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Background: North American health authorities recommend 0.4 mg/day folic acid before conception and throughout pregnancy to reduce the risk of neural tube defects. Folic acid is a synthetic form of folate that must be reduced by dihydrofolate reductase and then further metabolized. Recent evidence suggests that the maximal capacity for this process is limited and unmetabolized folic acid has been detected in the circulation. The biological effects of unmetabolized folic acid are unknown. A natural form of folate, (6S)-5-methyltetrahydrofolic acid (Metafolin®), may be a superior alternative because it does not need to be reduced in the small intestine. Metafolin® is currently used in some prenatal multivitamins; however, it has yet to be evaluated during pregnancy., Methods/design: This double-blind, randomized trial will recruit 60 pregnant women aged 19-42 years. The women will receive either 0.6 mg/day folic acid or an equimolar dose (0.625 mg/day) of (6S)-5-methyltetrahydrofolic acid for 16 weeks. The trial will be initiated at 8-21 weeks' gestation (after neural tube closure) to reduce the risk of harm should (6S)-5-methyltetrahydrofolic acid prove less effective. All women will also receive a prenatal multivitamin (not containing folate) to ensure adequacy of other nutrients. Baseline and endline blood samples will be collected to assess primary outcome measures, including serum folate, red blood cell folate and unmetabolized folic acid. The extent to which the change in primary outcomes from baseline to endline differs between treatment groups, controlling for baseline level, will be estimated using linear regression. Participants will have the option to continue supplementing until 1 week postpartum to provide a breastmilk and blood sample. Exploratory analyses will be completed to evaluate breastmilk and postpartum blood folate concentrations., Discussion: This proof-of-concept trial is needed to obtain estimates of the effect of (6S)-5-methyltetrahydrofolic acid compared to folic acid on circulating biomarkers of folate status during pregnancy. These estimates will inform the design of a definitive trial which will be powered to assess whether (6S)-5-methyltetrahydrofolic acid is as effective as folic acid in raising blood folate concentrations during pregnancy. Ultimately, these findings will inform folate supplementation policies for pregnant women., Trial Registration: ClinicalTrials.gov, ID: NCT04022135. Registered on 14 July 2019.

Objective: The objective of this study is to evaluate the prenatal diagnosis, postnatal characteristics, and the spectrum of associated findings in fetuses with holoprosencephaly (HPE)., Methods: Fetal neurosonograms, postnatal assessment, and chromosomal analysis were performed in a cohort of 25 fetuses with HPE., Results: The prevalence of HPE in high-risk pregnancies was 4.4:10 000. The alobar subtype was the most frequently encountered, with 17 cases (68%). Interestingly, among them, four cases (16%) presented with the rare agnathia-otocephaly complex. Chromosomal abnormalities were detected in 11 cases (44%), the most frequent being trisomy 13 in seven cases (five alobar, one semilobar, and one lobar HPE), followed by trisomy 18 in two cases with semilobar HPE. One case of alobar HPE had 45, XX, t(18;22) (q10;q10), -18p karyotyping, and one case of semilobar HPE was associated with triploidy. Facial malformations in HPE spectrum ranged from cyclopia, proboscis, and arrhinia that were associated with the alobar subtype to hypotelorism and median cleft that were frequent among the semilobar and lobar subtypes. Associated neural tube defects were identified in 12% of cases., Conclusion: Our study illustrates the clinical and genetic heterogeneity of HPE and describes different chromosomal abnormalities associated with HPE., (© 2020 John Wiley & Sons, Ltd.)

Background: Maternal folate status and obesity are known risk factors for neural tube defects (NTD) in the offspring. We examined the association between body mass index (BMI) categories and blood folate concentrations, specifically, red blood cell (RBC) folate concentrations indicative of NTD risk among nonpregnant women of child-bearing age (20-44 years) in the United States., Methods: We used data from 2007 to 2010 US National Health and Nutrition Examination Survey (NHANES). Overweight, obesity, and strata within obesity were examined. Serum and RBC folate concentrations were examined as continuous and categorical variables. RBC folate concentrations were grouped indicating high (≤585 nmol/L) and elevated risk (586-747 nmol/L) for NTDs. Unadjusted and adjusted prevalence odds ratios (aPOR) and their 95% confidence intervals (CI) were estimated using logistic regression., Results: Of the 30,878 participants, 25.6% were overweight, 32.7% obese, and 32.3% had RBC folate concentration indicating NTD risk (<748 nmol/L). Overweight was not associated with RBC folate level for NTD risk; however, a marginally significant negative association was noted for overall obesity and RBC folate concentrations indicative of elevated NTD risk (aPOR = 0.76; 95% CI = 0.45, 1.00). A significant protective association was noted between Class 3 obesity (BMI ≥40 kg/m 2 ) and folate concentration indicative of high NTD risk (≤585 nmol/L; aPOR = 0.46; 95% CI = 0.24, 0.89)., Conclusions: The prevalence of RBC folate concentrations indicating elevated or high NTD risk varied by level of obesity among nonpregnant women of child-bearing age. Further studies are needed to understand the folate pathway in overweight and obese women and subsequent NTD risk in their offspring., (© 2020 Wiley Periodicals, Inc.)

Rare earth elements (REEs) are ubiquitous in the environment. Animal experiments have shown that many REEs have adverse impacts on the health of fetuses. However, data from humans are scarce. In this study, we examined the associations between concentrations of 10 REEs in maternal serum and the risk for fetal neural tube defects (NTDs). The study included 200 pregnant women with pregnancies affected by NTDs and 400 pregnant women with healthy fetuses/infants. Fifteen REEs in maternal serum were assessed; 10 of them were detectable in over 60% of samples and were included in statistical analyses, including lanthanum (La), cerium (Ce), praseodymium (Pr), neodymium (Nd), samarium (Sm), europium (Eu), terbium (Tb), dysprosium (Dy), lutetium (Lu), and yttrium (Y). When the elements were considered individually with the use of Logistic regression model, the risk for NTDs increased by 2.78-fold (1.25-6.17) and 4.31-fold (1.93-9.62) for La, and 1.52-fold (0.70-3.31) and 4.73-fold (2.08-10.76) for Ce, in the second and third tertiles, respectively, compared to the lowest concentration tertile. When Bayesian kernel machine regression was used to examine the joint effect of exposure to all 10 REEs, the risk for NTDs increased with overall levels of these REEs and the association between La and NTD risk remained when other nine elements were taken into consideration simultaneously. Taken together, this study shows that the risk for NTDs increases with La concentrations when single REEs are considered and with concentrations of all 10 REEs when these REEs are considered as a co-exposure mixture., Competing Interests: Declaration of Conflicts of Interest The authors declare no actual or potential competing financial interests., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The potential association between maternal exposure to ambient PM 10 and offspring neural tube defects (NTDs) is a contentious issue. This study aims to evaluate the aforementioned association at a provincial level in China., Methods: 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 PM 10 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)., Results: PM 10 exposure was significantly associated with the risk of NTDs during the three months preconception (per 10 μg/m 3 increment: OR = 1.10, 95% CI 1.07-1.14; per standard deviation [27 μg/m 3 ] 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 PM 10 exposure from the third month before pregnancy to the third month after pregnancy. Sensitivity analyses using propensity score matching yielded consistent findings., Conclusions: Maternal exposure to PM 10 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., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Open neural tube defects (ONTDs) include open spina bifida (OSB) and anencephaly. These defects are caused by incomplete closure of the neural tube at about 4 weeks of pregnancy. Levels of early second-trimester maternal serum (ms) alpha-fetoprotein (AFP) are sufficiently elevated in affected pregnancies to be used as a population-based screening test. The basic screening methodology was described in the late 1970s and screening programs were active a few years later. By identifying pregnancies with the highest msAFP levels, about 80% of OSB and 95% of anencephaly can be identified as early as 16 weeks gestation. The interpretation of msAFP levels is complicated by the need to consider multiple factors such as gestational age, maternal weight, maternal race, multiple gestations, and more. Testing for AFP and acetylcholinesterase in amniotic fluid and/or identification of the lesion by targeted ultrasound is considered diagnostic of ONTD. When a diagnosis is made, options include termination, surgery after delivery, or in utero surgery, depending on factors such as location and size of the defect, and the presence of any additional anomalies. Screening for ONTD should be performed as part of a comprehensive program linking primary obstetrical care providers, laboratorians, and high-risk clinicians.

