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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.

Objectives To examine differences in growth trajectories of fetal brain fissures in the growth restricted fetus (FGR) compared to controls. Methods We selected a subgroup of 227 women with a singleton pregnancy from the Rotterdam Periconceptional Cohort. Participants received three-dimensional ultrasound (3D-US) examinations of the fetal brain at 22, 26 and 32 weeks of gestational age (GA). The left and right Sylvian, insula and parieto-occipital fissures (POF) were measured in standardized planes. Linear mixed models with adjustment for potential confounders were applied to estimate differences between the trajectories of brain fissure depth measurements of FGR and controls. Results 22 FGR and 172 controls provided 31 and 504 3D-US respectively for longitudinal brain fissure depth measurements. Success rates for the Sylvian and insula depth measurements were over 80% and for POF over 62% at all GA. In FGR compared to controls, the trajectory of the right Sylvian fissure depth was significantly decreased (s = -4.30, 95%CI = -8.03;-0.56, p = 0.024) while its growth rate was slightly increased (s = 0.02, 95%CI = 0.00;0.04, p = 0.04), after adjustment for GA, head circumference, gender, educational level and parity. Conclusions The small differences in brain fissure measurements between 22 and 32 weeks GA in FGR warrant further investigation in larger cohorts with postnatal follow-up.

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.

The name of the third author was spelled incorrectly. The correct name is: N.H. van Mil. The correct Citation is: Stolk L, Bouwland-Both MI, van Mil NH, Verbiest MMPJ, Eilers PHC, et al. (2013) Epigenetic Profiles in Children with a Neural Tube Defect; A Case-Control Study in Two Populations. PLoS ONE 8(11): e78462. doi:10.1371/journal.pone.0078462.

Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (IGF2-DMR, H19, KCNQ1OT1) and non-imprinted genes (the LEKR/CCNL gene region associated with birth weight, and MTHFR and VANGL1 associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of MTHFR (absolute decrease in methylation of -0.33% in cases, P-value = 0.001), and LEKR/CCNL (absolute increase in methylation: 1.36% in cases, P-value = 0.048), and a borderline significant association for VANGL (absolute increase in methylation: 0.17% in cases, P-value = 0.063). Only the association between MTHFR and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the MTHFR gene, and maybe VANGL and LEKKR/CNNL, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively.

BACKGROUND:Countries worldwide recommend women planning pregnancy to use daily 400 microg of synthetic folic acid in the periconceptional period to prevent birth defects in children. The underlying mechanisms of this preventive effect are not clear, however, epigenetic modulation of growth processes by folic acid is hypothesized. Here, we investigated whether periconceptional maternal folic acid use and markers of global DNA methylation potential (S-adenosylmethionine and S-adenosylhomocysteine blood levels) in mothers and children affect methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in the child. Moreover, we tested whether the methylation of the IGF2 DMR was independently associated with birth weight. METHODOLOGY/PRINCIPAL FINDINGS:IGF2 DMR methylation in 120 children aged 17 months (SD 0.3) of whom 86 mothers had used and 34 had not used folic acid periconceptionally were studied. Methylation was measured of 5 CpG dinucleotides covering the DMR using a mass spectrometry-based method. Children of mother who used folic acid had a 4.5% higher methylation of the IGF2 DMR than children who were not exposed to folic acid (49.5% vs. 47.4%; p = 0.014). IGF2 DMR methylation of the children also was associated with the S-adenosylmethionine blood level of the mother but not of the child (+1.7% methylation per SD S-adenosylmethionine; p = 0.037). Finally, we observed an inverse independent association between IGF2 DMR methylation and birth weight (-1.7% methylation per SD birthweight; p = 0.034). CONCLUSIONS:Periconceptional folic acid use is associated with epigenetic changes in IGF2 in the child that may affect intrauterine programming of growth and development with consequences for health and disease throughout life. These results indicate plasticity of IGF2 methylation by periconceptional folic acid use.