Showing papers in "Birth defects research in 2021"

A 2019 global update on folic acid-preventable spina bifida and anencephaly.

Abstract: Background Mandatory folic acid fortification of staples is a proven intervention to prevent spina bifida and anencephaly, two life-threatening and disabling neural tube defects. We estimated the global proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented through mandatory folic acid fortification of wheat and/or maize flour in 2019. Methods Using data from the Global Fortification Data Exchange, we identified countries with mandatory fortification policies that required at least 1.0 ppm folic acid be added to wheat and/or maize flour and had information on percentage of industrially milled flour that is fortified. We built FAP SBA prevention models assuming mandatory folic acid fortification at 200 μg/day of folic acid fully protects against FAP SBA and would lower the prevalence neural tube defects to 0.5 per 1,000 live births. Results In 2019, 56 countries met our criteria for mandatory folic acid fortification of wheat (n = 56 countries) and/or maize (n = 15 countries) flour and with complete data for our modeling. Overall, our prevention model estimated that 65,380 FAP SBA cases were prevented in 2019 through folic acid fortification of wheat and/or maize flour. We estimated the current global prevention proportion of all preventable FAP SBA cases worldwide to be at 23% of total possible prevention. Conclusion Global prevention efforts for FAP SBA are slow and have stalled. Mandatory fortification should be urgently implemented in all countries to prevent epidemics of FAP SBA, and to achieve health-related Sustainable Development Goals for year 2030 by reducing child mortality due to preventable FAP SBA.

Disparities in insurance coverage among hospitalized adult congenital heart disease patients before and after the Affordable Care Act

Abstract: BACKGROUND Data are lacking regarding the insurance status of adults with congenital heart disease (ACHD). We investigated whether the Affordable Care Act (ACA) impacted insurance status among hospitalized ACHD, identified associated sociodemographic factors, and compared coverage to adults with other chronic childhood conditions. METHODS Serial cross-sectional analysis of National Inpatient Sample hospitalizations from 2007 to 2016 was performed for patients 18-64 years old. ACHD were identified using ICD-9/10-CM codes and compared to patients with sickle cell disease (SCD), cystic fibrosis (CF), and the general population. Age was dichotomized as 18-25 years (transition aged) or 26-64 years. Groups were compared by era (pre-ACA [January 2007-June 2010]; early-ACA [July 2010-December 2013], which eliminated pre-existing condition exclusions; and full-ACA [January 2014-December 2016]) using interrupted time series and multivariable Poisson regression analyses. RESULTS Overall, uninsured hospitalizations decreased from pre-ACA (12.0%) to full-ACA (8.5%). After full ACA implementation, ACHD had lower uninsured rates than the general hospitalized population (6.0 vs. 8.6%, p < .01), but higher rates than those with other chronic childhood diseases (SCD [4.5%]; CF [1.6%]). Across ACA eras, transition aged ACHD had higher uninsured rates than older patients (8.9 vs. 7.6%, p < .01), and Hispanic patients remained less insured than other groups. CONCLUSIONS Hospitalized ACHD were better insured than the general population but less insured than those with SCD or CF. Full ACA implementation was associated with improved insurance coverage for all groups, but disparities persisted for transition aged and Hispanic patients. Ongoing evaluation of the effects of insurance and health policy on ACHD remains critical to diminish health disparities.

Prenatal alcohol exposure induced congenital heart diseases: From bench to bedside

Abstract: Alcohol consumption is increasing worldwide Many child-bearing-aged women consume alcohol during pregnancy, intentionally or unintentionally, thereby increasing the potential risk for severe congenital diseases Congenital heart disease (CHD) is the most common birth defect worldwide and can result from both hereditary and acquired factors Prenatal alcohol exposure (PAE) is considered a key factor that leads to teratogenesis in CHD and its specific phenotypes, especially defects of the cardiac septa, cardiac valves, cardiac canals, and great arteries, adjacent to the chambers, both in animal experiments and clinical retrospective studies The mechanisms underlying CHD and its phenotypes caused by PAE are associated with changes in retinoic acid biosynthesis and its signaling pathway, apoptosis and defective function of cardiac neural crest cells, disturbance of the Wntβ-catenin signaling pathway, suppression of bone morphogenetic protein (BMP) signaling, and other epigenetic mechanisms Drug supplements and early diagnosis can help prevent PAE from inducing CHDs

An exercise program throughout pregnancy: Barakat model.

Abstract: The physiologic processes of pregnancy and childbirth can determine the future well-being of mothers and children due to the great quantity and quality of modifications that these processes require in all areas of the female body and fetus. Recent evidence has confirmed that modern unhealthy lifestyles negatively affect pregnancy outcomes. Engaging in unhealthy habits during pregnancy increases the risk of chronic disease in both the mother and the fetus. Regarding physical exercise during pregnancy, throughout history, many professionals and scientists have reported the best gestational conditions for the mother, fetus, and newborn. The perspectives and advice have changed over time, including periods of strong conservatism. This history has affected the recommendations for the type and amount of exercise that a healthy woman should perform during pregnancy. The aim of this article is to determine the basic aspects that physical exercise programs during pregnancy should define in the near future. Additionally, from the results of this article, we propose an exercise program model that includes many exercises spanning throughout pregnancy (3 blocks = until 20 weeks, until 30 weeks and until the end of the pregnancy). An exercise session model divided into seven parts and recommendations of operative position to exercise during pregnancy are also provided.

Projected impact of mandatory food fortification with folic acid on neurosurgical capacity needed for treating spina bifida in Ethiopia.

