Down syndrome and associated atrioventricular septal defects in a nationwide Norwegian cohort: Prevalence, time trends, and outcomes.

INTRODUCTION: The prevalence of Down syndrome (DS) is approximately 1 per 1000 births and is influenced by increasing maternal age over the last few decades. DS is strongly associated with congenital heart defects (CHDs), especially atrioventricular septal defect (AVSD). Our objectives were to investigate the prevalence of live-born infants with DS having a severe CHD in the Norwegian population over the last 20 years and compare outcomes in infants with AVSD with and without DS. MATERIAL AND METHODS: Information on all births from January 1, 2000 to December 31, 2019 was obtained from the Medical Birth Registry of Norway. We also obtained data on all infants with severe CHDs in Norway registered in Oslo University Hospital's Clinical Registry for Congenital Heart Defects during 2000-2019 and accessed individual-level patient data from the electronic hospital records of selected cases. Infants with AVSD and DS were compared to infants with AVSD without chromosomal defects. Crude and adjusted odds ratios (ORs) of infant mortality and need for surgery during the first year of life, with associated 95% confidence intervals (CIs), were estimated by logistic regression. RESULTS: A total of 1 177 926 infants were live-born in Norway during the study period. Among these, 1456 (0.1%) had DS. The prevalence of infants with DS having a severe CHDs was relatively stable, with a mean of 17 cases per year. The most common CHD associated with DS was AVSD (44.4%). Infants with AVSD and DS were more likely to have cardiac intervention during their first year of life compared to infants with AVSD without chromosomal defects (adjusted OR [aOR]: 2.52; 95% CI 1.27, 4.98). However, we observed no difference in infant mortality during first year of life between the two groups (aOR: 1.08; 95% CI 0.43, 2.70). CONCLUSIONS: The prevalence of live-born infants with severe CHDs and DS has been stable in Norway across 20 years. Infants with AVSD and DS did not have higher risk of mortality during their first year of life compared to infants with AVSD without chromosomal defects, despite a higher risk of operative intervention.

Maternal risk factors for congenital heart defects in infants with Down syndrome from Western Mexico.

Atrioventricular septal defects (AVSDs) have been identified as intriguingly infrequent among Hispanics with Down syndrome (DS) born in the United States. The aim of this study was to evaluate the effect of possible maternal risk factors in the presence of congenital heart defects (CHDs) in Mexican infants with DS. A total of 231 live birth infants born with DS during 2009-2018 at the "Dr. Juan I. Menchaca" Civil Hospital of Guadalajara (Guadalajara, Mexico) were ascertained in a case-control study. Patients with DS with any major CHD were included as cases and those without major CHD as controls. Potential risk factors were analyzed using logistic regression. Of eligible infants with DS, 100 (43.3%) had ≥1 major CHDs (cases) and were compared with a control group of 131 infants (56.7%) with DS without CHDs. Prevalent CHDs were ostium secundum atrial septal defects (ASDs) (46.9%), ventricular septal defects (27.3%), and AVSDs (14%). Lack of folic acid supplementation before pregnancy had a significant risk for CHDs in infants with DS (adjusted odds ratio [aORs] = 2.9 (95% confidence interval [95% CI]: 1.0-8.6) and in the analysis by subtype of CHDs, also, for the occurrence of ASDs (aOR = 11.5, 95% CI: 1.4-94.4). Almost half of the infants with DS in our sample had CHDs, being ASD the commonest subtype and AVSD the rarest. Our ethnic background alone or in concomitance with observed nutritional disadvantages seems to contribute differences in CHD subtype rates in our DS patients.

Associations between low- and high-dose oral fluconazole and pregnancy outcomes: 3 nested case-control studies.

