Neural Tube Defects In Offspring Research Articles

Maternal factors for neural tube defects in offspring: An umbrella review.

We conducted an umbrella review focusing on maternal risk factors during pregnancy associated with neural tube defects (NTDs). Our search was in databases PubMed, Scopus, and Web of Science. We specifically targeted meta-analyses examining maternal factors during pregnancy in relation to NTDs. The comparison involved assessing metrics such as odds ratio (OR) or related risk ratios reported in the included studies, as well as parameters like heterogeneity (I²), 95% prediction interval, small-study effects, excess significance biases, and sensitivity analysis. Three risk factors for fetal NTDs, namely hyperthermia with an OR of 1.92, obesity with an OR of 1.68, and passive smoking with an OR of 1.90, were classified as highly suggestive evidence (Class II). Influenza, with an OR of 3.33, was considered a risk factor with suggestive evidence (Class III). Multivitamin supplementation during pregnancy, with an OR of 0.76, and low maternal vitamin B12, with an OR of 2.41, were categorized as weak evidence (Class IV). We identified four risk factors including hyperthermia, influenza, obesity, and passive smoking as suggestive or highly suggestive evidence for NTDs. Low maternal vitamin B12 was identified as a risk factor for NTDs, supported by weak evidence.

Preconception Folic Acid and Multivitamin Supplementation for the Prevention of Neural Tube Defect: An Umbrella Review of Systematic Review and Meta-analysis.

Previous reviews explored the association between maternal use of folic acid and multivitamin supplements and risk of neural tube defect (NTD) in children, with no definitive conclusion. These reviews had produced contradictory results, and there had been no umbrella review. Therefore, the objective of this umbrella review is to combine the inconsistent data on the effect of prenatal folic acid and/or multivitamin supplementation for the prevention of NTD in offspring. Using the PRISMA guideline, PubMed, Embase, Scopus, Web of Sciences, Cochrane Database of Systematic Reviews, Scopus, and Google Scholar reported that the effects of folic acid and/or multivitamin supplementation for the prevention of NTD in offspring were searched. The quality of the included studies was assessed using Assessment of Multiple Systematic Reviews (AMSTAR). A weighted inverse variance random-effects model was applied to find the pooled estimates. The subgroup analysis, heterogeneity, publication bias, and sensitivity analysis were also assessed. Ten SRM with 296,816 study participants were included. The random-effects model analysis from 10 included systematic review and meta-analysis revealed that the pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD globally is found to be 0.43 (95% CI: 0.29, 0.58) (I2 = 93.50%; p ≤0.001). In the subgroup analysis, the pooled effect was found to be 0.23 (0.09, 0.37) in folic acid group, while this estimate is 0.63 (0.53, 0.72) and 0.61 (0.46, 0.75) in groups who took multivitamin. The pooled effect of prevention of NTD was found to be 0.50 (0.34, 0.66) in SRMs aimed at occurrence prevention (primary prevention) group, while this estimate is 0.20 (-0.01, 0.41) among SRMs, which aimed at reoccurrence (secondary) prevention, and 0.61 (0.46, 0.75) among those SRMs aimed to assess the effect folic acid or multivitamin for the prevention of both occurrence and reoccurrence. The pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD was found to be 0.45 (0.03, 0.87) in SRMs of observational studies, while this estimate is 0.43 (0.32, 0.54) among SRMs of randomized controlled trials. This umbrella review of systematic review and meta-analysis found that prenatal folic acid and/or multivitamin supplementation was associated with a 57% reduction in NTD. Participants who took folic acid supplementation were associated with a slightly higher (77%) percentage of reduction in NTD compared with those who took multivitamin (37%). Reductions of 80% and 50% were observed for reoccurrence and occurrence prevention of NTD. Reductions of 57% and 55% of NTD have been found in SRM of RCTs and observational studies. This umbrella review revealed that both folic acid and multivitamin were associated with significantly lower levels of NTD in children. Considering the incorporation of those supplements in NTD prevention strategies during the preconception period is recommended. More large-scale prospective cohort and RCTs are needed to understand the protective effect of multivitamins and/or folic acid on NTD risk addressing the molecular mechanisms and to determine the optimal dose, duration, and timing of maternal multivitamin and folic acid intake for best child NTD risk reduction.