Abstract: Spina bifida, also known as meningomyelocele, is a major birth defect mostly associated with folate deficiency in the mother early in pregnancy. The prevalence of spina bifida is disproportionately high in Ethiopia compared to the global average; about 10,500 liveborn are affected annually. Many affected infants do not receive timely repair surgery. There are a high number of stillbirths, and neonatal, infant, and under-five deaths. Mandatory fortification of staple foods such as wheat and maize flour with folic acid, a B vitamin, is an effective primary prevention strategy for spina bifida. Survival in those with spina bifida increases if neurosurgical intervention is available soon after birth, along with continuous surgical and clinical aftercare throughout the lifespan. Currently, Ethiopia does not have mandatory food fortification for primary prevention or adequate neurosurgical capacity to meet the need to prevent adverse outcomes associated with spina bifida. We present in this paper two concurrent and complementary policy and practice solutions occurring in Ethiopia through global partnerships: (1) capacity-building of neurosurgery care through training programs; and (2) promoting national mandatory folic acid fortification of staples for primary prevention of spina bifida. These two policy and practice interventions ensure all affected infants can receive timely pediatric neurosurgery and sustained surgical aftercare through required neurosurgeon availability, and ensure primary prevention of spina bifida. Primary prevention of spina bifida frees up significant neurosurgical capacity in resource-poor settings that can then be directed to other critical neurosurgical needs thus lowering child mortality and morbidity.

Identifying environmental risk factors and gene-environment interactions in holoprosencephaly.

Abstract: BACKGROUND Holoprosencephaly is the most common malformation of the forebrain (1 in 250 embryos) with severe consequences for fetal and child development. This study evaluates nongenetic factors associated with holoprosencephaly risk, severity, and gene-environment interactions. METHODS For this retrospective case control study, we developed an online questionnaire focusing on exposures to common and rare toxins/toxicants before and during pregnancy, nutritional factors, maternal health history, and demographic factors. Patients with holoprosencephaly were primarily ascertained from our ongoing genetic and clinical studies of holoprosencephaly. Controls included children with Williams-Beuren syndrome (WBS) ascertained through online advertisements in a WBD support group and fliers. RESULTS Difference in odds of exposures between cases and controls as well as within cases with varying holoprosencephaly severity were studied. Cases included children born with holoprosencephaly (n = 92) and the control group consisted of children with WBS (n = 56). Pregnancy associated risk associated with holoprosencephaly included maternal pregestational diabetes (9.2% of cases and 0 controls, p = .02), higher alcohol consumption (adjusted odds ratio [aOR], 1.73; 95% CI, 0.88-15.71), and exposure to consumer products such as aerosols or sprays including hair sprays (aOR, 2.46; 95% CI, 0.89-7.19). Significant gene-environment interactions were identified including for consumption of cheese (p < .05) and espresso drinks (p = .03). CONCLUSION The study identifies modifiable risk factors and gene-environment interactions that should be considered in future prevention of holoprosencephaly. Studies with larger HPE cohorts will be needed to confirm these findings.

Examination of cortically projecting cholinergic neurons following exercise and environmental intervention in a rodent model of fetal alcohol spectrum disorders.

Abstract: Background Up to 1 in 5 infants in the United States are exposed to alcohol prenatally, resulting in neurodevelopmental deficits categorized as fetal alcohol spectrum disorders (FASD). Choline supplementation ameliorates some deficits, suggesting that alcohol exposure (AE) perturbs cholinergic neurotransmission and development. Behavioral interventions, which upregulate cholinergic neurotransmission, rescue cognitive deficits in rodent models of FASD. Methods We investigated the impacts of two interventions (either wheel-running (WR) or "super intervention," WR plus exposure to a complex environment) on cholinergic neuronal morphology in the nucleus basalis of Meynert (NBM), the source of cortical cholinergic input, and prefrontal cortex (PFC) in a rodent model of FASD. One third of the total 47 male pups received intragastric intubation of ethanol in milk substitute during postnatal days (PD) 4-9. Another third served as sham-intubated procedural controls while the final third served as suckle controls. Rats from each group were exposed to either intervention during PD 30-72. Choline acetyltransferase (ChAT+ ) and acetylcholinesterase staining were used to quantify cholinergic neuron number, soma volume, and axon number. Results Our data indicate a main effect of postnatal treatment on ChAT+ neuron number in NBM in adulthood. Post hoc analysis demonstrates that ChAT+ neuron number is reduced in AE compared to suckle control rodents (p Conclusions We examined the cytoarchitectonics of cholinergic neurons in NBM and PFC in adulthood following early postnatal AE and two interventions. We show that AE reduces ChAT+ neuron number in NBM, and this is not mitigated by either intervention.

Maternal-fetal outcomes of exercise applied in rats with mild hyperglycemia after embryonic implantation.