BACKGROUND: While topical azoles are the first-line treatment for fungal infections, oral fluconazole is frequently used during pregnancy. We aimed to assess the effect of exposure to low and high doses of fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. METHODS: Within the Quebec Pregnancy Cohort (1998-2015), we identified women exposed to low- (≤ 150 mg) and high-dose (> 150 mg) fluconazole, and women who were not exposed. For each case of spontaneous abortion or stillbirth, up to 5 controls were randomly selected using an incidence density sampling method matched on gestational age at diagnosis of spontaneous abortion or stillbirth (index date) and the year of the last menstrual period. For cases of major congenital malformation, we considered all liveborn babies as controls. Generalized estimation equation models were used to analyze the 3 main outcomes separately. RESULTS: Within a cohort of 441 949 pregnancies, 320 868 pregnancies were included in the analyses of spontaneous abortions, 226 599 of major congenital malformations and 7832 of stillbirths. Most (69.5%) women exposed to fluconazole in pregnancy received the common single therapeutic dose of 150 mg (low dose); the remainder received a dose of > 150 mg (high dose). Use of oral fluconazole during early pregnancy was associated with an increased risk of spontaneous abortion compared with no exposure (adjusted odds ratio [OR] for 345 cases exposed to low-dose treatment 2.23, 95% confidence interval [CI] 1.96-2.54; adjusted OR for 249 cases exposed to high-dose treatment 3.20, 95% CI 2.73-3.75). Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR 1.81, 95% CI 1.04-3.14; 13 exposed cases) compared with no exposure. No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth. INTERPRETATION: Any maternal exposure to fluconazole during pregnancy may increase risk of spontaneous abortion and doses higher than 150 mg during the first trimester may increase risk of cardiac septal closure anomalies.

Fetal pulmonary atresia with ventricular septal defect: Features, associations, and outcome in fetuses with different pulmonary circulation supply types.

OBJECTIVES: To assess features and outcome in fetuses with pulmonary atresia with ventricular septal defect (PA-VSD). METHODS: Fetuses with PA-VSD were prospectively enrolled and grouped on the basis of the pulmonary blood supply, including type A (only arterial duct [DA]), type B (both DA and major aortopulmonary collateral arteries [MAPCAs] present), and type C (MAPCAs only). The echocardiography features, associated chromosomal/genetic malformations, and postnatal outcome were compared among the three groups. RESULTS: Fifty-five fetuses with PA-VSD were enrolled. The presence of confluent PAs varied, with the highest displaying rate in type A and lowest rate in type C (100% vs 41.1%). The intrapericardial pulmonary arteries in all groups were hypoplastic but smaller in types B and C than in type A (P < .05). Deletion of 22q11.2 and right aortic arch were more frequently observed in types B and C than in type A. At the end of the study, overall survival rates in type C were lower than those in type A (22.1% vs 77.3%). CONCLUSION: There are great differences in the size of pulmonary arteries, associated genetic malformations, and perinatal outcomes among fetuses with PA-VSD. These results could be used for family counseling and surgical planning.

Atrioventricular Canal and Dextrocardia: A Case Report with Implications for Community-Based Providers.

Congenital heart defects (CHD) are the most common congenital malformation reported in the literature, with a global incidence of eight per every 1,000 live births. In the United States approximately 40,000 infants are born each year with a CHD. Of the infants diagnosed with a CHD, one in every four heart defects are life threatening in origin. Early identification and treatment of congenital heart lesions, beginning with a comprehensive physical assessment after birth, are critical. For infants delivered at community-based hospitals, the importance of the physical assessment, timing of diagnostic strategies, anticipatory planning, and interprofessional collaboration among referring and accepting centers cannot be understated. This article presents a rare case of an infant with atrioventricular canal complicated by dextrocardia. Embryology, pathophysiology, epidemiology, symptomology, cardiac assessment, diagnostics, treatment, and nursing strategies for facilitating transfer of care from community-based hospitals to tertiary medical centers are discussed.

Fluoxetine and congenital malformations: a systematic review and meta-analysis of cohort studies.