Maternal periconceptional exposure to drinking water disinfection by-products and neural tube defects in offspring.

Associations between maternal periconceptional exposure to disinfection by-products (DBPs) in drinking water and neural tube defects (NTDs) in offspring are inconclusive, limited in part by exposure misclassification. Maternal interview reports of drinking water sources and consumption from the National Birth Defects Prevention Study were linked with DBP concentrations in public water system monitoring data for case children with an NTD and control children delivered during 2000-2005. DBPs analyzed were total trihalomethanes, the five most common haloacetic acids combined, and individual species. Associations were estimated for all NTDs combined and selected subtypes (spina bifida, anencephaly) with maternal periconceptional exposure to DBPs in public water systems and with average daily periconceptional ingestion of DBPs accounting for individual-level consumption and filtration information. Mixed effects logistic regression models with maternal race/ethnicity and educational attainment at delivery as fixed effects and study site as a random intercept were applied. Overall, 111 case and 649 control children were eligible for analyses. Adjusted odds ratios for maternal exposure to DBPs in public water systems ranged from 0.8-1.5 for all NTDs combined, 0.6-2.0 for spina bifida, and 0.7-1.9 for anencephaly; respective ranges for average daily maternal ingestion of DBPs were 0.7-1.1, 0.5-1.5, and 0.6-1.8. Several positive estimates (≥1.2) were observed, but all confidence intervals included the null. Using community- and individual-level data from a large, US, population-based, case-control study, we observed statistically nonsignificant associations between maternal periconceptional exposure to total and individual DBP species in drinking water and NTDs and subtypes.

Inadvertent antibiotic exposure during pregnancy may increase the risk for neural tube defects in offspring

BackgroundAs emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. MethodsIn this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. ResultsOnly 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01–10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. ConclusionsIntentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.

Periconceptional intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further reduce the risk of neural tube defects in offspring: a United States population–based case-control study of women meeting the folic acid recommendations

BackgroundNeural tube defects (NTDs) still occur among some women who consume 400 μg of folic acid for prevention. It has been hypothesized that intakes of methyl donors and other micronutrients involved in one-carbon metabolism may further protect against NTDs. ObjectivesTo investigate whether intakes of vitamin B6, vitamin B12, choline, betaine, methionine, thiamine, riboflavin, and zinc, individually or in combination, were associated with NTD risk reduction in offspring of women meeting the folic acid recommendations. MethodsData were from the National Birth Defects Prevention Study (United States population–based, case-control). We restricted deliveries between 1999 and 2011 with daily periconceptional folic acid supplementation or estimated dietary folate equivalents ≥400 μg. NTD cases were live births, stillbirths, or terminations affected by spina bifida, anencephaly, or encephalocele (n = 1227). Controls were live births without a major birth defect (n = 7095). We categorized intake of each micronutrient as higher or lower based on a combination of diet (estimated from a food frequency questionnaire) and periconceptional vitamin supplementation. We estimated NTD associations for higher compared with lower intake of each micronutrient, individually and in combination, expressed as odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age, race/ethnicity, education, and study center. ResultsNTD associations with each micronutrient were weak to modest. Greater NTD reductions were observed with concurrent higher-amount intakes of multiple micronutrients. For instance, NTD odds were ∼50% lower among participants with ≥4 micronutrients with higher-amount intakes than among participants with ≤1 micronutrient with higher-amount intake (adjusted OR: 0.53; 95% CI: 0.33, 0.86). The strongest reduction occurred with concurrent higher-amount intakes of vitamin B6, vitamin B12, choline, betaine, and methionine (adjusted OR: 0.26; 95% CI: 0.09, 0.77) compared with ≤1 micronutrient with higher-amount intake. ConclusionsOur findings support that NTD prevention, in the context of folic acid fortification, could be augmented with intakes of methyl donors and other micronutrients involved in folate metabolism.

