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Cardinal and non-cardinal dysmorphic features are associated with prenatal alcohol exposure (PAE); however, their association with neurodevelopment is less clear. The objective of this study was to determine whether alcohol-related dysmorphic features predict neurodevelopmental delay in infants and toddlers.We analyzed a prospective pregnancy cohort in western Ukraine enrolled between 2008 and 2014. A dysmorphology examination comprising body size and three cardinal and 14 non-cardinal dysmorphic features was performed at approximately 6 to 12 months of age. PAE was self-reported and operationalized as absolute ounces of alcohol per day around the time of conception. Neurodevelopment was assessed at 6 to 12 months with the Bayley Scales of Infant Development-II (BSID-II), and at 3.5 to 4.5 years of age with the Differential Ability Scales-II, the Child Behavior Checklist, and multiple measures that were used to create an executive functioning factor score. We performed logistic regression to predict children's neurodevelopment from dysmorphic features, growth measures, sex, and PAE.From an analytic sample of 582 unique children, 566 had BSID-II scores in infancy, and 289 completed the preschool battery. Models with all cardinal and non-cardinal dysmorphic features, growth measures, sex, and PAE performed better than models with subsets of those inputs. In general, models had poor performance classifying delays in infancy (area under the curve (AUC)0.7) and acceptable performance on preschool-aged outcomes (AUC ~0.75). When the sample was limited to children with moderate-to-high PAE, predictive ability improved on preschool-aged outcomes (AUC 0.76 to 0.89). Sensitivity was relatively low for all models (12% to 63%), although other metrics of performance were higher.Predictive analysis based on dysmorphic features and measures of growth performed modestly in this sample. As these features are more reliably measured than neurodevelopment at an earlier age, the inclusion of dysmorphic features and measures of growth in predictive models should be further explored and validated in different settings and populations.

Background Aplasia cutis congenita (ACC) is a rare congenital anomaly characterized by localized or widespread absence of skin at birth, mainly affecting the scalp. Most information about ACC exists as individual case reports and medium-sized studies. Objectives This study aimed to investigate the epidemiology of ACC, using data from a large European network of population-based registries for congenital anomalies (EUROCAT). Methods Twenty-eight EUROCAT population-based registries in 16 European countries were involved. Poisson regression models were exploited to estimate the overall and live birth prevalence, to test time trends in prevalence between four 5-year periods and to evaluate the impact of the change of coding for ACC from the unspecific ICD9-BPA code to the specific ICD10 code. Proportions of ACC cases associated with other anomalies were reported. Results Five hundred cases were identified in the period 1998–2017 (prevalence: 5.10 per 100,000 births). Prevalence across 5-year periods did not differ significantly and no significant differences were evident due to the change from ICD9 to ICD10 in ACC coding. Heterogeneity in prevalence was observed across registries. The scalp was the most common site for ACC (96.4%) and associated congenital anomalies were present in 33.8% of cases. Patau and Adams–Oliver syndromes were the most frequent among the associated chromosomal anomalies (88.3%) and the associated genetic syndromes (57.7%), respectively. 16% of cases were associated with limb anomalies and 15.4% with congenital heart defects. A family history of ACC was found in 2% of cases. Conclusion To our knowledge, this is the only population-based study on ACC. The EUROCAT methodologies provide reliable prevalence estimates and proportions of associated anomalies.

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.

BACKGROUND: Congenital anomalies are a major cause of perinatal, neonatal and infant mortality.OBJECTIVES: The aim was to investigate temporal changes and geographical variation in survival of children with major congenital anomalies (CA) in different European areas.METHODS: In this population-based linkage cohort study, 17 CA registries members of EUROCAT, the European network for the surveillance of CAs, successfully linked data on 115,219 live births with CAs to mortality records. Registries estimated Kaplan-Meier survival at 28 days and 5 years of age and fitted Cox's proportional hazards models comparing mortality at 1 year and 1-9 years of age for children born during 2005-2014 with those born during 1995-2004. The hazard ratios (HR) from each registry were combined centrally using a random-effects model. The 5-year survival conditional on having survived to 28 days of age was calculated.RESULTS: The overall risk of death by 1 year of age for children born with any major CA in 2005-2014 decreased compared to 1995-2004 (HR 0.68, 95% confidence interval [CI] 0.53, 0.89). Survival at 5 years of age ranged between registries from 97.6% to 87.0%. The lowest survival was observed for the registry of OMNI-Net (Ukraine) (87.0%, 95% CI 86.1, 87.9).CONCLUSIONS: Survival of children with CAs improved for births in 2005-2014 compared with 1995-2004. The use of CA registry data linked to mortality data enables investigation of survival of children with CAs. Factors such as defining major CAs, proportion of terminations of pregnancy for foetal anomaly, source of mortality data and linkage methods are important to consider in the design of future studies and in the interpretation of the results on survival of children with CAs.