AIMS: To investigate the safety of fluoxetine use during pregnancy, and to better understand the relationship between maternal fluoxetine use during the first trimester and congenital malformations in infants. METHODS: PubMed and Web of Science databases were systematically searched from inception to 21 March 2016. Additional studies were identified in a manual search of the reference lists. Two reviewers independently extracted data. A third reviewer checked the data. Estimates were pooled using a random-effects model to calculate the summarized relative ratios (RR) and 95% confidence intervals (CI). RESULTS: Among 1918 initially identified articles, 16 cohort studies were included. The offspring of pregnant women exposed to fluoxetine during the first trimester had a statistically increased risk of major malformations (RR = 1.18, 95% CI = 1.08-1.29), cardiovascular malformations (RR = 1.36, 95% CI = 1.17-1.59), septal defects (RR = 1.38, 95% CI = 1.19-1.61), and non-septal defects (RR = 1.39, 95% CI = 1.12-1.73) with low heterogeneity in infants. There were no significant observations of other system-specific malformations in the nervous system, eye, urogenital system, digestive system, respiratory system, or musculoskeletal system, respectively. There was no indication of publication bias. CONCLUSIONS: The results of this meta-analysis indicate maternal fluoxetine use is associated with a slightly increased risk of cardiovascular malformations in infants. Health care providers and pregnant women must weigh the risk-benefit potential of these drugs when making decisions about whether to treat with fluoxetine during pregnancy.

Twenty-five-year survival for aboriginal and caucasian children with congenital heart defects in Western Australia, 1980 to 2010.

BACKGROUND: Australian Aboriginal children have increased infant and childhood mortality compared with Caucasian children, but their mortality related to congenital heart defects (CHDs) throughout life is unknown. METHODS: We conducted a retrospective cohort study using data on 8,110 live born, singleton infants with CHDs born January 1980 to December 2010 from the Western Australian Register of Developmental Anomalies. Vital status was determined from death and medical records. Data for infants with chromosomal anomalies (except Down syndrome) were excluded. Kaplan-Meier Product-Limit estimates and 95% confidence intervals (CIs) were computed by Aboriginality. Hazard ratios (HRs) and 95% CIs were calculated from multivariable Cox-Proportional Hazard Regression models. RESULTS: Aboriginal children had lower survival than Caucasians for all CHDs combined but most notably during the neonatal period for functional single ventricle (50.0% vs. 86.1%; p = 0.015) and during the postneonatal period for tetralogy of Fallot (87.0% vs. 97.4%; p = 0.021) and atrioventricular septal defect (60.0% vs. 94.6%; p = 0.010). After adjusting for covariates except remoteness and socioeconomic status (SES), Aboriginal children with all CHDs combined (HR = 1.4; 95% CI, 1.0-1.9), with transposition of the great arteries (HR = 4.3; 95% CI, 1.0-18.9) or functional single ventricle (HR = 8.6; 95% CI, 1.3-57.9) had increased risk of mortality compared with Caucasian children. When remoteness and SES were included, the risks were not statistically significant. CONCLUSION: Long-term survival was lower for Aboriginal children with CHDs, and Aboriginal children with specific CHD phenotypes had increased risk of mortality throughout life. Increased risk may be due to SES and environmental factors. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1016-1031, 2016. © 2016 Wiley Periodicals, Inc.

Detection and putative effect of GATA4 gene variants in patients with congenital cardiac septal defects.

The zinc finger transcription factor GATA4, located on chromosome 8p23.1-p22, has been implicated as a critical regulator of cardiac development during embryogenesis. Mutations of GATA4 appear to be responsible for some cardiac septal defects. The aim of this work was to screen for mutations in the GATA4 gene in sample of Egyptian patients affected by isolated and non-isolated cardiac septal defects. We examined 20 patients with atrial septal defect (ASD), ventricle septal defect (VSD), atrioventricular septal defects (AVSD) and A-V canal disturbance defect and compared with examined 10 unaffected individuals as normal control. The patients were referred from Congenital Heart Disease Clinic of the Clinical Genetics department at the National Research Centre. All patients were subjected to clinical evaluation, echocardiography and karyotyping. Genomic DNA was extracted from all cases and subjected to PCR followed by direct sequencing. The predicted effect of variants was done by a variety of proper prediction tools. We detected six variants in GATA4 gene, two of them are novel variants. Predicted functional analysis of the relevant variants was performed by In silico analysis. Further confirmatory studies on familial segregation and in vitro / in vivo functional analysis are recommended to support our results.