Abstract: Background Exercise is commonly recommended to control hyperglycemia, including during pregnancy. We conducted this study to understand the potential benefits and risks of exercise during pregnancy of women with diabetes. Specifically, we evaluated the effects of swimming on a diabetic rat during pregnancy and assayed maternal-fetal parameters. Methods Diabetes was induced in the female newborn from Wistar rats by the streptozotocin administration on first postnatal day. At 110 days of life, after confirm mild symptoms of diabetes, the rats were mated and randomly distributed into four experimental groups (minimum of 13 animals/group): Control (C)-nondiabetic animals without swimming; Control and Exercise (CEx)-nondiabetic animals submitted to swimming; Mild Diabetic (MD)-diabetic animals without swimming; Mild Diabetic and Exercise (MDEx)-diabetic animals submitted to swimming. The swimming program was performed from day 7 to 21 of pregnancy. Maternal parameters were evaluated during the pregnancy period. On day 21 of pregnancy, the rats were sacrificed and maternal and fetal parameters analyzed. Results There are no alterations in body weight, food consumption, water intake, and reproductive outcomes among the groups. The swimming program did not normalize maternal glycemia and other biochemical biomarkers. The diabetes and exercise combination increased organ weight. The fetuses born to these exercising diabetic rats had reduced fetal weight and increased skeletal anomalies (mainly incomplete ossification of sternebra). Conclusion The intense swimming exercise imposed on female rats during pregnancy impaired maternal metabolic repercussions, contributing to intrauterine growth restriction and fetal skeletal anomalies.

Associations between cumulative environmental quality and ten selected birth defects in Texas.

Abstract: Background Causes of most birth defects are largely unknown. Genetics, maternal factors (e.g., age, smoking) and environmental exposures have all been linked to some birth defects, including neural tube, oral cleft, limb reduction, and gastroschisis; however, the contribution of cumulative exposures across several environmental domains in association with these defects is not well understood. Methods The Environmental Quality Index (EQI) and its domains (air, water, land, sociodemographic, built) were used to estimate county-level cumulative environmental exposures from 2006-2010 and matched to birth defects identified from Texas Birth Defects Registry and live birth records from births in years 2007-2010 (N = 1,610,709). Poisson regression models estimated prevalence ratios (PR) and 95% confidence intervals (CI) for associations between 10 birth defects and the EQI. Results We observed some positive associations between worst environmental quality and neural tube, anencephaly, spina bifida, oral cleft, cleft palate, cleft lip with and without cleft palate, and gastroschisis [PR range: 1.12-1.55], but near null associations with limb reduction defects. Among domain specific results, we observed the strongest positive associations with the sociodemographic domain across birth defects but varied positive associations among the air and water domains, and negative or null associations with the land and built domains. Overall, few exposure-response patterns were evident. Conclusions Our results highlight the complexities of cumulative, simultaneous environmental exposures in the prevalence rates of 10 selected birth defects. We were able to explore the impact of overall and domain specific environmental quality on birth defects and identify potential domain specific drivers of these associations.

A life‐table analysis of the intrauterine fate of malformed human embryos and fetuses

Abstract: Background Various malformations are frequently encountered in spontaneously aborted embryos and fetuses. Thus, spontaneous abortion appears to be a screening device for abnormal conceptuses ("teratothanasia"). However, the prevalence rate of abnormal conceptuses at each gestational stage is unknown and the true picture of prenatal natural selection remains to be elucidated. Methods An in utero life-table of normal and malformed human conceptuses was constructed utilizing the data for human embryos and fetuses procured after therapeutic abortion and kept in the Kyoto Collection of Human Embryos (N = 21,798). Results The prevalence of external major malformations was estimated to be 9.6% at the start of the fifth week after fertilization and drop to 9.2, 8.5, and 7.5% during the following weeks. The malformation rate decreased to 5.3% by the end of the embryonic period (the eighth week), 2.8% by the 13th week and 1% at term. The prenatal mortality rate of externally malformed conceptuses between the fifth week of gestation and term was 92.8%, whereas the corresponding rate for externally normal embryos was 24.9%. The prenatal mortality rates of embryos with neural tube defects and holoprosencephaly were 96.0 and 99.7%, respectively. Conclusions Abnormal development occurs frequently early in development and many of the malformed embryos/fetuses die in utero to end in spontaneous abortion. Natural prenatal screening of abnormal conceptuses most likely contributes to reducing the birth of malformed infants.

Cardiopulmonary exercise testing during pregnancy.

Abstract: The goal of this review is to examine practical considerations when conducting cardiopulmonary exercise testing during pregnancy. In a clinical and research setting, cardiopulmonary exercise testing during pregnancy is valuable in identifying underlying cardiopulmonary conditions, stratifying the risk of adverse pregnancy outcomes, as well as establishing exercise tolerance/limitations. This review encompasses information regarding the unique physiological adaptations that occur throughout gestation (e.g., changes in resting heart rate, blood pressure, glucose, etc.) and how these adaptations impact the interpretation of physiological measurements. There are also key concerns that are unique to pregnant populations that should be considered when participating in exercise (i.e., fetus, ventilation, thermoregulation, urinary incontinence, low back pain, and pelvic girdle pain). This step-by-step review of cardiopulmonary exercise testing outlines pregnancy related adjustments to standardized methods (i.e., screening/documentation, pre- and post-test measurements, protocol specifics, modality selection, and fetal monitoring) which should be considered for the safety of both the participant and fetus. Currently, pregnancy specific exercise testing guidelines are lacking. Therefore, we will be discussing the limitations of current recommendations such as a safe cut off for resting heart rate and pregnancy specific test termination criteria.

Prenatal exposure to atrazine induces cryptorchidism and hypospadias in F1 male mouse offspring.

