Persistent Changes in Stress-Regulatory Genes in Pregnant Women or Children Exposed Prenatally to Alcohol.

BACKGROUND: We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (PAE). Results of the present study provided some support for this hypothesis. METHODS: We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from 3 separate cohorts of patients: (i) pregnant women who consumed moderate-to-high levels of alcohol or low/unexposed controls, (ii) children with PAE and non-alcohol-exposed controls, and (iii) children with PAE treated with or without choline. RESULTS: We found pregnant women who consumed moderate-to-high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone. Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. CONCLUSIONS: These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.

Gestational age and socioeconomic status as mediators for the impact of prenatal alcohol exposure on development at 6 months.

BACKGROUND: Of the many negative outcomes associated with gestational alcohol use, one that has received relatively little attention is preterm birth and its possible contribution to effects of prenatal alcohol exposure (PAE) on development. To examine the increased risk for premature delivery associated with PAE and the joint influence of preterm birth and alcohol on child outcomes, analysis was carried out in a longitudinal cohort recruited in Western Ukraine. METHODS: Alcohol-using women and low or nondrinking controls were identified prenatally for a clinical trial of multivitamins and minerals (MVM) in ameliorating effects of PAE. Women were interviewed to provide information about medical and social status and other drug use. At delivery, information was collected about infant (N = 686) status including gestational age (GA) in weeks. Finally, 441 infants were followed to 6 months of age and cognitive (Mental Developmental Index [MDI]) and motor development (Psychomotor Developmental Index [PDI]) (measured using the Bayley Scales of Infant Development, second Ed (BSID-II). RESULTS: Seven percent infants were born at <37 weeks GA. The odds ratio for preterm delivery for Alcohol Exposed versus Low/No Alcohol was 2.6 (95% Confidence Interval 1.37, 4.94) (p < .003); MVM supplements were associated with a lower rate of preterm delivery overall, but the relative proportion of preterm births did not vary by MVM supplement status between alcohol exposure groups. In mediation models of 6 month cognitive and motor development with reference to Barron and Kenney in 1986, GA significantly mediated alcohol effects (MDI: Z = -2.64, p < .008; PDI: Z = -2.35, p < .02) although PAE independently affected both outcomes (MDI: t = -5.6, p < .000; PDI: t = -3.19, p < .002). CONCLUSION: Results suggest that PAE is associated with higher rates of preterm birth and that alcohol's effect on development in infancy may be both direct and mediated by shortened length of gestation.

Most Frequently Reported Prescription Medications and Supplements in Couples Planning Pregnancy: The LIFE Study.

OBJECTIVE: To identify frequently reported prescription medications and supplements among couples planning pregnancy because there is a lack of descriptive information on these agents in women and men who are trying to conceive. METHODS: Five hundred one couples enrolled in the Longitudinal Study of Infertility and the Environment, which took place between 2005 and 2009. Participants reported prescription medications as well as prescription and over-the-counter supplements used through interviews at study enrollment and through daily dairies during the 12-month follow-up. We identified prescription medications and supplements prospectively reported by ≥1% of women and men at baseline and from daily journal information grouped into 3-month preconception follow-up intervals while couples tried for pregnancy. RESULTS: The 5 most reported prescription medications among women were levothyroxine (5.8%), cetirizine (2.6%), fluticasone (2.4%), escitalopram (1.8%), and fluoxetine (1.8%) and for men were lisinopril (2.0%), mometasone (2.0%), fexofenadine (1.8%), atorvastatin (1.6%), and montelukast (1.6%). The most reported supplements were multivitamins (63.3%, 43.5%) and fish oil (13.2%, 9.4%) for women and men, respectively, and prenatal vitamins (22.0%) for women. For women during the first 3 months of follow-up, prenatal vitamins (6.0%) and antibiotics (1.2%-2.6%) were among the most frequently started medications. During the next 3 months, clomiphene (4.5%) was the most frequently initiated medication. CONCLUSIONS: Couples trying for pregnancy reported a variety of prescription medications and supplements, and they differed by gender. Preconception guidance should address medication and supplement use to avoid potential exposures associated with adverse reproductive and perinatal outcomes.

