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Summary Background & aims Maternal gestational infection is a well-characterized risk factor for offsprings’ development of mental disorders including schizophrenia, autism, and attention deficit disorder. The inflammatory response elicited by the infection is partly directed against the placenta and fetus and is the putative pathogenic mechanism for fetal brain developmental abnormalities. Fetal brain abnormalities are generally irreversible after birth and increase risk for later mental disorders. Maternal immune activation in animals models this pathophysiology. SARS-CoV-2 produces maternal inflammatory responses during pregnancy similar to previously studied common respiratory viruses. Method Choline, folic acid, Vitamin D, and n-3 polyunsaturated fatty acids are among the nutrients that have been studied as possible mitigating factors for effects of maternal infection and inflammation on fetal development. Clinical and animal studies relevant to their use in pregnant women who have been infected are reviewed. Results Higher maternal choline levels have positive effects on the development of brain function for infants of mothers who experienced viral infections in early pregnancy. No other nutrient has been studied in the context of viral inflammation. Vitamin D reduces pro-inflammatory cytokines in some, but not all, studies. Active folic acid metabolites decrease anti-inflammatory cytokines. N-3 polyunsaturated fatty acids have no effect. Conclusions Vitamin D and folic acid are already supplemented in food additives and in prenatal vitamins. Despite recommendations by several public health agencies and medical societies, choline intake is often inadequate in early gestation when the brain is forming. A public health initiative for choline supplements during the pandemic could be helpful for women planning or already pregnant who also become exposed or infected with SARS-CoV-2.

Objectives Certain prescription medications should be avoided during pregnancy to reduce the risk of fetal harm. Identification of these medications to minimize exposure may be achieved through the integration of preconception care recommendations into medication therapy management (MTM) services. The primary objective of this study was to identify missed opportunities for pharmacists to provide preconception care support related to medications associated with adverse pregnancy outcomes for reproductive-aged women who received MTM consultations at a regional supermarket pharmacy chain. Secondary objectives examined the concurrent use of prenatal vitamins, folic acid, or hormonal contraception in patients receiving medications associated with adverse pregnancy outcomes. Methods The study examined all MTM and prescription drug claims submitted by a regional chain of supermarket pharmacies from January 1, 2018 to June 30, 2019, to identify female patients aged 15-45 years who received MTM services. Prescription claims were cross-referenced to determine which of these patients also received medications associated with adverse pregnancy outcomes. To identify patients with long-term use of opioids and nonsteroidal anti-inflammatory drugs, a restriction based on days supplied was then applied. Results Of the 2020 female patients who received MTM services and filled at least 1 prescription during the study period, 731 (36.2%) were found to have received at least 1 medication associated with adverse pregnancy outcomes for the minimal days’ threshold. Of these, 509 (69.6%) lacked evidence of concurrent prescription contraception, and 74 (10.1%) had a concurrent prescription for folic acid or prenatal vitamins. Conclusion The use of medications associated with adverse pregnancy outcomes was widespread in this sample of reproductive-aged women. The findings of this study indicate the need for additional research to investigate the implementation of targeted MTM interventions to build standard workflow processes and facilitate pharmacists’ management of this critical clinical issue.

Background Zinc and vitamin A supplementation have both been shown to affect iron status, hemoglobin (Hb) concentration, and anemia in animal and human studies. However, evidence on their combined use in pregnancy, in the context of iron-folic acid (IFA) supplementation, remains limited. Objective This study determined the effects of prenatal zinc, vitamin A, and iron supplementation on maternal hematologic and micronutrient status at delivery in Tanzania. Methods We analyzed 2 large randomized controlled trials, using generalized estimating equations, and examined the effect of daily zinc (25 mg) and vitamin A (2500 IU) supplementation starting in the first trimester of pregnancy compared with placebo (n = 2500), and separately evaluated the safety and efficacy of daily iron (60 mg) supplementation among iron-replete pregnant women (n = 1500). Blood samples from baseline and delivery were tested for Hb, serum ferritin, soluble transferrin receptor, plasma zinc, and zinc protoporphyrin. Results Zinc and vitamin A supplementation were associated with lower Hb concentrations at delivery of -0.26 g/dL (95% CI: -0.50, -0.02 g/dL) and -0.25 g/dL (95% CI: -0.49, -0.01 g/dL), respectively. Vitamin A increased mean ferritin concentrations at delivery (14.3 μg/L, 95% CI: 1.84, 29.11 μg/L), but was associated with increased risk of severe anemia (RR: 1.41; 95% CI: 1.06, 1.88). Among women who were iron replete at baseline, iron supplementation reduced the risk of iron depletion at delivery by 47% (RR: 0.53; 95% CI: 0.43, 0.65). There was no effect of zinc or iron supplements on plasma zinc concentrations. Conclusions Our findings support existing WHO guidelines on prenatal iron, vitamin A, and zinc supplementation among pregnant women. In this setting, scaling uptake of prenatal iron supplements is warranted, but prenatal zinc and vitamin A supplementation did not benefit maternal hematologic status at delivery. In settings where vitamin A deficiency is endemic, the efficacy and safety of the WHO recommended prenatal vitamin A supplementation require further evaluation.

BACKGROUND: There is evidence vitamin A plays a role in neuroblastoma. Not only is 13-cis-retinoic acid used as maintenance therapy for high-risk cases, but prenatal vitamin intake use may decrease neuroblastoma risk. We hypothesized that single nucleotide polymorphisms (SNPs) in vitamin A-related genes are may be associated with neuroblastoma risk and potentially be modified by vitamin A intake. METHODS: The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 case-parent sets through the Children’s Oncology Group’s Childhood Cancer Research Network. We ascertained dietary nutrient intake through questionnaires and genotyped 463 SNPs in vitamin A-related genes from saliva DNA. Offspring and maternal log-additive risk ratios (RR) and stratum-specific RR for gene-environment interaction were estimated with a log-linear model. We avoided false positives due to multiple testing by using the false discovery rate (FDR). RESULTS: When all neuroblastoma cases were considered together, no offspring variants met the significance criteria (FDR Q-value

Background Hypertensive disorders of pregnancy are among the leading causes of maternal morbidity and mortality. Studies suggest that the use of folic acid may lower the risk of hypertensive disorders in pregnant women. Aim The aim of this study was to assess the effects of timing and duration of folic acid-containing supplement use on the risk for gestational hypertension and preeclampsia. Methods Exposures and outcomes data were obtained through interviews and review of participant’s medical records from the MotherToBaby cohort studies across the United States and Canada. Demographics, medical history, lifestyle factors, substance use, and fetal sex were assessed as potential confounders. Unadjusted and adjusted risks for gestational hypertension and preeclampsia were examined using odds ratios and 95% confidence intervals. Findings 3247 women were included in the study. Compared to non-supplement use, early and late supplement use were not significantly associated with the development of gestational hypertension or preeclampsia. The odds of developing gestational hypertension and preeclampsia were significantly reduced as the duration of folic acid-containing supplement use increased. Conclusion Findings from this study suggest that the use of folic acid-containing supplements may mitigate the risk for gestational hypertension and preeclampsia.

Autism is a neurodevelopmental disease that presents in early life. Despite a considerable amount of studies, the neurobiological mechanisms underlying autism remain obscure. Both genetic and environmental factors are involved in the development of autism. Vitamin D deficiency is emerging as a consistently reported risk factor in children. One reason for the prominence now being given to this risk factor is that it would appear to interact with several other epidemiological risk factors for autism. Vitamin D is an active neurosteroid and plays crucial neuroprotective roles in the developing brain. It has important roles in cell proliferation and differentiation, immunomodulation, regulation of neurotransmission and steroidogenesis. Animal studies have suggested that transient prenatal vitamin D deficiency is associated with altered brain development. Here we review the potential neurobiological mechanisms linking prenatal vitamin D deficiency and autism and also discuss what future research targets must now be addressed.