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

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.

Introduction\ud Knowledge on the safety of medication use during pregnancy is often sparse. Pregnant women are generally excluded from clinical trials, and there is a dependence on post-marketing surveillance to identify teratogenic medications.\ud \ud Aims\ud This study aimed to identify signals of potentially teratogenic medications using EUROmediCAT registry data on medication exposure in pregnancies with a congenital anomaly, and to investigate the use of VigiBase reports of adverse events of medications in the evaluation of these signals.\ud \ud Methods\ud Signals of medication–congenital anomaly associations were identified in EUROmediCAT (21,636 congenital anomaly cases with 32,619 medication exposures), then investigated in a subset of VigiBase (45,749 cases and 165,121 exposures), by reviewing statistical reporting patterns and VigiBase case reports. Evidence from the literature and quantitative and qualitative aspects of both datasets were considered before recommending signals as warranting further independent investigation.\ud \ud Results\ud EUROmediCAT analysis identified 49 signals of medication–congenital anomaly associations. Incorporating investigation in VigiBase and the literature, these were categorised as follows: four non-specific medications; 11 likely due to maternal disease; 11 well-established teratogens; two reviewed in previous EUROmediCAT studies with limited additional evidence; and 13 with insufficient basis for recommending follow-up. Independent investigations are recommended for eight signals: pregnen (4) derivatives with limb reduction; nitrofuran derivatives with cleft palate and patent ductus arteriosus; salicylic acid and derivatives with atresia or stenosis of other parts of the small intestine and tetralogy of Fallot; carbamazepine with atrioventricular septal defect and severe congenital heart defect; and selective beta-2-adrenoreceptor agonists with posterior urethral valve and/or prune belly.\ud \ud Conclusion\ud EUROmediCAT data should continue to be used for signal detection, accompanied by information from VigiBase and review of the existing literature to prioritise signals for further independent evaluation.

Background Esophageal atresia (EA) affects around 2.3-2.6 per 10,000 births world-wide. Infants born with this condition require surgical correction soon after birth. Most survival studies of infants with EA are locally or regionally based. We aimed to describe survival across multiple world regions.Methods We included infants diagnosed with EA between 1980 and 2015 from 24 birth defects surveillance programs that are members of the International Clearinghouse for Birth Defects Surveillance and Research. We calculated survival as the proportion of liveborn infants alive at 1 month, 1- and 5-years, among all infants with EA, those with isolated EA, those with EA and additional anomalies or EA and a chromosomal anomaly or genetic syndrome. We also investigated trends in survival over the decades, 1980s-2010s.Results We included 6,466 liveborn infants with EA. Survival was 89.4% (95% CI 88.1-90.5) at 1-month, 84.5% (95% CI 83.0-85.9) at 1-year and 82.7% (95% CI 81.2-84.2) at 5-years. One-month survival for infants with isolated EA (97.1%) was higher than for infants with additional anomalies (89.7%) or infants with chromosomal or genetic syndrome diagnoses (57.3%) with little change at 1- and 5-years. Survival at 1 month improved from the 1980s to the 2010s, by 6.5% for infants with isolated EA and by 21.5% for infants with EA and additional anomalies.Conclusions Almost all infants with isolated EA survived to 5 years. Mortality was higher for infants with EA and an additional anomaly, including chromosomal or genetic syndromes. Survival improved from the 1980s, particularly for those with additional anomalies.

BackgroundFew 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.MethodsParticipants 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=6.93months). 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.ResultsHigher 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.ConclusionsPartner 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.

