Key Articles Published by OMNI-Net Specialists – Page 2

The impact of micronutrient supplementation in alcohol-exposed pregnancies on reaction time responses of preschoolers in Ukraine

The potential of micronutrients to ameliorate the impact of prenatal alcohol exposure (PAE) on attentional regulation skills was explored in a randomized clinical trial conducted in Ukraine. Women who differed in prenatal alcohol use were recruited during pregnancy and assigned to one of three groups [No study-provided supplements, Multivitamin/Mineral Supplement (MVM), or MVM plus Choline]. Their offspring were seen in the preschool period and a reaction time task was administered. Participants were asked to press a response button as quickly as possible as 30 stimuli from the same category (animals) were presented consecutively and then followed by six stimuli from a novel category (vehicles). Number correct, mean latency of the response over trials, and variability in the latency were analyzed separately by sex. During the initial animal trials, boys whose mothers received MVM during pregnancy had more correct responses and reduced response latency compared to boys whose mothers had no MVM treatment. During vehicle trials, maternal choline supplementation was associated with increased response speed in males without a PAE history. Females receiving supplements did not show the same benefits from micronutrient supplementation and were more adversely impacted by prenatal alcohol exposure. Relationships between maternal levels of choline, betaine, and dimethylglycine (DMG) and task performance were also assessed. Although no effects were found for choline after adjusting for multiple comparisons, lower baseline DMG level was associated with greater accuracy and shorter latency of responses in the initial animal trials and shorter latency in the vehicle trials in female preschoolers. Level of betaine in Trimester 3 was associated with reduced variability in the latency of male responses during the animal trials. Maternal micronutrient supplementation in pregnancy appears to improve preschool reaction time performance, but the effects varied as a function of sex and PAE exposure status.

Linking a European cohort of children born with congenital anomalies to vital statistics and mortality records: A EUROlinkCAT study

EUROCAT is a European network of population-based congenital anomaly (CA) registries. Twenty-one registries agreed to participate in the EUROlinkCAT study to determine if reliable information on the survival of children born with a major CA between 1995 and 2014 can be obtained through linkage to national vital statistics or mortality records. Live birth children with a CA could be linked using personal identifiers to either their national vital statistics (including birth records, death records, hospital records) or to mortality records only, depending on the data available within each region. In total, 18 of 21 registries with data on 192,862 children born with congenital anomalies participated in the study. One registry was unable to get ethical approval to participate and linkage was not possible for two registries due to local reasons. Eleven registries linked to vital statistics and seven registries linked to mortality records only; one of the latter only had identification numbers for 78% of cases, hence it was excluded from further analysis. For registries linking to vital statistics: six linked over 95% of their cases for all years and five were unable to link at least 85% of all live born CA children in the earlier years of the study. No estimate of linkage success could be calculated for registries linking to mortality records. Irrespective of linkage method, deaths that occurred during the first week of life were over three times less likely to be linked compared to deaths occurring after the first week of life. Linkage to vital statistics can provide accurate estimates of survival of children with CAs in some European countries. Bias arises when linkage is not successful, as early neonatal deaths were less likely to be linked. Linkage to mortality records only cannot be recommended, as linkage quality, and hence bias, cannot be assessed.

EUROlinkCAT protocol for a European population-based data linkage study investigating the survival, morbidity and education of children with congenital anomalies

Introduction: Congenital anomalies (CAs) are a major cause of infant mortality, childhood morbidity and long-term disability. Over 130000 children born in Europe every year will have a CA. This paper describes the EUROlinkCAT study, which is investigating the health and educational outcomes of children with CAs for the first 10 years of their lives.

Methods and analysis: EUROCAT is a European network of population-based registries for the epidemiological surveillance of CAs. EUROlinkCAT is using the EUROCAT infrastructure to support 22 EUROCAT registries in 14 countries to link their data on births with CAs to mortality, hospital discharge, prescription and educational databases. Once linked, each registry transforms their case data into a common data model (CDM) format and they are then supplied with common STATA syntax scripts to analyze their data. The resulting aggregate tables and analysis results are submitted to a central results repository (CRR) and meta-analyses are performed to summarize the results across all registries. The CRR currently contains data on 155594 children with a CA followed up to age 10 from a population of 6 million births from 1995 to 2014.

Ethics: The CA registries have the required ethics permissions for routine surveillance and transmission of anonymized data to the EUROCAT central database. Each registry is responsible for applying for and obtaining additional ethics and other permissions required for their participation in EUROlinkCAT.

Dissemination: The CDM and associated documentation, including linkage and standardization procedures, will be available post-EUROlinkCAT thus facilitating future local, national and European-level analyses to improve healthcare. Recommendations to improve the accuracy of routinely collected data will be made. Findings will provide evidence to inform parents, health professionals, public health authorities and national treatment guidelines to optimize diagnosis, prevention and treatment for these children with a view to reducing health inequalities in Europe.

Prevention of Neural Tube Defects in Europe: A Public Health Failure

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA.

Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation.

Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 μg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements.

Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year.

Measurement of neurodevelopmental effects of prenatal alcohol exposure in Ukrainian preschool children

Effects of prenatal alcohol exposure (PAE) are rarely measured in preschool children due to relative insensitivity of assessment methods at this age. To examine the potential of a nonverbal battery in early identification of cognitive problems in alcohol-exposed children, 291 prospectively identified Ukrainian children were evaluated using a test battery focusing on early executive functioning (EF) and visuospatial skills, areas of cognitive development particularly sensitive to PAE in older children. Tests included the Differential Ability Scales, 2nd Edition (DAS-2) and several NEPSY/NEPSY-II subtests, standardized in the United States. Others were adapted from commonly used non-standardized neuropsychological measures of EF (Preschool Spatial Span, Imitation Hand Game, A not B, Delayed Attention, Subject Ordered Pointing). Children in two sites in Ukraine, Rivne and Khmelnitsky, were tested at 3 ½-4 ½ years to identify effects of PAE. Although most children performed within the average range, Alcohol-Exposed preschoolers had lower scores on DAS-II Summary Scores as well as on specific subtests. To evaluate the effects of alcohol dose during the pre-pregnancy recognition period and during mid-gestation of pregnancy, generalized linear regression models were used controlling for demographic and individual variables. In addition to DAS-II variables, measures reflecting sustained attention, working memory and ability to shift cognitive set were impacted by alcohol dose. Early executive function appears to subsume these performance differences. In conclusion, findings indicate that the effects of PAE can be identified in the preschool period and reliably measured using tests assessing nonverbal and spatial skills supported by executive functioning.

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Partner influence as a factor in maternal alcohol consumption and depressive symptoms, and maternal effects on infant neurodevelopmental outcomes

Background: Few studies have investigated the partner’s influence on risk factors such as alcohol consumption and depression during pregnancy. Partner substance use and lower relationship satisfaction predict higher maternal alcohol use and depressive symptoms. Because prenatal alcohol use and maternal depression affect infant outcomes, it is imperative to examine how the partner affects these maternal risk factors. The current study examined the effect of a latent construct of partner influence on maternal alcohol use and depressive symptoms, and the effects on infant development of these maternal factors.

Methods: Participants were 246 pregnant women from 2 sites in Western Ukraine from whom longitudinal data were collected as part of a multisite study. In the first trimester, mothers reported on relationship satisfaction, partner substance use, and socioeconomic status (SES). In the third trimester, they reported on alcohol use and depressive symptoms. Infants were assessed using the Bayley Scale of Infant Development (average age = 6.93 months). A latent construct titled partner influence was formed using partner substance use and measures of relationship satisfaction, including the frequency of quarreling, happiness in the relationship, and the ease of talking with the partner. Using structural equation modeling, a model was specified in which partner influence and SES predicted maternal alcohol use and depressive symptoms, which in turn predicted infant neurodevelopmental outcomes.