Folic acid supplement use and the risk of gestational hypertension and preeclampsia.

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.

The Use of Cardiac Orienting Responses as an Early and Scalable Biomarker of Alcohol-Related Neurodevelopmental Impairment.

BACKGROUND: Considered the leading cause of developmental disabilities worldwide, fetal alcohol spectrum disorders (FASD) are a global health problem. To take advantage of neural plasticity, early identification of affected infants is critical. The cardiac orienting response (COR) has been shown to be sensitive to the effects of prenatal alcohol exposure and is an inexpensive, easy to administer assessment tool. The purpose of this study was to evaluate the COR effectiveness in assessing individual risk of developmental delay. METHODS: As part of an ongoing longitudinal cohort study in Ukraine, live-born infants of women with some to heavy amounts of alcohol consumption in pregnancy were recruited and compared to infants of women who consumed low or no alcohol. At 6 and 12 months, infants were evaluated with the Bayley Scales of Infant Development-II. CORs were also collected during a habituation/dishabituation learning paradigm. Using a supervised logistic regression classifier, we compared the predictive utility of the COR indices to that of the 6-month Bayley scores for identification of developmental delay based on 12-month Bayley scores. Heart rate collected at each second (Standard COR) was compared to key features (Key COR) extracted from the response. RESULTS: Negative predictive values (NPV) were 85% for Standard COR, 82% for Key COR, and 77% for the Bayley, and positive predictive values (PPV) were 66% for Standard COR, 62% for Key COR, and 43% for the Bayley. CONCLUSIONS: Predictive analysis based on the COR resulted in better NPV and PPV than the 6-month Bayley score. As the resources required to obtain a Bayley score are substantially more than in a COR-based paradigm, the findings are suggestive of its utility as an early scalable screening tool based on the COR. Further work is needed to test its long-term predictive accuracy.

Randomized, double-blind, placebo-controlled clinical trial of choline supplementation in school-aged children with fetal alcohol spectrum disorders.

BACKGROUND: Prenatal alcohol exposure results in a broad range of cognitive and behavioral impairments. Because of the long-lasting problems that are associated with fetal alcohol spectrum disorders (FASDs), the development of effective treatment programs is critical. Preclinical animal studies have shown that choline, which is an essential nutrient, can attenuate the severity of alcohol-related cognitive impairments. OBJECTIVE: We aimed to translate preclinical findings to a clinical population to investigate whether choline supplementation can ameliorate the severity of memory, executive function, and attention deficits in children with FASDs. DESIGN: In the current study, which was a randomized, double-blind, placebo-controlled clinical trial, we explored the effectiveness of a choline intervention for children with FASDs who were aged 5-10 y. Fifty-five children with confirmed histories of heavy prenatal alcohol exposure were randomly assigned to either the choline (n = 29) or placebo (n = 26) treatment arms. Participants in the choline group received 625 mg choline/d for 6 wk, whereas subjects in the placebo group received an equivalent dose of an inactive placebo treatment. Primary outcomes, including the performance on neuropsychological measures of memory, executive function, and attention and hyperactivity, were assessed at baseline and postintervention. RESULTS: Compared with the placebo group, participants in the choline group did not differentially improve in cognitive performance in any domain. Treatment compliance and mean dietary choline intake were not predictive of treatment outcomes. CONCLUSIONS: Findings of the current study do not support that choline, administered at a dose of 625 mg/d for 6 wk, is an effective intervention for school-aged (5-10 y old) children with FASDs. This research provides important information about choline's therapeutic window. Combined with other studies of choline and nutritional interventions in this population, this study emphasizes a further need for the continued study of the role of nutritional status and supplementation in children with FASDs and the contributions of nutrition to neurocognition. This trial was registered at clinicaltrials.gov as NCT01911299.

Dietary Nutrient Intake in School-Aged Children With Heavy Prenatal Alcohol Exposure.