Background The role of prenatal vitamin D sufficiency and supplementation in the development of childhood aeroallergen sensitization and allergic rhinitis remains uncertain. Objective To describe the association of prenatal vitamin D sufficiency with childhood allergic outcomes in participants of the Vitamin D Antenatal Asthma Reduction Trial, a randomized controlled trial of prenatal vitamin D supplementation. Methods We included 414 mother–offspring pairs with offspring aeroallergen sensitization data available at age 6 years in this analysis. We examined the association between prenatal vitamin D sufficiency status, based on vitamin D levels measured in the first and third trimesters, or vitamin D supplementation treatment assignment with the outcomes of aeroallergen sensitization, parent-reported clinical allergic rhinitis, parent-reported clinical allergic rhinitis with aeroallergen sensitization, food sensitization, any sensitization, eczema, and total IgE at ages 3 and 6 years. Results Compared with early and late insufficiency, early prenatal vitamin D insufficiency with late sufficiency was associated with reduced development of clinical allergic rhinitis with aeroallergen sensitization at 3 years (adjusted odds ratio [aOR] = 0.34; 95% confidence interval [CI], 0.13-0.82; P = .02) and 6 years (aOR = 0.54; 95% CI, 0.29-0.98; P = .05). At 6 years, clinical allergic rhinitis with sensitization was significantly decreased in offspring whose mothers received high-dose vitamin D (aOR = 0.54; 95% CI, 0.32-0.91; P = .02) compared with offspring whose mothers who received low-dose vitamin D. Associations of prenatal vitamin D with aeroallergen sensitization were strengthened among children who also developed asthma or who had a maternal history of atopy. Conclusions Among mothers with first-trimester vitamin D insufficiency, we detected a protective effect of third-trimester prenatal vitamin D sufficiency on the development of clinical allergic rhinitis with aeroallergen sensitization at ages 3 and 6 years.

OBJECTIVES: The human milk microbiome plays an important role in child health and is affected by several factors. We aim to examine whether prenatal diet and supplement intake are associated with human milk microbiota composition. METHODS: Among the CHILD Cohort Study members, 771 mothers provided data on diet and supplement intake during pregnancy and a milk sample between 2–6 months postpartum. Maternal diet was assessed using a food frequency questionnaire adapted from the Fred Hutchinson Cancer Center. Three dietary patterns were derived using principal component analysis: plant-based, Western, and balanced. The milk microbiome was analyzed using 16S rRNA gene sequencing. Associations between maternal intake and microbial diversity (Shannon index) and genera relative abundances were examined in R using the Wilcoxon signed-rank test adjusted for multiple comparisons. RESULTS: Maternal supplement intake, but not dietary patterns, was associated with human milk microbiota composition. Approximately 88% of the mothers took prenatal multivitamins. Mothers who took fish oil (18%) or folate supplements (17%) during pregnancy had lower microbial diversity than those who did not (mean ± SD: 1.61 ± 0.64 v. 1.79 ± 0.66 for fish oil [p = 0.01] and 1.64 ± 0.64 v. 1.78 ± 0.67 for folate [P = 0.02]). Mothers who took vitamin C supplements (4%), compared to those who did not, had higher microbial diversity (1.99 ± 0.59 v. 1.72 ± 0.65 [P = 0.03]) and higher relative abundance of Veillonella but lower abundances of Finegoldia and Stenotrophomonas (p(fdr )

Background Enamel hypoplasia (EH) increases risk for dental caries and also is associated with vitamin D deficiencies. This pilot study evaluates the feasibility to determine the association of human maternal circulating vitamin D concentrations during pregnancy and EH in infant's teeth that develop in utero. Methods A pilot population of 37 children whose mothers participated in a RCT of vitamin D supplementation during pregnancy was evaluated. Major outcome was EH and major exposure was maternal monthly serum circulating 25(OH)D concentrations during pregnancy. EH was assessed using the Enamel Defect Index and digital images made by a ProScope High Resolution™ handheld digital USB microscope at 50× magnification. Results During initial 8 weeks of study, 29/37 children had evaluable data with mean age of 3.6 ± 0.9 years; 48% male; and 45% White, 31% Hispanic, and 24% Black. EH was identified in 13 (45%) of the children. Maternal mean 25(OH)D concentrations were generally lower for those children with EH. Conclusions Preliminary results suggest follow-up of children of mothers in a vitamin D supplementation RCT during pregnancy provides an important approach to study the etiology of EH in the primary teeth. Further study is needed to discern thresholds and timing of maternal serum 25(OH)D concentrations during pregnancy associated with absence of EH in teeth that develop in utero. Potential dental public health implications for prevention of early childhood caries via sound tooth structure as related to maternal vitamin D sufficiency during pregnancy need to be determined.

Objectives To review the evidence-based management of nausea and vomiting of pregnancy and hyperemesis gravidarum. Evidence MEDLINE and Cochrane database searches were performed using the medical subject headings of treatment, nausea, vomiting, pregnancy, and hyperemesis gravidarum. The quality of evidence reported in these guidelines has been described using the Evaluation of Evidence criteria outlined in the Report of the Canadian Task Force on Preventative Health Care. Benefits Nausea and vomiting of pregnancy has a profound effect on women's health and quality of life during pregnancy as well as a financial impact on the health care system, and its early recognition and management is recommended. Cost Costs, including hospitalizations, additional office visits, and time lost from work, may be reduced if nausea and vomiting in pregnancy is treated early. Recommendations 1.Women experiencing nausea and vomiting of pregnancy may discontinue iron-containing prenatal vitamins during the first trimester and substitute them with folic acid or adult or children's vitamins low in iron. (II-2A) 2.Women should be counselled to eat whatever pregnancy-safe food appeals to them and lifestyle changes should be liberally encouraged. (III-C) 3.Ginger may be beneficial in ameliorating the symptoms of nausea and vomiting of pregnancy. (I-A) 4.Acupressure may help some women in the management of nausea and vomiting of pregnancy. (I-B) 5.Mindfulness-based cognitive therapy as an adjunct to pyridoxine therapy may be beneficial. (I-B) 6.Pyridoxine monotherapy or doxylamine/pyridoxine combination therapy is recommended as first line in treating nausea and vomiting of pregnancy due to their efficacy and safety. (I-A) 7.Women with high risk for nausea and vomiting of pregnancy may benefit from preemptive doxylamine/pyridoxine treatment at the onset of pregnancy. (I-A) 8.H 1 receptor antagonists should be considered in the management of acute or chronic episodes of nausea and vomiting of pregnancy. (I-A) 9.Metoclopramide can be safely used as an adjuvant therapy for the management of nausea and vomiting of pregnancy. (II-2B) 10.Phenothiazines are safe and effective as an adjunctive therapy for severe nausea and vomiting of pregnancy. (I-A) 11.Despite potential safety concerns of ondansetron use in pregnancy, ondansetron can be used as an adjunctive therapy for the management of severe nausea and vomiting of pregnancy when other antiemetic combinations have failed. (II-1C) 12.Corticosteroids should be avoided during the first trimester because of possible increased risk of oral clefting and should be restricted to refractory cases. (I-B) 13.When nausea and vomiting of pregnancy is refractory to initial pharmacotherapy, investigation of other potential causes should be undertaken. (III-A)

BACKGROUND: Childhood asthma developmental programming is complex. Maternal asthma is a strong risk factor for childhood asthma, while vitamin D (VD) has emerged as a modifiable prenatal exposure. OBJECTIVE: To examine the combined effect of early and late prenatal VD status in pregnancies with and without asthma on childhood asthma/recurrent wheeze development. METHODS: We conducted a cohort study using prospectively collected data from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), a randomized, double-blinded, placebo-controlled vitamin D supplementation trial in pregnant women at high risk of offspring asthma (N=806 mother-offspring pairs). 25-hydroxyvitamin-D [25(OH)D] was measured in early and late pregnancy. Our main exposure was an ordered variable representing early and late prenatal VD sufficiency [25(OH)D≥30ng/mL)] status in pregnancies with and without asthma. The primary outcome was offspring asthma or recurrent wheeze by age 3 years. We also examined the effect of prenatal VD on early life asthma/recurrent wheeze progression to active asthma at age 6 years. RESULTS: Among maternal asthmatics, compared to those with early and late prenatal VD insufficiency, those with early or late VD sufficiency (aOR=0.56; 95% CI 0.31-1.00) or early and late VD sufficiency (aOR=0.36; 95% CI 0.15-0.81) had lower risk of offspring asthma/recurrent wheeze by age 3 years (P(for trend)=0.008). This protective trend was reiterated in asthma/recurrent wheeze progression to active asthma from age 3 to 6 years (P(for trend)=0.04). CONCLUSION: This study implicates a protective role for VD sufficiency throughout pregnancy, particularly in attenuating the risk conferred by maternal asthma on childhood asthma/recurrent wheeze development. CLINICAL IMPLICATION: Early identification and correction of vitamin D insufficiency in asthmatic pregnant women have implications for the prevention of early offspring asthma/recurrent wheeze and the persistence of offspring asthma to later childhood. CAPSULE SUMMARY: Our data support the role of early and late-pregnancy vitamin D sufficiency in attenuation of the risk of offspring asthma or/and recurrent wheeze in early childhood and the progression to active asthma at later childhood.