Results: Higher partner influence significantly predicted lower prenatal alcohol use and lower depressive symptoms, controlling for the effect of SES. Higher maternal prenatal alcohol use significantly predicted lower infant mental and psychomotor development. Maternal depressive symptoms did not predict infant development over and above the effect of alcohol use.

Conclusions: Partner influence is an important contributor to prenatal alcohol use and maternal depressive symptoms, over and above the effect of SES. The significant paths from prenatal alcohol exposure to infant neurodevelopmental outcomes underscore the importance of partner influence during pregnancy.

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A teratology information system in vernacular: Closing an information gap

Background: Leading Teratology Information Systems (TIS) arose in major industrial nations and are mostly in English. The prevalence of anglophone speakers in Ukraine is among the lowest in Europe. A TIS in Ukrainian (UTIS) seeks to diminish an information gap concerning teratogens. The process and results related to UTIS are applicable to formulations of other TIS in vernacular languages.
Methods: Implementation of a free-access UTIS and analysis of utilization patterns. UTIS provides access to articles in Ukrainian (AU) which are summaries extracted from leading international TIS and other sources. AU are revised at least tri-annually.
Results: UTIS provides access to over 1,100 AU accrued since 2016 to the present. The number AU views increased from nearly 30,000 (2016) to over 80,000 (2020); the number of visitors increased from 3,500 to 58,000 during the same periods. The highest percent of users per urban population (2.09, 1.77, and 1.72) was in Ternopil, Ivano-Frankivsk, and Kyiv (capital), respectively; the lowest was in Odesa (0.17).
Conclusions: UTIS reduced an information gap in Ukraine concerning teratogenic risk factors. The process can be implemented elsewhere relying on generally available local resources.

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Infant Cardiac Orienting Responses Predict Later FASD in the Preschool Period

Background: Prenatal alcohol exposure (PAE) has been identified as one of the leading preventable causes of developmental disabilities but early identification of those impacted has been challenging. This study evaluated the use of infant cardiac orienting responses (CORs), which assess neurophysiological encoding of environmental events and are sensitive to the impact of PAE, to predict later Fetal Alcohol Spectrum Disorder (FASD) status.

Methods: Mother-infant dyads from Ukraine were recruited during pregnancy based on the mother’s use of alcohol. Participants (n = 120) were then seen at 6 and 12 months when CORs were collected and in the preschool period when they were categorized as having (1) fetal alcohol syndrome (FAS), (2) partial FAS (pFAS), (3) alcohol-related neurodevelopmental disorder (ARND), (4) PAE and no diagnosis, or (5) no PAE and no diagnosis. To assess CORs, stimuli (auditory tones and pictures) were presented using a fixed-trial habituation/dishabituation paradigm. Heart rate (HR) responses were aggregated across the first 3 habituation and dishabituation trials and converted to z-scores relative to the sample’s mean response at each second by stimuli. Z-scores greater than 1 were then counted by condition (habituation or dishabituation) to compute a total risk index.

Results: Significant group differences were found on total deviation scores of the CORs elicited from visual but not auditory stimuli. Those categorized as pFAS/FAS had significantly higher total deviation scores than did those categorized as ARND or as having no alcohol-related diagnosis with or without a history of PAE. Receiver operating characteristic curve analysis of the visual response yielded an area under the curve value of .765 for predicting to pFAS/FAS status.

Conclusions: A score reflecting total deviation from typical HR during CORs elicited using visual stimuli in infancy may be useful in identifying individuals who need early intervention as a result of their PAE.

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Prevalence and mortality in children with congenital diaphragmatic hernia: a multicountry study

Purpose: This study determined the prevalence, mortality, and time trends of children with congenital diaphragmatic hernia (CDH).

Methods: Twenty-five hospital- and population-based surveillance programs in 19 International Clearinghouse for Birth Defects Surveillance and Research member countries provided birth defects mortality data between 1974 and 2015. CDH cases included live births, stillbirths, or elective termination of pregnancy for fetal anomalies. Prevalence, cumulative mortality rates, and 95% confidence intervals (CIs) were calculated using Poisson regression and a Kaplan-Meier product-limit method. Joinpoint regression analyses were conducted to assess time trends.

Results: The prevalence of CDH was 2.6 per 10,000 total births (95% CI: 2.5-2.7), slightly increasing between 2001 and 2012 (average annual percent change = 0.5%; 95% CI:-0.6 to 1.6). The total percent mortality of CDH was 37.7%, with hospital-based registries having more deaths among live births than population-based registries (45.1% vs. 33.8%). Mortality rates decreased over time (average annual percent change = -2.4%; 95% CI: -3.8 to 1.1). Most deaths due to CDH occurred among 2- to 6-day-old infants for both registry types (36.3%, hospital-based; 12.1%, population-based).

Conclusions: The mortality of CDH has decreased over time. Mortality remains high during the first week and varied by registry type..

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A multi-country study of prevalence and early childhood mortality among children with omphalocele

Background: Omphalocele is the second most common abdominal birth defect and often occurs with other structural and genetic defects. The objective of this study was to determine omphalocele prevalence, time trends, and mortality during early childhood, by geographical region, and the presence of associated anomalies.

Methods: We conducted a retrospective study with 23 birth defect surveillance systems in 18 countries who are members of the International Clearinghouse for Birth Defects Surveillance and Research that submitted data on cases ascertained from 2000 through 2012, approximately 16 million pregnancies were surveyed that resulted in live births, stillbirths, or elective terminations of pregnancy for fetal anomalies (ETOPFA) and cases with omphalocele were included. Overall prevalence and mortality rates for specific ages were calculated (day of birth, neonatal, infant, and early childhood). We used Kaplan-Meier estimates with 95% confidence intervals (CI) to calculate cumulative mortality and joinpoint regression for time trend analyses.

Results: The prevalence of omphalocele was 2.6 per 10,000 births (95% CI: 2.5, 2.7) and showed no temporal change from 2000-2012 (average annual percent change = -0.19%, p = .52). The overall mortality rate was 32.1% (95% CI: 30.2, 34.0). Most deaths occurred during the neonatal period and among children with multiple anomalies or syndromic omphalocele. Prevalence and mortality varied by registry type (e.g., hospital- vs. population-based) and inclusion or exclusion of ETOPFA.

Conclusions: The prevalence of omphalocele showed no temporal change from 2000-2012. Approximately one-third of children with omphalocele did not survive early childhood with most deaths occurring in the neonatal period..

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Чорнобильська радіація—вроджені аномалії: дилема, що триває

У статті представлені популяційні частоти вад невральної трубки (ВНТ) і мікроцефалії (МІК), а також рівні радіоцезію-Cs137 (далі – РІР), інкорпорованого вагітними жінками з двох регіонів Рівненської області України. Один з них – Полісся – розташований у північній частині області, забруднений чорнобильською радіацією, другий – не-Полісся. Моніторинг вроджених вад розвитку (ВВР) здійснювався відповідно до стандартів Європейської організації систем моніторингу ВВР (EUROCAT). РІР Cs137 (Бк/кг) вимірювалися одночасно із проведенням пренатальної ультразвукової діагностики. РІР серед вагітних жінок з Полісся, а також частоти ВНТ і МІК є значно вищими, ніж у не-Поліссі. Частоти ВНТ і МІК у Поліссі є серед найвищих у Європі. Дискусія довкола тератогенної дії хронічного впливу низьких доз іонізуючої радіації була пожвавлена у нашому звіті за 2010 рік. Офіційні агенції підтримують думку про те, що дози чорнобильської радіації є занадто низькими, щоб вважатися тератогенними, але це не узгоджується з нашими спостереженнями. Ми вважаємо, що у результаті подальших майбутніх досліджень з міжнародною участю у Рівненській області, будуть отримані нові факти для існуючої дискусії. За допомогою нашої системи моніторингу, наявного досвіду і даних можливе одночасне дослідження тератогенних ризиків внаслідок впливу інших джерел іонізуючої радіації, алкоголю, дефіциту фолатів і цинку, а також інших факторів. Можливе також проведення досліджень впливу на геном людини.