BACKGROUND: Nutrition is an important factor that affects brain development. Nutritional deficiencies can exacerbate alcohol's damaging effects. Conversely, nutritional supplementation can serve a protective role against alcohol damage and may prove to be a worthwhile intervention strategy. This study investigated dietary intake in school-aged children with heavy prenatal alcohol exposure to understand their nutritional status, compared to a national sample of typically developing children and Dietary Reference Intakes. METHODS: Dietary intake data were collected from children with confirmed histories of heavy prenatal alcohol exposure (5 to 10 years, n = 55) using the Automated Self-Administered 24-Hour Dietary Recall (ASA24). Observed nutrient levels were compared to the Dietary Reference Intakes to evaluate adequacy of nutrient intake as well as to national averages for same-aged children (What We Eat in America, NHANES 2007-2008). RESULTS: Alcohol-exposed children exhibited poorer nutritional status compared to the typically developing NHANES sample, consuming lower levels of protein, omega-3 fatty acids, magnesium, potassium, zinc, vitamins C and K, niacin, and choline. Moreover, their diets did not meet Recommended Dietary Allowance or Adequate Intake for dietary fiber, potassium, vitamins E and K, omega-3 fatty acids, and choline. CONCLUSIONS: The present findings are consistent with prior studies investigating nutritional intake in preschoolers with FASD, indicating that these children are vulnerable to nutritional inadequacies. Moreover, data suggest a specific profile of dietary intake in this population. As several nutrients are important for cognitive development, targeted interventions in clinical populations might be effective in boosting outcomes. Thus, further clinical investigation into the role of nutrition in improving cognitive outcomes is warranted.

Dose and Timing of Prenatal Alcohol Exposure and Maternal Nutritional Supplements: Developmental Effects on 6-Month-Old Infants.

OBJECTIVES: Fetal alcohol spectrum disorders are more common in disadvantaged populations. Environmental factors, like suboptimal nutrition, may potentiate the developmental effects of prenatal alcohol exposure. To evaluate the impact of micronutrients, including choline, on reduction of effects of exposure, we examined timing and dose of alcohol and effects of nutritional supplementation at two OMNI-Net sites in Western Ukraine that included high and low risk individuals. METHODS: Alcohol-using and nondrinking women were randomized to one of three multivitamin/mineral supplement groups: none, multivitamins/minerals (MVM), and multivitamin/minerals plus choline. Children (N = 367) were tested at 6 months with the Bayley Scales of Infant Development (2nd ED) yielding standard scores for Mental Development Index (MDI), Psychomotor Development Index (PDI) and Behavior. RESULTS: Generalized linear modeling was used: (1) for factorial analysis of effects of alcohol group, multivitamin/minerals, and choline supplementation; and (2) to examine the relationship between amount and timing of alcohol (ounces of absolute alcohol/day [ozAA/day] peri-conception and on average in the second trimester) and MVM supplementation on developmental outcomes while controlling sex, social class, and smoking. MDI was significantly impacted by peri-conceptual alcohol dose (X2(1), p < .001) with more alcohol associated with lower scores and males more negatively affected than females (X2(1), p < .002). Micronutrient supplementation had a protective effect; those receiving supplements performed better ([Formula: see text], p < .005). The PDI motor scores did not differ by group but were affected by peri-conceptual alcohol dose (X2(1), p < .04). CONCLUSIONS FOR PRACTICE: Multivitamin/mineral supplementation can reduce the negative impact of alcohol use during pregnancy on specific developmental outcomes.

Associations between multivitamin supplement use and alcohol consumption before pregnancy: Pregnancy Risk Assessment Monitoring System, 2004 to 2008.

