Sadia Malik

Maternal Smoking and Congenital Heart Defects

OBJECTIVES. In a population-based case-control study, we investigated the association between congenital heart defects and maternal smoking. METHODS. The National Birth Defects Prevention Study enrolled 3067 infants with nonsyndromic congenital heart defects and their parents and 3947 infants without birth defects and their parents. Affected infants had ≥1 of the following defects: conotruncal, septal, anomalous pulmonary venous return, atrioventricular septal defects, and left-sided or right-sided obstructive heart defects. Mothers of case and control infants were asked if they smoked during the periconceptional period, defined as 1 month before pregnancy through the first trimester. Maternal home and workplace exposure to tobacco smoke during the same period was also determined. Logistic regression was used to compute odds ratios and 95% confidence intervals while controlling for potential confounders. RESULTS. Case infants were more likely to be premature and have lower birth weight than control infants. Women who smoked anytime during the month before pregnancy to the end of the first trimester were more likely to have infants with septal heart defects than women who did not smoke during this time period. This association was stronger for mothers who reported heavier smoking during this period. This relation was independent of potential confounding factors, including prenatal vitamin use, alcohol intake, maternal age, and race or ethnicity. Women who smoked ≥25 cigarettes per day were more likely than nonsmoking mothers to have infants with right-sided obstructive defects. There was no increased risk of congenital heart defects with maternal exposure to environmental tobacco smoke. CONCLUSIONS. Maternal smoking during pregnancy was associated with septal and right-sided obstructive defects. Additional investigation into the timing of tobacco exposure and genetic susceptibilities that could modify this risk will provide a more precise evidence base on which to build clinical and public health primary prevention strategies.

Association Between Congenital Heart Defects and Small for Gestational Age

OBJECTIVES. Infants with congenital heart defects may experience inhibited growth during fetal life. In a large case-control study, we addressed the hypothesis that infants with congenital heart defects are more likely to be small for gestational age than infants without congenital heart defects after controlling for selected maternal and infant characteristics. METHODS. Using data from population-based birth defect registries, the National Birth Defects Prevention Study enrolled infants with nonsyndromic congenital heart defects (case subjects) and infants without congenital heart defects or any other birth defect (control subjects). Small for gestational age was defined as birth weight below the 10th percentile for gestational age and gender. Association between congenital heart defects and small for gestational age was examined by conditional logistic regression adjusting for maternal covariates related to fetal growth. RESULTS. Live-born singleton infants with congenital heart defects (case subjects, n = 3395) and live-born singleton infants with no birth defect (control subjects, n = 3924) were included in this study. Case subjects had lower birth weights compared with control subjects. Small for gestational age was observed among 15.2% of case subjects and among only 7.8% of control subjects. Congenital heart defect infants were significantly more likely to be small for gestational age than control infants. CONCLUSIONS. Infants with congenital heart defects are approximately twice as likely to be small for gestational age as control subjects. Small for gestational age status may affect clinical management decisions, therapeutic response, and prognosis of neonates with congenital heart defects. Although the etiology of growth retardation among infants with congenital heart defects is uncertain, further exploration may uncover a common pathogenesis or causal relationship between congenital heart defects and small for gestational age.

Risk Factors for Prosthesis Failure in Pulmonary Valve Replacement

BACKGROUND After initial right ventricular outflow tract reconstruction, replacement of the pulmonary valve (PVR) with a bioprosthetic valve may be performed. Bioprosthetic valves fail (PVF) and require repeat replacement. Identification of risk factors for PVF would be useful for clinicians choosing among various options for the initial PVR. METHODS We retrospectively analyzed outcomes of 169 consecutive patients (55% male) with repaired tetralogy of Fallot or pulmonary stenosis undergoing a first PVR. Data were abstracted from the medical records, including gender, diagnosis, indication for PVR, age at PVR (< 10 years or ≥ 10 years), type of valve, and time of PVF. Actuarial freedom from PVF was compared by log rank and parametric survival analysis. Risk factors for PVF were analyzed by univariate and multivariate methods. Prosthesis types for PVR were pulmonary homograft in 56, stented porcine valve in 16, stented porcine valve in Dacron (DuPont, Wilmington, DE) conduit in 26, and bovine pericardial valve in 71. RESULTS Indication for PVR was pulmonary stenosis in 21% and insufficiency in 79%. Median follow-up for the entire cohort was 8 years. PVF occurred in 24 patients at a median time of 5.7 years. Actuarial freedom from PVF at 10 years was 72% for all valve types, 55% for porcine valve in Dacron conduit, 60% for homograft, 75% for porcine valve, and 78% for bovine pericardial valve (p = 0.36). By univariate analysis, young age (p < 0.0001), male gender (p = 0.0017), and indication of pulmonary stenosis (p = 0.015) were risk factors for PVF. In multivariate analysis, tetralogy of Fallot anatomy (p < 0.06), younger age (p < 0.02), and use of a homograft valve (p < 0.02) were risk factors for early PVF (<3 years). Young age (p < 0.0001) at time of PVR was associated with late PVF. CONCLUSIONS Freedom from reoperation for PVR during 10 years of follow-up is excellent. Younger age, tetralogy of Fallot, and use of a homograft valve were risk factors for early PVF. Only younger age at PVR was a significant risk factor for late PVF.