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Chornobyl radiation—congenital anomalies: A persisting dilemma

We report population prevalence rates of neural tube defects (NDT) and microcephaly (MIC) as well as levels of incorporated Cs137 by pregnant women in two areas of the Rivne Province of Ukraine, a northern half (Polissia) polluted by Chornobyl radiation and not‐Polissia areas. Monitoring of congenital malformations was conducted with adherence to methods adopted by a European surveillance network (EUROCAT). Incorporated Cs137 (Bq/kg) by pregnant women residing in the Polissia and not‐Polissia areas were obtained concurrently with prenatal ultrasound examinations. In Polissia, the incorporated Cs137 levels by pregnant women as well as the prevalence rates of NDTs and MIC are significantly higher than in not‐Polissia. In Polissia, the prevalence rates of NDTs and MIC are among the highest in Europe. The debate concerning the teratogenic impact of chronic exposures to low levels of ionizing radiation was re‐ignited by our 2010 report. Health agencies uphold the notion that exposure to Chornobyl radiation levels are too low to be teratogenic, which is inconsistent with our observations. Further investigations in Rivne by international teams can, we believe, contribute facts to the ongoing debate. Our monitoring system, experience and data can facilitate concurrent investigations of teratogenic risks from exposures to other sources of ionizing radiation, alcohol, folate, and zinc deficiencies, among other risk factors. Study of genomic impacts can likewise be undertaken.

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Patterns of Prenatal Alcohol Exposure and Alcohol-Related Dysmorphic Features

Background: In animal models, it is possible to induce different alcohol-related dysmorphic abnormalities based on the timing of prenatal alcohol exposure (PAE). Our objective was to assess whether patterns of PAE differentially predict alcohol-related dysmorphic features in 415 infants.

Methods: We analyzed a prospective pregnancy cohort in western Ukraine enrolled between 2008-2014. Five distinct trajectories were previously identified to summarize prenatal alcohol exposure: (A) minimal/no PAE (n=253), (B) low/moderate PAE with reduction early in gestation (n=78), (C) low/moderate sustained PAE (n=20), (D) moderate/high PAE with reduction early in gestation (n=45), and (E) high sustained PAE (n=19). A dysmorphology exam of body size, 3 cardinal and 15 non-cardinal dysmorphic features was performed at approximately 6-12 months of age. A modified dysmorphology score was created based on previously published weights. Univariate comparisons were made between each dysmorphic feature and trajectory group. Features that differed by trajectory group were assessed in multivariable analyses. Models were adjusted for maternal age, prenatal vitamin use, socioeconomic status, smoking, and child’s age at dysmorphology exam, with censoring weights for losses to follow-up.

Results: The three highest trajectories predicted total dysmorphology score, with larger effects in sustained exposure groups. Cardinal features: the three highest trajectories were each associated with a 2-3-fold increased risk of having 2+ cardinal facial features. When assessed individually, there were no consistent associations between the individual trajectories and each cardinal feature. Non-cardinal features: The three highest trajectories were associated with increased risk of hypotelorism. Only the highest trajectory was associated with heart murmur. The highest trajectory predicted <10th centile for sex and age on height, weight and head circumference; and moderate/high with reduction trajectory also predicted height.

Conclusions: While we did not observe differential results based on specific trajectories of exposure, findings support the wide range of dysmorphic features associated with PAE, particularly at high and sustained levels.

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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.

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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.

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Altered maternal immune networks are associated with adverse child neurodevelopment: Impact of alcohol consumption during pregnancy

Cytokines and chemokines are potent modulators of brain development and as such, dysregulation of the maternal immune system can result in deviations in the fetal cytokine balance, altering the course of typical brain development, and putting the individual on a “pathway to pathology”. In the current study, we used a multi-variate approach to evaluate networks of interacting cytokines and investigated whether alterations in the maternal immune milieu could be linked to alcohol-related and alcohol-independent child neurodevelopmental delay. This was achieved through the measurement of 40 cytokines/chemokines from maternal blood samples collected during the second and third trimesters of pregnancy. Importantly, during the second trimester we identified network enrichment in levels of cytokines including IFN-ɣ, IL-10, TNF-β, TNF-α, and CRP associated with offspring neurodevelopmental delay. However, as elevations in levels of these cytokines have previously been reported in a wide range of neurodevelopmental disorders including autism spectrum disorder and schizophrenia, we suggest that this cytokine profile is likely not disorder specific, but rather may be an indicator of neurodevelopmental delay in general. By contrast, distinct clusters of activated/inhibited cytokines were identified based on maternal alcohol consumption and child neurodevelopmental outcome. Specifically, cytokines including IL-15, IL-10, MDC, and members of the VEGF sub-family were highest in alcohol-consuming mothers of children with neurodevelopmental delay and were identified in both network analyses and examination of individual cytokines, whereas a differential and unique cytokine profile was identified in the case of alcohol-independent child neurodevelopmental delay. We propose that the current findings could provide a critical step towards the development of early biomarkers and possibly interventions for alcohol-related neurodevelopmental delay. Importantly, the current approach could be informative for understanding mechanisms linking maternal immune system dysfunction and adverse child outcomes in a range of other neurodevelopmental disorders.

Analysis of Mortality among Neonates and Children with Spina Bifida: An International Registry-Based Study, 2001-2012

Background: Medical advancements have resulted in better survival and life expectancy among those with spina bifida, but a significantly increased risk of perinatal and postnatal mortality for individuals with spina bifida remains.

Objectives: To examine stillbirth and infant and child mortality among those affected by spina bifida using data from multiple countries.

Methods: We conducted an observational study, using data from 24 population- and hospital-based surveillance registries in 18 countries contributing as members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). Cases of spina bifida that resulted in livebirths or stillbirths from 20 weeks’ gestation or elective termination of pregnancy for fetal anomaly (ETOPFA) were included. Among liveborn spina bifida cases, we calculated mortality at different ages as number of deaths among liveborn cases divided by total number of liveborn cases with spina bifida. As a secondary outcome measure, we estimated the prevalence of spina bifida per 10000 total births. The 95% confidence interval for the prevalence estimate was estimated using the Poisson approximation of binomial distribution.

Results: Between years 2001 and 2012, the overall first-week mortality proportion was 6.9% (95% CI 6.3, 7.7) and was lower in programmes operating in countries with policies that allowed ETOPFA compared with their counterparts (5.9% vs. 8.4%). The majority of first-week mortality occurred on the first day of life. In programmes where information on long-term mortality was available through linkage to administrative databases, survival at 5 years of age was 90%-96% in Europe, and 86%-96% in North America.

Conclusions: Our multi-country study showed a high proportion of stillbirth and infant and child deaths among those with spina bifida. Effective folic acid interventions could prevent many cases of spina bifida, thereby preventing associated childhood morbidity and mortality.

Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure

Background: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status.

Methods: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis.

Results: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1β, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-β, IL-10, and IL-15 was associated with neurodevelopmental delay.

Conclusions: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.

Altered Maternal Plasma Fatty Acid Composition by Alcohol Consumption and Smoking during Pregnancy and Associations with Fetal Alcohol Spectrum Disorders

Objective: Polyunsaturated fatty acids are vital for optimal fetal neuronal development. The relationship between maternal alcohol consumption and smoking with third trimester plasma fatty acids were examined and their association with Fetal Alcohol Spectrum Disorders (FASD).

Methods: Moderate to heavy alcohol-using and low/unexposed comparison women were recruited during mid-pregnancy from two prenatal clinics in Ukraine. The participants’ infants underwent physical and neurobehavioral exams prior to one-year of age and classified as having FASD by maternal alcohol consumption and neurobehavioral scores. A subset of mother-child pairs was selected representing three groups of cases and controls: Alcohol-Exposed with FASD (AE-FASD, n = 30), Alcohol-Exposed Normally Developing (AE-ND, n = 33), or Controls (n = 46). Third trimester maternal plasma samples were analyzed for fatty acids and levels were compared across groups.