BackgroundPrenatal 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.MethodsMother-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 12months when CORs were collected and in the preschool period when they were categorized as having (i) fetal alcohol syndrome (FAS), (ii) partial FAS (pFAS), (iii) alcohol-related neurodevelopmental disorder (ARND), (iv) PAE and no diagnosis, or (v) 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.ResultsSignificant 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 0.765 for predicting to pFAS/FAS status.ConclusionsA 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.

Most persons with fetal alcohol spectrum disorders (FASDs) remain undiagnosed or are diagnosed in later life. To address the need for earlier diagnosis, we previously assessed miRNAs in the blood plasma of pregnant women who were classified as unexposed to alcohol (UE), heavily exposed with affected infants (HEa), or heavily exposed with apparently unaffected infants (HEua). We reported that maternal miRNAs predicted FASD-related growth and psychomotor deficits in infants. Here, we assessed whether fetal sex influenced alterations in maternal circulating miRNAs following prenatal alcohol exposure (PAE). To overcome the loss of statistical power due to disaggregating maternal samples by fetal sex, we adapted a strategy of iterative bootstrap resampling with replacement to assess the stability of statistical parameter estimates. Bootstrap estimates of parametric and effect size tests identified male and female fetal sex-associated maternal miRNA responses to PAE that were not observed in the aggregated sample. Additionally, we observed, in HEa mothers of female, but not male fetuses, a network of co-secreted miRNAs whose expression was linked to miRNAs encoded on the X-chromosome. Interestingly, the number of significant miRNA correlations for the HEua group mothers with female fetuses was intermediate between HEa and UE mothers at mid-pregnancy, but more similar to UE mothers by the end of pregnancy. Collectively, these data show that fetal sex predicts maternal circulating miRNA adaptations, a critical consideration when adopting maternal miRNAs as diagnostic biomarkers. Moreover, a maternal co-secretion network, predominantly in pregnancies with female fetuses, emerged as an index of risk for adverse birth outcomes due to PAE.

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

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.

ObjectiveHeavy 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.MethodsWomen 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.ResultsA 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 < 20ng/mL] or insufficient [25(OH)D ≥ 20ng/mL and ≤30ng/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.ConclusionsThese 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.

Ukraine suffers from the neural tube defects epidemic. According to“Omni-Net” data (“Omni-Net” is the only Ukrainian International Charitable Organization that runs population-based monitoring of birth defects according to the international standarts and is a member of EUROCAT and ICBDSR) the rates of NTD in Northen and Western regions of Ukraine in 20002014 on Polissia territories reached 21 up to 25 per 10,000 live births, and on non-Polissia territories – from 14 to 18 per 10000 live births. This data was published in the European Journal of Medical Genetics in 2016 and these rates are the highest in Europe. 75% of all NTD cases in every country can be prevented by periconceptional (during 3 months before pregnancy and fi rst 2-3 months of pregnancy) intake of foic acid. Starting from 1999 USA and Canada implemented fl our fortifi cation with folic acid because of because of ineffectiveness of supplementation policy. Only ¼ – 1/3 of women took folic acid before pregnancy in Canada and USA, in Ukraine this number reaches only 7%. Since 1999, the prevalence of NTD decreased by 46% in Canada, and in USA there was observed a 38% reduction in prevalence for spina bifi da. Economic analysis showed a signifi cant benefi t from fortifi cation: as it is estimated by experts that all direct and indirect, medical and not medical cost for one child with spina bifi da are 20 times higher than fl our fortifi cation costs. Every year after fortifi cation policy was implemented, Health care system in USA saves appox. $508 mln. Ukraine already fortifi es fl our with folic acid and other microelemets but only for export. For example, in 2003 Ministery of Health of Indonesia implemented fortifi cation standarts for all fl our that is sold and consumed in their country, including mandatory folic acid fortifi cation (2ppm). Ukraine is second biggest exporter of fl our for Indonesia. But fortifi ed fl our is not sold in Ukraine… Every year in Ukraine approx. 23% of live birth children with NTD die. 99% of survivors are disabled. And this is happening while there is an effective way to prevent this tragedy. Experts estimate that 800 children born with NTD in Ukraine every year can be born healthy if fl our fortifi cation policy with folic acid is implemented.