BACKGROUND: Approximately 50 to 70% of childbearing-aged women consume alcohol and up to 23% of pregnancies have some level of prenatal alcohol exposure. METHODS: Using data from the Pregnancy Risk Assessment Monitoring System from 2004 to 2008, 111,644 women who completed questions relating to periconceptional alcohol use and multivitamin supplement use were included in the study. This study explored associations between periconceptional alcohol use and multivitamin supplementation use. Weighted multivariable logistic regression was used to explore associations, adjusting for maternal education, maternal ethnicity, maternal age, household income, and parity. RESULTS: During the periconceptional period, a dose-dependent association was found where women who consumed alcohol (≤3 drinks/wk, odds ratio [OR] = 0.76; 4 to 6 drinks/wk, OR = 0.60; 7 to 13 drinks/wk, OR = 0.49; ≥14 drinks/wk, OR = 0.39) and binged on alcohol (1 time, OR = 0.76; 2 to 3 times, OR = 0.66; 4 to 5 times, OR = 0.56; ≥6 times, OR = 0.50) were significantly less likely to take a multivitamin supplement compared with those that did not consume alcohol. CONCLUSIONS: These findings emphasize the importance of periconceptional multivitamin supplement use, especially among alcohol-consuming women of childbearing age.

The plausibility of maternal nutritional status being a contributing factor to the risk for fetal alcohol spectrum disorders: the potential influence of zinc status as an example.

There is increasing evidence that human pregnancy outcome can be significantly compromised by suboptimal maternal nutritional status. Poor diet results in a maternal-fetal environment in which the teratogenicity of other insults such as alcohol might be amplified. As an example, there is evidence that zinc (Zn) can interact with maternal alcohol exposure to influence the risk for fetal alcohol spectrum disorders (FASD). Studies with experimental animals have shown that the teratogenicity of alcohol is increased under conditions of Zn deficiency, whereas its teratogenicity is lessened when animals are given Zn-supplemented diets or Zn injections before the alcohol exposure. Alcohol can precipitate an acute-phase response, resulting in a subsequent increase in maternal liver metallothionein, which can sequester Zn and lead to decreased Zn transfer to the fetus. Importantly, the teratogenicity of acute alcohol exposure is reduced in metallothionein knockout mice, which can have improved Zn transfer to the conceptus relative to wild-type mice. Consistent with the above, Zn status has been reported to be low in alcoholic women at delivery. Preliminary data from two basic science and clinical nutritional studies that are ongoing as part of the international Collaborative Initiative on Fetal Alcohol Spectrum Disorders support the potential role of Zn, among other nutritional factors, relative to risk for FASD. Importantly, the nutrient levels being examined in these studies are relevant to general clinical populations and represent suboptimal levels rather than severe deficiencies. These data suggest that moderate deficiencies in single nutrients can act as permissive factors for FASD, and that adequate nutritional status or intervention through supplementation may provide protection from some of the adverse effects of prenatal alcohol exposure.

Prevalence of periconceptional folic acid use and perceived barriers to the postgestation continuance of supplemental folic acid: survey results from a Teratogen Information Service.

BACKGROUND: Fewer than 40% of U.S. women are taking folic acid supplements periconceptionally at a time when the risk of neural tube defects (NTDs) can be reduced by supplementation. A better understanding of the vitamin-taking habits of childbearing-age women and effective methods for improving periconceptional supplement use are needed. METHODS: A telephone survey conducted through the California Teratogen Information Service (TIS) between August 2003 and January 2004 assessed the prevalence and characteristics of pregnant callers who did not use folic acid supplements in the periconceptional period, and explored attitudes toward advice to continue vitamin use following pregnancy in order to be protected in a future pregnancy. RESULTS: A total of 327 pregnant women who called the TIS for information agreed to participate in the survey. More than half (53.2%) were not taking folic acid-containing supplements in the periconceptional period. Predictors of lack of use included a higher prepregnancy body mass index, younger maternal age, non-white race/ethnicity, lower education level, and unplanned pregnancy. One-quarter of the women said they would be willing to continue taking vitamins after the pregnancy if advised to do so by a physician. The remainder identified obstacles to following that advice--notably, not planning to become pregnant again and the belief that enough folate is derived from diet alone. CONCLUSIONS: More than half of the callers to the TIS were not compliant with recommendations regarding periconceptional folic acid supplementation. This represents an opportunity for TIS specialists and physicians to intervene in a current pregnancy to encourage maintenance of supplement use in the subsequent interpregnancy interval.