Results: The percent of C18:0 (p < 0.001), arachidonic acid (AA, C20:4n-6, p = 0.017) and C22:5n-6 (p = 0.001) were significantly higher in AE-FASD women than controls or AE-ND women. Alcohol-exposed women who smoked had lower C22:5n-3 (p = 0.029) and docosahexaenoic acid (DHA, C22:6n-3, p = 0.005) and higher C22:5n-6 (p = 0.013) than women consuming alcohol alone or abstainers.

Conclusion: Alterations in fatty acid profiles were observed in moderate to heavy alcohol-consuming mothers with infants classified with FASD compared to alcohol-exposed normally developing infants or controls.

Patterns of Prenatal Alcohol Use That Predict Infant Growth and Development

Background: Previous studies have had inconsistent findings regarding the quantity and frequency of prenatal alcohol exposure (PAE) that lead to deficits in growth and neurodevelopment. This may be due to imprecise methods of exposure classification. Our objective in this study was to employ longitudinal trajectory modeling of maternal drinking patterns associated with infant growth or neurodevelopmental deficits to a homogenous sample of mothers and infants.

Methods: From a sample of 471 pregnant women prospectively enrolled in a longitudinal study in the Ukraine, we performed a longitudinal cluster analysis of drinking patterns across gestation. We employed multivariable regression analyses to determine if each trajectory group was associated with infant weight, length, or head circumference at birth or psychomotor or mental deficits in infancy.

Results: We identified 5 distinct PAE trajectory groups: minimal or no PAE throughout gestation, low-to-moderate PAE with discontinuation early in gestation, low-to-moderate PAE sustained across gestation, moderate-to-high PAE with reduction early in gestation, and high PAE sustained across gestation. The highest-trajectory group was associated with deficits in infant weight and length at birth and deficits in psychomotor and mental performance at 6 to 12 months of age. Although confidence intervals overlapped, low-to-moderate sustained use was more strongly associated with most negative infant outcomes than moderate-to-high PAE with early reduction.

Conclusions: With these findings, we confirm that high, sustained PAE confers the highest risk for adverse infant outcomes but demonstrate that even low-to-moderate PAE continued across gestation is associated with certain deficits. This approach may be used to help clinicians identify high-risk infants for targeted early intervention.

Поширеність та прогностичні фактори (предиктори) вживання алкоголю матерями в двох областях України

Вступ: Фетальний алкогольний спектр порушень (ФАСП) вважається основною причиною порушень розвитку в світі. Однак, у багатьох країнах не вистачає даних щодо вживання алкоголю вагітними жінками. Метою цього дослідження було оцінити поширеність і предиктори вживання алкоголю вагітними жінками в Україні.

Методи: Міжсекторальний скринінг вагітних жінок був проведений у двох областях України під час фази набору учасників триваючого клінічного дослідження, яке є частиною Спільної ініціативи з дослідження фетального алкогольного спектру порушень (CIFASD). Жінкам під час рутинного пренатального візиту до одного з двох регіональних центрів-учасників програми задавали запитання щодо вживання алкоголю. Кількість і частоту алкогольних напоїв, які вживали жінки протягом місяця в період зачаття і в останній перед опитуванням місяць вагітності, оцінювали за допомогою стандартного інструменту опитування.

Результати: У 2007–2012 рр. в середньому у другому триместрі вагітності було обстежено 11909 вагітних. З них 92,7% повідомили про те, що вони постійно п’ють. Серед тих, хто постійно п’є, 54,8% повідомили про вживання алкоголю протягом місяця в період зачаття, а 12,9% вживали щонайменше три алкогольні напої на день в той період часу. У останній перед опитуванням місяць вагітності 46,3% продовжували повідомляти про вживання алкоголю, а 9,2% вживали щонайменше три алкогольні напої на день. До важливих предикторів середньої кількості вживання напоїв чи більшого пиття на день у будь-який період вагітності належать: менша кількість вагітностей, одинокий стан, неодруженість/життя з партнером або розлученість, низька освіта матері, куріння, початок вживання алкоголю в молодшому віці та високий бал при скринінговому тесті TWEAK на шкідливе вживання алкоголю.

Висновки: Ці знахідки підтверджують необхідність проведення освітніх заходів/інтервенцій у жінок дітородного віку в Україні і можуть допомогти при проведенні цілеспрямованих інтервенцій для жінок з ризиком вживання алкоголю під час вагітності. Ініціювання стандартного протоколу скринінгу під час вагітності є кроком у правильному напрямку.

Висока частота вад невральної трубки в Україні

Підгрунтя: Cпоживання синтетичної фолієвої кислоти може запобігти виникненню вад невральної трубки (ВНТ), які є одними з найтяжчих вроджених аномалій. Частота ВНТ в Україні та інших країнах колишнього СРСР є недостатньо вивченою. Ми встановили, що частота виникнення вагітностей плодом із ВНТ у північно-західному регіоні України є підгрунтям для прийняття рішень стосовно впровадження фортифікації борошна в країні.

Методи: Українсько-Американська Програма запобігання вродженим вадам розвитку, яка почала реалізовуватись в 1999 році, здійснює популяційний моніторинг вроджених вад в кількох областях України. Ми визначали частоту ВНТ у Волинській і Рівненській областях північно-західної України протягом 3 років – 2000-2002 рр.

Результати: Протягом 2000-2002 років в цих двох областях народилося 75928 новонароджених. Було зареєстровано 159 випадків ВНТ (включаючи народжених живими та мертвими і переривання вагітності). Частота вагітностей плодом із ВНТ у двох областях північно-західної України склала 2,1 на 1000 народжених.

Висновки: Частота вагітностей плодом із ВНТ, визначена нами у двох областях північно-західної України, майже в чотири рази перевищує допустимий рівень. Ця частота означає, що серед населення України широко розповсюджений дефіцит фолатів. Щоб припинити таку епідемію вроджених вад, необхідно терміново впроваджувати загальну фортифікацію борошна, що виробляється на українських млинах, фолієвою кислотою. Можна очікувати, що така фортифікація також знизить частоту розвитку фолатзалежної анемії, інфарктів та інсультів у населення.

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High Rates of Neural Tube Defects in Ukraine

Background: Oral consumption of synthetic folic acid can prevent neural tube defects (NTDs), which are some of the most severe congenital anomalies. The prevalence of NTDs in Ukraine and other countries of the former U.S.S.R. has not been well studied. We determined the prevalence of NTD-affected pregnancies in Northwestern Ukraine as background for policy decisions related to flour fortification in this country.

Methods: The Ukrainian-American Birth Defects Program was established in 1999 and conducts population-based surveillance of birth defects in several oblasts (states) of Ukraine. We determined the prevalence of NTDs in the Volyn and Rivne oblasts of Northwestern Ukraine for three years, 2000–2002.

Results: There were 75,928 births in the two oblasts in 2000–2002. There were 159 cases of NTDs among live births, stillbirths, and induced abortions. The prevalence of NTDs in the two oblasts in Northwestern Ukraine is 2.1 per 1000 births.

Conclusions: The prevalence of NTD-affected pregnancies we found in Northwestern Ukraine is almost four times what it should be. This prevalence suggests that population folate deficiency is widespread in Ukraine. Universal folic acid fortification of flour milled in Ukraine is urgently needed to end this epidemic of birth defects. Such fortification would be expected to prevent folate deficiency anemia, heart attacks, and strokes.