Prenatal detection of structural cardiac defects and presence of associated anomalies: a retrospective observational study of 1262 fetal echocardiograms.

OBJECTIVE: The aim of this study is to document the detection of fetal congenital heart defect (CHD) in relation to the following: (1) indication for referral, (2) chromosomal and (3) extracardiac abnormalities. METHOD: All fetal echocardiograms performed in our institution from 2007 to 2011 were reviewed retrospectively. Indication for referral, cardiac diagnosis based on the World Health Organization International Classification of Diseases tenth revision criteria and the presence of chromosomal and extracardiac defects were recorded. RESULTS: Of 1262 echocardiograms, 287 (22.7%) had CHD. Abnormal anatomy scan in pregnancies originally considered to be at low risk of CHD was the best indicator for detecting CHD (91.2% of positive cardiac diagnoses), compared with other indications of family history (5.6%) or maternal medical disorder (3.1%). Congenital anomalies of the cardiac septa comprised the largest category (n = 89), within which atrioventricular septal defects were the most common anomaly (n = 36). Invasive prenatal testing was performed for 126 of 287 cases, of which 44% (n = 55) had a chromosomal abnormality. Of 232 fetuses without chromosomal abnormalities, 31% had an extracardiac defect (n = 76). CONCLUSIONS: Most CHDs occur in pregnancies regarded to be at low risk, highlighting the importance of a routine midtrimester fetal anatomy scan. Frequent association of fetal CHD and chromosomal and extracardiac pathology emphasises the importance of thorough evaluation of any fetus with CHD.

Increased risk of severe congenital heart defects in offspring exposed to selective serotonin-reuptake inhibitors in early pregnancy--an epidemiological study using validated EUROCAT data.

BACKGROUND: Previous studies suggest a possible association between maternal use of selective serotonin-reuptake inhibitors (SSRIs) during early pregnancy and congenital heart defects (CHD). The purpose of this study was to verify this association by using validated data from the Danish EUROCAT Register, and secondary, to investigate whether the risk differs between various socioeconomic groups. METHODS: We conducted a cohort study based on Danish administrative register data linked with the Danish EUROCAT Register, which includes all CHD diagnosed in live births, fetal deaths and in pregnancies terminated due to congenital anomalies. The study population consisted of all registered pregnancies (n = 72,280) in Funen, Denmark in the period 1995-2008. SSRI-use was assessed using The Danish National Prescription Registry, information on marital status, maternal educational level, income, and country of origin from Statistics Denmark was used as indicators of socioeconomic situation, and the CHD were studied in subgroups defined by EUROCAT. Logistic Regression was used to investigate the association between redeemed prescriptions for SSRIs and CHD. RESULTS: The risk of severe CHD in the offspring of the 845 pregnant women who used SSRIs during first trimester increased four times (AOR 4.03 (95% CI 1.75-9.26)). We found no increased risk of septal defects. Socioeconomic position did not modify the association between maternal SSRI-use during pregnancy and severe CHD. CONCLUSION: This study, which is based on data with high case ascertainment, suggests that maternal use of SSRIs during first trimester increases the risk of severe CHD, but does not support findings from previous studies, based on administrative register data, regarding an increased risk of septal defects. The study was unable to document an interaction between socioeconomic status and maternal SSRI-use on the risk of severe CHD.

Prevalence of congenital heart defects associated with Down syndrome in Korea.