Maternal urinary tract infections and selected cardiovascular malformations

BACKGROUND In a population-based case-control study, we investigated the association between congenital cardiovascular malformations (CVMs) and maternal urinary tract infections (UTIs). METHODS Within the National Birth Defects Prevention Study, 3,690 women who had singleton livebirths with nonsyndromic CVMs, and 4,760 women who had infants without birth defects were identified. Affected infants had: conotruncal, septal, anomalous pulmonary venous return, atrioventricular septal defects, or left- or right-sided obstructive heart defects. Mothers had a UTI if they reported having at least one infection during the first trimester. Adjusted ORs and 95% CIs were computed to determine the association between CVMs and UTIs. Stratified analyses were conducted to investigate if sulfonamide use and/or fever modified the effect between CVMs and UTIs. RESULTS Women who had offspring with either left ventricular outflow tract obstructive defects or atrioventricular septal defects were more likely than controls to report a UTI. These associations remained among women who did not have fever or used sulfonamides. Maternal use of sulfonamides during the UTI did not appear to modify the relationship between CVM subtypes and maternal UTIs. CONCLUSIONS In the National Birth Defects Prevention Study there was little evidence to support an association between CVMs and UTIs during the first trimester of pregnancy. Associations between left ventricular outflow tract obstructive defects and maternal UTI as well as between atrioventricular septal defects and maternal UTI were found. Our findings, while not conclusive, suggest that the possible association between maternal UTI and CVMs should be investigated further.

Nitrosatable drug exposure during the first trimester of pregnancy and selected congenital malformations

BACKGROUND Nitrosatable drugs can react with nitrite in the stomach to form N-nitroso compounds, and results from animal studies suggest that N-nitroso compounds are teratogens. With data from the National Birth Defects Prevention Study, the relation between prenatal exposure to nitrosatable drugs and limb deficiencies, oral cleft, and heart malformations in offspring was examined. METHODS Maternal reports of drugs taken during the first trimester of pregnancy were classified with respect to nitrosatability for mothers of 741 babies with limb deficiencies, 2774 with oral cleft malformations, 8091 with congenital heart malformations, and 6807 without major congenital malformations. Nitrite intake was estimated from maternal responses to a food frequency questionnaire. RESULTS Isolated transverse limb deficiencies and atrioventricular septal defects were associated with secondary amine drug exposures (adjusted odds ratios [aORs], 1.51; 95% confidence limit [CI], 1.11-2.06 and aOR, 1.97; 95% CI, 1.19-3.26, respectively). Tertiary amines were associated with hypoplastic left heart syndrome (aOR, 1.50; 95% CI, 1.10-2.04) and single ventricle (aOR, 1.61; 95% CI, 1.06-2.45). These two malformations were also significantly associated with amide drugs. For several malformations, the strongest associations with nitrosatable drug use occurred among mothers with the highest estimated dietary nitrite intake, especially for secondary amines and atrioventricular septal defects (highest tertile of nitrite, aOR, 3.30; 95% CI, 1.44-7.58). CONCLUSION Prenatal exposure to nitrosatable drugs may be associated with several congenital malformations, especially with higher nitrite intake. The possible interaction between nitrosatable drugs and dietary nitrite on risk of congenital malformations warrants further attention.

Conotruncal heart defects and common variants in maternal and fetal genes in folate, homocysteine, and transsulfuration pathways

BACKGROUND We investigated the association between conotruncal heart defects (CTDs) and maternal and fetal single nucleotide polymorphisms (SNPs) in 60 genes in the folate, homocysteine, and transsulfuration pathways. We also investigated whether periconceptional maternal folic acid supplementation modified associations between CTDs and SNPs METHODS Participants were enrolled in the National Birth Defects Prevention Study between 1997 and 2008. DNA samples from 616 case-parental triads affected by CTDs and 1645 control-parental triads were genotyped using an Illumina® Golden Gate custom SNP panel. A hybrid design analysis, optimizing data from case and control trios, was used to identify maternal and fetal SNPs associated with CTDs RESULTS Among 921 SNPs, 17 maternal and 17 fetal SNPs had a Bayesian false-discovery probability of <0.8. Ten of the 17 maternal SNPs and 2 of the 17 fetal SNPs were found within the glutamate-cysteine ligase, catalytic subunit (GCLC) gene. Fetal SNPs with the lowest Bayesian false-discovery probability (rs2612101, rs2847607, rs2847326, rs2847324) were found within the thymidylate synthetase (TYMS) gene. Additional analyses indicated that the risk of CTDs associated with candidate SNPs was modified by periconceptional folic acid supplementation. Nineteen maternal and nine fetal SNPs had a Bayesian false-discovery probability <0.8 for gene-by-environment (G × E) interactions with maternal folic acid supplementation. CONCLUSION These results support previous studies suggesting that maternal and fetal SNPs within folate, homocysteine, and transsulfuration pathways are associated with CTD risk. Maternal use of supplements containing folic acid may modify the impact of SNPs on the developing heart.