Abstract: The main objective of the present study was to determine whether prenatal exposure to atrazine could affect testicle descent and penile masculinization. Atrazine has been demonstrated with a variety of endocrine disrupting activities and reproductive toxicities. However, the effects of prenatal atrazine exposure on male offspring's genital malformation, such as hypospadias and cryptorchidism, remain poorly understood. In this study, pregnant ICR mice were gavaged from gestational day 12.5-16.5 with different doses of atrazine. Although no sign of systemic toxicity was observed in F1 male pups, prenatal exposure to 100 mg/kg/day atrazine affected penile morphology, urethral meatus position and descent of testis, and reduced anogenital distance and penile size in postnatal day 21 F1 male pups. The comparative study with an androgen receptor (AR) antagonist vinclozolin suggested that these effects of atrazine on male genital development may not be through antagonism of AR. The results also revealed that atrazine exposure significantly reduced maternal serum testosterone levels, decreased AR nuclear translocation, and altered the expression levels of developmental gene networks in developing penis of mice. Atrazine exposure also affected the expression of insulin-like 3 (Insl3) and steroidogenic gene expression in developing reproductive tract. Therefore, our data indicate that prenatal atrazine exposure can induce hypospadias in F1 mice, likely through disruption of testosterone production, decreasing genomic androgen action, and then altering expression of developmental genes during sexual differentiation. Our data also suggest that prenatal atrazine exposure can induce cryptorchidism in F1 mice, possibly through down regulation of Insl3.

Zika virus‐induced brain malformations in chicken embryos

Abstract: Background Zika virus (ZIKV) was confirmed to be related to microcephaly in 2016. However, there is still a need for understanding the embryonic morphological changes induced by ZIKV and when they occur. Here, chicken embryos were chosen as experimental model of ZIKV to evaluate virus-associated morphological alterations that might take place during embryonic development. Methods A screening with different viral doses was conducted in embryos at HH Stage 10-12 (E1.5) as well as a follow up of the first 5 days postinfection (dpi) was performed to observe the main morphologic changes post ZIKV infection. Results ZIKV exposed embryos presented a higher prevalence of mortality and defects such as brain malformation when compared to controls. Moreover, we observed that the phenotypes become more evident at 4dpi, when the viral load quantification reaches a peak. Conclusions We found that ZIKV exposed embryos presented a high prevalence of mortality and central nervous system (CNS) abnormalities in a dose-dependent manner. The phenotype was more evident 4 days postinfection, when the viral load quantification reached a peak.

European trends in mortality in children with congenital anomalies: 2000-2015.

Abstract: OBJECTIVE To investigate if the survival of children with congenital anomalies has improved from 2000 to 2015 and whether there is heterogeneity in the improvements across Europe. DESIGN Population-based study of routine collected data from the WHO database on mortality and causes. SETTING Data on 31 European countries from 2000 to 2015. MAIN OUTCOME MEASURES All-cause and congenital anomaly mortality rates for infants and children up to age 9 in countries and regions of Europe. RESULTS The relative odds of all-cause mortality in 2015 compared with 2000 was 0.54 (95% CI: 0.50-0.59) for under 1, 0.48 (95% CI: 0.44-0.53) for ages 1-4, and 0.53 (95% CI: 0.49-0.56) for ages 5-9 with the relative odds of mortality from congenital anomalies being 0.49 (95% CI: 0.44-0.55), 0.51 (95% CI: 0.44-0.60), and 0.65 (95% CI: 0.53-0.80), respectively. The proportion of deaths from congenital anomalies remained relatively constant over time (26, 16, and 9% for under 1, ages 1-4, and ages 5-9, respectively) and was similar in all regions of Europe. For mortality from all causes and from congenital anomalies heterogeneity between countries and regions of Europe was high, with the countries in Eastern Europe having higher rates, but also experiencing greater relative reductions in mortality from 2000 to 2015. CONCLUSION There was a large geo-spatial disparity in all cause and congenital anomaly mortality for infants and children up to 9. However, all regions saw a significant decrease in all cause and congenital anomaly mortality rates, with the proportions of deaths from congenital anomalies remaining constant over this time.

Risk factors and time trends for isolated craniosynostosis.

Abstract: Background We sought to investigate associations between maternal/infant characteristics and isolated craniosynostosis as well as its subtypes sagittal, metopic, and coronal synostosis, and assess trends in the prevalence of these conditions. Methods We identified cases in the Texas Birth Defects Registry from 1999 to 2014. We used Poisson regression to identify associations between maternal/infant characteristics and craniosynostosis. We used joinpoint regression and unadjusted Poisson regression to evaluate temporal trends. Finally, we computed adjusted Poisson models to evaluate whether temporal trends were evident after accounting for changes in the population distributions of maternal/infant characteristics over time. Results Relative to all live births in the general population, cases were more frequently male or preterm. Mothers of cases were more frequently non-Hispanic white and more frequently obese. Non-Hispanic black or Hispanic maternal race/ethnicity was associated with a lower prevalence of all craniosynostosis subtypes. Previous live births were associated with sagittal synostosis; residence on the U.S.-Mexico border was associated with sagittal and coronal synostosis. The prevalence of any isolated craniosynostosis increased (average annual percent change estimated from joinpoint regression [AAPC]: 2.9%), as did the prevalences of sagittal (AAPC: 3.3%) and metopic synostosis (AAPC: 5.4%). In crude Poisson models, the same temporal trends were observed, however these were attenuated after adjusting for maternal/infant characteristics. Conclusions Prevalence of isolated craniosynostosis increased from 1999 to 2014. The largest AAPC was observed for metopic synostosis. Changes in the population distribution of associated maternal/infant characteristics may explain these trends.