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Розвиток нагляду за вродженими вадами розвитку в Україні

Нагляд за вродженими вадами розвитку (ВВР) за міжнародними стандартами був запроваджений в Україні мережею з п’яти центрів, які знаходяться в північно-західному, центральному і південному регіонах України. Ці центри надають доступ до сучасних фундаментальних джерел інформації, а також всебічно підтримують партнерство з лікарями, адміністраторами, групами батьківської підтримки, освітніми спеціалістами і гуманітарними організаціями. Одним з результатів такої діяльності став солідний і популярний інтернет-сайт – „Вроджені вади розвитку – Міжнародні інформаційні системи (IBIS). На сьогоднішній день вище згадана мережа зареєстрована в Україні як Українська ОМНІ-Мережа.

В ході моніторингу Програма задокументувала високу частоту виникнення вад невральної трубки (ВНТ), пов’язаних з алкоголем порушень розвитку у плодів (FAE), ідіопатичну затримку розвитку у дітей-сиріт, що спонукає до впровадження превентивних ініціатив і таких, які б допомогли ліквідувати ці проблеми. Наступні завдання Програми включають: універсальну фортифікацію борошна фолієвою кислотою за рекомендацією Академії медичних наук України; продовження пошуку методів зниження пов’язаних з алкоголем порушень розвитку у плодів у співпраці з партнерами з Каліфорнії (США); відкриття додаткових центрів ранньої стимуляції, фінансованих місцевою владою, за зразком вже працюючих в Рівному і Луцьку; сполучення запобігання ВВР з біоетичними питаннями, – ця тема набуває додаткового значення через наслідки Чорнобильської катастрофи.

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Birth Defects Surveillance in Ukraine: a Process

Birth defects (BD) surveillance using international standards was introduced in Ukraine by a network of five BD centers located in northwestern, central and southern regions. BD centers provide resources to access current and comprehensive information and to nurture partnerships with physicians, administrators, parental support groups, educators, and humanitarian assistance organizations. One outcome was the vigorous and popular website International BD Information Systems (IBIS). The network is now incorporated as OMNI-Net Ukraine.

The program has documented high prevalence rates of neural tube defects (NTD); fetal alcohol effects (FAE); and idiopathic developmental retardation among orphans that prompted prevention and amelioration initiatives. Further program objectives include: universal folic acid flour fortification, as recommended by the Ukrainian Academy of Medicine; continued research on methods to reduce FAE in collaboration with partners from California; opening other early infant stimulation centers funded by local authorities, modeled on those in Rivne and Lutsk; and linking BD prevention with bioethical considerations, which is a topic of interest in Ukraine in part enhanced by the effects of Chornobyl.

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Chronic Radiation Exposure in the Rivne-Polissia Region of Ukraine: Implications for Birth Defects

Objectives: The health effects of chronic low-dose radiation exposure remains a controversial question. Monitoring after the Chernobyl nuclear accident in Ukraine suggested that chronic low-dose radiation exposure was not linked to cancer mortality among the general population. However, elevated rates of birth defects in contaminated compared to uncontaminated regions suggest that exposure to radiation in utero might impact development and that chronic radiation exposure might represent an underestimated risk to human health.
Methods: We sought to determine current radiation exposure routes in Rivne-Polissia, a region of Ukraine contaminated by the Chernobyl accident. This represents a first step toward comprehensive studies of the effects of chronic radiation exposure on human health. We designed and administered a dietary and activity survey to 344 women in Polissia. We assessed types and sources of food consumed, types of outdoor activities, and alcohol intake.
Results: Alcohol intake was low and alone does not account for the observed high rates of birth defects. Wild foods, especially mushrooms and berries, and locally produced foods, especially milk related, were major radiation exposure routes. Additionally, women were exposed to radiation through inhalation while burning grasses and potato vines in fields, and wood for cooking and heating.
Conclusions: Twenty four years after the Chernobyl accident, women continue to be chronically exposed to low-dose radiation at levels exceeding current recommendations. This might contribute (especially synergistically with alcohol consumption and micronutrient deficiencies) to higher prevalence of birth defects in areas of Ukraine with high levels of radiation contamination compared to uncontaminated areas.

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Підвищена частота вроджених аномалій та інкорпорований цезій-137 в поліському регіоні України

Передумови: Проведені одразу ж після Чорнобильської катастрофи 1986 року дослідження постраждалого населення, що проживало в різних місцях Європи, спонукали урядові і міжнародні інстанції зробити висновок, що дія цезію-137 (Cs-137) не має тератогенних наслідків. Наші спостереження підвищених популяційних частот вад невральної трубки (ВНТ), мікроцефалії і мікрофтальмії (М/М) в Рівненській області України, які виявились одними з найвищих в Європі, спонукали провести дане дослідження, яке включало вивчення вмісту інкорпорованого Cs-137 в організмі амбулаторних пацієнтів і вагітних жінок, які проживають в Рівненському Поліссі, найбільш забрудненої частини Рівненської області.

Методи: Були проаналізовані щорічні (2000-2012) популяційні частоти ВНТ і М/М, а також рівні інкорпо-рованого Cs-137 в організмі амбулаторних пацієнтів (2001-2010) і вагітних жінок (2011-2013) з Поліського і не-Поліського регіонів Рівненської області.

Результати: Популяційні частоти ВНТ і М/М в Рівненській області залишаються на підвищеному рівні і є статистично достовірно вищі в Поліссі ніж в не-Поліссі. Також рівні радіації, інкорпорованої жителями Полісся, є статистично достовірно вищими за рівні, накопичені жителями не-Полісся.

Висновки: Частоти ВНТ і М/М є найвищими в Поліському регіоні Рівненської області, вони також є одними з найвищих в Європі. В Поліссі рівні інкорпорованого Cs-137 перевищують офіційно встановлені гранично допустимі дози. Наші результати базуються на сукупних даних про ВНТ і М/М та на середніх значеннях інкорпорованої радіації. Потрібні подальші дослідження причин високих частот ВНТ і М/М, розробка термінових заходів для зменшення впливу тератогенів, включаючи радіонукліди і алкоголь, а також посилення споживання харчових добавок з фолієвою кислотою.

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Elevated Congenital Anomaly Rates and Incorporated Cesium-137 in the Polissia Region of Ukraine

Background: Investigations soon after the 1986 Chornobyl (Chernobyl in Russian) accident of exposed populations residing elsewhere in Europe led government and international agencies to conclude that exposures to cesium-137 (Cs-137) were not teratogenic. Our observations of elevated population rates of neural tube defects (NTDs) and microcephaly and microphthalmia (M/M) in the Rivne Province in Ukraine, which were among the highest in Europe, prompted this follow-up investigation inclusive of whole-body counts (WBCs) of Cs-137 among ambulatory patients and pregnant women residing in Polissia, the most polluted region in Rivne.

Methods: Yearly (2000–2012) population rates of NTDs and M/M and WBC patterns of ambulatory patients (2001–2010) and pregnant women (2011–2013) in Polissia and non-Polissia regions of Rivne were analyzed.

Results: The NTD and M/M population rates in Rivne remain elevated and are statistically significantly higher in Polissia than in non-Polissia. The WBCs among residents in Polissia are statistically significantly higher than among those from non-Polissia.

Conclusion: NTD and M/M rates are highest in the Polissia region of Rivne and are among the highest in Europe. In Polissia, the WBCs of Cs-137 are above officially set permissible upper limits. The results are based on aggregate data of NTDs and M/Ms and average WBC values. Further investigations of causality of the high rates of NTDs and M/Ms are needed and urgent strengthening policies and implementations to reduce exposures to teratogens, in particular radioactive nuclides and alcohol, and consumption of folic acid supplements are indicated.

