Systematic review and meta-analysis of birth weight and PFNA exposures.

We used a systematic review that included risk of bias and study sensitivity analysis to identify 34 studies examining changes in birth weight (BWT) in relation to PFNA biomarker measures (e.g., maternal serum/plasma or umbilical cord samples). We fit a random effects model of the overall pooled estimate and stratified estimates based on sample timing and overall study confidence. We conducted a meta-regression to further examine the impact of gestational age at biomarker sample timing. We detected a -32.9 g (95%CI: -47.0, -18.7) mean BWT deficit per each ln PFNA increase from 27 included studies. We did not detect evidence of publication bias (pE = 0.30) or between-study heterogeneity in the summary estimate (pQ = 0.05; I2 = 36%). The twelve high confidence studies yielded a smaller pooled effect estimate (ß = -28.0 g; 95%CI: -49.0, -6.9) than the ten medium (ß = -39.0 g; 95%CI: -61.8, -16.3) or four low (ß = -36.9 g; 95%CI: -82.9, 9.1) confidence studies. The stratum-specific results based on earlier pregnancy sampling periods in 11 studies showed smaller deficits (ß = -22.0 g; 95%CI: -40.1, -4.0) compared to 10 mid- and late-pregnancy (ß = -44.2 g; 95%CI: -64.8, -23.5) studies and six post-partum studies (ß = -42.9 g; 95%CI: -88.0, 2.2). Using estimates of the specific gestational week of sampling, the meta-regression showed results consistent with the categorical sample analysis, in that as gestational age at sampling time increases across these studies, the summary effect estimate of a mean BWT deficit got larger. Overall, we detected mean BWT deficits for PFNA that were larger and more consistent across studies than previous PFAS meta-analyses. Compared to studies with later sampling, BWT deficits were smaller but remained sizeable for even the earliest sampling periods. Contrary to earlier meta-analyses for PFOA and PFOS, BWT deficits that were detected across all strata did not appear to be fully explained by potential bias due to pregnancy hemodynamics from sampling timing differences.

Selection bias and confounding in case-crossover analyses of environmental time-series data.

The case-crossover study design is a popular analytic tool for estimating the effects of triggers of acute outcomes by environmental exposures. Although this approach controls for time-invariant confounders by design, it may allow for selection bias and confounding by time-varying factors. We conducted a simulation study of the sensitivity of the symmetric bidirectional case-crossover design to time-varying patterns in exposure and outcome. We identified the effects of selection bias and confounding on symmetric bidirectional case-crossover results and offer strategies to eliminate or reduce these biases. Selection bias results when exposure in the reference periods is not identically representative of exposure in the hazard periods, even when the distribution of exposure is stationary. This bias can be estimated and removed. Selection bias also occurs when the distribution of exposure is nonstationary, but the adjusted symmetric bidirectional case-crossover methodology substantially controls for this. Confounding results from a common temporal pattern in the exposure and the outcome time series, but can also be the result of patterns in exposure and outcome that, although asymptotically uncorrelated, are correlated at finite series lengths. All three biases are reduced by choosing shorter referent-spacing lengths. This effect is illustrated using data on air pollution and daily deaths in Chicago.

Control for seasonal variation and time trend in case-crossover studies of acute effects of environmental exposures.

The case-crossover study design is used to study the triggers of acute outcomes in populations. It controls for all measured and unmeasured time-invariant confounders by design. Studies of environmental triggers of morbidity are potentially confounded by temporal trends in the outcome owing to omitted covariates. We conducted a simulation study of the case-crossover design's ability to control for temporal confounding patterns by design rather than through modeling. We compared five case-crossover control sampling strategies including the matched pair, a symmetric bi-directional, a total history approach, and two approaches proposed by Navidi (Biometrics 1998;54:596-605). We simulated true relative risks (RR) of 1.10 and 2.00 and induced confounding by seasonal patterns as well as linear and nonlinear long-term trends to yield estimated RR values as high as 3.18. The symmetric bi-directional approach was compared across four lag times and controlled for temporal confounding best when the lag was shortest. With a 1-week lag, it estimated the RR values as 1.10 and 2.01. The four other approaches failed to control for the temporal trends. Our simulations show that the symmetric bi-directional case-crossover design can substantially control for temporal confounding by design although it is not as efficient (66%) as Poisson regression analysis.

The epidemiology of infantile hypertrophic pyloric stenosis.