Maternal biomarkers for early prediction of the neural tube defects pregnancies

Abstract: BACKGROUND Neural tube defects (NTD) are one of the most common congenital birth defects. The reason for the NTD cause is still not completely known, but it is believed that some genetic and environmental factors might play a role in its etiology. Among the genetic factors the polymorphism in the folate gene pathway is crucial. Numerous studies have suggested the possible role of maternal higher plasma concentration of homocysteine and low concentration of folate and cobalamin in the development of NTD but some negative studies are also published. AIM Aim of the present was to find out the exact relation between NTD and maternal biomarkers like folate, cobalamin and homocysteine by conducting a meta-analysis. METHOD Different electronic databases were searched for the eligible studies. Standardized mean difference (SMD) with 95% confidence interval (CI) was used to determine association between maternal markers as risk for NTD pregnancy. The p value <0.05 was considered statistically significant in all tests. All the statistical analyses were done in the Open Meta-Analyst program. RESULTS The homocysteine is significantly associated with the increased risk of NTD (SMD = 0.57; 95% CI: 0.35-0.80, p = <0.001; I2 = 93.01%), s-folate showed protective role in NTD (SMD = -0.48; 95% CI: -0.77 to -0.19, p = 0.001; I2 = 95.73%), similarly cobalamin is also having protective role (SMD = -0.28; 95% CI: -0.43 to -0.13, p = <0.001; I2 = 80.40%). CONCLUSION In conclusion this study suggest that different maternal biomarkers may be used for the early prediction of the NTDs.

Exposures influencing the developing central autonomic nervous system.

Abstract: Autonomic nervous system function is critical for transition from in-utero to ex-utero life and is associated with neurodevelopmental and neuropsychiatric outcomes later in life. Adverse prenatal and neonatal conditions and exposures can impair or alter ANS development and, as a result, may also impact long-term neurodevelopmental outcomes. The objective of this article is to provide a broad overview of the impact of factors that are known to influence autonomic development during the fetal and early neonatal period, including maternal mood and stress during and after pregnancy, fetal growth restriction, congenital heart disease, toxic exposures, and preterm birth. We touch briefly on the typical development of the ANS, then delve into both in-utero and ex-utero maternal and fetal factors that may impact developmental trajectory of the ANS and, thus, have implications in transition and in long-term developmental outcomes. While many types of exposures and conditions have been shown to impact development of the autonomic nervous system, there is still much to be learned about the mechanisms underlying these influences. In the future, more advanced neuromonitoring tools will be required to better understand autonomic development and its influence on long-term neurodevelopmental and neuropsychological function, especially during the fetal period.

Gene-environment interactions between air pollution and biotransformation enzymes and risk of birth defects.

Abstract: Genetic and environmental factors have been observed to influence risks for birth defects, though few studies have investigated gene-environment interactions. Our aim was to examine the interaction terms of gene variants in biotransformation enzyme pathways and air pollution exposures in relation to risk of several structural birth defects. We evaluated the role of ambient air pollutant exposure (nitrogen dioxide [NO2 ], nitrogen oxide, carbon monoxide, particulate matter <10 [PM10 ] and <2.5 [PM2.5 ] microns) during pregnancy and 104 gene variants of biotransformation enzymes from infant bloodspots or buccal cells in a California population-based case-control study in 1997-2006. Cases included cleft lip with or without cleft palate (N = 206), gastroschisis (N = 94), tetralogy of Fallot (N = 69), and dextro-transposition of the great arteries (d-TGA; N = 40) and were compared to 208 nonmalformed controls. Overall, the results were not consistent, though did highlight some associations for further investigation as indicated by Wald chi-square test p value <.1. Increased risk of cleft lip was associated with exposure to high PM10 and two CYP gene variants. High PM2.5 and the variant of SLCO1B1 was associated with increased risk of teratology of Fallot. Higher NO2 and two gene variants, CYP2A6 and SLC01B1, were associated with increased risk of d-TGA. Results for gastroschisis were inconsistent in direction and across pollutants. These exploratory results suggest that some individuals based on their genetic background may be more susceptible to the adverse effects of air pollution.

Prenatal developmental toxicity of alkyl dimethyl benzyl ammonium chloride and didecyl dimethyl ammonium chloride in CD rats and New Zealand White rabbits.

Abstract: The prenatal developmental toxicity potential of alkyl dimethyl benzyl ammonium chloride (ADBAC) and didecyl dimethyl ammonium chloride (DDAC) was evaluated in regulatory-compliant studies. Pregnant female CD rats (25/group) and New Zealand White rabbits (16/group) were administered ADBAC (0, 10, 30, or 100 mg/kg/day and 0, 1, 3, or 9 mg/kg/day, respectively), or DDAC (0, 1, 10, or 20 mg/kg/day and 0, 1, 3, or 10 mg/kg/day, respectively), by oral gavage on gestation days (GD) 6-15 for rats and GD 6-18 for rabbits. At scheduled termination (GD 21 for rats; GD 29 for rabbits), maternal necropsies were conducted and live fetuses were weighed and examined for external, visceral, and skeletal malformations and variations. Clinical signs of maternal toxicity were observed in rats and rabbits dosed with ADBAC, resulting in no-observed-adverse-effect levels (NOAELs) of 10 and 3 mg/kg/day, respectively. Despite the treatment-related maternal toxicity of ADBAC, the NOAEL for prenatal developmental toxicity was 100 and 9 mg/kg/day for rats and rabbits, respectively, the highest doses evaluated. Repeated oral doses of DDAC resulted in maternal toxicity in both species at the top two doses, with 25% mortality noted in rabbits at 10 mg/kg/day. No teratogenic effects were observed at any dose for either species. However, increased incidence of dead fetuses per litter and decreased fetal body weights were observed in rabbits at the maternally lethal dose of 10 mg/kg/day. The NOAEL for maternal toxicity of DDAC was 1 mg/kg/day for both species and the NOAEL for prenatal developmental toxicity was 20 and 3 mg/kg/day, for rats and rabbits, respectively.

