Richard S. Olney

Vitamin supplements and the risk for congenital anomalies other than neural tube defects.

Randomized trials, supported by many observational studies, have shown that periconceptional use of folic acid, alone or in multivitamin supplements, is effective for the primary prevention of neural tube defects (NTDs). Whether this is true also for other congenital anomalies is a complex issue and the focus of this review. It is useful to consider the evidence not only for specific birth defects separately but, importantly, also for all birth defects combined. For the latter, the Hungarian randomized clinical trial indicated, for periconceptional multivitamin use, a reduction in the risk for all birth defects (odds ratio (OR) = 0.53, 95% confidence interval (CI) = 0.35–0.70), even after excluding NTDs (OR = 0.53, 95% CI = 0.38–0.75). The Atlanta population‐based case‐control study, the only large observational study to date on all major birth defects, also found a significant risk reduction for all birth defects (OR = 0.80, 95% CI = 0.69–0.93) even after excluding NTDs (OR = 0.84, 95% CI = 0.72–0.97). These and other studies also evaluated specific anomalies, including those of the heart, limb, and urinary tract, as well as orofacial clefts, omphalocele, and imperforate anus. For cardiovascular anomalies, two studies were negative, whereas three, including the randomized clinical trial, suggest a possible 25–50% overall risk reduction, more marked for some conotruncal and septal defects. For orofacial clefts, six of seven case‐control studies suggest an apparent reduced risk, which could vary by cleft type and perhaps, according to some investigators, by pill dosage. For limb deficiencies, three case‐control studies and the randomized trial estimated approximately a 50% reduced risk. For urinary tract defects, three case‐control studies and the randomized trial reported reduced risks, as did one study of nonsyndromic omphalocele. All these studies examined multivitamin supplement use. With respect to folic acid alone, a reduced rate of imperforate anus was observed among folic acid users in China. We discuss key gaps in knowledge, possible avenues for future research, and counseling issues for families concerned about occurrence or recurrence of these birth defects.

Trends in pediatric sickle cell disease-related mortality in the United States, 1983-2002.

OBJECTIVE To analyze trends in sickle cell disease (SCD)-related mortality among black children during 1983-2002. STUDY DESIGN Using the multiple-cause mortality files compiled by the Centers for Disease Control and Preventions National Center for Health Statistics, we analyzed deaths among children classified as black who were age 14 years and younger and had SCD identified on their death certificates. RESULTS Relative to the rate for 1983-1986, the SCD mortality rate for 1999-2002 decreased by 68% (95% confidence interval [CI]=58% to 75%) at age 0 to 3 years, by 39% (95% CI=16% to 56%) at age 4 to 9 years, and by 24% (95% CI= -9% to 47%) at age 10 to 14 years. For the most recent period studied, a significant (42%) reduction in mortality at age 0 to 3 years was seen between 1995-1998 and 1999-2002, with essentially no reduction in SCD mortality at older ages. CONCLUSIONS Recent decreases in SCD mortality in black children under age 4 years coincided with the introduction of the 7-valent pneumococcal conjugate vaccine in 2000, although temporal association is not evidence of causation. The lack of significant recent reduction in SCD mortality in older children indicates the need for new treatment approaches.

Antihypertensive Medication Use During Pregnancy and the Risk of Cardiovascular Malformations

We used data from the National Birth Defects Prevention Study, a population-based, case-control study, to examine whether previously reported associations between antihypertensive medications and cardiovascular malformations could be confirmed and to explore whether new associations might be identified. Cases (n=5021) were ascertained through birth defects surveillance systems from 1997 through 2003 in 10 US states. Controls (n=4796) were live births without birth defects selected randomly from birth certificates or hospital discharge listings in the same geographic regions. Logistic regression was used to examine the relationship between antihypertensive medication treatment and the occurrence of cardiovascular malformations while controlling for confounding variables. First-trimester treatment with antihypertensive medication was associated with pulmonary valve stenosis (odds ratio [OR]: 2.6; 95% CI: 1.3 to 5.4), Ebstein malformation (crude OR: 11.4; exact 95% CI: 2.8 to 34.1), coarctation of the aorta (OR: 3.0; 95% CI: 1.3 to 6.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Treatment initiated after the first trimester was associated with pulmonary valve stenosis (OR: 2.4; 95% CI: 1.1 to 5.4), perimembranous ventricular septal defects (OR: 2.3; 95% CI: 1.2 to 4.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Untreated hypertension was associated with Ebstein malformation (OR: 2.1; 95% CI: 1.0 to 4.3) and secundum atrial septal defects (OR: 1.3; 95% CI: 1.0 to 1.6). Antihypertensive medication use and/or the underlying hypertension might increase the risk of having an infant with specific left and right obstructive and septal defects. Additional studies with adequate power will be needed to confirm these findings.