Background: 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., Methods: 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., Results: 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., Conclusions: 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., (© 2020 Wiley Periodicals, Inc.)

The United States implemented mandatory fortification of cereal grains with folic acid in 1998 to prevent neural tube defects (NTDs) during pregnancy. The health benefits of folate (vitamin B9) are well documented; however, there are potential risks of exceeding the upper tolerable limit, particularly in vulnerable populations. We conducted a population-based analysis of the Food Fortification Initiative dataset to determine the strength of the evidence regarding reports of decreased NTDs at the national level in response to mandatory folic acid fortification of cereal grains. We found a very weak correlation between NTD prevalence and the level of folic acid fortification, irrespective of the cereal grain fortified (wheat, maize or rice). Stratification of the data based on socioeconomic status (SES) indicated a strong linear relationship between reduced NTDs and better SES. We conclude that national fortification with folic acid is not associated with a significant decrease in the prevalence of NTDs at the population level., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services † (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive. § Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Background: Surgical site infections (SSIs) are one of the most common complications following pediatric complex tethered spinal cord release. This patient population is similar in some ways to the neuromuscular scoliosis population, in which higher-than-expected rates of gram-negative SSIs have been identified., Methods: We conducted a single-center retrospective chart review of all patients who underwent complex tethered spinal cord release over a 10-year period between 2007 and 2017., Results: A total of 69 patients were identified, with 10 documented SSIs (14%). 50% of the SSIs were polymicrobial or included at least 1 gram-negative organism. Among the organisms isolated, 3 were fully or -partially resistant to cefazolin, the most common antibiotic prophylaxis in this population., Conclusion: Among children undergoing complex tethered spinal cord release, gram-negative and polymicrobial infections are a significant cause of SSIs. Although further multicenter data are needed, these findings suggest that standard antibiotic prophylaxis with cefazolin may not be sufficient., (© 2020 S. Karger AG, Basel.)

Until 2015, systematic statistical data on micronutrient deficiency was not available in Georgia, to provide developing national strategy. In the same year, the National Centre for Disease Control and Public Health of Georgia (NCDC) in collaboration with the USA CDC launched the project "Strengthening surveillance of micronutrient deficiency in Georgia". In 2015 we did choose sentinel surveillance approach. For setting nutrition surveillance system 8 sentinel sites (2 sites in each region/children and pregnant health facilities) in four regions of Georgia (Tbilisi, Kakheti, Achara, and Samegrelo) were selected, using the criteria of geographical, social, ethnical, urban/rural, and religion. Also, existing information about malnutrition and dietary habits from the above mentioned regions. The project protocols was approved by the Institutional review board (IRB) at the NCDC and by the Research Review Committee and Ethical review committee of the US CDC. As a result of surveillance system functioning (2016-2019) we reviled that, about 36% out of 1021 studied children U2 (12-23 months) were anemic, 74% of them were identified as iron deficient. Hemoglobin was tested among 963 pregnant women and about 21% of them were found anemic, 57% were iron deficient, and 28% tested positive for folate deficiency. Neural tube defects (NTDs) prevalence per 1000 live births registered in sentinel sites was high 3.7. Our results show that anemia and iron deficiency are prevalent among both pregnant women and children of the specified age group in Georgia. Additionally, folate deficiency was quite common during the1st trimester of pregnancy. Our findings will inform public health policy decision makers to take relevant decisions on required interventions, such as health education, distribution of relevant supplements, and food fortification.

Background: Recent surveillance studies in Ethiopia show an epidemic of spina bifida and anencephaly, two major neural tube birth defects that are severe and life-threatening. Our objective was to estimate proportional reductions in current stillbirth and child mortality rates in Ethiopia through folic acid-based interventions to prevent spina bifida and anencephaly., Methods: Using secondary data from multiple sources, we estimated percent reductions in stillbirth, neonatal, infant, and under-five child mortality rates that would have occurred in Ethiopia in the year 2016 had all folic acid-preventable spina bifida and anencephaly been prevented; and the contributions of these reductions toward Ethiopia's Year 2030 Every Newborn Action Plan (ENAP) goal on stillbirth, and sustainable development goal (SDG) on child mortality rates. The 2016 prevalence of spina bifida and anencephaly in Ethiopia was assumed as 13 per 1,000 total births, with the prevention goal reaching 0.5 per 1,000 total births., Results: Folic acid interventions in Ethiopia would have prevented about 41,610 cases of folic acid-preventable spina bifida and anencephaly-affected pregnancies during the year 2016. We estimate that this prevention is associated with reduction of 31,830 stillbirths and 7,335 under-five child deaths annually. The proportional contribution of this prevention toward achieving Ethiopia's ENAP goal is 54% for stillbirth, and toward SDG is 4.5% for neonatal- and 6.8% for under-five mortality., Conclusions: Spina bifida and anencephaly contribute to substantial stillbirths and child death in Ethiopia. Large-scale fortification of foods like wheat flour and salt can help achieve Ethiopia's ENAP and SDG targets addressing preventable stillbirth, neonatal, and under-five mortality., (© 2019 Wiley Periodicals, Inc.)

Neural tube defects (NTDs) are the second most common congenital malformations in humans affecting the development of the central nervous system. Although NTD pathogenesis has not yet been fully elucidated, many risk factors, both genetic and environmental, have been extensively reported. Classically divided in two main sub-groups (open and closed defects) NTDs present extremely variable prognosis mainly depending on the site of the lesion. Herein, we review the literature on the histological and pathological features, epidemiology, prenatal diagnosis, and prognosis, based on the type of defect, with the aim of providing important information based on NTDs classification for clinicians and scientists., (© 2018 Wiley Periodicals, Inc.)

Objective: Neural tube defects [NTDs] are severe congenital anomalies. The etiology of NTDs is not fully known, and studies on the potential risk factors of NTDs present inconsistent results. Thus, we conducted a systematic review and meta-analysis to investigate the maternal, paternal, and neonatal risk factors for NTDs., Study Design: We systematically reviewed relative original studies published through October 6, 2018 available in Pubmed, Embase and the Cochrane Library without restrictions for language. The selected studies measured maternal, paternal, and neonatal risk factors and examined their associations with NTDs. A meta-analysis, including subgroup analysis and sensitivity analysis, was conducted to estimate the pooled effect measures. Two reviewers independently extracted data using a predesigned data collection form., Results: Forty-five studies were eligible for inclusion in the meta-analysis, and twelve potential risk factors were analyzed. The factors that were associated with NTDs risk included stressful life events [odds ratio [OR],1.61; 95% confidence interval [CI], 1.24-2.08; p < 0.001; I 2  = 59.2%], low maternal education level [OR, 1.42; 95% CI, 1.19-1.70; p < 0.001; I 2  = 47.7%], pregestational diabetes [OR, 2.24; 95% CI, 1.21-4.12; p < 0.010; I 2  = 56.3%], low paternal age [OR, 1.41; 95% CI, 1.10-1.81; p = 0.007; I 2  = 0.0%], low birth weight [OR, 5.53; 95% CI, 1.95-15.70; p = 0.001; I 2  = 98.5%], and neonatal female gender [OR, 1.54; 95% CI, 1.10-2.14; p = 0.012; I 2  = 67.8%]., Conclusion: Stressful life events, pregestational diabetes, low birth weight, and neonatal female gender are risk factors associated with NTDs. Low maternal education level and low paternal age are factors that are moderately associated with NTDs. Further cohort studies are required to verify the factors associated with NTDs and control the risk of this severe birth defect., (Copyright © 2019 ISDN. Published by Elsevier Ltd. All rights reserved.)