An infant presented with bilateral disk edema and an acute left sixth cranial nerve (CN VI) palsy because of pseudotumor cerebri (PTC). PTC is rare in infants where it is often associated with endocrine abnormalities, medications, viral infections, systemic conditions, and nutritional etiologies such as vitamin A toxicity. We report a case of PTC in an infant associated with hypervitaminosis A with an unlikely source-a common prenatal vitamin.

Vitamin D deficiency has been widely reported among pregnant women and infants around the world. Women with low sun exposure, high BMI, low vitamin D intakes and socioeconomic disadvantage with poor quality diets are at greatest risk of vitamin D deficiency, leading to very low serum concentrations of 25-hydroxyvitamin D (25(OH)D) in their offspring and an increased risk of nutritional rickets. Many observational studies, supported by compelling in vitro and in vivo data, have generated evidence suggesting that low vitamin D status in pregnancy may also contribute to the risk of adverse perinatal outcomes including hypertensive disorders (e.g., preeclampsia), fetal growth restriction, and preterm birth. However, the few large randomized controlled trials (RCTs) conducted to date have generated conflicting evidence for a role of vitamin D supplementation in improving perinatal outcomes. Vitamin D supplementation policies during pregnancy and implementation of policies vary within and between jurisdictions. Regulatory authorities have cited insufficient evidence to establish pregnancy-specific targets for serum 25(OH)D concentrations or prenatal vitamin D intake that effectively reduce the risks of adverse perinatal and infant outcomes. This paper arises from a Debate on Vitamin D Requirements during Pregnancy, held at the 22nd Vitamin D Workshop, 2019. From varied perspectives, our objectives were to evaluate the evidence for: vitamin D metabolism in pregnancy and the prevalence of gestational vitamin D deficiency worldwide; the translation of laboratory research findings to clinical studies on the role of vitamin D in perinatal health; the challenges of designing and conducting clinical trials to establish prenatal vitamin D requirements; and results to date of major large RCTs of prenatal vitamin D supplementation. Lastly, we explored potential next steps towards generating robust clinical data in this field to address both public health protection and patient care.

Background Environmental phenols and parabens are endocrine disrupting chemicals (EDCs) with the potential to affect child neurodevelopment including autism spectrum disorders (ASD). Our aim was to assess whether exposure to environmental phenols and parabens during pregnancy was associated with an increased risk of clinical ASD or other nontypical development (non-TD). Methods This study included mother-child pairs (N = 207) from the Markers of Autism Risks in Babies – Learning Early Signs (MARBLES) Cohort Study with urinary phenol and paraben metabolites analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) from repeated pregnancy urine samples. Because family recurrence risks in siblings are about 20%, MARBLES enrolls pregnant women who already had a child with ASD. Children were clinically assessed at 3 years of age and classified into 3 outcome categories: ASD, non-TD, or typically developing (TD). Single analyte analyses were conducted with trinomial logistic regression and weighted quantile sum (WQS) regression was used to test for mixture effects. Results Regression models were adjusted for pre-pregnancy body mass index, prenatal vitamin use (yes/no), homeowner status (yes/no), birth year, and child's sex. In single chemical analyses phenol exposures were not significantly associated with child's diagnosis. Mixture analyses using trinomial WQS regression showed a significantly increased risk of non-TD compared to TD (OR = 1.58, 95% CI: 1.04, 2.04) with overall greater prenatal phenol and paraben metabolites mixture. Results for ASD also showed an increased risk, but it was not significant. Discussion This is the first study to provide evidence that pregnancy environmental phenol exposures may increase the risk for non-TD in a high-risk population.

Prenatal exposure to vitamin D is thought to be critical for optimal fetal neurodevelopment, yet vitamin D deficiency is apparent in a growing proportion of pregnant women. The aim of this study was to determine whether a mouse model of vitamin D-deficiency alters fetal neurodevelopment. Female BALB/c mice were placed on either a vitamin D control (2,195 IU/kg) or deficient (0 IU/kg) diet for 5 weeks prior to and during pregnancy. Fetal brains were collected at embryonic day (E) 14.5 or E17.5 for morphological and gene expression analysis. Vitamin D deficiency during pregnancy reduced fetal crown-rump length and head size. Moreover, lateral ventricle volume was reduced in vitamin D-deficient foetuses. Expression of neurotrophin genes brain-derived neurotrophic factor (Bdnf) and transforming growth factor-β1 (Tgf-β1) was altered, with Bdnf reduced at E14.5 and increased at E17.5 following vitamin D deficiency. Brain expression of forkhead box protein P2 (Foxp2), a gene known to be important in human speech and language, was also altered. Importantly, Foxp2 immunoreactive cells in the developing cortex were reduced in vitamin D-deficient female foetuses. At E17.5, brain tyrosine hydroxylase (TH) gene expression was reduced in females, as was TH protein localization (to identify dopamine neurons) in the substantia nigra of vitamin D-deficient female foetuses. Overall, we show that prenatal vitamin D-deficiency leads to alterations in fetal mouse brain morphology and genes related to neuronal survival, speech and language development, and dopamine synthesis. Vitamin D appears to play an important role in mouse neurodevelopment.

Background Poor vitamin D status (i.e. low serum 25-hydroxyvitamin D (25(OH)D)) has been associated with adverse clinical outcomes during pregnancy and childhood. However, the interpretation of serum 25(OH)D levels may be complicated by the presence of the C3-epimer of 25(OH)D. We aimed to quantify C3-epi-25(OH)D 3 in pregnant women and fetuses, to explore the relationship of the C3-epimer between maternal and cord samples, and to establish whether infant C3-epimer abundance is explained by prenatal formation. Methods In a sub-study of a randomized trial of prenatal vitamin D 3 , 25(OH)D 3 and C3-epi-25(OH)D 3 were quantified by LC–MS/MS in 71 sets of mother–fetus–infant serum samples, including maternal delivery specimens, cord blood, and infant specimens acquired at 3–28 weeks of age. Results Without supplementation, median concentrations of C3-epi-25(OH)D 3 were higher in infants (6.80 nmol/L) than mothers (0.45 nmol/L) and cord blood (0 nmol/L). However, there was substantial variation such that C3-epi-25(OH)D 3 accounted for up to 11% (maternal), 14% (cord), and 25% (infant) of the total 25(OH)D 3 . Supplemental vitamin D 3 significantly increased maternal–fetal C3-epi-25(OH)D 3 , and was a preferential source of C3-epi-25(OH)D 3 compared to basal vitamin D, possibly due to C3-epi-cholecalciferol in the supplement. Multivariate regression did not suggest transplacental transfer of C3-epi-25(OH)D 3 , but rather indicated its generation within the fetal–placental unit from maternally-derived 25(OH)D 3 . Neither maternal nor fetal C3-epi-25(OH)D 3 is accounted for the relatively high concentrations of infant C3-epi-25(OH)D 3 , suggesting rapid postnatal generation. Conclusions C3-epi-25(OH)D 3 is present in some pregnant women and fetuses, but does not appear to be efficiently transferred transplacentally. High C3-epimer concentrations in infancy are probably due to postnatal formation rather than fetal stores.