Infants with infantile hypertrophic pyloric stenosis (IHPS) born from 1983 to 1988 and recorded in the California Birth Defects Monitoring Program (CBDMP) database were compared with their birth cohort by demographic characteristics and selected associated birth defects. We identified 1963 cases of IHPS for a cumulative incidence of 1.9 per 1000 livebirths. The cumulative incidence per 1000 livebirths was 2.4 in White, 1.8 in Hispanic, 0.7 in Black, and 0.6 in Asian infants. Between weeks 3-12 after birth, 1871 (95%) IHPS cases were diagnosed. Premature infants were diagnosed with IHPS later than term or post-term infants. The incidence of IHPS declined for those born to maternal age groups of > or = 25 years and, independently, for successive birth ranks. The probandwise concordance rate for IHPS in monozygous twins was less than unity (0.25-0.44), although higher than the concordance for dizygous twins (0.05-0.10). The incidence of Smith-Lemli-Opitz syndrome (SLO) diagnosed in infants with IHPS (3 of 1963) was 157-fold higher than the incidence of SLO diagnosed in the CBDMP population. IHPS occurs in all of the largest racial and ethnic groups in California, most frequently in White and Hispanic infants. Pyloric stenosis presents only within a brief phase of development, which may be delayed in premature infants. A predominant discordance of disease state in monozygous twins implies an aetiological role for undetermined environmental factors. The association between SLO, caused by deficient cholesterol synthesis, and IHPS deserves additional study. Infants with suspected SLO require close observation for the onset of IHPS.

Population-based study of tracheoesophageal fistula and esophageal atresia.

From a multiracial population of 1,035,384 births monitored by the California Birth Defects Monitoring Program (CBDMP) from 1983 to 1988, we ascertained 34 cases of esophageal atresia (EA), 204 cases of tracheoesophageal fistula (TEF) with an EA (TEF/EA), and 54 cases of TEF without EA. The total prevalence rate was 2.82 per 10,000 live births and stillbirths and showed no secular trend nor marked seasonal variation. Rates of multiple birth were high for each defect (TEF 3.7%, TEF/EA 4.9%, EA 8.8%; population 1.1%). Non-Hispanic whites were overrepresented for TEF and TEF/EA, but not for EA. Excluding trisomies, mean maternal age was above the population mean (26.8 years) for TEF (27.9 years) and TEF/EA (28.0 years), but not for EA (26.2 years). The proportion of trisomies was significantly higher for EA (23.5%) than for TEF (9.3%; P < 0.02) or for TEF/EA (7.4%; P < 0.003). We subdivided each defect into five mutually exclusive types: isolated, multiple, syndromic, chromosomal, and trisomic. Male-to-female (M/F) ratios varied considerably between types, both within and between defects. The highest M/F ratios within each defect were for the multiple type (TEF 2.29, TEF/EA 1.44, EA 1.33; population 1.05), and the lowest for trisomies (TEF 0.25; TEF/EA 0.25, and EA 0.60). All types except trisomies were significantly associated with a single umbilical artery. We found an association of EA and TEF/EA with dextrocardia (3.1% of cases), and confirmed the association of primary hydrocephalus with TEF and TEF/EA (2.7% of cases). The proportion of cases with additional midline defects or VATER or VACTERL type anomalies was similar for all three defects, suggesting a common developmental pathogenesis. Epidemiologic differences between defects, and between types within defects, may reflect differences in timing of the pathological process or differences in susceptibilities (e.g., by sex or aneuploidy) and emphasize the need to evaluate each defect and its types separately in epidemiologic studies.

A population-based study of congenital diaphragmatic hernia.