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Stillbirth and neonatal mortality in pregnancies complicated by major congenital anomalies: Findings from a large European cohort

Objective: To provide prognostic information to help parents to reach an informed decision about termination or continuation of the pregnancy and to shape peripartum policy based on a large European cohort.
Method: Thirteen registries from the European Surveillance of Congenital Anomalies (EUROCAT) network contributed data from January 1, 1998, to December 31, 2011. Terminations for fetal anomalies were excluded. Chromosomal anomalies, syndromes and isolated anomaly groups were distinguished according to EUROCAT guidelines. Perinatal mortality, stillbirths, and early and late neonatal mortality rates (NMRs) were analyzed by anomaly group and gestational age.
Results: Among 73 337 cases, perinatal mortality associated with congenital anomaly was 1.27 per 1000 births (95% confidence interval, 1.23‐1.31). Average stillbirth rate was 2.68% (range 0%‐51.2%). Early and late NMR were 2.75% (range 0%‐46.7%) and 0.97% (range 0%‐17.9%), respectively. Chromosomal anomalies and syndromes, and most isolated anomalies, had significant differences regarding timing of fetal demise compared to the general population. Chromosomal and central nervous system anomalies had higher term stillbirth rates.
Conclusions: We found relevant differences between anomalies regarding rates of stillbirth, NMR, and timing by gestational age. Our data can help parents to decide about their unborn child with a congenital anomaly and help inform maternal‐fetal medicine specialists regarding peripartum management.

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Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N = 149) and low or no alcohol-exposed (LNA) (N = 92) women were recruited into the study during mid pregnancy (mean of 19.8 ± 5.8 weeks’ gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p = 0.020 and p = 0.036, respectively) and 12 months (p = 0.043 and p = 0.029, respectively), and with MDI scores at 12 months (p = 0.013 and p = 0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1β, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1β and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p = 0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

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Chornobyl, radiation, neural tube defects, and microcephaly

Pregnant women residing in areas impacted by the Chornobyl ionizing radiation of the Rivne Province in Ukraine have persistent higher levels of incorporated cesium-137. In these areas the neural tube defects and microcephaly rates are significantly higher than in areas with lower maternal cesium-137 incorporated levels. In two Rivne counties with populations proximal to nuclear power plants the rates of neural tube defects and microcephaly are the highest in the province. The neural tube defects rates in Rivne are persistently among the highest in Europe.

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Prevalence and Predictors of Maternal Alcohol Consumption in Two Regions of Ukraine

Background: Fetal Alcohol Spectrum Disorders (FASD) are thought to be a leading cause of developmental disabilities worldwide. However, data are lacking on alcohol use among pregnant women in many countries. The purpose of this study was to evaluate the prevalence and predictors of alcohol consumption by pregnant women in Ukraine.

Methods: Cross sectional screening of pregnant women was conducted in two regions of Ukraine during the recruitment phase of an ongoing clinical study that is part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). Women attending a routine prenatal visit at one of two participating regional centers were asked about alcohol consumption. Quantity and frequency of alcoholic beverages consumed in the month around conception and in the most recent month of pregnancy were measured using a standard interview instrument.

Results: Between 2007 and 2012, 11,909 pregnant women were screened on average in the second trimester of pregnancy. Of these, 92.7% reported being ever-drinkers. Among ever-drinkers, 54.8% reported drinking alcohol in the month around conception, and 12.9% consumed at least three drinks on at least one day in that time period. In the most recent month of pregnancy, 46.3% continued to report alcohol use and 9.2% consumed at least three drinks per day. Significant predictors of average number of drinks or heavier drinking per day in either time period in pregnancy included lower gravidity, being single, unmarried/living with a partner, or separated, lower maternal education, smoking, younger age at initiation of drinking and higher score on the TWEAK screening test for harmful drinking.

Conclusions: These findings support the need for education/intervention in women of childbearing age in Ukraine, and can help inform targeted interventions for women at risk of an alcohol exposed pregnancy. The initiation of a standard screening protocol in pregnancy is a step in the right direction.

Вроджені вади розвитку в регіоні, що постраждав внаслідок Чорнобильської катастрофи

Мета: Одна з популяцій, що найбільше піддалась впливу хронічного опромінення низькими дозами радіації внаслідок Чорнобильської аварії, проживає на Поліссі – північній частині Рівненської області. Ми наводимо дані про поширеність деяких вроджених вад (ВВР) у цій популяції та досліджуємо можливі етіологічні фактори та регіональні контрасти.

Матеріли і методи: Cтатистично проаналізовано вроджені вади розвитку згідно міжнародних стандартів у Рівненської області за 2000-2006 рр. За цей період в області було зареєстровано 96438 живонароджених. Було також досліджено контрасти частот на Поліссі порівняно з іншою частиною Рівненської області.

Результати: Загальна частота вад невральної трубки у Рівненській області є однією з найвищих у Європі (22,2 на 10000 живонароджених). Частоти зрощених близнюків та тератом також є підвищеними. Виявлено ще вищу загальну частоту вад невральної трубки на Поліссі (27,0 порівняно із 18,3; OR 1.46; 95% CI 1,13-1,93). Також, ймовірно, вищими є частоти мікроцефалії та мікрофтальмії.

Висновки: Приклади проаналізованих вад свідчать про можливе раннє порушення бластогенезу, що проявляється змінами вісі тіла, появою близнюків, дуплікаціями, порушеннями процесу латералізації та формування середньої лінії. Результати є переконливими та обгрунтовують необхідність продовження та поширення цього дослідження у регіонах України, що піддаються хронічній дії низьких доз радіації.

Malformations in a Chornobyl-Impacted Region

Objective: One of the populations most exposed to chronic low-dose radiation from Chornobyl (Chernobyl in Russian) lives in Polissia, the region representing the northern half of Rivne Province (Oblast) in Ukraine. Here the patterns and population rates of malformations are reported and possible etiologic factors and regional contrasts are explored.
Patients and methods: Malformations, as defined by international standards, noted among all 96,438 births in Rivne between 2000 and 2006, were analyzed statistically. Contrasts of rates in Polissia compared with the rest of Rivne also were investigated.
Results: The overall rate of neural tube defects in Rivne is among the highest in Europe (22.2 per 10,000 live births). The rates of conjoined twins and teratomas also seem to be elevated. In Polissia, the overall rates of neural tube defects are even higher (27.0 vs 18.3, respectively; odds ratio: 1.46 [95% confidence interval: 1.13–1.93]), and the rates of microcephaly and microphthalmia may also be elevated.
Conclusions: The malformation patterns observed suggest early disruptions of blastogenesis, manifesting as alterations of body axes, twinning, duplications, laterality, and midline formation. The results are sufficiently compelling to justify continuing and expanding this investigation of malformations in chronic low-dose radiation-impacted regions of Ukraine.

Бластопатії і мікроцефалія в регіоні України, що постраждав внаслідок Чорнобильської катастрофи

Дане популяційне дескриптивне епідеміологічне дослідження показує, що частоти зрощених близнюків, тератом, вад невральної трубки, мікроцефалії і мікрофтальмії в Рівненській області України є серед найвищих в Європі. Рівненська область знаходиться на відстані 200 км від Чорнобильської атомної електростанції, а її північна частина – регіон, відомий як Полісся, – значно забруднена іонізуючою радіацією. Частоти вад невральної трубки, мікроцефалії і мікрофтальмії в Поліссі є статистично достовірно вищі, ніж в іншій частині області. Дослідження розміру голови дітей при народженні показало, що обвід голови статистично достовірно менший у хлопчиків і у дівчаток, народжених матерями, які проживали в одному з Поліських районів, у порівнянні з тими, що проживали в обласному центрі. Усі ці спостереження дають підґрунтя для проведення проспективних досліджень типу «причина-наслідок» з метою їх підтвердження і встановлення причин. Переваги даного дослідження полягають в тому, що воно ґрунтується на міжнародних стандартах, які існують в Європі, а також на даних, зібраних під час десятирічного моніторингу вроджених аномалій в двох великих і відмінних одна від іншої популяцій. Обмеження цього дослідження, як і усіх інших дескриптивних епідеміологічних досліджень, полягає в тому, що виявлені причинно-наслідкові асоціації вимагають подальшої оцінки шляхом проведення додаткових проспективних досліджень специфічних тератогенних факторів.