Periconceptional folic acid (FA) supplementation is recommended to prevent neural tube defects (NTDs), but little information is known about its use in Vietnam. It is important that FA supplements start to be taken when planning a pregnancy and continued through the first trimester to prevent NTDs, as the neural tube closes in the first month of pregnancy. However, FA supplementation in Vietnam is usually recommended to commence from the first antenatal visit, which is usually at 16 weeks, and very few women take FA before their first visit. This multicenter study aimed to determine the prevalence of FA supplement use and associated maternal characteristics in Vietnam. FA supplementation was assessed in 2030 singleton pregnant women between 2015 and 2016. In total, 654 (32.2%) women reported taking either supplements containing FA alone or multivitamins containing FA, and 505 (24.9%) reported correctly taking supplements containing FA alone. Women who were aged 30 years or over, had low education levels, had formal employment, and whose current pregnancy was first or unplanned were less likely to supplement with FA. Education programs are needed to encourage FA supplementation when contemplating pregnancy., Competing Interests: The authors declare no conflict of interest. The sponsors had no role in the design, execution, interpretation, or writing of the study.

Objective: Multiple-site neural tube defects (MNTDs) are very uncommon, with the predominant number of cases being reported in developing countries. The classic theory of neural tube closure fails to explain the occurrence of these defects. Multisite closure theory, first proposed in 1995, explains most of the occurrences with a few modifications specific to a few defects. In this paper, the authors endeavor to explain all the defects, along with their genetic and embryological bases, and to review the available literature and discuss their own experience in the management of these complex cases., Methods: The authors retrospectively reviewed the data of all the patients treated surgically for MNTDs over that past 14 years. All possible demographic data, clinical details, and radiological imaging data were reviewed. In addition, surgical parameters, complications, and status at follow-up of more than 12 months were evaluated. All previously reported cases of MNTD were analyzed, and comparisons with the present series were made., Results: A total of 3 major series (including the present one) on MNTDs have been from India. A total of 57 such cases (including those of the present series) have been reported in the available literature. While previous series reported a higher incidence of spinal defects, the present series had a higher rate of cephalic defects (55%). Among the reported cases, insertion of a ventriculoperitoneal shunt was necessary in 12 (26%), and only 4 patients were operated on in 2 stages. Neurological status at presentation dictated outcome., Conclusions: MNTDs are extremely rare, and their embryogenesis is different from that of single neural tube defects. Simultaneous repair of 2 or even 3 defects is possible in a single-stage surgery. The requirement of a shunt is uncommon, and complications following surgery are rare. Folic acid supplementation may reduce the incidence of defects.

Objective: To assess the three key issues for congenital anomalies (CAs) prevention and care, namely, CA prevalence, risk factor prevalence and survival, in a longitudinal cohort in Riyadh, Saudi Arabia., Setting: Tertiary care centre, Riyadh, Saudi Arabia., Participants: Saudi women enrolled during pregnancy over 3 years and their 28 646 eligible pregnancy outcomes (births, stillbirths and elective terminations of pregnancy for foetal anomalies). The nested case-control study evaluated the CA risk factor profile of the underlying cohort. All CA cases (1179) and unaffected controls (1262) were followed through age 2 years. Referred mothers because of foetal anomaly and mothers who delivered outside the study centre and their pregnancy outcome were excluded., Primary Outcome Measures: Prevalence and pattern of major CAs, frequency of CA-related risk factors and survival through age 2 years., Results: The birth prevalence of CAs was 412/10 000 births (95% CI 388.6 to 434.9), driven mainly by congenital heart disease (148 per 10 000) (95% CI 134 to 162), renal malformations (113, 95% CI 110 to 125), neural tube defects (19, 95% CI 25.3 to 38.3) and chromosomal anomalies (27, 95% CI 21 to 33). In this study, the burden of potentially modifiable risk factors included high rates of diabetes (7.3%, OR 1.98, 95% CI 1.04 to 2.12), maternal age >40 years (7.0%, OR 2.1, 95% CI 1.35 to 3.3), consanguinity (54.5%, OR 1.5, 95% CI 1.28 to 1.81). The mortality for live births with CAs at 2 years of age was 15.8%., Conclusions: This study documented specific opportunities to improve primary prevention and care. Specifically, folic acid fortification (the neural tube defect prevalence was >3 times that theoretically achievable by optimal fortification), preconception diabetes screening and consanguinity-related counselling could have significant and broad health benefits in this cohort and arguably in the larger Saudi population., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Congenital abnormalities when present, according to VACTERL theory, occur nonrandomly with other congenital anomalies. This study estimates the prevalence of congenital spinal anomalies, and their concurrence with other systemic anomalies., Methods: A retrospective cohort analysis on Health care Cost and Utilization Project's Kids Inpatient Database (KID), years 2000, 2003, 2006, 2009 was performed. ICD-9 coding identified congenital anomalies of the spine and other body systems., Outcome Measures: Overall incidence of congenital spinal abnormalities in pediatric patients, and the concurrence of spinal anomaly diagnoses with other organ system anomalies. Frequencies of congenital spine anomalies were estimated using KID hospital-and-year-adjusted weights. Poisson distribution in contingency tables tabulated concurrence of other congenital anomalies, grouped by body system., Results: Of 12,039,432 patients, rates per 100,000 cases were: 9.1 hemivertebra, 4.3 Klippel-Fiel, 56.3 Chiari malformation, 52.6 tethered cord, 83.4 spina bifida, 1.2 absence of vertebra, and 6.2 diastematomyelia. Diastematomyelia had the highest concurrence of other anomalies: 70.1% of diastematomyelia patients had at least one other congenital anomaly. Next, 63.2% of hemivertebra, and 35.2% of Klippel-Fiel patients had concurrent anomalies. Of the other systems deformities cooccuring, cardiac system had the highest concurrent incidence (6.5% overall). In light of VACTERL's definition of a patient being diagnosed with at least 3 VACTERL anomalies, hemivertebra patients had the highest cooccurrence of ≥3 anomalies (31.3%). With detailed analysis of hemivertebra patients, secundum ASD (14.49%), atresia of large intestine (10.2%), renal agenesis (7.43%) frequently cooccured., Conclusions: Congenital abnormalities of the spine are associated with serious systemic anomalies that may have delayed presentations. These patients continue to be at a very high, and maybe higher than previously thought, risk for comorbidities that can cause devastating perioperative complications if not detected preoperatively, and full MRI workups should be considered in all patients with spinal abnormalities., Level of Evidence: Level III.

Background: A preliminary safety signal for neural-tube defects was previously reported in association with dolutegravir exposure from the time of conception, which has affected choices of antiretroviral treatment (ART) for human immunodeficiency virus (HIV)-infected women of reproductive potential. The signal can now be evaluated with data from follow-up of additional pregnancies., Methods: We conducted birth-outcomes surveillance at hospitals throughout Botswana, expanding from 8 to 18 sites in 2018. Trained midwives performed surface examinations of all live-born and stillborn infants. Research assistants photographed abnormalities after maternal consent was obtained. The prevalence of neural-tube defects and major external structural defects according to maternal HIV infection and ART exposure status was determined. In the primary analyses, we used the Newcombe method to evaluate differences in prevalence with 95% confidence intervals., Results: From August 2014 through March 2019, surveillance captured 119,477 deliveries; 119,033 (99.6%) had an infant surface examination that could be evaluated, and 98 neural-tube defects were identified (0.08% of deliveries). Among 1683 deliveries in which the mother was taking dolutegravir at conception, 5 neural-tube defects were found (0.30% of deliveries); the defects included two instances of myelomeningocele, one of anencephaly, one of encephalocele, and one of iniencephaly. In comparison, 15 neural-tube defects were found among 14,792 deliveries (0.10%) in which the mother was taking any non-dolutegravir ART at conception, 3 among 7959 (0.04%) in which the mother was taking efavirenz at conception, 1 among 3840 (0.03%) in which the mother started dolutegravir treatment during pregnancy, and 70 among 89,372 (0.08%) in HIV-uninfected mothers. The prevalence of neural-tube defects was higher in association with dolutegravir treatment at conception than with non-dolutegravir ART at conception (difference, 0.20 percentage points; 95% confidence interval [CI], 0.01 to 0.59) or with other types of ART exposure. Major external structural defects were found in 0.95% of deliveries among women exposed to dolutegravir at conception and 0.68% of those among women exposed to non-dolutegravir ART at conception (difference, 0.27 percentage points; 95% CI, -0.13 to 0.87)., Conclusions: The prevalence of neural-tube defects was slightly higher in association with dolutegravir exposure at conception than with other types of ART exposure at conception (3 per 1000 deliveries vs. 1 per 1000 deliveries). (Funded by the National Institutes of Health.)., (Copyright © 2019 Massachusetts Medical Society.)

