International Charitable Fund "OMNI-Net for Children"
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.