Blastopathies and Microcephaly in a Chornobyl Impacted Region of Ukraine

This population-based descriptive epidemiology study demonstrates that rates of conjoined twins, teratomas, neural tube defects, microcephaly, and microphthalmia in the Rivne province of Ukraine are among the highest in Europe. The province is 200 km distant from the Chornobyl site and its northern half, a region known as Polissia, is significantly polluted by ionizing radiation. The rates of neural tube defects, microcephaly and microphthalmia in Polissia are statistically significantly higher than in the rest of the province. A survey of at-birth head size showed that values were statistically smaller in males and females born in one Polissia county than among neonates born in the capital city. These observations provide clues for confirmatory and cause-effect prospective investigations. The strength of this study stems from a reliance on international standards prevalent in Europe and a decade-long population-based surveillance of congenital malformations in two distinct large populations. The limitations of this study, as those of other descriptive epidemiology investigations, is that identified cause-effect associations require further assessment by specific prospective investigations designed to address specific teratogenic factors.

Cardiac Orienting Responses Differentiate the Impact of Prenatal Alcohol Exposure in Ukrainian Toddlers

Background: Prenatal alcohol exposure (PAE) has been found to impact neurophysiological encoding of environmental events negatively in the first year of life but has not been evaluated in older infants or toddlers. Cardiac orienting responses (ORs) collected during a habituation/dishabituation learning paradigm were obtained from 12- to 18-month-olds to assess the impact of PAE beyond the first year of life.
Methods: Participants included women and their toddlers who differed in PAE histories and enrolled in a randomized clinical trial of multivitamin/mineral usage during pregnancy. Those who were randomly assigned to the no intervention group were used for this analysis. The habituation/dishabituation paradigm consisted of 10 habituation and 5 dishabituation trials. Baseline heart rate (HR) was collected for 30 seconds prior to stimulus onset, and responses to the stimuli were assessed by sampling HR for 12 seconds poststimulus onset.
Results: The speed of the OR in response to auditory stimuli in the dishabituation condition was found to be altered as a function of maternal alcohol use around conception. For visual stimuli, positive histories of PAE were predictive of the magnitude but not the speed of the response on habituation and dishabituation trials. A history of binge drinking was associated with reduced magnitude of the OR response on visual encoding trials, and level of alcohol exposure at the time of conception was predictive of the magnitude of the response on visual dishabituation trials.
Conclusions: Cardiac ORs collected in the toddler period were sensitive to the effects of PAE. The magnitude of the OR was more sensitive to the impact of PAE than in previous research with younger infants, and this may be a function of brain maturation. Additional research assessing the predictive utility of using ORs in making decisions about individual risk was recommended.

Second-Trimester Ultrasound as a Tool for Early Detection of Fetal Alcohol Spectrum Disorders

Background: Early detection of fetal alcohol spectrum disorders (FASDs) is desirable to allow earlier and more comprehensive interventions to be initiated for the mother and infant. We examined prenatal ultrasound as an early method of detecting markers of the physical features and neurobehavioral deficits characteristic of FASD.
Methods: A longitudinal cohort of pregnant women in Ukraine was recruited as part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Women were enrolled into a moderately to heavy-alcohol-exposed group or a low- or no-alcohol exposure group and were followed to pregnancy outcome. In the second trimester, a fetal ultrasound was performed to measure transverse cerebellar diameter, occipital frontal diameter (OFD), caval–calvarial distance, frontothalamic distance (FTD), interorbital distance (IOD), outer orbital diameter, and orbital diameter (OD). Live born infants received a dysmorphological examination and a neurobehavioral evaluation using the Bayley Scales of Infant Development. These data were used to classify infants with respect to FASD. Comparisons were made on the ultrasound measures between those with and without features of FASD, adjusting for gestational age at ultrasound and maternal smoking.
Results: A total of 233 mother/child dyads were included. Children classified as FASD had significantly longer IOD and lower FTD/IOD, OFD/IOD, and FTD/OD ratios (p <0.05). Children with a Bayley score <85 had significantly shorter FTD, longer IOD, lower OFD/IOD, and FTD/IOD ratios (p <0.05). In general, mean differences were small. Ultrasound variables alone predicted <10% of the variance in the FASD outcome.
Conclusions: Some ultrasound measurements were associated with FASD, selected facial features of the disorder, and lower neurobehavioral scores. However, mean differences were relatively small, making it difficult to predict affected children based solely on these measures. It may be advantageous to combine these easily obtained ultrasound measures with other data to aid in identifying high risk for an FASD outcome.

Plasma miRNA Profiles in Pregnant Women Predict Infant Outcomes following Prenatal Alcohol Exposure

Fetal alcohol spectrum disorders (FASD) are difficult to diagnose since many heavily exposed infants, at risk for intellectual disability, do not exhibit craniofacial Dysmorphology or growth deficits. Consequently, there is a need for biomarkers that predict disability. In both animal models and human studies, alcohol exposure during pregnancy resulted in significant alterations in circulating microRNAs (miRNAs) in maternal blood. In the current study, we asked if changes in plasma miRNAs in alcohol-exposed pregnant mothers, either alone or in conjunction with other clinical variables, could predict infant outcomes. Sixty-eight pregnant women at two perinatal care clinics in western Ukraine were recruited into the study. Detailed health and alcohol consumption histories, and 2nd and 3rd trimester blood samples were obtained. Birth cohort infants were assessed by a geneticist and classified as unexposed (UE), heavily prenatally exposed and affected (HEa) or heavily exposed but apparently unaffected (HEua). MiRNAs were assessed in plasma samples using qRT-PCR arrays. ANOVA models identified 11 miRNAs that were all significantly elevated in maternal plasma from the HEa group relative to HEua and UE groups. In a random forest analysis classification model, a combination of high variance miRNAs, smoking history and socioeconomic status classified membership in HEa and UE groups, with a misclassification rate of 13%. The RFA model also classified 17% of the HEua group as UElike, whereas 83% were HEa-like, at least at one stage of pregnancy. Collectively our data indicate that maternal plasma miRNAs predict infant outcomes, and may be useful to classify difficult-to-diagnose FASD subpopulations.

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.

Chornobyl 30 years later: Radiation, pregnancies, and developmental anomalies in Rivne, Ukraine

In the 30 years since the Chornobyl nuclear power plant disaster, there is evidence of persistent levels of incorporated ionizing radiation in adults, children and pregnant women in the surrounding area. Measured levels of Cesium-137 vary by region, and may be influenced by dietary and water sources as well as proximity to nuclear power plants. Since 2000, comprehensive, population-based birth defects monitoring has been performed in selected regions of Ukraine to evaluate trends and to generate hypotheses regarding potential causes of unexplained variations in defect rates. Significantly higher rates of microcephaly, neural tube defects, and microphthalmia have been identified in selected regions of Ukraine collectively known as Polissia compared to adjacent regions collectively termed non-Polissia, and these significantly higher rates were evident particularly in the years 2000-2009. The Polissia regions have also demonstrated higher mean whole body counts of Cesium-137 compared to values in individuals residing in other non-Polissia regions. The potential causal relationship between persistent ionizing radiation pollution and selected congenital anomaly rates supports the need for a more thorough, targeted investigation of the sources of persistent ionizing radiation and the biological plausibility of a potential teratogenic effect.

Vitamin D Deficiency in Pregnant Ukrainian Women: Effects of Alcohol Consumption on Vitamin D Status

Objective: Heavy alcohol consumption can alter vitamin D status; however, the relationships between alcohol consumption and vitamin D concentrations in pregnant women have not been well studied. The aim of this study was to investigate the vitamin D status in a population of alcohol-exposed (N=180) and low/ unexposed control (N=179) Ukrainian pregnant women.