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

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.

Background: Dandy-Walker (DW) malformation is a rare and severe congenital anomaly of the posterior fossa affecting the development of the cerebellum and the fourth ventricle. Objective: The aim of this study was to investigate the epidemiology of DW malformation, using data from the European population-based registries of congenital anomalies in the European Surveillance of Congenital Anomalies network. Methods: Anonymous individual data on cases of DW malformation diagnosed in 2002–2015 from 28 registries in 17 countries were included. Prevalence, prenatal detection rate, proportions and types of associated anomalies were estimated. Cases of DW variant were considered and analysed separately. Results: Out of 8,028,454 surveyed births we identified a total of 734 cases, including 562 DW malformation cases and 172 DW variant cases. The overall prevalence of DW malformation was 6.79 per 100,000 births (95% CI 5.79–7.96) with 39.2% livebirths, 4.3% foetal deaths from 20 weeks gestational age, and 56.5% terminations of pregnancy after prenatal diagnosis of foetal anomaly at any gestation (TOPFA). The livebirth prevalence was 2.74 per 100,000 births (95% CI 2.08–3.61). The prenatal detection rate was 87.6%. Two-hundred and seventy-three cases (48.6%) had an isolated cerebral anomaly and 24.2, 19.2 and 5.5% cases were associated with other structural non-cerebral anomalies, chromosomal anomalies and genetic syndromes respectively. The prevalence of DW variant was 2.08 per 100,000 (95% CI 1.39–3.13). Conclusions: This European population-based study provides the epidemiological profile of DW malformation. All birth outcomes were analysed and TOPFA represented more than half of the cases. About 50% of the cases of DW malformation were associated with other non-cerebral anomalies. Large populations and all birth outcomes are essential in epidemiological studies of rare and severe congenital anomalies.

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: In the context of the European Surveillance of Congenital Anomalies (EUROCAT) surveillance response to the 2009 influenza pandemic, we sought to establish whether there was a detectable increase of congenital anomaly prevalence among pregnancies exposed to influenza seasons in general, and whether any increase was greater during the 2009 pandemic than during other seasons.METHODS: We performed an ecologic time series analysis based on 26,967 pregnancies with nonchromosomal congenital anomaly conceived from January 2007 to March 2011, reported by 15 EUROCAT registries. Analysis was performed for EUROCAT-defined anomaly subgroups, divided by whether there was a prior hypothesis of association with influenza. Influenza season exposure was based on World Health Organization data. Prevalence rate ratios were calculated comparing pregnancies exposed to influenza season during the congenital anomaly-specific critical period for embryo-fetal development to nonexposed pregnancies.RESULTS: There was no evidence for an increased overall prevalence of congenital anomalies among pregnancies exposed to influenza season. We detected an increased prevalence of ventricular septal defect and tricuspid atresia and stenosis during pandemic influenza season 2009, but not during 2007-2011 influenza seasons. For congenital anomalies, where there was no prior hypothesis, the prevalence of tetralogy of Fallot was strongly reduced during influenza seasons.CONCLUSIONS: Our data do not suggest an overall association of pandemic or seasonal influenza with congenital anomaly prevalence. One interpretation is that apparent influenza effects found in previous individual-based studies were confounded by or interacting with other risk factors. The associations of heart anomalies with pandemic influenza could be strain specific.

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 73337 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.

Previous studies have shown that over 40% of babies with Down syndrome have a major cardiac anomaly and are more likely to have other major congenital anomalies. Since 2000, many countries in Europe have introduced national antenatal screening programs for Down syndrome. This study aimed to determine if the introduction of these screening programs and the subsequent termination of prenatally detected pregnancies were associated with any decline in the prevalence of additional anomalies in babies born with Down syndrome. The study sample consisted of 7,044 live births and fetal deaths with Down syndrome registered in 28 European population-based congenital anomaly registries covering seven million births during 2000-2010. Overall, 43.6% (95% CI: 42.4-44.7%) of births with Down syndrome had a cardiac anomaly and 15.0% (14.2-15.8%) had a non-cardiac anomaly. Female babies with Down syndrome were significantly more likely to have a cardiac anomaly compared to male babies (47.6% compared with 40.4%, P

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.