OBJECTIVES: We have previously found that vitamin D supplementation may slow down epigenetic aging in young adults. Recently, new epigenetic clocks have been developed to estimate gestational age in newborn babies. We tested the hypothesis that vitamin D supplementation would slow down the epigenetic gestational aging. METHODS: A total of 92 participants (51% whites, 21% blacks, 28% Hispanics) were randomly selected from 450 pregnant women who were enrolled in a randomized controlled trial. Each mother was randomized to receive either 4000 IU/day vitamin D(3) or placebo plus the standard prenatal vitamins containing 400 IU vitamin D(3). Cord blood genome-wide methylation analyses were performed on the Illumina Infinium MethylationEPIC Beadchip. DNA methylation gestational age (DNAmGA) was calculated based on two methods developed by Knight and Bohlin. The effects of vitamin D(3) supplementation on DNA methylation-based gestational age acceleration (∆DNAmGA) were estimated in linear regressions adjusted for maternal age, race, smoking status and sex of the babies. RESULTS: Gestational age was highly correlated with DNAmGA(Knight) and DNAmGA(Bohlin) having the same correlation coefficients of 0.88 (ps

OBJECTIVES: To assess the effect of 3(rd) trimester maternal choline supplementation on child memory at 7 y of age. Animal studies have provided strong evidence that maternal choline supplementation improves offspring cognition, including memory, but few experimental studies have evaluated this intervention in humans. METHODS: Pregnant women (n = 26) were randomized to consume 480 mg (approx. the Adequate Intake [AI]) or 930 mg choline/d from gestational wk 27 until delivery as part of a controlled-feeding study. All food (providing 380 mg choline/d), choline supplements (100 mg or 550 mg/d), and prenatal vitamins were provided by the study. An ancillary follow-up was conducted to assess offspring cognitive functioning, including memory, at age 7 y (n = 20). Children performed a computer-based color-location memory task in which the location of dots on a cartoon figure were recalled after a retention interval (RI) of 1 or 8 s. The task increased in difficulty level (number of dots to be recalled; 1 to 5 dots) every 4 trials. Data were analyzed using mixed models; pairwise comparisons were corrected for multiplicity. RESULTS: Children in the 930 mg/d group passed more levels than those in the 480 mg/d group (P = .048; see Figure), indicative of superior memory span. While the choline group by RI interaction was non-significant (P = .31), contrasts revealed that the 930 (v. 480) mg/d group tended to pass more levels at the 1 s RI (P = .052), but not at the 8 s RI (P = .58). Similarly, the analysis of total dots correct revealed a choline group by RI interaction (P = .08) such that children in the 930 (v. 480) mg/d group recalled more dots correctly at the 1 s RI (P = .02), but not at the 8 s RI (P > .99). CONCLUSIONS: Children whose mothers consumed 930 (v. 480) mg choline/d performed significantly better on a task of color-location memory at age 7 y, suggesting a long-term beneficial effect of prenatal choline supplementation on offspring cognition in humans. These findings indicate that the choline AI for pregnant women may not be sufficient for optimal offspring cognitive functioning and raise concerns about choline intake during pregnancy in North America, which on average is only approx. 70% of the AI. FUNDING SOURCES: Funded by NIFA/USDA and the Balchem Corp. JEHN and CLB were supported by NIH Traineeships. CLB was supported by an Egg Nutrition Center Young Investigator Research Award for Early Exploration. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

OBJECTIVES: To determine the effect of prenatal vitamin D supplementation on expression of angiogenic factors in the placenta. METHODS: This is a secondary analysis of the Maternal Vitamin D for Infant Growth trial, a randomized controlled trial of maternal vitamin D supplementation in Dhaka, Bangladesh. We examined the expression of angiogenic factors in placental tissues. Women (n = 1300) were enrolled at 17–24 weeks gestation and randomized to receive: placebo, 4200 IU/week, 16,800 IU/week or 28,000 IU/week until delivery. We examined a subset of randomly selected placentas (n = 80) collected at birth, which included 20 tissues (10 male & 10 female offspring) from each treatment group in maternal/fetal pairs. A full thickness placental core was collected; fixed in formalin and embedded in paraffin. Tissue sections were stained for vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) using immunofluorescence. ImageJ was used to quantify intensity and % area of expression. T-tests were used to estimate the effects of each vitamin D dose on expression of angiogenic factors, compared to placebo. Interactions by fetal sex were also examined. RESULTS: The mean (SD) for % area of expression was 17.0 (4.0) for VEGF and 14.8 (1.9) for PlGF. The mean (SD) for intensity was 6520 (1549) for VEGF and 5716 (734) for PlGF. There were no significant differences in VEGF and PlGF between any vitamin D treatment groups versus placebo for % area or intensity of expression (Table 1). The effect of vitamin D treatment was not modified by fetal sex. CONCLUSIONS: Vitamin D supplementation starting from mid-pregnancy until delivery did not effect expression of two key angiogenic factors in the placenta at term. The impact of periconception vitamin D supplementation on expression of angiogenic factors in the placenta remains unknown. FUNDING SOURCES: Bill and Melinda Gates Foundation. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

OBJECTIVES: To estimate the dose-dependent effect of prenatal and postpartum vitamin D supplementation on circulating concentrations of biomarkers of maternal bone formation (osteoprotegerin [OPG], osteocalcin [OC], procollagen type 1 amino-terminal propeptide [P1NP], and OPG/RANKL ratio), bone resorption (receptor activator nuclear factor kappa-β ligand [RANKL], and carboxyterminal telopeptide of type 1 collagen [CTX]), and general markers of bone metabolism (fibroblast growth factor 23 [FGF23]), in a pregnancy cohort in Dhaka, Bangladesh. METHODS: This study is a sub-study of the Maternal Vitamin D for Infant Growth trial, a randomized controlled trial in which women were enrolled at 17–24 weeks gestation and randomized to one of five weekly oral vitamin D3 supplements or placebo regimens during pregnancy and up to 6 months postpartum: group A (placebo), group B (4200 IU/week), group C (16,800 IU/week), group D (28,000 IU/week), group E (28,000 IU/week during pregnancy and postpartum). Postpartum, all groups other than group E received placebo. Maternal venous blood samples were collected from MDIG participants at enrolment, delivery and 6 months postpartum. Concentrations of FGF23, CTX, and P1NP were determined using ELISAs and OPG, OC, and RANKL concentrations were determined using a Luminex/Millipore magnetic beads kit. For each biomarker (n range, 344 to 606), linear regression was used to compare each treatment group versus the placebo group adjusting for baseline concentrations. For delivery time point analyses, treatment groups D and E (same prenatal vitamin D dose) were combined, while in postpartum analyses the two groups were separated to estimate the postpartum effect. RESULTS: At delivery and 6 months postpartum, there were no significant differences in OPG, OC, OPG/RANKL, RANKL, and FGF23 concentrations between each treatment group versus the placebo group (Table 1 and Table 2). CONCLUSIONS: Vitamin D supplementation during the 2(nd)half of pregnancy and up to 6 months postpartum had no effect on markers of bone formation or resorption. Analyses for CTX are underway and will also be presented. FUNDING SOURCES: Bill and Melinda Gates Foundation. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

BACKGROUND: Low early life vitamin D status is associated with an increased risk of schizophrenia and psychotic experiences. Here we examine if maternal pregnancy vitamin D concentrations are associated with offspring psychotic experiences as young adults. METHODS: A community sample of 2047 participants was investigated. Maternal prenatal 25 hydroxyvitamin D (25(OH)D) concentrations were assessed with tandem mass spectroscopy. Psychotic experiences were assessed at age 18years using a semi-structured clinical interview. RESULTS: 177 cohort members reported suspected or definite psychotic experiences, There was no evidence of an association between maternal 25(OH)D concentrations as quartiles (p=0.85 hypothesis test of general association versus no association across the quartiles) or as a continuous variable (p=0.89) versus experience of suspected and definite psychotic experiences at 18years. Within the cohort, only 29 subjects met criteria for a psychotic disorder at age 18. Based on this sample, there was no significant association between maternal 25(OH)D and psychotic disorder at 18years. DISCUSSION: Maternal vitamin D levels were not associated with risk of psychotic experiences nor psychotic disorders in this birth cohort.

Background The effect of maternal exposure to essential minerals and heavy metals on fetus is an important issue, which affects women around the world. Few data are available on the concentration of both essential minerals and heavy metals in maternal/fetal medicine. The aims of this study were to (1) assess the correlation of mercury (Hg), manganese (Mn), iron (Fe), and copper (Cu) in paired maternal/fetal blood samples, and (2) study potential confounding factors during pregnancy. Methods Our study recruited 145 healthy pregnant women with a mean age of 28.06 years, gathering information by collecting interviewer-administered questionnaires. Paired maternal/fetal blood samples were collected by delivery. Results There was a positive correlation of Hg ( r = 0.78, p r = 0.31, p r = 0.17, p = 0.038), and Cu ( r = 0.21, p = 0.010) in paired maternal/fetal samples. Prenatal vitamin use (>3 times/wk) was significantly associated with lower maternal Hg (adjusted odds ratio 0.272, p = 0.005) and lower maternal Cu (adjusted odds ratio 0.267, p = 0.004) levels. Median fetal Hg, Mn, and Fe levels were higher than corresponding maternal levels, while median fetal Cu level was lower than maternal Cu level. Conclusion There was a positive correlation of Hg, Fe, Cu, and Mn in paired maternal/fetal samples in this series. Our findings have raised the possibility of reducing maternal Hg and Cu by way of prenatal vitamin supplementation.