Trisomies 13 and 18: Population prevalences, characteristics, and prenatal diagnosis, metropolitan Atlanta, 1994–2003

In recent years, prenatal diagnosis and elective pregnancy termination have affected the reported birth prevalence of trisomies 13 and 18. We examined the prevalence and characteristics of these conditions using 1994–2003 data from a population‐based surveillance system, the Metropolitan Atlanta Congenital Defects Program. Including fetal deaths and elective terminations increased the number of affected pregnancies by 58.7% for trisomy 13 and 72.2% for trisomy 18. Prenatal cytogenetic testing was reported in 70.8% of trisomy 13 cases and 76.1% of trisomy 18 cases. Among those with prenatal cytogenetic tests, 60.8% of trisomy 13 and 59.7% of trisomy 18 cases were electively terminated. Compared with non‐Hispanic whites, non‐Hispanic black race was associated with a decreased frequency of prenatal cytogenetic testing for both trisomy 13 and trisomy 18 (OR 0.24, 95% CI: 0.08–0.78 and OR 0.32, 95% CI: 0.14–0.69, respectively). The reported rates of prenatal cytogenetic testing remained stable throughout the period. As expected, maternal age ≥35 years was a risk factor for both conditions. However, while 67.1% (n = 55) of the trisomy 18 case mothers were ≥35 years, only 46.9% (n = 15) of the trisomy 13 case mothers were ≥35 years. Among live‐born infants, the sex ratio among trisomy 18 infants showed an increased proportion of females: 60.4% female versus 39.6% male. However, the proportion was 48.3% female and 51.7% male among fetuses that were electively terminated in the second trimester. Inclusion of pregnancies that are prenatally diagnosed is critical for accurate surveillance and population‐based analyses of these conditions. Published 2008 Wiley‐Liss, Inc.

Cost-Effectiveness of Routine Screening for Critical Congenital Heart Disease in US Newborns

OBJECTIVES: Clinical evidence indicates newborn critical congenital heart disease (CCHD) screening through pulse oximetry is lifesaving. In 2011, CCHD was added to the US Recommended Uniform Screening Panel for newborns. Several states have implemented or are considering screening mandates. This study aimed to estimate the cost-effectiveness of routine screening among US newborns unsuspected of having CCHD. METHODS: We developed a cohort model with a time horizon of infancy to estimate the inpatient medical costs and health benefits of CCHD screening. Model inputs were derived from new estimates of hospital screening costs and inpatient care for infants with late-detected CCHD, defined as no diagnosis at the birth hospital. We estimated the number of newborns with CCHD detected at birth hospitals and life-years saved with routine screening compared with no screening. RESULTS: Screening was estimated to incur an additional cost of

Goldenhar syndrome among infants born in military hospitals to Gulf War veterans

6.28 per newborn, with incremental costs of

Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004

20 862 per newborn with CCHD detected at birth hospitals and

Late Detection of Critical Congenital Heart Disease Among US Infants: Estimation of the Potential Impact of Proposed Universal Screening Using Pulse Oximetry

40 385 per life-year gained (2011 US dollars). We estimated 1189 more newborns with CCHD would be identified at birth hospitals and 20 infant deaths averted annually with screening. Another 1975 false-positive results not associated with CCHD were estimated to occur, although these results had a minimal impact on total estimated costs. CONCLUSIONS: This study provides the first US cost-effectiveness analysis of CCHD screening in the United States could be reasonably cost-effective. We anticipate data from states that have recently approved or initiated CCHD screening will become available over the next few years to refine these projections.

Prevalence of Congenital Hypothyroidism—Current Trends and Future Directions: Workshop Summary

Reports in the popular press described the occurrence of Goldenhar syndrome among children of Persian Gulf War veterans (GWVs). The objective of this investigation was to compare the birth prevalence of Goldenhar syndrome among infants born in military hospitals to GWVs and to military personnel who were not deployed to the Gulf War (NDVs). Computerized hospital discharge data were reviewed for infants conceived after the war and born prior to the 1st of October, 1993, in medical treatment facilities (MTFs) operated by the U.S. Department of Defense. Medical records were evaluated for infants diagnosed at birth with at least one abnormality that might be related to Goldenhar syndrome. Two pediatricians, blinded to the parental Gulf War status of each infant, reviewed records. An estimated 75,414 infants were conceived after the Gulf War and born in MTFs during the study period (34,069 GWV infants and 41,345 NDV infants). Seven infants fulfilled the case criteria (five GWV infants and two NDV infants). All infants had fathers who served in the military at the time of their conception and birth. The birth prevalence was 14.7 per 100,000 live births among GWV infants (95% confidence interval [CI]: 5.4-36.4) and 4.8 per 100,000 live births (95% CI: 0.8-19.5) among NDV infants (relative risk: 3.03; 95% CI: 0.63-20.57; P values: [2-tailed] = 0.26, [1-tailed] = 0.16). The few affected cases and the broad confidence intervals surrounding the relative risk require that these results be interpreted with caution and do not exclude chance as an explanation for these findings.

Maternal caffeine consumption and risk of neural tube defects.

PURPOSE The objective of this study was to examine the associations between paternal age and birth defects of unknown etiologies while carefully controlling for maternal age. METHODS By using 1997 to 2004 data from the National Birth Defects Prevention Study, we fit logistic regression models with paternal and maternal age as continuous variables while adjusting for demographic and other factors. RESULTS Elevated odds ratios (ORs) for each year increase in paternal age were found for cleft palate (OR. 1.02, 95% confidence interval [95% CI], 1.00-1.04), diaphragmatic hernia (OR, 1.04; 95% CI, 1.02-1.06), right ventricular outflow tract obstruction (OR, 1.03; 95% CI, 1.01-1.04), and pulmonary valve stenosis (OR, 1.02, 95% CI, 1.01-1.04). At younger paternal ages, each year increase in paternal age correlated with increased odds of having offspring with encephalocele, cataract, esophageal atresia, anomalous pulmonary venous return, and coarctation of the aorta, but these increased odds were not observed at older paternal ages. The effect of paternal age was modified by maternal age for gastroschisis, omphalocele, spina bifida, all orofacial clefts, and septal heart defects. CONCLUSIONS Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects.