- Wertelecki W, Yevtushok L, Kuznietsov I, Komov O, Lapchenko S, Akhmedzanova D, Ostapchuk L. Chornobyl, radiation, neural tube defects, and microcephaly. Eur J Med Genet. 2018 Jun 13. pii: S1769-7212(18)30166-6. doi: 10.1016/j.ejmg.2018.06.005. [Epub ahead of print] PubMed PMID: 29908351.
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.
- Sowell KD, Uriu-Adams JY, Van de Water J, Chambers CD, Coles CD, Kable JA, Yevtushok L, Zymak-Zakutnya N, Wertelecki W, Keen CL; Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD). Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure. Alcohol. 2018 May;68:49-58. doi: 10.1016/j.alcohol.2017.08.006. Epub 2017 Aug 12. PubMed PMID: 29453023; PubMed Central PMCID: PMC5820219.
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.
- Groen H, Bouman K, Pierini A, Rankin J, Rissmann A, Haeusler M, Yevtushok L, Loane M, Erwich JJHM, de Walle HEK. Stillbirth and neonatal mortality in pregnancies complicated by major congenital anomalies: Findings from a large European cohort. Prenat Diagn. 2017 Nov;37(11):1100-1111. doi: 10.1002/pd.5148. Epub 2017 Oct 6. PubMed PMID: 28837248..
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.
- Carlson CR Jr, Uriu-Adams JY, Chambers CD, Yevtushok L, Zymak-Zakutnya N, Chan PH, Schafer JJ, Wertelecki W, Keen CL. Vitamin D Deficiency in Pregnant Ukrainian Women: Effects of Alcohol Consumption on Vitamin D Status. J Am Coll Nutr. 2017 Jan;36(1):44-56. doi: 10.1080/07315724.2016.1174091. PubMed PMID: 28169608.
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.
- Wertelecki W, Chambers CD, Yevtushok L, Zymak-Zakutnya N, Sosyniuk Z, Lapchenko S, Ievtushok B, Akhmedzhanova D, Komov O. Chornobyl 30 years later: Radiation, pregnancies, and developmental anomalies in Rivne, Ukraine. Eur J Med Genet. 2017 Jan;60(1):2-11. doi: 10.1016/j.ejmg.2016.09.019. Epub 2016 Sep 30. PubMed PMID: 27697599.
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.
- Mesa DA, Kable JA, Coles CD, Jones KL, Yevtushok L, Kulikovsky Y, Wertelecki W, Coleman TP, Chambers CD; CIFASD. The Use of Cardiac Orienting Responses as an Early and Scalable Biomarker of Alcohol-Related Neurodevelopmental Impairment. Alcohol Clin Exp Res. 2017 Jan;41(1):128-138. doi: 10.1111/acer.13261. Epub 2016 Nov 24. PubMed PMID: 27883195; PubMed Central PMCID: PMC5205554.
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.
- Balaraman S, Schafer JJ, Tseng AM, Wertelecki W, Yevtushok L, Zymak-Zakutnya N, Chambers CD, Miranda RC. Plasma miRNA Profiles in Pregnant Women Predict Infant Outcomes following Prenatal Alcohol Exposure. PLoS One. 2016 Nov 9;11(11):e0165081. doi: 10.1371/journal.pone.0165081. PubMed PMID: 27828986.
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 UE-like, 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.
- Montag AC, Hull AD, Yevtushok L, Zymak-Zakutnya N, Sosyniuk Z, Dolhov V, Jones KL, Wertelecki W, Chambers CD; CIFASD. Second-Trimester Ultrasound as a Tool for Early Detection of Fetal Alcohol Spectrum Disorders. Alcohol Clin Exp Res. 2016 Nov;40(11):2418-2425. doi: 10.1111/acer.13232. PubMed PMID: 27688069.
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.
- Kable JA, Coles CD, Jones KL, Yevtushok L, Kulikovsky Y, Wertelecki W, Chambers CD; CIFASD. Cardiac Orienting Responses Differentiate the Impact of Prenatal Alcohol Exposure in Ukrainian Toddlers. Alcohol Clin Exp Res. 2016 Nov;40(11):2377-2384. doi: 10.1111/acer.13221. PubMed PMID: 27650880; PubMed Central PMCID: PMC5073038.
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.
- Bandoli G, Coles CD, Kable JA, Wertelecki W, Granovska IV, Pashtepa AO, Chambers CD; CIFASD. Assessing the Independent and Joint Effects of Unmedicated Prenatal Depressive Symptoms and Alcohol Consumption in Pregnancy and Infant Neurodevelopmental Outcomes. Alcohol Clin Exp Res. 2016 Jun;40(6):1304-11. doi: 10.1111/acer.13081. PubMed PMID: 27129610; PubMed Central PMCID: PMC4889502.
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.
- Wertelecki W, Koerblein A, Ievtushok B, Zymak-Zakutnia N, Komov O, Kuznietsov I, Lapchenko S, Sosyniuk Z. Elevated congenital anomaly rates and incorporated cesium-137 in the Polissia region of Ukraine. Birth Defects Res A Clin Mol Teratol. 2016 Mar;106(3):194-200. doi: 10.1002/bdra.23476. PubMed PMID: 26871487.
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.