Maternal prenatal screening programs that predict trisomy 21, trisomy 18, and neural tube defects in offspring.

To determine the efficacy of three different maternal screening programs (first-trimester screening [FTS], individual second-trimester screening [ISTS], and first- and second-trimester combined screening [FSTCS]) in predicting offspring with trisomy 21, trisomy 18, and neural tube defects (NTDs). A retrospective cohort involving 108,118 pregnant women who received prenatal screening tests during the first (9-13+6 weeks) and second trimester (15-20+6 weeks) in Hangzhou, China from January-December 2019, as follows: FTS, 72,096; ISTS, 36,022; and FSTCS, 67,631 gravidas. The high and intermediate risk positivity rates for trisomy 21 screening with FSTCS (2.40% and 5.57%) were lower than ISTS (9.02% and 16.14%) and FTS (2.71% and 7.19%); there were statistically significant differences in the positivity rates among the screening programs (all P < 0.05). Detection of trisomy 21 was as follows: ISTS, 68.75%; FSTCS, 63.64%; and FTS, 48.57%. Detection of trisomy 18 was as follows; FTS and FSTCS, 66.67%; and ISTS, 60.00%. There were no statistical differences in the detection rates for trisomy 21 and 18 among the 3 screening programs (all P > 0.05). The positive predictive values (PPVs) for trisomy 21 and 18 were highest with FTS, while the false positive rate (FPR) was lowest with FSTCS. FSTCS was superior to FTS and ISTS screening and substantially reduced the number of high risk pregnancies for trisomy 21 and 18; however, FSTCS was not significantly different in detecting fetal trisomy 21 and 18 and other confirmed cases with chromosomal abnormalities.

Indoor air pollution from coal combustion and tobacco smoke during the periconceptional period and risk for neural tube defects in offspring in five rural counties of Shanxi Province, China, 2010–2016

Indoor air pollution may increase the risk for neural tube defects (NTDs) in Chinese rural populations. However, this association remains a subject of debate. We conducted a population-based case-control study of 222 NTD and 517 control mothers recruited between 2010 and 2016 in five rural areas in northern China. An indoor air pollution exposure evaluation index (IAPEEI) was used to evaluate mothers’ exposure to tobacco-sourced and coal-sourced indoor air pollution. Essential characteristics were collected using structured questionnaires within 10 days of delivery. We found that exposure to indoor air pollution (IAPEEI ≥ 1) can lead to 3.41 times the risk of conceiving NTD fetuses compared with the no-exposure group (IAPEEI = 0) (adjusted odds ratio and 95 % confidence interval: 3.41 [2.34–5.02]). The risk increased with increasing IAPEEI score, indicating a clear dose–response trend (P < 0.001). Using a coal stove for heating (especially in the bedroom) and passive smoking are significantly associated with an increased likelihood of NTD occurrence. Exposure to indoor air pollution is a daily reality for rural women in China, and its impact on reproductive health deserves extensive attention.

A High Concentration of Polycyclic Aromatic Hydrocarbons in Umbilical Cord Tissue is Associated with an Increased Risk for Fetal Neural Tube Defects

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and have detrimental effects on human health. Embryos are particularly susceptible to environmental insults such as PAHs. We examined the association between prenatal exposure to PAHs and the risk for fetal neural tube defects (NTDs). A case–control study was conducted with 119 NTD cases and 119 controls. A total of 16 PAHs in umbilical cord tissue, determined with gas chromatography–mass spectrometry, were used as in utero exposure markers. Logistic regression and Bayesian kernel machine regression (BKMR) were performed to evaluate the individual and overall effects of PAH exposure on the risk for NTDs, respectively. Median concentrations of 10 PAHs were significantly higher in cases than in controls. In logistic regression, concentrations of four PAHs above the median of all participants were significantly associated with an increased NTD risk, even when potential covariates were adjusted for: phenanthrene, 2.35-fold (95% confidence interval [CI] 1.04–5.34); fluoranthene, 2.37-fold (95% CI 1.02–5.48); pyrene, 2.41-fold (95% CI 1.04–5.62); and benzo(b)fluoranthene, 2.95-fold (95% CI 1.27–6.86). In BKMR, although the risk for NTD was increased with PAH concentrations above the 50th percentile, it was only when PAH concentrations exceeded the 65th percentile, the association between PAH concentration and risk for NTDs became statistically significant, while no statistical association between a single compound and NTD risk was observed when the remaining nine PAHs were taken into consideration simultaneously. The use of an indoor stove for heating and use of coal or wood for cooking were positively correlated with PAH levels in cord tissue. In conclusion, these results show that prenatal PAH exposure may be a risk factor for NTDs in offspring.