Congenital heart defect (CHD) is common in infants with Down syndrome (DS), which is the principle cause of mortality. However, there is no data available for the frequency and types of CHD in infants with DS in Korea. We investigated the frequency of CHD in infants with DS in Korea. After the survey on birth defects was conducted throughout the country, the prevalence of CHD in DS in 2005-2006 was calculated. This study was conducted based on the medical insurance claims database of the National Health Insurance Corporation. The number of total births in Korea was 888,263 in 2005-2006; of them, 25,975 cases of birth defects were identified. The prevalence of DS was 4.4 per 10,000 total births, accounting for 1.5% of all birth defects. Of the 394 infants with DS, 224 (56.9%) had a CHD. Atrial septal defect was the most common defect accounting for 30.5% of DS followed by ventricular septal defect (19.3%), patent duct arteriosus (17.5%), and atrioventricular septal defect (9.4%). Our study will be helpful to demonstrate the current status of DS and to identify the distribution of CHD in infants with DS in Korea.

Incidences and sociodemographics of specific congenital heart diseases in the United States of America: an evaluation of hospital discharge diagnoses.

Current estimates of the incidence of congenital heart disease (CHD) are derived from small clinical studies and metaanalyses. For the true incidence of CHD in the United States of America to be estimated, a single large representative population must be analyzed. All the data in this study were derived from the Nationwide Inpatient Sample database. The study determined the overall and lesion-specific incidences of CHD diagnoses among all birth hospitalizations in 2008, stratified by race, gender, socioeconomic status, and hospital geographic location. The study identified 13,093 CHD diagnoses among 1,204,887 birth hospitalizations, yielding an incidence of 10.8 per 1,000, with a predominance of mild lesions and septal defects. Atrial septal defect (ASD) and pulmonic stenosis were more common among females, whereas aortic stenosis, coarctation of the aorta, hypoplastic left heart syndrome, and d-transposition of great arteries were more common among males. No racial difference was observed in the overall CHD incidence. However, isolated patent ductus arteriosus (PDA) and ventricular septal defects (VSDs) were more common among Caucasians, whereas ASDs were more common among Hispanics. The incidences of CHD diagnoses were similar for all socioeconomic classes except the lowest socioeconomic class, which had a significantly lower CHD incidence. There was no geographic or seasonal variation in CHD incidence. This study demonstrated the incidence of echocardiographically confirmed CHD diagnosis to be 10.8 per 1,000 live births, marked by a high proportion of mild cardiac lesions and isolated PDAs. The high incidence of isolated PDAs in this study may be explained by the inclusion of only CHD diagnoses during birth hospitalization.

Maternal medication use, fetal 3435 C>T polymorphism of the ABCB1 gene, and risk of isolated septal defects in a Han Chinese population.

The fundamental etiology of the majority of nonsyndromic congenital heart defects is commonly believed to involve the interaction of multiple environmental and genetic factors. This study aimed to explore the joint effects of fetal 3435 C>T polymorphism in the ABCB1 gene and maternal medication use on the risk of septal defects in a Han Chinese population. An age- and gender-matched case-control study involving 265 pairs was conducted from March 2012 to September 2013. Information on maternal periconceptional medication use was obtained through questionnaires. The genotyping of 3435 C>T polymorphism was performed by sequencing. Logistic regression analysis was performed to assess the joint effects of ABCB1 gene 3435 C>T polymorphism and maternal medication use on the risk of septal defects. Use of maternal medication periconceptionally was significantly associated with an increased risk of septal defects [adjusted odds ratio (OR) 2.133; 95 % confidence interval (CI) 1.361-3.444; P = 0.001)]. The genotype distributions of 3435 C>T polymorphism differed significantly between cases and control subjects (P < 0.001). Meanwhile, more patients were carriers of the ABCB1 CC/CT genotypes, which were significantly associated with an increased risk of septal defects (OR 2.414; 95 % CI 1.418-4.110; P = 0.001). Children who carry the CC/CT genotype and have been exposed periconceptionally to medication have an almost fourfold increased risk of having septal defects than nonexposed children with the TT genotype (adjusted OR 3.932; 95 % CI 1.708-9.051), particularly perimembranous ventricular septal defects (VSD) (adjusted OR 4.070; 95 % CI 1.570-10.552). In conclusion, fetal 3435 C>T polymorphism in the ABCB1 gene increases the risk for isolated septal defects in the presence of maternal medication use periconceptionally, particularly for perimembranous VSD.

