Gastroschisis is a severe congenital malformation that results in the herniation of the bowel and occasionally other organs through a hole usually to the right of the umbilicus in newborns. Although rare, gastroschisis occurs more frequently in the offspring of mothers < 25 years old relative to mothers ≥ 25 years old (Jones et al. 2016), and the prevalence of gastroschisis has increased over time in the United States (Jones et al. 2016; Kirby et al. 2013) and internationally (Loane et al. 2007).

While many studies have sought to identify environmental and maternal factors that increase the risk for gastroschisis after controlling for potential confounding by maternal age, it is not clear whether previously identified risk factors explain the strong inverse association with maternal age or the increasing trend over time. We examined whether previously reported risk factors for gastroschisis identified in the National Birth Defects Prevention Study (NBDPS) explain the associations with time or maternal age.

The NBDPS was a multisite, population-based, case–control study designed to investigate risk factors associated with pregnancies affected by major congenital anomalies with deliveries during or after October 1997 and estimated dates of delivery (EDD) during or before December 2011. Cases were identified from birth defects surveillance systems in Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah, and included live births, stillbirths, and terminations. Controls were live-born infants without major structural malformations, randomly selected from birth certificates or hospitals in the same catchment areas as cases. After informed consent, mothers of cases and controls were interviewed by telephone within 2 years after EDD about demographics, reproductive history, occupation, medication use, illnesses, lifestyle, and other exposures. The study was approved by the institutional review board at each participating site and the Centers for Disease Control and Prevention (CDC).

A clinical geneticist reviewed gastroschisis case records, and those with known chromosomal anomalies, genetic defects, and phenotypes consistent with amniotic band sequence or limb–body wall complex were excluded. Data for this study were from previous NBDPS investigations (Feldkamp et al. 2014; Lupo et al. 2012; Werler et al. 2018) and included gastroschisis cases with or without other structural malformations. Other details of the study design have been described previously (Reefhuis et al. 2015).

Factors selected for inclusion in this study included those previously reported to be associated with an increased risk for gastroschisis in NBDPS publications, including genitourinary infection (Feldkamp et al. 2019), estimated cumulative exposure to PAHs across all jobs (Lupo et al. 2012), years lived in the United States at the time of delivery (Khodr et al. 2013), language spoken at home (Khodr et al. 2013), cold or flu with fever (Waller et al. 2018), diet quality index (Feldkamp et al. 2014), maternal alcohol use (Richardson et al. 2011; Werler et al. 2018), cigarette smoking (Werler et al. 2018), maternal illicit drug use (Werler et al. 2018), parental race and ethnicity (Khodr et al. 2013), household income (Neo et al. 2023; Petersen et al. 2021), parity (Khodr et al. 2013), interpregnancy interval (Petersen et al. 2021), paternal age (Green et al. 2010), oral contraceptive use (Waller et al. 2010), and prepregnancy body mass index (BMI) (Siega-Riz et al. 2009). For alcohol use, cigarette smoking, illicit drug use, oral contraceptive use, genitourinary infection, cold or flu with fever, and estimated cumulative exposure to PAHs (including restriction to assignment with greatest confidence by industrial hygienist) (Lupo et al. 2012), we considered mothers exposed if they reported exposure for the interval beginning 1 month before through the first 3 months of pregnancy. Additional details on exposure definitions have been published previously (Feldkamp et al. 2019; Feldkamp et al. 2014; Green et al. 2010; Khodr et al. 2013; Lupo et al. 2012; Neo et al. 2023; Petersen et al. 2021; Richardson et al. 2011; Siega-Riz et al. 2009; Waller et al. 2010; Waller et al. 2018; Werler et al. 2018).

There were 1278 cases and 10,611 controls. The crude OR for the time trend (2005–2011 vs. 1997–2004) in gastroschisis was 1.28 (95% CI: 1.14, 1.44). Adjustment for estimated cumulative exposure to PAHs across all jobs (OR = 1.08; 95% CI: 0.92, 1.26), parental race and ethnicity (OR = 1.24; 95% CI: 1.11, 1.40), years lived in the United States (OR = 1.26; 95% CI: 1.12, 1.42), and illicit drug use (OR = 1.27; 95% CI: 1.13, 1.43) resulted in the OR for the gastroschisis year parameter moving closer to the null (Table 1). The OR for the time trend was most attenuated with adjustment for estimated cumulative exposure to PAHs across all jobs (15.6%).

The crude OR for maternal age (< 25 years vs. ≥ 25 years) and gastroschisis was 7.76 (95% CI: 6.71, 8.97), which decreased with adjustment for paternal age, interpregnancy interval, parity, cigarette smoking, maternal illicit drug use, estimated cumulative exposure to PAHs across all jobs, parental race and ethnicity, household income, genitourinary infection, oral contraceptive use, prepregnancy BMI, and cold or flu with fever (Table 2). We observed the largest attenuation of the OR with adjustment for factors known to be strongly correlated with maternal age, particularly paternal age (OR = 5.43; 95% CI: 4.55, 6.48; 30.0% change), interpregnancy interval, (OR = 5.45; 95% CI: 4.43, 6.69; 29.8% change), and parity (OR = 6.61; 95% CI: 5.70, 7.67; 14.8% change). The adjusted OR accounting for these three factors in a multivariable model was 4.19 (95% CI: 3.26, 5.37; 46.0% change).