Academic achievement and needs of school-aged children born with selected congenital anomalies: A systematic review and meta-analysis.

Abstract: Children with congenital anomalies have poorer intellectual and cognitive development compared to their peers, but evidence for academic achievement using objective measures is lacking. We aimed to summarize and synthesize evidence on academic outcomes and special education needs (SEN) of school-aged children born with selected major structural congenital anomalies. Electronic databases (MEDLINE, EMBASE, Scopus, PsycINFO, CINAHL, ProQuest Natural Science and Education Collections), reference lists and citations for 1990-2020 were systematically searched. We included original-research articles on academic achievement in children with non-syndromic congenital anomalies that involved school test results, standardized tests and/or SEN data. Random-effects meta-analyses were performed to estimate pooled mean test scores in mathematics and/or reading where possible and pooled odds ratios (ORs) for SEN in children with severe congenital heart defects (CHDs) and children with orofacial clefts (OFCs). Thirty-nine eligible studies (n = 21,066 children) were synthesized narratively. Sixteen studies were included in meta-analyses. Children with non-syndromic congenital anomalies were at a higher risk of academic underachievement than controls across school levels. Children with severe CHD (pooled OR = 2.32, 95% CI: 1.90, 2.82), and children with OFC (OR = 1.38 (95% CI: 1.20, 1.57), OR = 3.07 (95% CI: 2.65, 3.56), and OR = 3.96 (95% CI: 3.31, 4.72) for children with cleft lip, cleft palate and cleft lip/palate, respectively) had significantly higher ORs for SEN than controls. Children with non-syndromic congenital anomalies underperform academically and have higher SEN rates compared to their peers. Early monitoring and development of differential SEN are important to promote academic progress in these children.

Maternotoxicity and fetotoxicity in Rattus norvegicus albinus exposed to tramadol during the late phase of pregnancy.

Abstract: OBJECTIVES Tramadol, an atypical opioid, is clinically efficacious in treating moderate to severe pain. The aim of current study was to find out the toxicological effects of tramadol exposure to pregnant rats and fetuses during the late phase of pregnancy. METHODS Wistar pregnant rats were exposed to 1.25, 2.5, or 5 mg/kg/day tramadol from 14th to 20th day of pregnancy. The same therapy was given to nonpregnant rats for 7 days. The body weight, oral glucose and lipid tolerance tests, and effect on complete blood parameters in both pregnant and nonpregnant rats were determined. On 20th day, maternal placentas were excised and weighed while fetuses were observed for any deformity and growth retardation. Oxidative stress biomarkers were estimated in the liver and kidney tissue homogenates of the pregnant and nonpregnant rats while the whole fetus homogenate was processed for the same. Moreover, histopathology of the liver and kidney of pregnant and nonpregnant rats were carried out. RESULTS Tramadol administration did not significantly alter the area under curve of the blood glucose and triglyceride levels in both the pregnant and nonpregnant rats. It reduced the live fetuses, placental weights, fetal length, and fetal weights. Tramadol treated pregnant rats showed significantly (p < .05) reduced red blood cells, hematocrit, hemoglobin, and platelets with reference to control group. Similarly, structural abnormalities and malfunctioning of the liver and kidney of pregnant rats were instituted; however, it did not affect the structural integrity of nonpregnant rats. A substantial (p < .001-.0001) altered glutathione and malondialdehyde levels in the fetuses, pregnant, and nonpregnant animals (tissue homogenates) at all dosage levels were indicative of tramadol induced oxidative stress. Furthermore, tramadol exposure resulted in more significant (p < .01-.001) alteration of lipid profile in the pregnant than the nonpregnant animals. CONCLUSION Acquired results suggested the maternotoxic and fetotoxic effects of tramadol exposure during the late gestation period.

Prevalence of structural birth defects among infants with Down syndrome, 2013-2017: A US population-based study.

Abstract: BACKGROUND Down syndrome is the most common chromosomal disorder at birth and is often accompanied by structural birth defects. Current data on major structural defects in this population are limited. METHODS States and territorial population-based surveillance programs submitted data on identified cases of Down syndrome and identified structural birth defects during 2013-2017. We estimated prevalence by program type and maternal and infant characteristics. Among programs with active case ascertainment, we estimated the prevalence of birth defects by organ system and for specific defects by maternal age (<35, ≥35) and infant sex. RESULTS We identified 13,376 cases of Down syndrome. Prevalence among all programs was 12.7 per 10,000 live births. Among these children, 75% had at least one reported co-occurring birth defect diagnosis code. Among 6,210 cases identified by active programs, 66% had a cardiovascular defect with septal defects being the most common: atrial (32.5%), ventricular (20.6%), and atrioventricular (17.4%). Defect prevalence differed by infant sex more frequently than by maternal age. For example, atrioventricular septal defects were more common in female children (20.1% vs. 15.1%) while limb deficiencies were more prevalent in male children (0.4% vs. 0.1%). CONCLUSIONS Our study provides updated prevalence estimates for structural defects, including rare defects, among children with Down syndrome using one of the largest and most recent cohorts to date. These data may aid clinical care and surveillance.