Evidence from animal experiments now demonstrates that prenatal vitamin D levels influence brain development. The aims of this study were to examine isolation-induced pup ultrasonic vocalizations and maternal-infant interactions using a pup-retrieval test in developmental vitamin D (DVD) deficient and control rats. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. In two separate experiments we recorded ultrasonic vocalizations at 46 KHz in isolated pups and we performed a pup-retrieval test on the day of birth. There was no significant effect of maternal diet on the calling rate of isolation-induced ultrasonic vocalizations by pups. We found that DVD-deficient dams retrieved their pups sooner than control dams and engaged in more pup directed activities (sniffing and carrying pups) and had a longer latency for self-grooming and rearing than control dams. We also assessed vitamin D related measures from a terminal blood sample immediately after the pup-retrieval test and found that DVD-deficient dams and pups had significantly lower levels of 25 OHD(3), 1,25 (OH)(2)D(3) and phosphate, elevated levels of parathyroid hormone (PTH) but there was no significant effect of maternal diet on calcium levels. We speculate that the altered maternal-pup interactions identified in the DVD model may impact on early periods of brain development and behaviour. (C) 2010 Elsevier Inc. All rights reserved.

Introduction Prenatal vitamin D status may influence offspring's respiratory and allergic outcomes; however, evidence is inconclusive. A systematic review and meta-analysis was conducted on the association between 25-hydroxyvitamin D [25(OH)D] levels in maternal blood in pregnancy or cord blood at birth with the risk of offspring's respiratory and allergic conditions. Methods Two independent researchers conducted systematic searches for observational studies published using defined keywords on vitamin D and health outcomes, including respiratory tract infections (RTIs), wheeze, asthma, atopic eczema, allergic rhinitis, allergic sensitization and lung function. Random-effects meta-analyses were conducted. Heterogeneity among studies was tested by using the Cochran Q test and quantified by using the I2 statistic. Publication bias was examined by using Funnel plot and Egger's regression asymmetry test. Modification of effects by selected factors was assessed, including time at exposure assessment, offspring's age at health endpoint, outcome assessment, optimal 25(OH)D blood levels (30 ng/mL or greater) versus all the rest and geographical location. Results A total of 34 from 547 retrieved articles were included. Articles were based on 26 separate study populations, including 25 longitudinal birth cohorts and one case control study, from 16 different countries (latitude ranging from 55°N to 31°S). Increased prenatal exposure to 25(OH)D was inversely associated with risk of RTIs. Comparing the highest with the lowest category of 25(OH)D levels, the pooled odds ratio was 0.64 (95% CI 0.47, 0.87). A positive borderline association was found for lung function at school age (FEV1 z-score coefficient 0.07, 95% CI −0.01, 0.15). No associations were found for wheeze, asthma, atopic eczema, allergic rhinitis and allergic sensitization. After subgroup analysis, stronger inverse associations were found between prenatal vitamin D and risk of RTIs within the first 6 months of life, and between cord blood vitamin D levels and RTIs. A stronger inverse association was found for asthma occurrence within the first 5 years of life, but no later in childhood. A stronger association between prenatal vitamin D levels and risk of atopic eczema during childhood was detected at higher latitude. Conclusions Current evidence from observational studies indicates that exposure to higher levels of vitamin D in utero may protect against early-life respiratory tract infections in offspring during childhood. However, epidemiological evidence from observational studies does not support an impact of prenatal vitamin D status in offspring's risk of asthma and allergic manifestations. Additional studies are warranted to confirm the potential benefits for lung function development.

The last few years have witnessed the emergence of a multitude of supplements for pregnant and lactating women with n-3 fatty acids, predominantly as marine or fish oil. These marine oils have been added to prenatal vitamins and minerals as well as to food products specifically designed for women in the perinatal period. The main motivation behind these supplements appears to be the suggestion that an increased supply of docosahexaenoic acid (DHA, 22:6n-3), a key n-3 longchain polyunsaturated fatty acid, during the last trimester of pregnancy and early postnatal life may enhance development of the fetal and infant brain, clearly building on the extensive body of work relating to long-chain polyunsaturated fatty acid supplementation of infant formulas for term and preterm infants (1).

After review of current evidence related to the potential risks and benefits of folic acid supplementation, we conclude that unless clinicians can be assured that pregnant women will reliably use prenatal vitamin supplements containing 0.8–1.1 mg of folate, the prenatal vitamin supplements should be combined with 5 mg of folate.

Pregnancy is associated with increased susceptibility to oxidative stress. Deficiencies in antioxidants during pregnancy and placental oxidant-antioxidant imbalance may impair the development of the fetoplacental unit or the eventual offspring. In order to elucidate the association of prenatal status of vitamin C with the oxidative stress and apoptotic activity in normal full-term placentas, we evaluated the content of placental lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the trophoblast apoptotic index in normal-term human pregnancies. Tissue samples of placentas obtained from 80 normal-term pregnancies were categorized into 40 cases with a lower level of prenatal vitamin C (8.997 microg/ml) and 40 cases with a higher level of prenatal vitamin C (or =11.734 microg/ml). We evaluated the placental LOX-1 content and the trophoblast apoptotic index with Western blot analysis and immunohistochemistry, and then determined their correlation with the prenatal status of vitamin C. We confirmed that the trophoblast expression for the endothelial scavenger receptor LOX-1 and the apoptotic activity were significantly lower in the group with a higher prenatal level of vitamin C, indicating that placental oxidative stress and the apoptotic index were associated with the maternal status of vitamin C. We therefore postulate that the maternal status of antioxidant vitamins during pregnancy can affect fetal development.

Transient prenatal vitamin D deficiency produces hyperlocomotion in the adult rat. The aim of this study was to examine the effects of acute restraint on the behaviour of DVD and control rats in the open field. Rats were conceived and born to developmentally vitamin D (DVD) deficient or replete (control) dams and, at 8 weeks of age, were monitored for 30 min in an open field using automated video tracking software. Half of the rats were restrained within a towel for 5 min immediately before the open field test. The remainder received minimal handling prior to the open field test. Repeating previous findings, DVD deficient animals had enhanced locomotion during the first 10 min of the open field test compared to control rats. By contrast, there were no differences in locomotor activity after acute restraint stress. The time rats spent in the corners and side of the open field was affected by prenatal diet. DVD rats spent less time in the corners and more time in the side than control rats across the whole 30 min test. This difference was not seen in rats with acute restraint stress. The time spent in the centre was not altered by prenatal diet or acute restraint. Thus, transient prenatal vitamin D deficiency induces a transient spontaneous hyperlocomotion in adulthood that is modulated by acute restraint stress.

Among women of Mexican descent, increased acculturation in the United States has been associated with poorer health behaviors during pregnancy. This study examined a population of low-income women of Mexican descent in an agricultural community to determine whether social support patterns were associated with age at arrival in the U.S.; whether social support was associated with pregnancy behaviors; and whether increased social support could prevent some of the negative pregnancy behaviors that accompany acculturation. Participants were 568 pregnant women enrolled in prenatal care in the Salinas Valley, California. Participants were predominantly Spanish-speaking, born in Mexico, and from farmworker families. Information on social networks, social support, age at arrival in the United States, and pregnancy health behaviors was gathered during interviews conducted during pregnancy and immediately after delivery. Poorer health behaviors were observed among women who had come to the U.S. at a younger age. Social support during pregnancy was lowest among women who had come to the U.S. at an older age. High parity, low education, and low income were also associated with low social support. Higher social support was associated with better quality of diet, increased likelihood of using prenatal vitamins, and decreased likelihood of smoking during pregnancy. High social support also appeared to prevent the negative impact of life in the U.S. on diet quality. Women with intermediate or low levels of social support who had spent their childhoods in the U.S. had significantly poorer diet quality than women who had spent their childhoods in Mexico. However, among women with high social support, there was no difference in diet quality according to country of childhood. Thus, in the case of diet quality, increased social support appears to prevent some of the negative pregnancy behaviors that accompany time in the U.S. among women of Mexican descent.