Gastroschisis has two distinct epidemiologic features that set it apart from other congenital anomalies: increased birth prevalence during past decades and higher prevalence among younger mothers. Although biological mechanisms that result in this condition have been proposed (Bargy and Beaudoin 2014; Opitz, Feldkamp, and Botto 2019; Rittler, Vauthay, and Mazzitelli 2013) and numerous risk factors have been identified, it remains unclear why gastroschisis risk is higher in young mothers and why it increased over time. It is widely hypothesized that exposures thought to be more common among younger mothers explain these unique trends. Using data from the NBDPS, we show that previously reported risk factors for gastroschisis generally do not explain the increasing time trend or inverse maternal age association.

The 1.28-fold greater risk of gastroschisis for births in the second half of the NBDPS study period was altered after controlling for estimated cumulative exposure to PAHs across all jobs, reducing the time trend OR to 1.08. To our knowledge, this is the first study to evaluate the role of PAHs in time trend analyses of gastroschisis. All other exposures we examined did not account for the increasing time trend. A study that used birth certificate data also found that maternal and infant characteristics did not independently account for the increasing time trend (Vo and Langlois 2015). Additionally, an ecologic study that compared trends in gastroschisis with concurrent trends in prenatal use of illicit drugs reported no association (Forrester and Merz 2006).

The 7.76-fold increased risk of gastroschisis for mothers < 25 years old (vs. ≥ 25) was attenuated to some extent by paternal age, parity, interpregnancy interval, income, and parental race and ethnicity. Maternal illicit drug use, cigarette smoking, oral contraceptive use, and genitourinary infections have each been suspected to underlie the inverse maternal age association; although some evidence of attenuation by these exposures was observed, they accounted for only a small amount of the 7.76-fold OR. Estimated cumulative exposure to PAHs is the only exogenous exposure that was observed to partially attenuate both the maternal age and time trend associations but left both associations largely unexplained. Reports of effect modification by maternal age for some gastroschisis risk factors, often with higher ORs for older mothers (Lupo et al. 2012; Weber et al. 2019; Werler et al. 2018), do not have bearing on our exploration of adjustments of the association between maternal age and gastroschisis.

Typically, multivariable models to estimate associations of exposures and risk of gastroschisis adjust for maternal age as a potential confounder (Feldkamp et al. 2019; Feldkamp et al. 2014; Khodr et al. 2013; Lupo et al. 2012; Neo et al. 2023; Petersen et al. 2021; Richardson et al. 2011; Waller et al. 2018). Calendar time is less often considered a potential confounder, but it has been examined as such in at least one study (Neo et al. 2023). In the present study, we considered maternal age and calendar time as separate, primary factors in association with gastroschisis, not as causal factors for gastroschisis. Therefore, our analysis of risk factors to explain either the birth year or maternal age associations is not within a causal framework. ORs were estimated as measures of association, but not causation. We do not believe that birth year or maternal age cause gastroschisis in and of themselves; therefore, the 16 risk factors examined are not considered confounders or intermediates. We are, however, particularly interested in learning whether the previously identified risk factors might explain the unique descriptive epidemiology of gastroschisis.

The present findings should be interpreted within the context of several limitations. The NBDPS collected exposure information retrospectively and is susceptible to recall inaccuracies, which can also lead to misclassification and residual confounding. Second, average participation rates were 65% for cases and 65% for controls (Reefhuis et al. 2015), and did decline across all NBDPS years. If risk factors were associated with participation differentially for cases and controls, selection bias is possible. Third, unknown, and unmeasured factors may account for both time and maternal age associations with gastroschisis. However, a previous study examining over 200 parental exposures and activities during the periconceptional period did not find many previously unreported associations with gastroschisis (Weber et al. 2019). Indeed, studies of self-reported exposures are limited, and measures of biomarkers would likely advance knowledge. Lastly, the data for these analyses are from an earlier period, which may not reflect current trends. In more recent years, the prevalence of gastroschisis in the United States has appeared to decrease; however, the higher risk among young maternal age remains (Clark et al. 2020; Stallings et al. 2024). Strengths of the study include the use of a population-based study spanning over a decade with data on a wide range of exposures, which allowed for in-depth analyses. Additionally, as part of this study, all cases were reviewed for eligibility based on standard case definitions and classified by clinical geneticists at each study site.

While there is some evidence that gastroschisis risk factors account for small amounts of the calendar time trend and maternal age associations, it remains unclear what factors underlie the complete associations. To advance our understanding of the causes of gastroschisis, studies of early pregnancy biomarkers are necessary.