No developmental toxicity observed with dolutegravir in rat whole embryo culture

Abstract: Background An in vitro rat whole embryo culture study investigated whether direct exposure to dolutegravir (TivicayTM ) during the critical period for neural tube development would result in abnormal development. Methods Dolutegravir (DTG), and HIV integrase inhibitor, was administered at 0 (vehicle), 5.3 μg/mL and 9.3 μg/mL on Gestation Day (GD) 9 through 11 (approximate 40 hour exposure period) along with positive (Valproic Acid) and negative (Penicillin G) controls. The DTG concentrations tested were selected based on clinical exposure at the maximum human recommended dose and maximum feasible concentration that could be formulated under the experimental conditions. Results Approximately 6% of DTG present in the culture media was absorbed into the embryos, demonstrating embryonic exposure at a similar level to that observed in a rat DTG placental transfer study. There was no effect in either the DTG or Penicillin G groups on visceral yolk sac size/morphology, embryo size, somite number and embryo morphology at any concentration tested. Valproic Acid, by contrast, produced statistically significant decreases in visceral yolk sac size, embryo size and somite number along with defects in visceral yolk sac and embryonic morphology, including neural tube defects (NTDs), in all embryos. Conclusion DTG at the maximum human recommended dose administered to rats in a whole embryo culture assay did not produce any abnormal effects, while the positive control Valproic Acid produced abnormal effects, including neural tube defects.

Inpatient admissions and costs for adolescents and young adults with congenital heart defects in New York, 2009-2013.

Abstract: OBJECTIVES Most individuals born with congenital heart defects (CHDs) survive to adulthood, but healthcare utilization patterns for adolescents and adults with CHDs have not been well described. We sought to characterize the healthcare utilization patterns and associated costs for adolescents and young adults with CHDs. METHODS We examined 2009-2013 New York State inpatient admissions of individuals ages 11-30 years with ≥1 CHD diagnosis codes recorded during any admission. We conducted multivariate linear regression using generalized estimating equations to examine associations between inpatient costs and sociodemographic and clinical variables. RESULTS We identified 5,100 unique individuals with 9,593 corresponding hospitalizations over the study period. Median inpatient cost and length of stay (LOS) were $10,720 and 3.0 days per admission, respectively; 55.1% were emergency admissions. Admission volume increased 48.7% from 2009 (1,538 admissions) to 2013 (2,287 admissions), while total inpatient costs increased 91.8% from 2009 ($27.2 million) to 2013 ($52.2 million). Inpatient admissions and costs rose more sharply over the study period for those with nonsevere CHDs compared to severe CHDs. Characteristics associated with higher costs were longer LOS, severe CHD, cardiac/vascular hospitalization classification, surgical procedures, greater severity of illness, and admission in New York City. CONCLUSION This study provides an informative baseline of health care utilization patterns and associated costs among adolescents and young adults with CHDs in New York State. Structured transition programs may aid in keeping this population in appropriate cardiac care as they move to adulthood.

Melatonin inhibits embryonic rat H9c2 cells growth through induction of apoptosis and cell cycle arrest via PI3K-AKT signaling pathway.

Abstract: Background Our recent epidemiological study revealed that maternal sleep during the periconceptional period should be involved in the risk of congenital heart disease (CHD) in offspring. Melatonin, a sleep related hormone, has been suggested to play a crucial role in embryonic development based on the emerging evidence. In this study, we set out to assess the effect of melatonin on the embryonic cardiac cell growth and to explore the underlying mechanisms. Methods We observed the effect of different gradient doses of melatonin as 10, 100, or 1,000 μM on cell proliferation in H9c2 embryonic rat cardiac cells. Furthermore, flow cytometry was applied to evaluate the impact on apoptosis and cell cycle. RNA-seq was conducted to screen the changes in expression of mRNA and signaling pathways. Quantitative Real-Time-PCR (qRT-PCR) was then conducted to validate the results. Results It was observed that melatonin could inhibit H9c2 cell growth, at the doses of 100 and 1,000 μM, but not at 10 μM. Moreover, melatonin ranged from 100 to 1,000 μM could instigate cell cycle arrest at G1 phase and simulate apoptosis, in a dose-dependent manner. In addition, melatonin was found to down-regulate the expression of a number of genes, which are related to heart development (SPARC, IFITM3, TNNT2, LOX), and PI3K-Akt signaling pathway activation (FN1, HSP90B1, THBS1, MFGE8, and CLU). Conclusions Our findings suggested that high level of melatonin could be capable of inhibiting growth through the induction of apoptosis and cell cycle arrest via PI3K-AKT signaling pathway, thereby interfering with embryonic heart development. Considering this study is based on H9c2 embryonic rat cardiac cells, future additional studies using human embryonic cardiac cell are warranted.

Survival of infants born with esophageal atresia among 24 international birth defects surveillance programs

Abstract: 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. (Less)

Maternal ethnicity and the prevalence of British pregnancies affected by neural tube defects