Birth weight is known to fluctuate with season of birth, however, there is little information about seasonal variation in neonatal anthropometric measures.The aim of this study was to examine seasonal fluctuations in birth weight and selected anthropometric measures.The birth weight of singletons born after at least 37 weeks gestation was extracted from a perinatal register in south-east Queensland (n=350,171). Mean monthly birth weights for this period were examined. Based on a separate birth cohort, principal component analysis was undertaken on neonatal anthropometric measures (n=1233). Seasonality was assessed by (a) spectral analysis of time series data, (b) monthly and seasonal comparison of outcomes.Based on register data, birth weight displayed clear annual periodicity. Birth weight differed significantly when compared by month and season. Infants born in October were the heaviest (3484 g), while May-born infants were the lightest (3459 g; P=0.001). Based on the cohort anthropometric data, three components were identified related to (a) overall size, (b) limb length, and (c) head size and skin-fold thickness. Each of these components displayed significant seasonal variation. In particular, prominent seasonal fluctuations in limb length were identified, with peak limb length associated with winter/spring birth.Environmental factors that have regular seasonal fluctuation influence both the size and shape of neonates. Animal experiments suggest that prenatal hypovitaminosis D may underlie greater limb length. Because birth weight and limb length are associated with a broad range of important health outcomes, the seasonal exposures underlying these effects warrant further scrutiny from a public health perspective.

Based on clues from epidemiology, low prenatal vitamin D has been proposed as a candidate risk factor for schizophrenia. Recent animal experiments have demonstrated that transient prenatal vitamin D deficiency is associated with persistent alterations in brain morphology and neurotrophin expression. In order to explore the utility of the vitamin D animal model of schizophrenia, we examined different types of learning and memory in adult rats exposed to transient prenatal vitamin D deficiency. Compared to control animals, the prenatally deplete animals had a significant impairment of latent inhibition, a feature often associated with schizophrenia. In addition, the deplete group was (a) significantly impaired on hole board habituation and (b) significantly better at maintaining previously learnt rules of brightness discrimination in a Y-chamber. In contrast, the prenatally deplete animals showed no impairment on the spatial learning task in the radial maze, nor on two-way active avoidance learning in the shuttle-box. The results indicate that transient prenatal vitamin D depletion in the rat is associated with subtle and discrete alterations in learning and memory. The behavioural phenotype associated with this animal model may provide insights into the neurobiological correlates of the cognitive impairments of schizophrenia.

In the United States, the prevalence of third trimester anemia among low-income pregnant women is 29% and has not improved since the 1980s. Although low adherence has been linked to the ineffectiveness of iron supplementation programs, data regarding adherence to supplementation in low-income women are currently lacking. Hence this study was conducted to better understand the factors associated with adherence to the use of iron-containing prenatal multivitamin/mineral supplements among low-income pregnant women. Adherence to supplement use was assessed by pill counts among 244 pregnant women of 867 women who were initially randomized to receive 1 of 3 prenatal supplements. All women received care at a public prenatal clinic. Maternal characteristics associated with adherence were identified using predictive modeling. Women took 74% of supplements as prescribed. Adherence was higher among non-Hispanic white women than among non-Hispanic black women (79% vs. 72%, P

Rat experiments have shown that prenatal Vitamin D deficiency leads to altered neonatal brain morphology, cell density and neurotrophin expression. In the current study we examined the hypothesis that Vitamin D deficiency during early development alters adult behaviour even when there is an intervening period in which the animal receives normal Vitamin D in later development. Rats were conceived and born to Vitamin D deficient dams (Birth); conceived, born and weaned from Vitamin D deficient dams (Weaning); or deficient in Vitamin D from conception to 10 weeks of age (Life). Litters were standardized to three males and three females per litter. All rat offspring were rendered normocalcaemic with calcium supplemented water (2 mM) after weaning. Control animals were born to mothers fed a normal diet but subject to similar litter size and calcium supplementation. At 10 weeks all animals were tested on the holeboard test, elevated plus maze test, social interaction observation, acoustic startle response test, prepulse inhibition of the acoustic startle response and a forced swim test. Early Vitamin D deficiency (Birth group) enhanced locomotion in the holeboard test and increased activity in the elevated plus maze. Thus, transient prenatal Vitamin D deficiency induces hyperlocomotion in adulthood, without severe motor abnormalities.

Objective We sought to determine whether vitamins C and E could be delivered to the fetal-placental unit through maternal oral supplementation. Study design In a randomized, double-blind study, 20 women received a daily prenatal vitamin with or without 400 IU of vitamin E and 500 mg of vitamin C, starting at 35 weeks' gestation. At randomization, a nutritional questionnaire, plasma vitamin C and E and red blood cell (RBC) vitamin E levels were determined. At delivery, concentrations of maternal and fetal plasma vitamin C and E, maternal and fetal RBC vitamin E, amniotic fluid vitamin C, and chorioamnion vitamin E and tensile strength were determined. Results Maternal plasma vitamin E levels increased in the supplemented women but not in the control subjects. No changes in maternal vitamin C levels were noted. Maternal plasma vitamin C concentrations at delivery correlated closely with amniotic fluid vitamin C levels. Similarly, maternal plasma vitamin E levels at delivery correlated with the chorioamnion concentration of vitamin E. Conclusions Maternal plasma vitamin E levels are increased by oral supplementation. Maternal plasma vitamin C and E concentrations correlate with the concentration of vitamin C in the amniotic fluid and vitamin E in the chorioamnion, respectively.

We studied the dose requirements of thyroxine (T(4)) and serum concentrations of thyrotropin-stimulating hormone (TSH) and free T(4) in 16 pregnant women with primary hypothyroidism due to autoimmune thyroid disease (ATD, n = 11) or thyroidectomy (n = 5). All patients had been advised by their obstetricians to take prenatal vitamins enriched with iron ( approximately 90mg/tablet) and calcium ( approximately 200 mg/tablet), known to inhibit absorption of T(4). We asked patients to take their vitamins 4 hours after ingesting T(4) in the morning. The mean T(4) dose of 0.10 +/- 0.01 (mean +/- SEM, mg/d) during pregnancy did not differ significantly from that (0.09 +/- 0.005) before or after (0.10 +/- 0.01) pregnancy. Similarly, mean serum TSH of 2.7 +/- 0.28 mIU/L during pregnancy did not differ significantly from that before (2.2 +/- 0.47) or after (3.2 +/- 1.31) pregnancy. The mean serum free T(4) concentration during pregnancy (16 +/- 0.97 pmol/L) was significantly (P.05) lower than that (22 +/- 1.5) before or after (23 +/- 2.2) pregnancy and similar to that observed with our free T(4) measurement technique in normal (healthy) pregnant women. We next examined the data separately in patients with ATD and thyroidectomy. The mean T(4) dose (0.08 +/- 0.009) and TSH (2.4 +/- 0.29) during pregnancy in 11 ATD patients did not differ appreciably from those before (T(4) dose, 0.08 +/- 0.0006; TSH, 2.7 +/- 0.54) or after (T(4) dose 0.09 +/- 0.0063; TSH, 4.1 +/- 1.91) pregnancy. Similarly, the mean T(4) dose (0.12 +/- 0.022, n = 5) during pregnancy in thyroidectomized patients was similar to that before (0.12 +/- 0.017, n = 3) or after (0.12 +/- 0.022) pregnancy. However, serum TSH increased significantly, albeit within the normal range, during pregnancy in thyroidectomized patients (3.2 +/- 0.62, n = 5 v 0.41 +/- 0.017, n = 3, P.05) and it (1.3 +/- 0.60) decreased significantly (P.05) after pregnancy. Our data suggest that (1) the dose requirement of T(4) does not change systematically in pregnancy in most hypothyroid women. There may occur a modest increase in T(4) dose requirement during pregnancy in some thyroidectomized patients; (2) diminished absorption of T(4), possibly related to ingestion of exogenous agents (eg, iron, calcium, vitamins), may have contributed to previous suggestions of substantial increased T(4) requirement in pregnancy; (3) ingestion of T(4) dose absorption-inhibiting agents some 4 hours away from T(4) markedly diminishes or obviates their effect in many patients. Although many hypothyroid patients may not require an adjustment in their T(4) dose during pregnancy, it is prudent to monitor all such patients carefully as the consequences of inadequate therapy may be very important.