Periconceptional paternal smoking and the risk of congenital heart defects: a case-control study.

BACKGROUND: Maternal smoking during pregnancy has been consistently associated with an increased risk of congenital heart defects (CHDs). However, few studies have reported the association between paternal smoking during pregnancy and CHDs among offspring. This report presents the first case-control study to investigate the possible association between periconceptional paternal smoking and CHDs in China. METHODS: From February 2010 through October 2011, 284 case fetuses with nonsyndromic CHDs and 422 control fetuses with no birth defects were recruited. The mothers of cases and controls were interviewed regarding whether the fathers of fetuses smoked and avoided the mothers while smoking during the periconceptional period. An unconditional logistic regression was used to calculate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) while controlling for potential confounders. RESULTS: Light paternal smoking increased the risk of isolated conotruncal heart defects (AOR, 2.23; 95% CI, 1.05, 4.73). Medium paternal smoking seemed to be associated with septal defects (AOR, 2.04; 95% CI, 1.05, 3.98) and left ventricular outflow tract obstructions (AOR, 2.48; 95% CI, 1.04, 5.95). Heavy paternal smoking was also associated with isolated conotruncal heart defects (AOR, 8.16; 95% CI, 1.13, 58.84) and left ventricular outflow tract obstructions (AOR, 13.12; 95% CI, 2.55, 67.39). Paternal smoking with no avoidance behavior was associated with an increased risk of these CHDs subtypes. CONCLUSIONS: Periconceptional paternal smoking increased the risk of isolated conotruncal heart defects, septal defects and left ventricular outflow tract obstructions. The avoidance behavior of paternal smokers may decrease the risk of selected CHDs.

Ambient air pollution and traffic exposures and congenital heart defects in the San Joaquin Valley of California.

BACKGROUND: Congenital anomalies are a leading cause of infant morbidity and mortality. Studies suggest associations between environmental contaminants and some anomalies, although evidence is limited. METHODS: We used data from the California Center of the National Birth Defects Prevention Study and the Children's Health and Air Pollution Study to estimate the odds of 27 congenital heart defects with respect to quartiles of seven ambient air pollutant and traffic exposures in California during the first 2 months of pregnancy, 1997-2006 (n = 822 cases and n = 849 controls). RESULTS: Particulate matter < 10 microns (PM10 ) was associated with pulmonary valve stenosis [adjusted odds ratio (aOR)Fourth Quartile = 2.6] [95% confidence intervals (CI) 1.2, 5.7] and perimembranous ventricular septal defects (aORThird Quartile = 2.1) [95% CI 1.1, 3.9] after adjusting for maternal race/ethnicity, education and multivitamin use. PM2.5 was associated with transposition of the great arteries (aORThird Quartile = 2.6) [95% CI 1.1, 6.5] and inversely associated with perimembranous ventricular septal defects (aORFourth Quartile = 0.5) [95% CI 0.2, 0.9]. Secundum atrial septal defects were inversely associated with carbon monoxide (aORFourth Quartile = 0.4) [95% CI 0.2, 0.8] and PM2.5 (aORFourth Quartile = 0.5) [95% CI 0.3, 0.8]. Traffic density was associated with muscular ventricular septal defects (aORFourth Quartile = 3.0) [95% CI 1.2, 7.8] and perimembranous ventricular septal defects (aORThird Quartile = 2.4) [95% CI 1.3, 4.6], and inversely associated with transposition of the great arteries (aORFourth Quartile = 0.3) [95% CI 0.1, 0.8]. CONCLUSIONS: PM10 and traffic density may contribute to the occurrence of pulmonary valve stenosis and ventricular septal defects, respectively. The results were mixed for other pollutants and had little consistency with previous studies.