Abstract: Background Few data are available on the prevalence of neural tube defects (NTDs) within different ethnic communities of the United Kingdom. This study aimed to calculate prevalence estimates for NTD-affected pregnancies, classified by maternal ethnicity, and to explore why variations in prevalence might exist. Methods A cross-sectional study was performed with data from regional congenital anomaly registers in England and Wales, for NTD-affected pregnancies between 2006 and 2011. Using binomial regression models, we examined NTD-affected pregnancy prevalence estimates and rate ratios (PRRs), by maternal ethnicity. Results The prevalence of NTDs was 12.14 per 10,000 births, with no differences between study years. Anencephaly, encephalocele and spina bifida occurred at 4.98, 1.37 and 5.80 per 10,000 births respectively. Mothers of Indian ethnicity were 1.84 times more likely (95% CI: 1.24, 2.73) and Bangladeshi mothers 2.86 times more likely (95% CI: 1.48, 5.53) than White mothers to have an NTD-affected pregnancy, after adjusting for maternal deprivation and maternal age. The excess prevalence in Indian mothers was specifically for anencephaly (PRR 2.57; 95% CI: 1.52, 4.34), and in Bangladeshi mothers the trend was for increased spina bifida (PRR 3.86; 95% CI: 0.72, 8.69). Anencephaly in Indian mothers was especially associated with other congenital anomalies (non-isolated NTDs). Conclusions Different British ethnic groups vary in NTD prevalence. The excess prevalence of anencephaly as a non-isolated NTD in pregnancies of Indian mothers could indicate involvement of genetic or other unmeasured behavioral factors. Future work is needed to seek etiological explanations for the ethnicity differences and to develop improved methods for primary prevention.

The accuracy of hospital discharge data in recording major congenital anomalies in Australia.

Abstract: BACKGROUND There has been increasing use of hospital discharge data to identify congenital anomalies, with limited information about the accuracy of these data. OBJECTIVES To evaluate the accuracy of hospital discharge data in ascertaining major congenital anomalies in infants. METHODS All liveborn infants with major congenital anomalies born between 2004 and 2009 in New South Wales, Australia were included. They were separated into two study groups: (a) infants identified from the Register of Congenital Conditions with a corresponding record in linked hospital discharge data; and (b) infants with a recorded congenital anomaly in hospital data, but without a register record. For the first group, we assessed agreement (concordant diagnoses) and the proportion of anomalies with discrepant diagnoses in each dataset. For the second group, we determined the number of anomalies recorded only in hospital data and applied specific conditions restricting to those recorded in the birth admission, excluding nonspecific diagnoses, or those with relevant surgical procedures to minimize potential false positives or over-reporting. RESULTS The first study group included 9,346 infants with an average 84% agreement in the ascertainment of major anomalies between hospital and registry data, and >93% agreement for cardiac, abdominal wall, and gastrointestinal anomalies. Discrepant diagnoses occurred on average in 20% of cases from hospital data and 17% from registry data, and were slightly reduced with the use of diagnoses recorded only in tertiary pediatric hospitals. The second group included 25,893 infants where anomalies were only recorded in hospital data, most commonly skin and unspecified anomalies. Excluding unspecified cases, those only diagnosed at the birth admission and restricting to surgical procedures reduced over-reporting by up to 96%. CONCLUSIONS Hospital discharge data provide an acceptable means to ascertain congenital anomalies, but with variable accuracy for different anomalies. Application of specific conditions and limited to surgical procedures improves the utility of using hospital discharge data to ascertain congenital anomalies.

Perinatal nicotine exposure alters lung development and induces HMGB1-RAGE expression in neonatal mice

Abstract: Background Maternal nicotine exposure during gestation and lactation adversely affect lung development of their children. High-mobility group box 1 (HMGB1) is the encoded non-histone, nuclear DNA-binding protein that regulates transcription, and is involved in organization of DNA. Receptors for advanced glycation end products (RAGE) is a receptor for HMGB1 and activates nuclear factor-κB (NF-κB) signaling. Animal and human studies have found cigarette smoke exposure upregulates RAGE expression, suggesting that the HMGB1-RAGE pathway might be involved in maternal nicotine-induced lung injury. Methods This study evaluated prenatal and perinatal nicotine effects on lung development and HMGB1 and RAGE expression in mouse offspring. Nicotine was administered to pregnant mice by subcutaneous osmotic mini-pump at a dose of 6 mg kg-1 day-1 from gestational Day 14 to birth (prenatal) or to postnatal Day 21 (perinatal). A control group received an equal volume of saline by the same route. Three study groups were obtained: prenatal normal saline (NS), prenatal nicotine, and perinatal nicotine groups. The mice were euthanized on postnatal Day 21, and the lung tissues were collected for histological and Western blot analyses. Results Mice exposed to prenatal nicotine exhibited significantly higher lung mean chord length and oxidative stress marker 8-hydroxy-2'-deoxyguanosine and NF-κB expression compared to mice exposed to NS. Perinatal nicotine exposure further enhanced these harmful effects. These perinatal nicotine effects on lung development were associated with increased HMGB1 and RAGE expression. Conclusions HMGB1-RAGE pathway may be involved in the pathogenesis of altered lung development induced by perinatal nicotine exposure.

Limited surface examination to evaluate potential teratogens in a resource-limited setting.

Abstract: Background To determine the frequency of malformations that would be identified in the limited surface examination of a newborn by the delivering nurse midwife in a resource-limited setting Methods The limited surface examination will identify visible external anomalies, but not abnormalities inside the mouth, most heart defects, undescended testes, inguinal hernias, hip dysplasia, peripheral vascular anomalies, and some internal anomalies The findings in a malformations surveillance program, involving 289,365 births in Boston, have been used to establish the prevalence rate of malformations that would be identified and not identified In African countries, the number of anomalies to be identified should also be reduced by excluding polydactyly, postaxial, type B, a common minor finding, from the list of potential malformations Results Of note, 205% (n = 5,941) of the 289,365 births surveyed had one or more malformations The abnormalities that would have been missed, using surface exam alone, accounted for 05% of all of malformations identified and reduced the overall prevalence rate of malformations to 15% In addition, excluding all infants with isolated postaxial polydactyly, type B reduced the expected prevalence rate of malformations to 13% in unexposed newborn infants Conclusion A limited surface examination can detect the majority of malformations among newborn infants