Maternal Folic Acid-Containing Supplement Use in Relation to Offspring Motor Function. A Prospective Study of 503 Mother-Child Dyads.

BackgroundThe preventive effect of maternal folic acid use on offspring neural tube defects is well-established. However, a putative link between supplement use and other neurodevelopmental outcome is inconsistent. The aim of this study was to examine the association of folic acid-containing supplement use before and during pregnancy with motor function in children aged 3–18 months.MethodThe study has a prospective cohort design including 503 mother-infant dyads. Motor function was measured by the Infant Motor Profile (IMP) and Ages and Stages Questionnaire Second Edition (ASQ-2). Associations between exposure and outcome were examined using linear regression analysis with robust standard error estimation.ResultsOffspring total IMP score was not associated with any maternal folic acid-containing supplement use when they were used during pregnancy only (adjusted β = 0.11 95% CI = −1.19, 1.40; p = 0.87) or when they were used both before and during pregnancy (adjusted β = 0.22 95% CI = −0.95, 1.40; p = 0.70). When examining the five domain scores separately, only the IMP domain adaptability showed some association with supplement use during pregnancy (adjusted β = 2.87; 95% CI = 0.08, 5.68; p = 0.04), but the strength of the association was weak. Further, supplement use was not associated with any of the two motor domains of ASQ-2.ConclusionAlthough no association between folic acid-containing supplement use and offspring motor function was found, the complexity of this topic and its potential mechanisms, requires further investigation. This research should include robust and accurate measures on maternal nutritional status along with thorough endpoint assessments.

Placental concentrations of alkali metals and their associations with neural tube defects in offspring.

The role of alkali metals in the development of neural tube defects (NTDs) is little known. We examined the associations between placental concentrations of lithium (Li), sodium (Na), potassium (K), rubidium (Rb), and cesium (Cs), and the occurrence of NTDs in fetuses. 408 women who had NTD-affected pregnancies and 593 women who delivered healthy infants were included. Logistic regression, weight quantile sum regression (WQSR), and Bayesian kernel machine regression (BKMR) were applied to assess whether these metals are associated with the occurrence of NTDs. Cs showed an inverse association with the odds of NTDs [adjusted odds ratio (aOR): 0.58, 95% confidence interval (CI): 0.36-0.91] in single-metal logistic model. Estimates did not change much in the multiple-metal logistic model. In WQSR, the WQS index was inversely associated with the odds of NTDs (aOR: 0.62, 95%CI: 0.51-0.75), in which Cs (weighted 0.45) had the highest weight. In BKMR, the odds of NTDs decreased with the levels of the five-metal mixtures. Cs was associated with decreased odds of NTDs when the remaining four metals were fixed at their 25th and 50th percentiles, while Na was associated with increased odds of NTDs when setting other metals at the 25th, 50th, or 75th percentile. A high concentration of Cs and Na in placental tissue was respectively associated with decreased and increased odds of NTDs. In addition, the occurrence of NTDs decreased with the levels of the five-metal mixtures.