Methods: Women who attended prenatal care facilities in 2 regions of Ukraine (Rivne and Khmelnytsky) for a routine prenatal visit were screened for the study. At the time of enrollment (20.4 ± 7.0 weeks of gestation), blood samples and alcohol consumption data (during a typical week around conception and the most recent 2 weeks) were collected. Vitamin D status was assessed by 25-hydroxyvitamin D [25(OH)D] concentrations.

Results: A high prevalence of suboptimal vitamin D status in pregnant Ukrainian women was observed. Overall, 50.1% and 33.4% of the women were classiﬁed as vitamin D deﬁcient [25(OH)D <20 ng/mL] or insufﬁcient [25(OH)D ≥20 ng/mL and ≤30 ng/mL], respectively, based on 2011 Endocrine Society guidelines. Alcohol-exposed women had signiﬁcantly lower 25(OH)D concentrations than low/unexposed women in Spring (p=0.006) and Winter (p=0.022). When vitamin D concentrations were grouped into sunny season (Summer + Fall) compared to not sunny season (Winter + Spring), there was a signiﬁcant ethanol by season interaction (p=0.0028), with alcohol-drinking women having lower circulating vitamin D compared to low/unexposed women in seasons of low sun availability.

Conclusions: These data suggest that when vitamin D concentrations are generally low (e.g., during seasons of low sun availability), alcohol consumption during pregnancy has a negative impact on vitamin D status.

Birth Defects, Polissia, Chornobyl

Introduction. Rivne Polissia inhabitants constitute a population that was most influenced by chronic ionizing radiation due to the Chornobyl disaster. The aim of our investigation was to establish population rates of some congenital anomalies (CA) in Rivne Region during 2000-2014 and their contrasts within the Rivne Region (Polissia vs. non-Polissia), as well as to analyze probable etiological factors.
Materials and methods. Introduced in Rivne Region system of active population monitoring of CA and
conducted using EUROCAT (European Surveillance of Congenital Anomalies) and ICBDSR (International Clearinghouse for Birth Defects Surveillance and Research) methods, allows controlling data completeness and quality, establishing CA rates and finding their contrasts. We performed statistical analysis of CA registered in 2000-2014. During that period, 231,390 live births were registered in the region. We also studied whole-body counts (WBC) of Cesium-137 (Cs-137) among pregnant women.
Results. Rivne population rates of neural tube defects (NTD), microcephaly (MIC) and microphthalmia (mOPH) are among the highest in Europe. These rates are statistically significantly higher in Polissia than in non-Polissia. Mean WBC of Cs-137 among pregnant women were statistically significantly higher in Polissia than in non-Polissia. Alcohol screening among 5,226 pregnant women conducted during 2010-2014 showed that 3.9% in Polissia and 1.7% in non-Polissia used considerable doses of alcohol. Survey of 4,798 pregnant women in Rivne Region showed that only 7% consumed folic acid (alone or as multivitamin complexes) in preconception period.
Conclusions. It is necessary to continue investigations of causes of NTD, MIC and mOPH elevated population rates and their associations with other malformations in Rivne Region and particularly in Polissia, because these associations may have common etiological and pathophysiological mechanisms. The results of such investigations may probably elucidate new important for society facts and help to understand better a complex of causes leading to CA formation, as well as to develop and introduce effective preventive measures.

Assessing the Independent and Joint Effects of Unmedicated Prenatal Depressive Symptoms and Alcohol Consumption in Pregnancy and Infant Neurodevelopmental Outcomes

Background: Prenatal alcohol exposure (PAE) is an established risk factor for neurodevelopmental deficits in the offspring. Prenatal depression has been associated with neurodevelopmental deficits in the offspring, although investigations into unmedicated prenatal depression have been inconsistent. We hypothesized that unmedicated prenatal depressive symptoms would independently and jointly with PAE predict neurodevelopmental outcomes in infant offspring.
Methods: We studied 344 participants from a randomized clinical trial of multivitamin supplements in pregnant women in Ukraine. Women were recruited based upon periconceptional alcohol use and followed up to 12 months postpartum. Prenatal depressive symptoms were assessed at approximately 32 weeks of gestation using the Beck Depression Inventory score. Neurodevelopment was assessed with the Bayley Scales of Infant Development II Mental Development Index (MDI) and Psychomotor Development Index (PDI) at 6 and 12 months postpartum. Generalized linear regression models were constructed to assess the independent and joint effects of prenatal depressive symptoms and PAE in models adjusted for sociodemographic and pregnancy characteristics.
Results: PAE was independently associated with deficits in neurodevelopmental outcomes at 6 and 12 months, however, level of prenatal depressive symptoms was not. We found marginal evidence of synergism of depressive symptoms and PAE, with larger deficits in those with both exposures observed for the PDI-6 months (p=0.05) and MDI-12 months (p=0.09). Additionally, there was a suggestion of sexual dimorphism; females had stronger deficits from joint exposures than males (depressive symptom [MDI-6 months] female: 8.28, 95% CI 13.06, 3.49; male: 0.68, 95% CI 4.58, 5.94; p for interaction 0.04). While not statistically significant for the MDI or PDI at 12 months, the trend persisted.
Conclusions: Infants exposed to PAE and prenatal depression may be at an increased risk of neurodevelopmental deficits. Healthcare providers should be aware of this possible synergism in their
efforts to mitigate the neurodevelopmental effects of these co-occurring exposures.

Вроджені вади розвитку, Полісся, Чорнобиль

Вступ. Населення рівненського Полісся – популяція, що найбільше зазнала хронічного опромінення іонізуючою радіацією внаслідок Чорнобильської катастрофи. Метою нашого дослідження було визначити популяційні частоти вроджених вад розвитку (ВВР) у Рівненській області за 2000-2014 рр. та їх контрасти у поліському та не-Поліському регіонах області, провести аналіз ймовірних етіологічних факторів.
Матеріали і методи. Запроваджена в області система активного популяційного моніторингу ВВР, що проводиться за методологією ЄВРОКАТ (European Surveillance of Congenital Anomalies) та ICBDSR (Міжнародною Палатою Моніторингу і Досліджень ВВР) дозволяє контролювати повноту і якість даних, відслідковувати частоти ВВР, а також знаходити контрасти в їх пропорціях. Проведено статистичний аналіз ВВР за 2000-2014 рр. За цей період в області було зареєстровано 231390 живонароджених дітей. Вивчалися також рівні інкорпорованої радіації (Cs-137) у вагітних жінок.
Результати. Популяційні частоти вад невральної трубки (ВНТ), мікроцефалії та мікрофтальмії у Рівненській області є одними з найвищих у Європі, причому ці частоти статистично достовірно вищі в Поліссі, ніж в не-Поліссі. Середні рівні інкорпорованої радіації (РІР) у вагітних з Полісся є статистично достовірно вищими за рівні, накопичені вагітними з не-Полісся. Скринінг 5226 вагітних жінок щодо вживання алкоголю у 2010-2014 рр. показав, що 3,9% вагітних жінок з не-Полісся і 1,7% з Полісся вживали алкоголь у значних дозах (“heavy drinkers”). За результатами проведеного опитування 4798 вагітних жінок Рівненської області, лише біля 7% з них вживали преконцепційно фолієву кислоту в таблетках окремо або у складі мультивітамінних комплексів.
Висновки. Необхідно продовжувати подальші дослідження причин високих частот ВНТ, мікроцефалії, мікрофтальмії та їх асоціацій з іншими вадами в Рівненській області і Поліссі, зокрема. Адже асоціації цих ВВР можуть мати спільні етіологічні і патогенетичні механізми. Дуже вірогідно, що результати таких досліджень висвітлять нові важливі для українського суспільства факти і допоможуть краще зрозуміти весь комплекс причин, що призводять до виникнення ВВР, а також дозволять розробити і впровадити ефективні профілактичні заходи.