Atrioventricular septal defects among infants in Europe: a population-based study of prevalence, associated anomalies, and survival.

OBJECTIVE: To describe the epidemiology of chromosomal and non-chromosomal cases of atrioventricular septal defects in Europe. METHODS: Data were obtained from EUROCAT, a European network of population-based registries collecting data on congenital anomalies. Data from 13 registries for the period 2000-2008 were included. RESULTS: There was a total of 993 cases of atrioventricular septal defects, with a total prevalence of 5.3 per 10,000 births (95% confidence interval 4.1 to 6.5). Of the total cases, 250 were isolated cardiac lesions, 583 were chromosomal cases, 79 had multiple anomalies, 58 had heterotaxia sequence, and 23 had a monogenic syndrome. The total prevalence of chromosomal cases was 3.1 per 10,000 (95% confidence interval 1.9 to 4.3), with a large variation between registers. Of the 993 cases, 639 cases were live births, 45 were stillbirths, and 309 were terminations of pregnancy owing to foetal anomaly. Among the groups, additional associated cardiac anomalies were most frequent in heterotaxia cases (38%) and least frequent in chromosomal cases (8%). Coarctation of the aorta was the most common associated cardiac defect. The 1-week survival rate for live births was 94%. CONCLUSION: Of all cases, three-quarters were associated with other anomalies, both chromosomal and non-chromosomal. For infants with atrioventricular septal defects and no chromosomal anomalies, cardiac defects were often more complex compared with infants with atrioventricular septal defects and a chromosomal anomaly. Clinical outcomes for atrioventricular septal defects varied between regions. The proportion of termination of pregnancy for foetal anomaly was higher for cases with multiple anomalies, chromosomal anomalies, and heterotaxia sequence.

Analysis of selected maternal exposures and non-syndromic atrioventricular septal defects in the National Birth Defects Prevention Study, 1997-2005.

Although the descriptive epidemiology of atrioventricular septal defects (AVSDs), a group of serious congenital heart defects (CHDs), has been recently reported, non-genetic risk factors have not been consistently identified. Using data (1997-2005) from the National Birth Defects Prevention Study, an ongoing multisite population-based case-control study, the association between selected non-genetic factors and non-syndromic AVSDs was examined. Data on periconceptional exposures to such factors were collected by telephone interview from 187 mothers of AVSD case infants and 6,703 mothers of unaffected infants. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated from logistic regression models. Mothers who reported cigarette smoking during the periconceptional period were more likely to have infants with AVSDs compared with non-smokers, independent of maternal age, periconceptional alcohol consumption, infant gestational age, family history of CHDs, and study site (aOR 1.5, 95% CI 1.1-2.4). The association was strongest in mothers who smoked more than 25 cigarettes/day. In addition, mothers with periconceptional passive smoke exposure were more likely to have infants with AVSDs than unexposed mothers, independent of maternal age, active periconceptional smoking, infant gestational age, and family history of CHDs (aOR 1.4, 95% CI 1.0-2.0). No associations were observed between AVSDs and maternal history of a urinary tract infection or pelvic inflammatory disease, maternal use of a wide variety of medications, maternal occupational exposure, parental drug use, or maternal alcohol consumption. If the results of this preliminary study can be replicated, minimizing maternal active and passive smoke exposure may decrease the incidence of AVSDs.

Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome.