Maternal status of trace elements and risk of neural tube defects in offspring: a meta-analysis of 6121 pregnancies

Maternal status of trace elements and risk of neural tube defects in offspring: a meta-analysis of 6121 pregnancies

Total mercury concentration in placental tissue, a good biomarker of prenatal mercury exposure, is associated with risk for neural tube defects in offspring

ObjectiveTo examine the role of total mercury (T-Hg) in placenta as a biomarker of prenatal mercury (Hg) exposure and determine the association between prenatal Hg exposure and risk for neural tube defects (NTDs) in offspring. MethodsTotal Hg concentrations in placental tissue were detected in 408 NTD cases and 593 healthy controls enrolled in Shanxi province in northern China. Methylmercury (MeHg) and T-Hg were also detected in the umbilical cord of 147 NTD cases and 140 healthy controls. In addition, MeHg and T-Hg were detected in fetal kidney, liver, and brain tissues of 51 NTD cases. Spearman’s rank correlation (rs) was used to evaluate the correlations between placental T-Hg and T-Hg in umbilical cord and fetal kidney, liver, and brain tissues. The Wilcoxon rank-sum test was used to compare T-Hg amounts between case and control groups. Logistic regression was used to examine the association between placental T-Hg and risk for NTDs. ResultsPlacental T-Hg was significantly correlated with T-Hg in umbilical cord (rs = 0.479), kidney (rs = 0.718), liver (rs = 0.656), and brain (rs = 0.512) tissues (all p < 0.001). The median (25th percentile–75th percentile) concentration for placental T-Hg in the NTD case group was 8.91 (5.00–17.1) ng/g dry weight (d.w.), significantly higher than that in the healthy control group (4.99 [3.26–7.93] ng/g d.w., p < 0.001). After adjusting for potential confounders, higher levels of T-Hg in placenta were associated with increased risk for NTDs in offspring (OR = 1.76, 95% CI: 1.13–2.76), and a dose–response relationship was found (p < 0.001). ConclusionThe concentration of T-Hg in placenta is a good biomarker for estimating prenatal Hg exposure, which is associated with increased risk for NTDs.

Passive Smoking During the Periconceptional Period and Risk for Neural Tube Defects in Offspring - Five Counties, Shanxi Province, China, 2010-2016.

What is already known about this topic?Passive smoking during pregnancy, which is prevalent in China, has been reported to be associated with an increased risk for neural tube defects (NTDs) in five counties of Shanxi Province in northern China.What is added by this report?After 4 years since the implementation of the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) in China, 59.4% of mothers of NTDs cases and 29.4% of mothers of healthy controls reported passive smoking during the periconceptional period. The association between periconceptional passive smoking and an increased risk for NTDs remains in the study population.What are the implications for public health practice?It’s urgent to take measures to prevent passive smoking among pregnant women to minimize the harmful effects on offspring.

Prenatal exposure to barium and the occurrence of neural tube defects in offspring

Neural tube defects (NTDs) have a complex etiology. Few studies have assessed alkaline earth metals exposures and occurrence of NTDs. We examined the association between prenatal exposure to magnesium (Mg), calcium (Ca), strontium (Sr) and barium (Ba) and risk for NTDs in a case-control study, and assessed the teratogenic effects of Ba on mice. Placentas were collected from 408 women with NTD-affected pregnancies and 593 women who delivered healthy infants, and concentrations of these metals were determined as prenatal exposure markers. The single effect of individual exposure and joint effect of coexposure to these metals were evaluated with logistic regression and Bayesian kernel machine regression (BKMR), respectively. Barium chloride (BaCl2) was intragastrically administered to pregnant ICR mice and fetal mice were examined for NTDs. Median concentrations of Mg and Ba were higher in NTD cases than in controls (Pall < 0.001). In logistic regression, higher levels of Ba were associated with 1.6-fold increased risk for NTDs (95% confidence interval: 1.06–2.43). In BKMR, the joint effect of the four-metal mixture on NTD risk increased steadily with the levels of the mixture. A change in Ba concentration from the 25th to 75th percentile displayed a risk effect when the other three metals were fixed at the 25th, 50th or 75th percentile, while such a change in Ca concentration showed a protective effect when the other metals were held at the 25th or 50th percentile. No interactions among metals were found. In the mouse experiment, dams treated with 200 mg/kg BaCl2 showed 16.8% of NTDs in fetal mice, compared to 2.6% in the untreated control group (P < 0.01). Taken together, higher mixture levels of the four alkaline earth metals were associated with increased risk for NTDs, with Ba being the major contributor for the joint effect. Intragastric administration of Ba can induce NTDs in mice.