OBJECTIVES: Polyunsaturated fatty acids (PUFA) are vital for optimal fetal neuronal development. This study examined the relationship between maternal alcohol consumption and smoking with plasma fatty acids measured in the third trimester and their association with Fetal Alcohol Spectrum Disorders (FASD). METHODS: In the parent study, moderate to heavy alcohol-using and low/unexposed comparison women were recruited during mid-pregnancy from two prenatal clinics in Ukraine. The participants’ live-born infants underwent physical and neurobehavioral exams prior to one-year of age. Infants were classified as having FASD if their mothers reported moderate to heavy alcohol consumption and the infant had at least one standardized score below 85 on the Bayley Scales of Infant Development II (BISD-II) with or without physical features of FASD. From the overall cohort, a subset of mother-child pairs was selected representing three groups of cases and controls: Alcohol-Exposed with FASD (n = 30), Alcohol-Exposed Normally Developing (n = 33), or low/unexposed Controls (n = 46). Third trimester maternal plasma samples were analyzed for fatty acids and levels were compared across groups. RESULTS: Plasma compositions of omega-6 fatty acids were altered in mothers with FASD infants compared to other groups. More specifically, the % of stearic acid (C18:0), arachidonic acid (AA, C20:4n6) and docosapentaenoic acid (DPAn6, C22:5n6) were significantly higher in mothers with FASD infants than low/unexposed controls or alcohol-exposed mothers with typically developing infants. Alcohol-exposed women who smoked had lower n3-docosapentaenoic acid (DPAn3, C22:5n3) and docosahexaenoic acid (DHA, C22:6n3) and higher DPAn6 than women consuming alcohol alone or abstainers. CONCLUSIONS: Alterations in fatty acid profiles were observed in moderate to heavy alcohol-consuming mothers with infants classified with FASD compared to alcohol-exposed typically developing infants or controls. These results support the idea that maternal fatty acid status can play a role in the etiology of FASD. FUNDING SOURCES: This research was funded by support from NIH Research Grant and conducted in conjunction with the Collaborative Initiative on Fetal Alcohol Spectrum Disorders(CIFASD).

BACKGROUND: Fetal alcohol spectrum disorders 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 2 regions of Ukraine during the recruitment phase of an ongoing clinical study that is part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders. Women attending a routine prenatal visit at 1 of 2 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 3 drinks on at least 1 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 3 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. Language: en

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.

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.

Maternal alcohol consumption during pregnancy and fetal alcohol spectrum disorders (FASDs) represent a significant public health problem. The influence of the male partner's alcohol consumption patterns and the quality of the partner's intimate relationship might be important factors to consider in the design of successful FASD prevention programs.As part of the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, 166 pregnant women in two regions in Ukraine participated in an in-person interview at an average gestational age of 18-19 weeks. Subjects were classified cross-sectionally as abstainers/light drinkers (n = 80), defined as low or no consumption of alcohol in the periconceptional period and none in the most recent 2 weeks of pregnancy; discontinuers (n = 43), defined as moderate to heavy alcohol use in the periconceptional period but none during the most recent 2 weeks of pregnancy; or continuing drinkers (n = 43), defined as continued moderate to heavy alcohol use within the most recent 2 weeks of pregnancy. Women also reported on their partner's drinking behavior and on the quality of their intimate relationship.Heavy paternal drinking was significantly associated with both continuing maternal drinking in the most recent 2 weeks (adjusted odds ratio [OR] = 34.1; 95% CI [5.9, 195.8]) and being a risky drinker only around conception (adjusted OR = 27.0; 95% CI [5.0, 147.7]). In addition, women who consumed alcohol during pregnancy had lower mean scores for satisfaction with partners' relationship and ability to discuss problems (p.05) compared with light drinkers/abstainers.This study suggests that development of partner-based interventions, as opposed to those solely focused on maternal drinking, might be warranted as a strategy to prevent FASD.

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.