From 1983 through 1987, in a California population of 718,208 births, 237 infants were born with a congenital diaphragmatic hernia (CDH), a birth prevalence of 3.30 per 10,000 total births (live births and stillbirths). We proposed that the various types of this defect, characterized by their different pathogeneses, would be reflected in differences in their descriptive epidemiologies. We evaluated various demographic, maternal, and infant characteristics for three major types of defects, the Morgagni hernia, the pars sternalis hernia, and the posterolateral hernia, categorizing the latter type into isolated defect (N = 129), multiple congenital anomalies including nonchromosomal syndromes (N = 86), trisomies (N = 10), and chromosomal anomalies other than trisomies (N = 2). For the posterolateral hernia, we present the distribution of associated anomalies (43%) and specifically of midline defects (19%). Although the number of cases for the Morgagni hernia (N = 5) and the pars sternalis hernia (N = 5) were small, comparisons with the posterolateral hernia suggested lower sex ratios, of borderline significance for the pars sternalis hernia (P < 0.09), and higher mean maternal ages for both groups. Within the posterolateral type, we found a significantly higher male to female ratio (M/F = 1.58) only for the isolated subgroup compared to the population (P < 0.03), and a borderline significant rural/urban difference in prevalences (2.12 vs. 1.45 per 10,000) (P < 0.06). Additionally, the distribution of monthly prevalence rates adjusted for gestational age suggested opposite seasonal trends between the isolated and the other posterolateral hernias; within this latter subgroup the difference between the highest monthly rate (1.68) and the lowest (0.96) was of borderline significance (P < 0.09). Our results suggest the need to consider the respective types and subgroups of CDH separately in epidemiologic studies.

A population-based study of gastroschisis: demographic, pregnancy, and lifestyle risk factors.

Gastroschisis, an abdominal wall defect, most often occurs in infants of young mothers. To identify risk factors for gastroschisis, we conducted a case-control study in the population surveyed by the California Birth Defects Monitoring Program (CBDMP). From structured questionnaire data, we compared sociodemographic, reproductive, and lifestyle factors for 110 mothers of infants with gastroschisis with those for 220 age-matched mothers of normal infants. Univariate matched-pair analysis showed significant associations of gastroschisis with mother's education, yearly family income, marital status, a history of mother's mother smoking, mother's father's absence from home during the mother's youth, more than one elective abortion, a short interval between menarche and first pregnancy, siblings from different fathers, and use of either a recreational drug (either cocaine, amphetamine, marijuana, or LSD), alcohol, or tobacco during the trimester preceding pregnancy. For cocaine, amphetamine, and marijuana, use of more than one drug showed a stronger association than single drug use. The association was stronger if both parents used drugs. Although many variables were correlated, odds ratios (OR) were significant (95% confidence intervals) in multivariate conditional logistic analysis for: yearly family income < $10,000 [OR = 4.34 (1.54, 12.22)] or $10,000-$49,999 [OR = 3.93 (1.43, 10.80)]; mother's mother's smoking status not known [OR = 3.99 (1.66, 9.56)]; mother's father's absence from home during her youth [OR = 3.11 (1.14, 8.46)]; and drug use by mother [OR = 2.21 (1.21, 4.03)], father [OR = 1.66 (1.02, 2.69)], or both [OR = 3.05 (1.48, 6.28)]. The best predictive model explained 32% of the deviance. Young, socially disadvantaged women with a history of substance use were at highest risk for a child with a gastroschisis.

Maternal medications and environmental exposures as risk factors for gastroschisis.

In a case-control study of gastroschisis, we evaluated the risks associated with mother's first-trimester use of medications and with hobby or occupational exposures for 110 cases and 220 controls without a birth defect. Mothers of cases and controls were age-matched. For hobby or occupational exposures, we found significantly elevated risks for high levels of solvents (odds ratio (OR) = 3.8; 95% confidence interval (CI) = 1.6-9.2) and for colorants (OR = 2.3; 95% CI = 1.3-4.0). For medications, we found significantly elevated risks for two strong cyclooxygenase inhibitors, aspirin (OR = 4.7; 95% CI = 1.2-18.1) and ibuprofen (OR = 4.0; 95% CI = 1.0-16.0), but not for acetaminophen, a weak cyclooxygenase inhibitor. Periconceptional exposure to X rays was also associated with gastroschisis (OR = 2.5; 95% CI = 1.2-5.5), but exposure to antibiotics, antinauseants, sulfonamides, or oral contraceptives was not. We also found elevated risks for two decongestants, pseudoephedrine (OR = 2.1; 95% CI = 0.8-5.5) and phenylpropanolamine (OR = 10.0; 95% CI = 1.2-85.6). For the group of all decongestants, including also oxymetazoline and ephedrine, the risk was significantly elevated (OR = 2.4; 95% CI = 1.0-5.4). Controlling in multivariate analyses for several demographic and pregnancy variables associated with gastroschisis in a previous analysis [Torfs et al. (1994) Teratology 50: 44-53] did not substantially change the level or direction of the associations. Most of these associations are for vasoactive substances, which supports a vascular hypothesis for the pathogenesis of gastroschisis.