P.112 Effects of early-life fluvoxamine exposure on social behaviours of white rats depend on the timing of its perinatal administration

Valproic acid (VPA), an antiepileptic and mood-stabilizing drug, is prescribed to women of reproductive age. VPA is associated with a 1–2% increase in neural tube defects in offspring following gestational exposure and results in epigenetic modifications induced by perturbations in transcription cofactors. Cbp and p300, two transcription cofactors, play key roles in embryonic neural development. p300 is a downstream target of Akt, a protein kinase B associated with cell survival and anti-apoptotic mechanisms, as part of the Akt-p300 axis. We examined the effects of in utero VPA exposure on Cbp, p300, and Akt in gestational day (GD)9, GD10 and GD13 CD-1 mouse embryos following a teratogenic maternal dose of 400 mg/kg. Embryos were collected at 0, 1, 3 and 6 h post-dosing on GD9, 24 h post-dosing on GD10 and on GD13. GD10 embryos were grouped according to the status of neural tube closure in control, closed and open groups. GD13 heads were grouped as control, exposed but non-exencephalic and exencephalic. Our data indicate that Cbp, p300 and Akt mRNA levels were downregulated at 1 and 3 h post-exposure in GD9 embryos while Cbp and p300 protein levels remained stable. Akt protein levels were significantly increased 1 h post-exposure. No significant changes were observed in either mRNA or protein expression in embryos with closed or open neural tubes compared to the control group at GD10. Downregulated expression of Cbp, p300, and Akt may play a key role in VPA-induced neural tube defects considering their vitally important role in embryonic development.

Association of paternal smoking with the risk of neural tube defects in offspring: A systematic review and meta-analysis of observational studies.

The present study aimed at providing some epidemiological evidences to assess the association of paternal smoking with the risk of neural tube defects (NTDs) and its specific subtypes in offspring, and explore the possible dose-response relationship between paternal smoking and risk of NTDs. English and Chinese databases were systematically searched from 1984 to May 2020. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. We also examined the dose-response relationship between parental smoking and risk of NTDs in offspring. Subgroup analyses and sensitivity analyses were conducted to explore possible sources of heterogeneity. A total of 10 case-control studies involving 2,593 cases of NTDs and 45,100 controls were included for analysis. Findings from our study showed that paternal smoking was significantly associated with risk of total NTDs (odds ratio [OR] = 1.68; 95% confidence interval (CI): 1.48-1.92) and two subtypes including anencephaly (OR=1.41; 95% CI: 1.06-1.86) and encephaloceles (OR=2.90; 95% CI: 1.00-8.41). Additionally, a linear dose-response relationship between paternal smoking and risk of NTDs was observed, which indicated that the risk of NTDs in offspring was significantly increased by 45% (OR=1.45, 95% CI: 1.14-1.84) for each increment of half a pack of cigarettes per day. Sensitivity analyses yielded consistent results. No evidence of publication bias was found. Paternal smoking is significantly associated with the risk of NTDs in offspring. Therefore, it should be recommended that fathers quit smoking before pregnancy to prevent NTDs in offspring.

Role of Cbp, p300 and Akt in valproic acid induced neural tube defects in CD-1 mouse embryos

Valproic acid (VPA), an antiepileptic and mood-stabilizing drug, is prescribed to women of reproductive age. VPA is associated with a 1–2% increase in neural tube defects in offspring following gestational exposure and results in epigenetic modifications induced by perturbations in transcription cofactors. Cbp and p300, two transcription cofactors, play key roles in embryonic neural development. p300 is a downstream target of Akt, a protein kinase B associated with cell survival and anti-apoptotic mechanisms, as part of the Akt-p300 axis. We examined the effects of in utero VPA exposure on Cbp, p300, and Akt in gestational day (GD)9, GD10 and GD13 CD-1 mouse embryos following a teratogenic maternal dose of 400 mg/kg. Embryos were collected at 0, 1, 3 and 6 h post-dosing on GD9, 24 h post-dosing on GD10 and on GD13. GD10 embryos were grouped according to the status of neural tube closure in control, closed and open groups. GD13 heads were grouped as control, exposed but non-exencephalic and exencephalic. Our data indicate that Cbp, p300 and Akt mRNA levels were downregulated at 1 and 3 h post-exposure in GD9 embryos while Cbp and p300 protein levels remained stable. Akt protein levels were significantly increased 1 h post-exposure. No significant changes were observed in either mRNA or protein expression in embryos with closed or open neural tubes compared to the control group at GD10. Downregulated expression of Cbp, p300, and Akt may play a key role in VPA-induced neural tube defects considering their vitally important role in embryonic development.

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

BackgroundPericonception 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.MethodsReview 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.ResultsEmbryonic 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.ConclusionsFrom 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.

Association between maternal periconceptional alcohol consumption and neural tube defects: Findings from the National Birth Defects Prevention Study, 1997-2011.

Neural tube defects (NTD)s are common birth defects with a multifactorial etiology. Findings from human studies examining environmental (non-inherited) exposures tend to be inconclusive. In particular, although animal studies of alcohol exposure and NTDs support its teratogenic potential, human studies are equivocal. Using data from the National Birth Defects Prevention Study (NBDPS), associations between maternal periconceptional (1 month before through 1 month after conception) alcohol consumption and NTDs in offspring were examined. NTD cases and unaffected live born singleton controls with expected dates of delivery from October 1997-December 2011 were enrolled in the NBDPS. Interview reports of alcohol consumption (quantity, frequency, variability, type) from 1,922 case and 11,251 control mothers were analyzed. Crude and adjusted odds ratios (aOR)s and 95% confidence intervals (CI)s for alcohol consumption and all NTDs combined and selected subtypes (spina bifida, anencephaly, encephalocele) were estimated using unconditional logistic regression analysis. Among mothers in the NBDPS, 28% of NTD case and 35% of control mothers reported any periconceptional alcohol consumption. For each measure of alcohol consumption, inverse associations were observed for all NTDs combined (aORs = 0.6-1.0). Results for NTD subtypes tended to be similar, but CIs for spina bifida and encephalocele were more likely to include the null. These findings suggest a lack of positive associations between maternal periconceptional alcohol consumption and NTDs. Future studies should continue to evaluate the association between maternal alcohol consumption and NTDs in offspring accounting for methodological limitations such as potential misclassification from self-reported alcohol consumption.

Association between maternal exposure to ambient PM10 and neural tube defects: A case-control study in Liaoning Province, China.

The potential association between maternal exposure to ambient PM10 and offspring neural tube defects (NTDs) is a contentious issue. This study aims to evaluate the aforementioned association at a provincial level in China. A total of 2736 cases and 7950 randomly selected healthy infants included in the Maternal and Child Health Certificate Registry of Liaoning Province and delivered between 2010 and 2015 were recruited. Daily PM10 concentrations were obtained from all available monitoring stations located within the study area. A multivariable logistic regression model was established to calculate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). PM10 exposure was significantly associated with the risk of NTDs during the three months preconception (per 10μg/m3 increment: OR=1.10, 95% CI 1.07-1.14; per standard deviation [27μg/m3] increment: OR=1.29, 95% CI 1.18-1.41; highest tertile: OR=1.61, 95% CI 1.37-1.91) and the first trimester (highest tertile: OR=1.57, 95% CI: 1.31-1.87). When focusing on shorter exposure windows, similar associations were observed for PM10 exposure from the third month before pregnancy to the third month after pregnancy. Sensitivity analyses using propensity score matching yielded consistent findings. Maternal exposure to PM10 is positively associated with NTDs during the critical period of fetal neural tube development. However, due to the limitation of the exposure assessment as well as potential residual confounding, further research is warranted to confirm our findings.