Objectives The aim of this pilot study was to explore possible ultrasound parameters for the early detection of alcohol-mediated fetal somatic and central nervous system (CNS) maldevelopment. Maternal alcohol ingestion during pregnancy may lead to fetal alcohol spectrum disorders (FASD), which encompass a broad range of structural abnormalities including growth impairment, specific craniofacial features and CNS abnormalities. Early detection of fetuses at risk of FASD would support earlier interventions. Methods We performed a longitudinal prospective pilot study from 2004 to 2006 at two sites in Ukraine. A sample of pregnant women who reported consuming moderate-to-heavy amounts of alcohol participated in a comprehensive maternal interview, and received ultrasound evaluation of fetal growth and specific fetal brain measurements during the second and third trimesters. These measurements were compared with those collected from a group of pregnant women who consumed little-to-no alcohol during pregnancy, and who were recruited and followed in the same manner. Results From 6745 screened women, 84 moderate-to-heavy alcohol users and 82 comparison women were identified and ultrasound examinations performed. After controlling for maternal smoking, alcohol-exposed fetuses had shorter mean femur length, caval–calvarial distance and frontothalamic measurements in the second trimester (P < 0.05), and alcohol-exposed fetuses also had shorter frontothalamic distance measurements in the third trimester relative to comparison fetuses (P < 0.05). In addition, after controlling for maternal smoking, both mean orbital diameter and biparietal diameter measurements were significantly smaller on average in the alcohol-exposed group in the third trimester relative to comparison fetuses (P < 0.05). Conclusions Significant differences in selected somatic and brain measurements were noted between alcohol-exposed and comparison fetuses, suggesting these markers may be further explored for clinical utility in prenatal identification of affected children. Further study correlating these findings with alcohol-related physical features of the newborn and subsequent comparisons of neuro-developmental outcomes will help define potential uses of prenatal ultrasound for intervention and prevention of FASD. Copyright © 2009 ISUOG. Published by John Wiley & Sons, Ltd.

Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in Large 11001 of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), WERE evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated: (h) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes. 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardiovascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could he however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated, with,in older Maternal age more than isolated cases. On consideration of our Data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolted cases and a thorough case-by-case review. (c) 2007 Wiley-Liss, Inc.

BackgroundThis study describes seasonality of congenital anomalies in Europe to provide a baseline against which to assess the impact of specific time varying exposures such as the H1N1 pandemic influenza, and to provide a comprehensive and recent picture of seasonality and its possible relation to etiologic factors. Methods: Data on births conceived in 2000 to 2008 were extracted from 20 European Surveillance for Congenital Anomalies population-based congenital anomaly registries in 14 European countries. We performed Poisson regression analysis encompassing sine and cosine terms to investigate seasonality of 65,764 nonchromosomal and 12,682 chromosomal congenital anomalies covering 3.3 million births. Analysis was performed by estimated month of conception. Analyses were performed for 86 congenital anomaly subgroups, including a combined subgroup of congenital anomalies previously associated with influenza. Results: We detected statistically significant seasonality in prevalence of anomalies previously associated with influenza, but the conception peak was in June (2.4% excess). We also detected seasonality in congenital cataract (April conceptions, 27%), hip dislocation and/or dysplasia (April, 12%), congenital hydronephrosis (July, 12%), urinary defects (July, 5%), and situs inversus (December, 36%), but not for nonchromosomal anomalies combined, chromosomal anomalies combined, or other anomalies analyzed. Conclusion: We have confirmed previously described seasonality for congenital cataract and hip dislocation and/or dysplasia, and found seasonality for congenital hydronephrosis and situs inversus which have not previously been studied. We did not find evidence of seasonality for several anomalies which had previously been found to be seasonal. Influenza does not appear to be an important factor in the seasonality of congenital anomalies. Birth Defects Research (Part A) 100:260-269, 2014. (c) 2014 Wiley Periodicals, Inc.

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35 þ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7–22.4) for trisomy 21, 5.0 (95% CI 4.8–5.1) for trisomy 18 and 2.0 (95% CI 1.9–2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9–11.5) for trisomy 21, 1.04 (95% CI 0.96–1.12) for trisomy 18 and 0.48 (95% CI 0.43–0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence., peer-reviewed

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