Background The objective was to assess the association between increasing autism incidence rates and the increasing dose of folic acid in prescription prenatal and pediatric vitamins. Methods We used published autism incidence rates from the Rochester Epidemiological Project in Rochester, MN, for 1976–1997. Additionally, we used the percent of prescription prenatal vitamins containing 1mg folic acid and the percent of prescription pediatric vitamins with any folic acid from Physicians' Desk References for roughly the same time period. Results The Pearson product moment correlation coefficient ( r ) for the association between the percentage of prescription prenatal vitamins containing 1mg folic acid and research-identified autism incidence in Olmsted County was 0.87 [95% confidence interval (CI)=0.19–0.99]. In contrast, there was a weak association between pediatric vitamins containing any folic acid and autism incidence using the same statistical method ( r =0.62, 95% CI=−0.38–0.95). Conclusions If it is true that too little folic acid results in nervous tissue damage, as is accepted by the scientific community in regard to neural tube defects (NTDs), then it seems plausible that too much folic acid may result in nervous tissue damage associated with autism. Although the correlations described here do not provide proof of causation, these data provide an impetus for further study. Children who develop autism may be receiving a massive dose of folic acid in utero, as well as, after birth. It would be of interest to carry out a case–control study using medical record data to document folic acid intake for pregnant women whose offspring were later diagnosed with autism and controls.

We propose that generation of reactive oxygen species may be a potentially reversible pathophysiologic pathway leading to preterm premature rupture of the membranes. Reactive oxygen species generated by the body's response to diverse insults such as infection, cigarette smoking, bleeding, or cocaine use can activate collagenolytic enzymes and impair fetal membrane integrity. Vitamin E, a lipid-soluble antioxidant, inhibits membrane-damaging effects of reactive oxygen species-induced lipid peroxidation. Vitamin C, a water-soluble antioxidant in plasma, stimulates and protects collagen synthesis while recycling vitamin E. Prior evidence shows that (1) damage by reactive oxygen species can impair fetal membrane integrity, (2) reduced midgestation levels of vitamin C are associated with preterm premature rupture of membranes, and (3) these vitamins can be safely and effectively absorbed and delivered to gestational tissues. Current prenatal vitamin preparations contain vitamins C and E in concentrations that are less than 1/3 and 1/10, respectively; these levels have been suggested for effective antioxidant protection. We hypothesize that increased dietary consumption or supplementation of vitamins C and E during pregnancy may reduce physiologically the risks of that portion of preterm premature rupture of membranes that is mediated by excessive or undamped peroxidation of fetal membranes. This hypothesis, if confirmed, should stimulate initiation of therapeutic trials to test the efficacy of enhanced supplementation with vitamins C and E during pregnancy to prevent preterm premature rupture of membranes.

The global HIV epidemic is having a profound impact on the health and survival of children. As of 1994, it is estimated that about 2 million children worldwide (WHO, 1994) and 12 thousand children in the United States are HIV infected (Davis et al. 1995). Almost all HIV infection among infants and young children are from mother-to-infant transmission. By the year 2000, HIV is projected to infect 40 million men, women, and children unless effective prevention strategies are developed. Perinatal HIV transmission rates currently vary from 14-40% with the lowest rates being seen in Europe and highest rates in Africa. Known risk factors for perinatal transmission include advanced maternal HIV disease, lower CD4+ counts, and increased viral burden during pregnancy. Observational cohort data suggest that prenatal vitamin A levels, maternal drug use, and duration of membrane rupture during labor also are related to risk of transmission. The United States clinical trial utilizing an antiretroviral (zidovudine [AZT]) prenatally, intrapartum, and for 6 weeks to the infant demonstrated that perinatal HIV transmission was reduced by two-thirds. This dramatic result gives strong encouragement that simpler perinatal prevention strategies applicable to developing countries may also be successful. A number of international studies are underway or planned including perinatal vitamin A and micronutrient trials in Africa.

Among a culturally diverse group of 344 low-income pregnant women, self-reported rates of supplement use prior to confirmation of pregnancy were much lower than those reported for young women in national surveys (16% vs. up to 40%, respectively). Prenatal vitamins, prescribed routinely for all patients, were reportedly taken at least four times a week by 86% of the subjects and two to three times a day by 5%. About 5% of the sample reported consuming highly fortified cereal at least once daily. There is a possibility of higher than recommended use of supplemental vitamins among these women resulting from misunderstanding of the number of pills to be taken and/or high consumption of highly fortified cereals.

Introduction Maternal tobacco use increases the incidence of numerous adverse pregnancy outcomes including miscarriage, small for gestational age infants, spontaneous preterm birth and placental abruption. Objectives We evaluated the relationship between prenatal vitamin C/E supplementation and perinatal outcomes by maternal smoking status. Methods Secondary analysis of a multicenter trial of vitamin C/E starting at 9–16 weeks in low-risk nulliparous women with singletons. We examined the effect of vitamin supplementation by reported smoker or non-smoker at time of randomization. The primary outcomes were preeclampsia (new onset hypertension and proteinuria) and a composite outcome of severe pregnancy associated hypertension (severe hypertension OR mild or severe hypertension with elevated liver enzymes, elevated serum creatinine, thrombocytopenia, eclamptic seizure, fetal growth restriction, medically indicated preterm birth or perinatal death). Perinatal outcomes included preterm birth and abruption. The Breslow-Day test was used to ascertain whether there was an interaction between smoking status and vitamin supplementation. Results Of 9969 women, 4993 received vitamins C/E and 4976 received placebo. The prevalence of smoking (15.6% overall; 788 vitamin, 763 placebo) was similar in treatment groups. The analysis of vitamin C/E by smoking status for perinatal outcomes is given (Table 1). The effect of prenatal vitamin C/E on the risk preeclampsia or pregnancy associated hypertension composite outcome did not differ by smoking status. Vitamin C/E was protective for placental abruption and preterm birth among smokers. Conclusion The effect of vitamin C/E supplementation on preeclampsia/pregnancy associated hypertension did not differ by smoking status. However, vitamin C/E supplementation was associated with a >40% reduction in placental abruption and >30% reduction in preterm birth among smokers warranting further study. Acknowledgement This project supported in part by National Institutes of Health Grant PO1-HD30367 .

Background Pet keeping has been linked with decreased risk of allergic sensitization, which has been associated with the Hygiene Hypothesis; and more recently, by ourselves and others, to particular home microbiome patterns. Another factor possibly associated with pet ownership is increased Vitamin D among family members as pet keeping may be correlated with lifestyles involving increased outdoor exposure, such as dog walking. Prenatal vitamin D inadequacy has been hypothesized as a risk factor for pediatric atopy and asthma. Methods To investigate potential relationships between household pet exposure and cord blood vitamin D concentrations, we analyzed information from a large, geographically-based, general risk birth cohort. Household pets were assessed during pregnancy and serum level of 25 (OH)D (25-hydroxyvitamin D) in cord blood was used as the measure of vitamin D and a marker of maternal level. Because of notable differences in vitamin D concentrations between African Americans and Whites, analyses were stratified by race. Results A total of 1055 newborns were included in the study: 62.4% were African Americans and 49.4% were female. For Whites, but not African Americans, having no pet compared to 1 or >1 pet during pregnancy was associated with lower cord blood vitamin D concentrations (37.7, 45.2, 47.0 nmol/L, respectively, P = 0.001). Considering type of pet, the relationship for no pet compared to 1 or >1 dog (37.7, 46.1, 49.9 nmol/L, respectively, P = 0.001) was similar to that for no pet versus 1 or >1 cat (37.7, 43.0, 46.5 nmol/L, respectively, P = 0.065). Conclusions In a large ethnically diverse cohort of newborns, the presence of a pet in the home during the prenatal time period was associated with higher cord blood vitamin D, but only among Whites. This racial difference may reflect an impact on pet owner behavior resulting in increased outdoor exposure that is limited to lighter skinned individuals. However, as the effect doesn't vary by cats versus dogs, differences by race in factors correlated with pet ownership or variations in pet keeping styles may be more important. Vitamin D should be considered in studies of pets and atopic conditions.

