occurring Oppositional defiant disorder and total symptoms. Lower DNA methylation levels of the 7 genes assessed at birth, were associated with more ADHD symptoms of the child at 6 years of age. Further studies are needed to confirm our results and to investigate the possible underlying mechanism. (C) 2013 Elsevier Ltd. All rights reserved.

Nonsyndromic orofacial clefting (nsOFC) is a common, complex congenital disorder. The most frequent forms are nonsyndromic cleft lip with or without cleft palate (nsCL/P) and nonsyndromic cleft palate only (nsCPO). Although they are generally considered distinct entities, a recent study has implicated a region around the FOXE1 gene in both nsCL/P and nsCPO. To investigate this hypothesis, we analyzed the 2 most strongly associated markers (rs3758249 and rs4460498) in 2 independent samples of differing ethnicities: Central European (949 nsCL/P cases, 155 nsCPO cases, 1163 controls) and Mayan Mesoamerican (156 nsCL/P cases, 10 nsCPO cases, 338 controls). While highly significant associations for both single-nucleotide polymorphisms were obtained in nsCL/P (rs4460498: pEurope = 6.50 × 10−06, pMayan = .0151; rs3758249: pEurope = 2.41 × 10−05, pMayan = .0299), no association was found in nsCPO ( p > .05). Genotyping of rs4460498 in 472 independent European trios revealed significant associations for nsCL/P ( p = .016) and nsCPO ( p = .043). A meta-analysis of all data revealed a genomewide significant result for nsCL/P ( p = 1.31 × 10−08), which became more significant when nsCPO cases were added ( pnsOFC = 1.56 × 10−09). These results strongly support the FOXE1 locus as a risk factor for nsOFC. With the data of the initial study, there is now considerable evidence that this locus is the first conclusive risk factor shared between nsCL/P and nsCPO.