Comparison of in-hospital and longer-term outcomes of hybrid and Norwood stage 1 palliation of hypoplastic left heart syndrome

OBJECTIVES The hybrid approach for the initial management of hypoplastic left heart syndrome shifts the risks of major open surgery from the vulnerable neonatal period to an older age. This study determined differences between the hybrid and the standard Norwood procedures in postoperative in-hospital mortality, renal failure, and survival to at least 2 years of age. METHODS Data from the Pediatric Health Information System, a detailed hospital discharge database of 43 freestanding childrens hospitals, were analyzed. The Pediatric Health Information System includes demographic information, diagnosis, and procedure and clinical service data. Instrumental variable regression techniques were used to estimate the predicted probability of in-hospital mortality, renal failure, and survival to 24 months of age for infants with hypoplastic left heart syndrome who received a hybrid or Norwood procedure. The statistical models controlled for demographics and comorbid chromosomal anomalies. RESULTS A total of 3654 infants with hypoplastic left heart syndrome underwent intervention from 1998 to 2012. Of these, 242 underwent the hybrid approach and the remainder underwent the Norwood procedure. Instrumental variable models showed significantly reduced odds of patients who underwent the hybrid approach being diagnosed with renal failure (adjusted risk ratio [ARR], 0.48; 95% confidence interval [CI], 0.26-0.89); increased odds of surviving initial hospitalization (ARR, 1.28; 95% CI, 1.06-1.55); increased odds of survival, indicated by readmissions more than 6 months after initial hospitalization (ARR, 1.53; 95% CI, 1.05-2.22); and a decrease in length of stay by 20 days for the initial surgical hospitalization (95% CI, -27.4 to -13.9). CONCLUSIONS The short term hospital-based outcomes and longer-term survival outcomes of the hybrid approach for hypoplastic left heart syndrome may be better than those of the Norwood procedure.

Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Congenital Heart Defects among Offspring in the National Birth Defects Prevention Study

BACKGROUND There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring. METHODS Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring. RESULTS The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58-1.67), septal defects (AOR, 1.28; 95% CI, 0.86-1.90), or with any isolated CHD subtype. CONCLUSIONS Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism. Birth Defects Research (Part A), 2012.

Doppler tissue imaging and catheter-derived measures are not independent predictors of rejection in pediatric heart transplant recipients

The purpose of the study is to determine the association of Doppler Tissue Imaging (DTI) and catheter-derived measures with rejection in pediatric heart transplant (PHT) recipients and to determine any correlation between DTI and catheter-derived measurements. Sixty echocardiograms were prospectively performed in 37 PHT recipients at the time of surveillance cardiac biopsy. During right-heart cardiac catheterization, sequential pressures of the right heart and pulmonary capillary wedge pressures (PCWP) were measured. DTI was performed to obtain peak systolic (S’), early (E’) and late (A’) diastolic velocities (cm/s) at tricuspid annulus, septum and mitral annulus. Septal S’ and tricuspid annular A’ were associated with rejection, but had low sensitivity and specificity. Elevated lateral mitral E/E’ did not predict rejection. The mean pulmonary capillary wedge pressure (PCWP) and cardiac index were similar in those with and without rejection. The lateral mitral and septal E/E’ did not correlate with PCWP. Some DTI-derived measures were altered during rejection, but were not clinically useful predictors of rejection. Catheter-derived measures were not significantly altered during rejection and did not correlate with DTI-derived measures. None of these measures can replace the current practice of performing cardiac biopsy for surveillance of rejection.

Timing of complete repair of non-ductal-dependent tetralogy of Fallot and short-term postoperative outcomes, a multicenter analysis.

OBJECTIVE There is cross-center variability with regard to timing repair of non-ductal-dependent tetralogy of Fallot (TOF). We hypothesized that earlier repair in the neonatal period is associated with increased mortality and morbidity. METHODS This was a retrospective analysis of the Pediatric Health Information System of tetralogy of Fallot patients undergoing complete repair from 2004 through 2010 between the ages of 1 day to younger than 19 years. Patients with pulmonary valve atresia, those who received prostaglandin during hospital admission, and those who underwent prior shunt palliation were excluded. RESULTS A total of 4698 patients met our inclusion criteria, of whom 202 were younger than 30 days old (group A), 861 were 31 to 90 days old (group B), 1796 were 91 to 180 days old (group C), and 1839 were older than 180 days (group D). In-hospital mortality, intensive care unit length of stay, and total hospital length of stay were significantly higher in group A. Patients in group A had a significantly increased postoperative requirement for mechanical ventilation, intravenous blood pressure support, medical diuresis, extracorporeal membrane oxygenation, gastrostomy tube insertion, heart catheterization, and surgical revision. Significant institutional variability was noted for timing of TOF complete repair, with one third of the centers performing 75% of the repairs at younger than 30 days old. The institutional approach to timing TOF complete repair showed no relation to surgical volume. CONCLUSIONS Across all centers analyzed, primary neonatal elective TOF repair (<30 days of age) is associated with significantly higher postoperative in-hospital morbidity and mortality, although a few centers have shown an ability to use this strategy with excellent survivability.