Background: Neural tube defects (NTDs) are an important category of birth defect, but surveillance remains inadequate in South Africa., Objectives: To assess the identification of NTDs at a tertiary hospital using a range of prenatal, perinatal and postnatal data sources, and to estimate the impact of prenatal diagnosis and birth prevalence for the referral area., Methods: Cases of anencephaly, encephalocele and spina bifida (SB) in a 6-year period were retrospectively identified from 5 data sources covering prenatal, perinatal and postnatal care. These were cross-correlated to avoid duplicate entries and to determine the contribution of different data sources. Details of prenatal diagnosis and termination of pregnancy (TOP) were obtained for 10 years, and birth prevalence over 2 years., Results: During a 6-year period 195 NTDs were identified at a Western Cape Province tertiary hospital. These included 59 (30%) cases of anencephaly, 28 (14%) of encephalocele and 108 (55%) of SB. The majority of NTDs (71%) were detected prenatally, although SB was less commonly diagnosed prenatally than cranial defects (56% v. 88%; p&lt;0.001). Of SB cases ascertained pre- or postnatally, 57% of patients were born alive and 50% discharged alive, but 72% of survivors had not been diagnosed prenatally. Women receiving prenatal diagnosis of any type of NTD before 24 weeks' gestation were nearly always offered TOP, and the majority accepted termination after non-directive counselling. For SB, later prenatal diagnosis was associated with much lower termination rates because the option was less often offered (51% v. 100%; p&lt;0.001), and perhaps less often accepted (57% v. 78%; p=0.06). The estimated NTD birth prevalence for the referral area was 0.76 - 0.80 per 1 000 live births, but perhaps up to 1.18 per 1 000 when considering under-referral of lethal cranial lesions from rural areas., Conclusions: A substantial number of NTDs can be ascertained from a tertiary hospital environment if multiple data sources are used, even though adding data from the Perinatal Problem Identification Program for outlying health facilities increases detection of lethal defects. Hospital-based surveillance can be considered, especially for SB. Prenatal diagnosis was fairly common and pregnancy termination was often offered and accepted if detected before 24 weeks' gestation. A regional prenatal ultrasound programme, predominantly based in primary care but with ready access to a tertiary centre, can be quite effective, although limited or delayed access to prenatal diagnosis must be addressed.

Objectives: Mothers need a nutrient-rich diet for healthy neural tube development. Neural tube defect risk can be reduced through fortifying grain products with folic acid and taking folic acid supplements. Fortification is not required in Bangladesh. Maternal supplement use rates are low, similar to other countries. This study evaluates maternal dietary intake during pregnancy to identify possible interventions., Methods: A food frequency questionnaire (FFQ) assessed maternal diet. The primary aim compared dietary intake (calories, fat, carbohydrate, protein, fiber, vitamins, and minerals) between mothers of infants with myelomeningocele (cases) and mothers of controls. Secondary aims included (i) comparing foods consumed and (ii) evaluating if rice intake correlated with arsenic exposure. Paired t-tests, Wilcoxon signed rank tests, McNemar's chi-squared test, and linear regression were used., Results: This study included 110 matched mother-infant pairs (55 cases/55 controls). Mothers of cases and mothers of controls had similar caloric intake [median 2406 kcal/day vs. 2196 kcal/day (p = 0.071)]. Mothers in both groups consumed less than half the daily recommended 600 μg of folate. Diets were potentially deficient in vitamins A, D, E, potassium, sodium, and iron. Steamed rice was the primary food consumed for both groups, and this rice intake was not associated with toenail arsenic., Conclusions: Dietary interventions should increase folate, vitamins A, D, E, potassium, sodium, and iron intake in Bangladeshi mothers. Folic acid fortification of grain products maybe the only viable strategy to achieve adequate folate intake for mothers. Given the central role of rice to the Bangladeshi diet, fortifying rice may be a viable option., (© 2019 Wiley Periodicals, Inc.)

Objective: Although infant mortality because of birth defect has increased in both developed and developing countries, had not got attention like other health issues at national, regional, or local levels. Documenting the risk factors that influence the occurrence of birth defects and its seasonality will help to inform the community and to develop preventive strategies for the country., Results: Factors associated with higher likelihood of a major structural birth defects included maternal age; neonates born from women living in urban; and in Dega; history of fever during pregnancy; intake of herbal medicine; and drinking alcohol. Counselling for pregnancy preparation and folic acid supplementation was found protective for the likelihood of birth defect.

Background: Dolutegravir, an integrase strand transfer inhibitor (InSTI), is a major antiretroviral agent for HIV infection. Its use is promising, especially in low- and middle-income countries, because of a high resistance barrier and a good safety profile. Very recently, a World Health Organization safety signal has been raised regarding neural tube defects after the first-trimester exposure. Furthermore, to date, the experience is limited regarding the use of the other InSTI drugs (raltegravir and elvitegravir) during pregnancy. Our objective is to analyze the safety of InSTI drugs in pregnant women., Setting: Nation-wide database cohort analysis., Methods: We evaluated the risk of major birth defects according to EUROCAT classification in pregnant women, which had had a first-trimester exposure to dolutegravir, raltegravir, or elvitegravir., Results: We found a major birth defect rate of 1.9% in the general population between 2012 and 2016. As InSTI drugs are not used as first-line therapy in pregnant women, we found a very low exposure in this population. Among 49, 240, and 70 pregnancy outcomes exposed to dolutegravir, raltegravir, and elvitegravir, respectively, during the first trimester, there were 2, 3, and 1 major birth defects, respectively. There was no case of neural tube defect., Conclusions: Drug exposure to InSTI is limited in our nation-wide database. Nevertheless, our data do not support a pharmacovigilance signal on neural tube defects in women exposed to dolutegravir, raltegravir or elvitegravir during pregnancy. Owing to a small number of pregnancy outcomes, these results need to be confirmed with further studies.

Background: At the end of the 1980s, several studies suggested a potential increased risk of neural tube defects (NTDs) with ovulation induction/fertility drugs, especially with clomiphene citrate (CC). A previous meta-analysis of observational studies evaluating the risk of NTDs associated with the use of CC performed in 1995 found a risk ratio of 1.08 (95% CI 0.76-1.51). Since then, additional studies have been published and the risk of NTDs associated with periconceptional CC exposure may have changed., Objective: To perform an updated quantitative meta-analysis of the risk of NTDs associated with periconceptional CC exposure., Search Strategy: MEDLINE, Web of Science, and Scopus were searched (October 2018)., Selection Criteria: Comparative cohort and case-control studies investigating the risk of NTDs after periconceptional CC exposure., Data Collection and Analysis: Pooled effect sizes with corresponding 95% CIs were calculated using random effects models, comparing the risk of NTDs between pregnancies exposed and not exposed to CC., Main Results: Thirteen studies met the inclusion criteria, totalling 218 819 pregnancies. Periconceptional exposure to CC was not significantly associated with an increased risk of NTDs (pooled odds ratio 1.21, 95% CI 0.88-1.66). No heterogeneity between studies was observed (I 2  = 26%). A funnel plot and asymmetry test were not suggestive of publication bias., Conclusion: Our meta-analysis confirms that exposure to CC before or in early pregnancy was associated with a 21% increased risk of NTD in relation to CC exposure; however, this increased risk is not statistically significant., Tweetable Abstract: A new meta-analysis finds that clomiphene citrate exposure before or in early pregnancy is not associated with an increased risk of NTDs., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural tube defects (NTDs) in newborns associated with exposure to dolutegravir at the time of conception. Folate deficiency is a common cause of NTDs. Dolutegravir and other HIV integrase inhibitor drugs were evaluated in vitro for inhibition of folate transport pathways: proton-coupled folate transporter (PCFT), reduced folate carrier (RFC), and folate receptor α (FR α )-mediated endocytosis. Inhibition of folate transport was extrapolated to the clinic by using established approaches for transporters in intestine, distribution tissues, and basolateral and apical membranes of renal proximal tubules (2017 FDA Guidance). The positive controls, methotrexate and pemetrexed, demonstrated clinically relevant inhibition of PCFT, RFC, and FR α in folate absorption, distribution, and renal sparing. Valproic acid was used as a negative control that elicits folate-independent NTDs; valproic acid did not inhibit PCFT, RFC, or FR α At clinical doses and exposures, the observed in vitro inhibition of FR α by dolutegravir and cabotegravir was not flagged as clinically relevant; PCFT and RFC inhibition was not observed in vitro. Bictegravir inhibited both PCFT and FR α , but the observed inhibition did not reach the criteria for clinical relevance. Elvitegravir and raltegravir inhibited PCFT, but only raltegravir inhibition of intestinal PCFT was flagged as potentially clinically relevant at the highest 1.2-g dose (not the 400-mg dose). These studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Clinically relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed. SIGNIFICANCE STATEMENT: Preliminary analysis of ongoing birth surveillance study identified evidence of potential increased risk for neural tube defects (NTDs) in newborns associated with exposure to the HIV integrase inhibitor dolutegravir at the time of conception; folate deficiency is a common cause of NTDs. Dolutegravir and other HIV integrase inhibitor drugs were evaluated in vitro for inhibition of the major folate transport pathways: proton-coupled folate transporter, reduced folate carrier, and folate receptor α -mediated endocytosis. The present studies showed that dolutegravir is not a clinical inhibitor of folate transport pathways, and it is not predicted to elicit clinical decreases in maternal and fetal folate levels. Furthermore, clinically relevant HIV integrase inhibitor drug class effect on folate transport pathways was not observed., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: During the first three months of pregnancy, the developing embryo may be susceptible to external and internal factors, which may lead to structural and functional congenital anomalies. The main objective of this study was to determine the prevalence of congenital anomalies in Addis Ababa and the Amhara region, Ethiopia., Methods: A descriptive cross-sectional study was conducted on children 0-17 years of age who visited the 16 selected hospitals in Addis Ababa and the Amhara Region between January 1 and July 5, 2015. The proportions of neonates, infants, and children with external and internal congenital anomalies whether the anomalies were major or minor were estimated., Results: Out of 76,201 children, 1518 of whom 57.6% were male identified with congenital anomalies. The overall proportion of congenital anomaly was 1.99% (95% CI: 1.89-2.091) i.e., 199 per 10,000 children. The proportion of neural tube defects, orofacial clefts, masculo-skeletal system anomalies, syndrome disorders, and cardiovascular system problems were 40.3% 37.7-43, 23.3% 21.3-25.4, 23.1% 20.9-25.2, 8% 6.7-9.4, and 2.6% 1.8-3.4, with a 95% CI, respectively. The majority (72.5%) of the mothers were multigravidae; 38(2.5%) of the mothers and 32(2.1%) of the fathers had history of other children with congenital anomalies. Similarly, 20(1.3%) of the participant children's mothers and 17(1.1%) of the fathers had familial history of congenital anomaly. Iron folate and multivitamin use by mothers during preconception and early pregnancy was found to be low., Conclusion: Neural tube defects, orofacial clefts, and musculoskeletal anomalies were the observed prevalent problems. Maternal illness, viral infections, and malnutrition were seen in a significant number of the mothers. Iron folate/folic acid and multivitamin use by the mothers during and before pregnancy was very low.

We evaluated the relationship between preconception folic acid supplementation and the occurrence of neural tube defects (NTDs) in offspring, using data from the Japan Environment and Children's Study (a nationwide prospective birth cohort study) database. Of 92 269 participants with single pregnancies, 74 cases (offspring or fetuses) had NTDs, including 32 cases of spina bifida, 24 cases of anencephaly, and 19 cases of encephalocele. A total of 7634 participants (8.27%) used preconception folic acid supplementation, and of these, 621 (0.67%) also took in dietary folic acid at ≥480 μg/day. Multivariate logistic regression analyses demonstrated no association between preconception folic acid supplementation and NTDs in offspring or fetuses (odds ratio [OR] 0.622; 95% confidence interval [CI]: 0.226-1.713). Moreover, the participants who combined preconception folic acid supplement use with dietary folic acid intake ≥480 μg/day demonstrated no incidence of NTDs in offspring or fetuses. Our analysis is limited by the absence of the data on the daily amount of supplementary folic acid intake, requiring careful attention to the interpretation. Additional surveys are required in Japan to resolve those limitations for further comprehensive assessment., (© 2018 Japanese Teratology Society.)

The vital role of folic acid is to reduce the risk of having a neonate afflicted with neural tube defects. The prevalence of neural tube defects (myelomeningocele and anencephaly) has been reported in an incomplete form over the last 40 years in Japan. We aimed to evaluate the total number of neural tube defects including those delivered or terminated, to clarify the proportion of those terminated, and to internationally compare their prevalence. Through information on >311 000 deliveries obtained from 262 hospitals/clinics for 2 years of 2014 and 2015, we identified that the rate of total neural tube defects (termination of pregnancy, live births and stillbirths) was 8.29 per 10 000 deliveries for the year 2014 and was 8.72 for 2015, which were 1.5 and 1.6 times higher than the respective values (live births and stillbirths) reported. It is also observed that the ratio of the total number of myelomeningocele (termination of pregnancy, live births, and stillbirths) to that of anencephaly was approximately 1:1.2, that a half of pregnancies afflicted with neural tube defects were terminated, and that the proportion of termination of pregnancy due to myelomeningocele and due to anencephaly was 20% and 80%, respectively. Internationally, the real prevalence of neural tube defects in Japan was comparatively high, ranking fifth among the seven developed countries. In conclusion, the real prevalence of total neural tube defects was approximately 1.5 times higher than that currently reported by the Japan Association of Obstetricians and Gynecologists., (© 2019 Japanese Teratology Society.)

Background: We examined the association between the maternal genotype for celiac disease-associated variants and risk of neural tube defects (NTDs)., Methods: We conducted a case-control study, using data from the National Birth Defects Prevention Study. We evaluated 667 cases (women with an offspring with NTD) and 743 controls (women with an offspring without a birth defect). We classified women as having low, intermediate, or high risk of celiac disease based on human leukocyte antigen (HLA) variants. We used logistic regression to assess the relationship between HLA celiac risk group (low, intermediate, high) and risk of NTDs. Fifteen non-HLA variants (identified from genome-wide association studies of celiac disease) were individually evaluated and modeled additively., Results: There was no association between HLA celiac risk group and NTDs (intermediate vs. low risk: aOR, 1.0; 95% CI, 0.8-1.3; high vs. low risk: aOR, 0.8; 95% CI, 0.5-1.3). Of the fifteen non-HLA variants, we observed five significant associations after accounting for multiple comparisons. Three negative associations were observed with rs10903122, rs13314993, rs13151961 (aOR range: 0.69-0.81), and two positive associations were observed with rs13003464 and rs11221332 (aOR range: 1.27-1.73)., Conclusion: If confirmed, our results suggest that the maternal variants related to celiac disease may be involved in the risk of NTDs., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Most professional and international organizations recommend folic acid supplementation for women planning pregnancy. Various studies have shown high levels of non-compliance with this recommendation. This study aimed to identify sociodemographic characteristics related to this compliance. The analyses were based on 16,809 women from the French nationwide ELFE cohort (Etude Longitudinale Française depuis l'Enfance). Folic acid supplementation was assessed at delivery, and sociodemographic characteristics were collected at two months postpartum. The association between sociodemographic characteristics and compliance with recommendations on folic acid supplementation (no supplementation, periconceptional supplementation, and supplementation only after the periconceptional period) was examined using multivariate multinomial logistic regression. Only 26% of French women received folic acid supplementation during the periconceptional period, 10% of women received supplementation after the periconceptional period, and 64% received no supplementation. Young maternal age, low education level, low family income, multiparity, single parenthood, maternal unemployment, maternal overweight, and smoking during pregnancy were related to lower likelihood of folic acid supplementation during the periconceptional period compared to no supplementation. These associations were not explained by unplanned pregnancy. Immigrant and underweight women were more likely to receive folic acid supplementation after the periconceptional period. Our study confirms great social disparities in France regarding the compliance with the recommendations on folic acid supplementation.

Background: Dolutegravir is superior to efavirenz for HIV antiretroviral therapy (ART) but may be associated with an increased risk for neural tube defects (NTDs) in newborns if used by women at conception., Objective: To project clinical outcomes of ART policies for women of child-bearing potential in South Africa., Design: Model of 3 strategies: efavirenz for all women of child-bearing potential (EFV), dolutegravir for all women of child-bearing potential (DTG), or World Health Organization (WHO)-recommended efavirenz without contraception or dolutegravir with contraception (WHO approach)., Data Sources: Published data on NTD risks (efavirenz, 0.05%; dolutegravir, 0.67% [Tsepamo study]), 48-week ART efficacy with initiation (efavirenz, 60% to 91%; dolutegravir, 96%), and age-stratified fertility rates (2 to 139 per 1000 women)., Target Population: 3.1 million South African women with HIV (aged 15 to 49 years) starting or continuing first-line ART, and their children., Time Horizon: 5 years., Perspective: Societal., Intervention: EFV, DTG, and WHO approach., Outcome Measures: Deaths among women and children, sexual and pediatric HIV transmissions, and NTDs., Results of Base-Case Analysis: Compared with EFV, DTG averted 13 700 women's deaths (0.44% decrease) and 57 700 sexual HIV transmissions, but increased total pediatric deaths by 4400 because of more NTDs. The WHO approach offered some benefits compared with EFV, averting 4900 women's deaths and 20 500 sexual transmissions while adding 300 pediatric deaths. Overall, combined deaths among women and children were lowest with DTG (358 000 deaths) compared with the WHO approach (362 800 deaths) or EFV (367 300 deaths)., Results of Sensitivity Analysis: Women's deaths averted with DTG exceeded pediatric deaths added with EFV unless dolutegravir-associated NTD risk was 1.5% or greater., Limitation: Uncertainty in NTD risks and dolutegravir efficacy in resource-limited settings, each examined in sensitivity analyses., Conclusion: Although NTD risks may be higher with dolutegravir than efavirenz, dolutegravir will lead to many fewer deaths among women, as well as fewer overall HIV transmissions. These results argue against a uniform policy of avoiding dolutegravir in women of child-bearing potential., Primary Funding Source: National Institutes of Health, National Institute of Allergy and Infectious Diseases and Eunice Kennedy Shriver National Institute of Child Health and Human Development; Massachusetts General Hospital; and Harvard University Center for AIDS Research.

Background: Nutritional deficiency in pregnant women is a confirmed cause of neural tube defects (NTDs). Alongside to this background, We sought to determine the nutritional status and level of awareness on the issue of the NTDs as well as folic acid (FA) utilization among women who born infants with NTDs in Tigray region of Ethiopia., Method: A standard interviewer and a food frequency questionnaire was used to obtain information from mothers of cases with neural tube defects (n = 205) and their controls (n = 412). Demographic information, weekly food frequency consumption, information on awareness on the issue of the NTDs as well as folic acid (FA) use was collected., Result: The mean age of the mothers of the cases and controls was 26.5 years (range 17-43 years) and 26.05 years (range 18-40 years), respectively. Approximately 92.2% (189/205) of the cases and 90.5% (373/412) control mothers do not know the term folic acid (FA). Notably, all participant mothers (100%) did not understand that NTDs are a serious health problem associated with inadequate intake of FA and none of them used FA prior to conception. Food frequency analysis revealed that except for cereals (p = 0.12) and milk products (p = 0.8), the proportion of the consumed food type within seven days recalls period showed a statistically significant difference (p < 0.05) as compared with controls. The dietary diversity score assessment showed those attained low and high dietary diversity score were a statistically significant difference (p = 0.0003) and (p = 0.0002) respectively) as compared with controls, but the medium dietary diversity score no significant variation was found (p = 0.35)., Conclusion: This study has shown none of the study participants do understand that NTDs are a serious health problem associated with inadequate intake of FA. Dietary diversity score was significantly associated with incidence of NTDs. This Ethiopian study also highlighted the need of considering the basic food in future programs of food fortification with folic acid, preconceptional folic acid supplementation and adequate dietary intake counseling. Advance research is required to find out the gene-nutrient and gene environment interactions, as well as particular causative factors associated with NTDs in Ethiopia., (Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Numerous animal studies have shown that high arsenic exposure can induce neural tube defect (NTD) formation. However, epidemiological evidence related to this finding is scarce. The key objective of our study is to evaluate whether maternal arsenic exposure is associated with NTD risk in Northern China. Our case-control study was conducted in 11 countries or cities in Shanxi and Hebei provinces during 2003-2007. A total of 774 mothers were included as participants: 511 controls and 263 cases (including 123 with anencephaly, 115 with spina bifida, 18 with encephalocele, and 7 with other NTD subtypes). The arsenic concentration was measured in a specific section of hair that grew from 3 months before to 3 months after conception. We found a higher hair arsenic concentration in the NTD cases with median (inter-quartile range) of 0.093 (0.025-0.387) μg/g hair than that in the controls with a value of 0.082 (0.030-0.414) μg/g hair. Maternal hair arsenic concentration above its median of the controls was associated with an increased risk of the total NTDs with an adjusted odds ratio (OR) of 1.32 [95% confidence interval (CI): (0.91-1.92)], which was not statistically significant (p = 0.14), although the crude OR without adjusting for the confounders of 1.68 (95% CI: 1.24-2.27; p < 0.001) suggested that hair arsenic is a risk factor of NTDs. There was no dose-response relationship between maternal hair arsenic concentration and the risk of total NTDs. Similar phenomena were found for anencephaly and spina bifida, respectively. Overall, our findings showed that maternal periconceptional arsenic exposure may not significantly contribute to the risk of NTD development in Northern China; other risk factors need to be further examined in future studies., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In 2009, mandatory folic acid fortification of bread-making flour was introduced in Australia to reduce the birth prevalence of preventable neural tube defects (NTDs) such as spina bifida. Before the introduction of the policy, modelling predicted a reduction of 14-49 NTDs each year., Objective: Using real-world data, this study provides the first ex-post evaluation of the cost effectiveness of mandatory folic acid fortification of bread-making flour in Australia., Methods: We developed a decision tree model to compare different fortification strategies and used registry data to quantify the change in NTD rates due to the policy. We adopted a societal perspective that included costs to industry and government as well as healthcare and broader societal costs., Results: We found 32 fewer NTDs per year in the post-mandatory folic acid fortification period. Mandatory folic acid fortification improved health outcomes and was highly cost effective because of the low intervention cost. The policy demonstrated improved equity in outcomes, particularly in birth prevalence of NTDs in births from teenage and indigenous mothers., Conclusions: This study calculated the value of mandatory folic acid fortification using real-world registry data and demonstrated that the attained benefit was comparable to the modelled expected benefits. Mandatory folic acid fortification (in addition to policies including advice on supplementation and education) improved equity in certain populations and was effective and highly cost effective for the Australian population.

Purpose: In lower-income populations, high rates of neural tube defects (NTDs) are a concern. Nutritional folate deficiencies and mycotoxins in contaminated food supplies increase risk of NTDs. As physicians in public health and involved in the care of children with NTDs, pediatric neurosurgeons have an interest in the treatment and prevention of NTDs. We aimed to evaluate the literature to assess the awareness and the existence of best practices/educational materials on this issue to better guide management., Methods: A systematic review using the National Library of Medicine PubMed database was conducted to find articles related to mycotoxins in foods causing neural tube defects. Additional citation searches of key publications and personal collections were used. Two reviewers evaluated the resulting studies for subject area analysis. Best practice recommendations were drawn from articles selected for full-text review., Results: Seventy-three articles were identified. Most articles were found in "nutritional sciences" (18), "teratology" (14), and "toxicology" (13). No articles were found in neurosurgery. Thirty-two additional articles were identified through other sources to screen best practice recommendations. Of the 105 articles, 34 journal articles were included in best practice recommendation guidelines. Key recommendations included education of proper food storage, hygienic agricultural practices, decontamination techniques, diet diversification, folate supplementation, risk assessment, and food safety policy and public health initiatives., Conclusion: There is an absence of neurosurgical literature-related mycotoxins and NTDs. We suggest a set of best practices/educational materials on this topic and advocate pediatric neurosurgery engagement in public health initiatives targeted towards populations most affected by mycotoxins.