structure and function from the first trimester to 6 months postpartum Janet Burlingame, Hyeong Jun Ahn, Todd Seto University of Hawaii, John A. Burns School of Medicine, Obstetrics, Gynecology and Womens Health, Honolulu, HI, Queens Medical Center, Center for Outcomes Research and Evaluation, Honolulu, HI, University of Hawaii, John A. Burns School of Medicine, Biostatistics Core, Honolulu, HI OBJECTIVE: To document temporal changes in diastolic function, systolic function and cardiac structure due to pregnancy. STUDY DESIGN: We performed a prospective observational study of pregnant women who were recruited in the first or second trimesters of pregnancy, and echocardiograms were done at 6 to 7 time points until 6 to 12 months postpartum. Women with hypertensive or cardiac disease were excluded from analysis. Linear mixed models were used to evaluate the changes of ECHO measures over time accounting for missing data. Tukey-Kramer method was also used for multiple comparisons as a post-hoc analysis. P values 0.05 were regarded as statistically significant. RESULTS: The Figure outlines the changes in diastolic function and the changes in structure and systolic function throughout pregnancy and the postpartum periods. Comparisons between pregnancy and nonpregnancy were also made using visit 7 (6-12 months postpartum as the non-pregnant measurement). Diastolic function changes included significant decreases in E/A and isovolumic relaxation time and an increase in transmitral E/peak medial velocity (E/E’) with a return to baseline postpartum. There was a significant increase in left atrial volume. There were trends toward increases in left ventricular volume and mitral valve deceleration time. CONCLUSION: As one of the largest prospective studies and one of the few that follows participants out to 6 months postpartum, this study confirms previous data and presents new data highlighting changes in cardiovascular physiology during pregnancy and the puerperium. Diastolic changes reflected a general decrease in function with return to baseline postpartum. Cardiac output peaks in the mid trimester in our series versus third trimester as found in previous studies. These changes are likely related to the concomitant increase in left atrial size as reflective of preload increase. The research described was supported in part by the NIH grants NCRR U54MD007584 and NIMHD G12MD007601. 209 Vitamin D deficiency: can non-pregnant treatment norms be used in pregnancy? Janyne Althaus, Sarahn Wheeler, Haitham Baghlaf, Harold Fox, Irina Burd Johns Hopkins University School of Medicine, Gynecology and Obstetrics, Baltimore, MD OBJECTIVE: To date, no treatment guidelines exist for vitamin D deficiency in pregnancy. A common treatment for non-pregnant adults is 50,000 international units (IU) weekly, but many OBs are reluctant to treat vitamin D deficiency for fear of toxicity. There are varied protocols among practices and still no consensus. The purpose of this study was to determine if treatment of low vitamin D in pregnancy with 50,000 IU weekly leads to adverse perinatal outcomes. STUDY DESIGN: This was a retrospective cohort study (2009-2011) comparing vitamin D-deficient patients ( 32ng/mL) treated with 50,000 IU weekly for 12 weeks (“treated”) during pregnancy with patients given prenatal vitamins (PNV) only (“untreated”). Inclusion criteria was D 32 ng/mL at first prenatal visit. Exclusion criteria were treatment for vitamin D deficiency within the past year or any regimens other than PNV or 50,000 IU weekly. Study data were derived from electronic and paper charts. Outcomes examined included rates of preterm delivery, pre-eclampsia, and cesarean section. Neonatal outcomes studied were rates of NICU admission, Apgar 7 at 5 minutes and umbilical cord pH. Power analysis was performed, and the two groups were compared using standard statistics. RESULTS: 231 patients met inclusion criteria: 117 in the untreated group and 114 in the treated group. Maternal demographics did not differ between the two groups in regards to age, parity, or diabetes (p 0.05 for all). For obstetrical outcomes, cesarean section, pre-eclampsia, and preterm delivery rates did not differ between the two groups (p 0.05 for all). For neonatal outcomes, there were no differences in NICU admissions, Apgar scores, or neonatal cord pHs between the two groups (p 0.05 for all). CONCLUSION: This is the first study to demonstrate that treatment of vitamin D deficiency with non-pregnancy treatment norms during pregnancy does not lead to increased rates of adverse perinatal outcomes. Studies with a larger n are needed.

The objective of this cohort study of a consecutive sample of infants exposed during pregnancy to anticonvulsant drugs was to determine if the mother received late pregnancy prophylaxis with vitamin K, and if any infants had signs of hemorrhagic disease. The medical records of 204 neonates exposed to anticonvulsant drugs in utero and 77 unexposed control neonates were retrospectively reviewed. No hemorrhagic disease was observed, and the incidence of bleeding tendencies was not higher in infants exposed to these drugs compared with control infants, despite no prenatal vitamin K supplementation in all but 1 epileptic woman.

standard prenatal vitamins decrease anemia at delivery? Samantha Boreland, Clones Lans, Chaur-Dong Hsu, Vinette Greenland, Elsi Santana-Fox, Maggie Tetrokalashvili, Scott Stanislawski, Joshua Fogel Nassau University Medical Center, OBGYN, East Meadow, NY OBJECTIVE: To investigate whether the addition of iron supplementation to the standard prenatal vitamins, improve hemoglobin/hematocrit levels, at delivery. STUDY DESIGN: This is a retrospective review of 300 medical charts of women delivered at our medical health system from January 2009 to December 2009. The patients were divided equally in 2 groups: group 1 consisted of patients who had prenatal care at Hospital Medical Center (HMC) obstetric clinic and received only standard prenatal vitamins, and group 2 consisted of patients followed at the outreach obstetric clinics of Federal Qualified Health Centers (FQHC) affiliated to HMC and received ferrous sulfate in addition to the standard prenatal vitamins. The hemoglobin and hematocrit levels at the first prenatal visit were compared to those at delivery for both groups. ANOVA, Chi-square test, McNemar test and ANCOVA were used for statistical analysis. Data were expressed as mean standard deviation. RESULTS: There were no significant differences for any of the baseline laboratory variables between the two groups. The mean comparisons for the laboratory variables at delivery showed both hemoglobin and hematocrit had significantly lower mean values for the HMC group as compared to FQHC group (Hemoglobin: 11.9 1.26 vs. 12.2 1.26 g/dL, p 0.0001; hematocrit: 34.9% vs. 35.8%, p 0.01). In analyses comparing within each of the two groups, hematocrit significantly decreased (p 0.001) from the first prenatal visit (35.9 3.02%) to delivery (34.9 3.53%) and hemoglobin significantly decreased (p 0.001) from the first prenatal visit (12.3 1.05g/dL) to delivery (11.9 1.26 g/dL). In categorical variable comparisons, there was significant increase of anemia percentage in HMC group from the first prenatal visit to delivery. In the FQHC group, both hematocrit and hemoglobin did not significantly differ from the first prenatal visit to delivery. CONCLUSION: Our data suggests that additional iron supplementation from antepartum at the first prenatal visit to delivery can benefit woman by keeping their hemoglobin/hematocrit levels stable prior to delivery. 222 Birth weight, breast cancer and the potential mediating hormonal environment Radek Bukowski, Rowan Chlebowski, Inger Thune, Anne-Sofie Furberg, Gary Hankins, Fergal Malone, Mary D’Alton University of Texas Medical Branch, Department of Obstetrics and Gynecology, Galveston, TX, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, Oslo University Hospital, Department of Oncology, Oslo, Norway, University of Troms, Faculty of Health Sciences, Department of Community Medicine, Troms, Norway, The University of Texas Medical Branch, Obsterics & Gynecology, Galveston, TX, Royal College of Surgeons in Ireland, Obstetrics and Gynaecology, Dublin, Ireland, Columbia University, Department of Obstetrics and Gynecology, New York, NY OBJECTIVE: A womans breast cancer risk is proportional to her birth weight and the birth weight of her children. The relative contributions of these factors and their mediating mechanisms are not known. STUDY DESIGN: Risk of breast cancer in relation to a mothers birth weight and her first infants birth weight were evaluated in a prospective cohort of 410 women in the Framingham Study. Serum concentrations of estriol (E3), anti-estrogen alpha-fetoprotein (AFP), and pregnancy-associated plasma protein-A (PAPP-A) were measured in 23,824 pregnant women from a separate perspective cohort, the FASTER trial. RESULTS: During follow-up (median, 14 years) 31 women (7.6%) were diagnosed with breast cancer. Women with large birth weight infants (in the top quintile) had a higher breast cancer risk compared to other women (hazard ratio (HR), 2.5; 95% confidence interval (CI), 1.2-5.2; P 0.012). The finding was not affected by adjustment for birth weight of the mother and traditional breast cancer risk factors (adjusted HR, 2.6; 95% CI, 1.2-5.7; P 0.016). An infants birth weight had a strong positive relationship with the mothers serum E3/AFP ratio and PAPP-A concentration during pregnancy. Adjustment for breast cancer risk factors did not have a material effect on these relationships. CONCLUSION: Maternal risk of breast cancer was associated with giving birth to an infant with high birth weight, independent of a mothers own birth weight and traditional breast cancer risk factors. Having an infant with high birth weight was also associated with a hormonal environment during pregnancy favoring breast cancer development and progression.