Cardiac abnormalities are one of the most common congenital defects observed in individuals with Down syndrome. Considerable research has implicated both folate deficiency and genetic variation in folate pathway genes with birth defects, including both congenital heart defects (CHD) and Down syndrome (DS). Here, we test variation in folate pathway genes for a role in the major DS-associated CHD atrioventricular septal defect (AVSD). In a group of 121 case families (mother, father, and proband with DS and AVSD) and 122 control families (mother, father, and proband with DS and no CHD), tag SNPs were genotyped in and around five folate pathway genes: 5,10-methylenetetrahyrdofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR), cystathionine beta-synthase (CBS), and the reduced folate carrier (SLC19A1, RFC1). SLC19A1 was found to be associated with AVSD using a multilocus allele-sharing test. Individual SNP tests also showed nominally significant associations with odds ratios of between 1.34 and 3.78, depending on the SNP and genetic model. Interestingly, all marginally significant SNPs in SLC19A1 are in strong linkage disequilibrium (r(2)> or = 0.8) with the nonsynonymous coding SNP rs1051266 (c.80A>G), which has previously been associated with nonsyndromic cases of CHD. In addition to SLC19A1, the known functional polymorphism MTHFR c.1298A was over-transmitted to cases with AVSD (P=0.05) and under-transmitted to controls (P=0.02). We conclude, therefore, that disruption of the folate pathway contributes to the incidence of AVSD among individuals with DS.

Pregnancy outcome following in-utero exposure to ondansetron: A prospective comparative observational study.

The objective of the study was to evaluate the rate of major congenital anomalies after first trimester exposure to ondansetron for nausea and vomiting of pregnancy (NVP). The design is a prospective, comparative, observational cohort study, performed at the Israeli Teratology Information Service between 2010 and 2014. Follow-up was obtained for 195 ondansetron-exposed, 110 metoclopramide-exposed, and 778 pregnancies with non-teratogenic exposure (NTE). The overall rate of major anomalies did not significantly differ between the groups [4/200 = 2.0 % (ondansetron), 1/109 = 0.9 % (metoclopramide), and 13/731 = 1.8 % (NTE)]. All the anomalies in both the ondansetron and metoclopramide groups, and 6/13 anomalies in the NTE group, were cardiac septal defects most of which spontaneously resolved. Both ondansetron (adjHR = 0.29, 95 % CI 0.10-0.80) and metoclopramide (adjHR = 0.27, 95 % CI 0.08-0.86) were associated with lower miscarriage rate compared to NTE. Based on the present study, ondansetron during pregnancy is not associated with an increased risk for overall major anomalies, nor for clinically important cardiac defects. It may be a reasonable alternative for women with severe NVP who do not respond to first line medications.

Folic acid flour fortification: impact on the frequencies of 52 congenital anomaly types in three South American countries.

The aim of the present investigation was to search for a reduction in birth prevalence estimates of 52 selected types of congenital anomalies, associated with folic acid fortification programs in Chile, Argentina, and Brazil. The material included 3,347,559 total births in 77 hospitals of the three countries during the 1982-2007 period: 596,704 births (17 hospitals) in Chile, 1,643,341 (41 hospitals) in Argentina, and 1,107,514 (19 hospitals) in Brazil. We compared pre- and post-fortification rates within each hospital and the resulting Prevalence Rate Ratios (PRRs) were pooled by country. Statistically significant reductions in birth prevalence estimates after fortification were observed for neural tube defects (NTDs), septal heart defects, transverse limb deficiencies, and subluxation of the hip. However, only the reduction of NTDs appeared to be associated with folic acid fortification and not due to other factors, because of its consistency among the three countries, as well as with previously published reports, and its strong statistical significance. Among the NTDs, the maximum prevalence reduction was observed for isolated cephalic (cervical-thoracic) spina bifida, followed by caudal (lumbo-sacral) spina bifida, anencephaly, and cephalocele. This observation suggests etiologic and pathogenetic heterogeneity among different levels of spina bifida, as well as among different NTD subtypes. We concluded that food fortification with folic acid prevents NTDs but not other types of congenital anomalies.