Background: Neural tube defects (NTDs) are birth defects of the brain, spine, or spinal cord invoked by the insufficient intake of folic acid in the early stages of pregnancy and have a complex etiology involving both genetic and environmental factors. So the study aimed to explore the association between alterations in maternal one-carbon metabolism and NTDs in the offspring., Methods: We conducted a case-control study to get a deeper insight into this association, as well as into the role of genetic polymorphisms. Plasma concentrations of folate, homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) and genotypes and alleles distributions of 52 SNPs in 8 genes were compared for 61 women with NTDs-affected offspring and 61 women with healthy ones., Results: There were significant differences between groups with regard to plasma folate, SAM, SAH and SAM/SAH levels. Logistic regression results revealed a significant association between maternal plasma folate level and risk of NTDs in the offspring. For MTHFD1 rs2236225 polymorphism, mothers having GA genotype and A allele exhibited an increased risk of NTDs in the offspring (OR = 2.600, 95%CI: 1.227-5.529; OR = 1.847, 95%CI: 1.047-3.259). For MTHFR rs1801133 polymorphism, mothers having TT and CT genotypes were more likely to affect NTDs in the offspring (OR = 4.105, 95%CI: 1.271-13.258; OR = 3.333, 95%CI: 1.068-10.400). Moreover, mothers carrying T allele had a higher risk of NTDs in the offspring (OR = 1.798, 95%CI: 1.070-3.021). For MTRR rs1801394 polymorphism, the frequency of G allele was significantly higher in cases than in controls (OR = 1.763, 95%CI: 1.023-3.036). Mothers with NTDs-affected children had higher AG genotype in RFC1 rs1051226 polymorphism than controls, manifesting an increased risk for NTDs (OR = 3.923, 95%CI: 1.361-11.308)., Conclusion: Folic acid deficiency, MTHFD1 rs2236225, MTHFR rs1801133, MTRR rs1801349 and RFC1 rs1051226 polymorphisms may be maternal risk factors of NTDs.

Objectives: To describe and compare placental and amniotic histology in women who underwent a fetoscopic myelomeningocele repair to those who underwent an open hysterotomy myelomeningocele repair. Also, we intended to compare findings from both prenatal repair groups to age-matched control pregnant patients., Methods: Placental and membrane histopathology from 43 prenatally repaired spina bifida cases (17 fetoscopic and 26 open) and 18 healthy controls were retrospectively assessed. Quantitative assessment of histopathology included apoptosis count and maternal and fetal underperfusion scores. Qualitative assessment included the detection of pigmented macrophages and/or signs of placental/amniotic inflammation. Associations between the duration of surgery or the duration of CO 2 insufflation and quantitative histological parameters were tested., Results: Fetoscopic surgery cases did not show significant differences in any of the studied parameters when compared against controls. No differences were detected either when compared with open repaired cases, except for lower proportion of pigmented laden macrophages in the fetoscopic group (11.8% vs 61.5%, P < 0.01). No associations between the duration of surgery or the duration of CO 2 exposure and any of the quantitative histological parameters were detected., Conclusions: These preliminary results support the lack of detrimental effects of the use of heated and humidified CO 2 gas for uterine insufflation to fetal membranes and placenta., (© 2019 John Wiley & Sons, Ltd.)

Background: We sought to assess the recent trend in NTD prevalence at birth in the post-folic acid food fortification era and to identify the maternal risk factors associated with that trend., Methods: We carried out a population-based study of all livebirths and stillbirths (including late pregnancy terminations) delivered in hospitals in Canada (excluding Quebec) from 2004 to 2015 (n = 3 439 330). We examined NTD birth prevalence by year, multiple pregnancy, maternal age, parity, pregestational diabetes, chronic illness, and problematic substance use. Poisson regression was used to quantify the association between spina bifida and cranial defects and maternal characteristics and other risk factors., Results: We identified 1517 non-chromosomal NTDs, yielding a birth prevalence of 4.4 per 10 000 total births. NTD prevalence rose from 3.6 in 2004 to 4.6 per 10 000 in 2015 (P trend  = 0.03). Among NTD subtypes, only spina bifida showed a temporal increase (P trend  = 0.03). Birth prevalence of spina bifida was higher among younger mothers, those with type 2 diabetes (rate ratio (RR) 3.74, 95% confidence interval (CI) 2.21, 6.35), chronic illness (RR 3.16, 95% CI 1.97, 5.07), and problematic substance use (RR 1.88, 95% CI 1.31, 2.71). Adjusting for risk factors attenuated the significant temporal trend in spina bifida (unadjusted average annual prevalence ratio (aAAPR) 1.016, 95% CI 1.001, 1.032; adjusted AAPR 1.014, 95% CI 0.998, 1.029)., Conclusions: Increases in the frequency of maternal risk factors such as pregestational diabetes mellitus, substance use, and chronic illness may be partly responsible for the recent rise in NTDs, particularly spina bifida., (© 2019 John Wiley & Sons Ltd.)

Background: Despite a substantial prevention of neural tube defects with mandatory folic acid (FA) fortification, a significant number of cases still exist in Alberta, Canada, particularly spina bifida (SB). The purpose of this study was to review cases with SB to provide a possible explanation as to why SB is still prevalent in Alberta., Methods: Cases with SB born between 2001 and 2015, ascertained by the Alberta Congenital Anomalies Surveillance System, were reviewed. Cases were classified as lipomeningomyelocele, syndrome/recognized condition, chromosome, associated multiple congenital anomalies, and isolated. The notice of birth forms were reviewed to determine FA supplement use before and/or during pregnancy. Socioeconomic status (SES) was also examined., Results: The majority of cases were isolated (58%). The total prevalence of SB for 2001-2015 was 0.37/1,000 births, with isolated SB being 0.21/1,000 births. Urinary and congenital heart defects were the most frequently identified associated anomalies. FA supplementation could not be determined for 69% of our cases because of a lack of completeness of the notice of birth forms. There was no significant difference regarding SES between mothers of cases and all mothers in Alberta., Conclusions: It is important to examine cases with isolated SB to determine why mandatory FA fortification has not completely prevented SB and to identify which cases are not folate-responsive. A more concerted effort of public health education and promotion with the identification of women with suboptimal folate status and a better understanding of the role of other micronutrients is necessary., (© 2018 Wiley Periodicals, Inc.)

Several countries, as Brazil, have public policies for periconceptional folic acid supplementation (FAS) in order to prevent unfavorable outcomes. Our aim was to evaluate the FAS situation in a public reference hospital from Southern Brazil. This study included all mothers who had children born at the Hospital Materno Infantil Presidente Vargas, RS, Brazil, in a 1-year period. Data collection was conducted through interviews with application of a clinical protocol and analysis of the patients' records. FAS was defined as the use of folic acid in any period of the periconceptional period, irrespective of the duration and amount. We also classified those mothers who correctly followed the national recommendation proposed by the Health Ministry of Brazil. The sample consisted of 765 mothers evaluated soon after childbirth. Their ages ranged from 12 to 45 years (mean 25.2 years). The overall level of FAS was 51.5%, and the use according to the national recommendation occurred in only 1.6%. Factors associated with non-FAS consisted of lower maternal age (p = .009) and maternal schooling (p = .023), higher number of pregnancies (p = .003), fewer prenatal visits (p = .050) and later prenatal care onset (p = .037). Periconceptional FAS in our midst seems to be very far from the ideal goal. Susceptible groups appeared to be mothers who were younger, less educated, multiparous, and had inadequate prenatal care. We believe that efforts of education and awareness should be especially targeted for these groups. These recommendations should also be strengthened among those who prescribe the FAS., (© 2018 Wiley Periodicals, Inc.)

Objectives: Neurenteric cysts (NCs) of the central nervous system (CNS) are cystic congenital lesions that may occur anywhere along the neural tube. They are most common in the spinal region, in the lower part of the cervical and upper thoracic spine. Intracranial NCs occur rarely and there are only small series of patients published in literature worldwide. Microsurgical resection is the treatment of choice. We present our experience in treatment of NCs and review of literature., Methods: Seven patients with NC of CNS who were operated at the Department of Neurosurgery of Comenius University at University Hospital Bratislava within nine years (2010-2018) were included in the study. The series was retrospectively evaluated with an emphasis on symptomatology, surgery and postoperative course., Results: In three of the seven patients, NC was localized intracranially, in the other four, NC was in the spinal canal. In three patients, a complete removal of NC was achieved (2 intracranial NC, 1 spinal NC). In other patients, a portion of the cyst wall was left to prevent the development of a postoperative neurological deficit. After surgery, the neurological symptoms were completely resolved in six patients, while in one patient, they were alleviated. In one patient, a complication occurred during the postoperatove course. There was no recurrence during the follow-up (3-111 months, mean duration 39 months)., Conclusion: In our series of patients with intracranial and intraspinal tumors, the incidence of NC was higher than presented in the published data. Our own surgical experience has shown that complete tumor resection is not always possible for intimate adherence to the surrounding structures. Leaving a tiny portion of the cyst wall allowed us to achieve good clinical results with no recurrence. Long-term follow-up of patients is required due to the risk of recurrence. However, it can already be stated that an adequate extent of resection leads to good clinical results (Tab. 1, Fig. 4, Ref. 33).

Introduction: Unlike developing countries, including Ethiopia the identification of the risk factors in decreasing the burden of neural tube defects (NTDs) is well established in the developed world. Hence, we sought to determine the factors associated with NTDs in Tigray - Ethiopia., Methods: We undergo a case-control analysis where all NTDs cases were compared to a group of controls derived randomly from the same hospitals where cases were recruited from. The NTDs survey tool which contains a standard questionnaire was prepared. Parental socio-demographic and clinical information such, maternal age, obstetric history, illnesses, drug intake, radiation, occupation, education, history of congenital anomalies, residence, exposure to pollutants such as smoking, chemicals, paternal history, and folic acid utilization was collected and analyzed using SPSS version 20., Result: This study has shown the maternal age, and residency, birth order 3 and 4, unplanned pregnancy, history of breastfeeding above 2 years, history of stillbirths, history of male gender predominance were found to have a strong association with an occurrence of NTDs (p = 0.0001). Though the binary logistic regression analysis showed no significant association in some of the risk factors such as maternal health and drug history, the frequency analysis showed they may have an impact on the incidence of NTDs., Conclusion: This study has shown the majority of the maternal risk factors and other lifestyle patterns had a significant impact on the occurrence of NTDs. Therefore, efficient monitoring of NTDs in Ethiopia is vital, so our study could be groundwork information in Ethiopia for future programs., (Copyright © 2018. Published by Elsevier B.V.)

Background: Folic acid (FA) supplementation is known to prevent neural tube defects (NTDs). We examined whether this preventive effect differs by the sex of the infant., Methods: Data were gathered from a large population-based cohort study in China that evaluated the effects of FA supplementation on NTDs. All births at 20 complete gestational weeks, including live births, stillbirths, and pregnancy terminations, and all NTDs, regardless of gestational age, were recorded. In a northern China province, a total of 30,801 singleton live births to women whose use of FA supplements during the first trimester was known at the time were included in the study. The birth prevalence of NTDs was classified by sex, subtype, and maternal FA supplementation. Male to female rate ratios [RR] and their 95% confidence intervals [CI] were calculated., Results: A total of 106 NTDs cases were recorded. The overall prevalence of NTDs was 2.5‰ among males and 4.4‰ among females; NTDs were less prevalent among males than among females (RR, 0.58; 95% CI, 0.54-0.63). There was a higher prevalence of anencephaly (RR, 0.34; 95% CI, 0.27-0.43) and spina bifida (RR, 0.73; 95% CI, 0.63-0.84) among females. However, FA supplementation led to significantly greater decreases in the rates of anencephaly (4.8‰) and total NTDs (7.6‰) in females than in males (1.6‰ and 2.8‰, respectively)., Conclusions: FA supplementation successfully reduces the prevalence of NTDs in both male and female infants, although we found a significantly greater decrease in anencephaly and total NTDs in females than in males. How the protective effects of FA supplementation affect the sexes differently needs to be studied further.

Chiari malformations are structural defects in the posterior fossa where the cerebellum displaces caudally into the foramen magnum and upper spinal canal. These malformations are classified by severity as Types 1-4, each presenting with different associated and/or concurrent conditions and anomalies. The aim of this study was to utilize a nationwide database to study patients with Chiari malformations including their concurrent diagnoses and associated anomalies. Using a retrospective review of the Nationwide Inpatient Sample (NIS) database from 2003 to 2012, Chiari malformations were assessed by Chiari type and rates of concurrence for various additional anomalies were evaluated using cross-tabulations. There were 305,726 national cases of Chiari Type 1, 119,632 cases of Chiari Type 2, 15,540 cases of Type 3, and 79,663 cases of Type 4. Overall 44.3% of Chiari patients have at least one concurrent anomaly. Stratified by Chiari Type, 7.1% of Type 1 patients, 12.3% of Type 2, and 100% of Type 3 and 4 have at least one concurrent anomaly. The most common isolated neurologic associations were tethered cord, syringomyelia, and hydrocephalus, while the most common anomaly clusters were syringomyelia and scoliosis in Type 1 (0.63), tethered cord syndrome and scoliosis (0.72%) in Type 2, encephalocele and acquired hydrocephalus (11.45%) in Type 3, and reduction deformity of the brain with acquired hydrocephalus (15.95%) in Type 4. Chiari malformations have strong associations with other abnormalities outside of known relationships in the current classification. While neurologic abnormalities are most common, additional body systems are frequently involved especially with worsening hindbrain defects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The aims of this quality improvement project were to identify secondary conditions and medical co-morbidities in adult patients with spina bifida and to determine which factors were associated with an earlier age of death., Design: Retrospective chart review of 487 patients who attended the University of Pittsburgh Medical Center Adult Spina Bifida Clinic between August 1, 2005, and June 6, 2017, was conducted., Results: Of 487 patients who had received care at the University of Pittsburgh Medical Center Adult Spina Bifida Clinic, 48 were deceased. The most commonly reported causes of death included infection, respiratory failure, renal failure, shunt malfunction, and metastatic cancer. Underlying co-morbidities and secondary conditions included hydrocephalus, Chiari II malformation, tethered cord, scoliosis, and abnormal renal function. In deceased patients, earlier age of death was significantly associated with myelomeningocele subtype and the presence of hydrocephalus and Chiari II malformation., Conclusions: Clinicians treating individuals with spina bifida should be aware of the potential for earlier mortality in individuals with myelomeningocele, hydrocephalus, and Chiari II malformation, especially with regard to infection, respiratory failure, renal failure, shunt malfunction, and cancer., To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Discuss the importance of recognizing co-morbidities in adult individuals with spina bifida; (2) Describe secondary conditions and medical co-morbidities associated with spina bifida; and (3) Identify which conditions are associated with earlier age of death in adult individuals with spina bifida., Level: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Background: The association between maternal consumption of sprouted potato during periconceptional period on the development of neural tube defects (NTDs) or orofacial clefts (OFCs) remains unclear. We aimed to examine the association between maternal consumption of sprouted potatoes during periconceptional period and risks of NTDs or OFCs., Methods: Subjects included 622 NTD cases, 135 OFC cases and 858 nonmalformed controls, were recruited from a case-control study in Shanxi Province of northern China between 2002 and 2007. Information on demographics, maternal sprouted potato consumption, lifestyle behaviors and folic acid supplementation was collected., Results: Consumption of sprouted potatoes was associated with elevated odds of total NTDs (OR = 2.20; 95% CI, 1.12-4.32) and anencephaly (OR = 2.48; 95% CI, 1.10-5.58); no association for spina bifida or encephalocele. Sprouted potato consumption increased the risk of total OFCs (OR = 3.49; 95% CI, 1.29-9.49) and cleft lip with or without cleft palate (CL ± P) (OR = 4.03; 95% CI, 1.44-11.28)., Conclusion: Maternal consumption of sprouted potatoes during periconceptional period may increase the risks of NTDs and OFCs. Given that potato is commonly consumed around the world, improper preservation and use should be a matter of concern in respect of the potential teratogenicity.