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Gastroschisis, a congenital defect of the abdominal wall, occurs disproportionately more in offspring of young mothers and has been increasing in prevalence over the past decades. A wide range of exposures have been reported in association with an increased gastroschisis risk, independent of mother’s age; many have also been correlated with stress responses.We explored cumulative exposures to such stressor exposures among 1,261 mothers of gastroschisis cases and 10,682 mothers of controls in the National Birth Defects Prevention Study (1997–2011). We considered 16 exposures as stressors in the first trimester: fever, genitourinary infection, anti-herpetic medication use, injury, bronchodilator use, cigarette smoking, alcohol intake, illicit drug use, prescription opioid use, oral contraceptive use, interpregnancy interval < 12 months, residential move, aspirin use, ibuprofen use, venlafaxine use, and paroxetine use.Mothers of cases reported more stressor exposures than controls. For 1, 2, 3, and ≥ 4 stressor exposures compared with none, the age-adjusted odds ratios (95% confidence interval) were 1.3 (1.1, 1.6), 1.7 (1.4, 2.1), 2.5 (2.0, 3.1), and 3.6 (2.9, 4.4), respectively. When we weighted cumulative stress scores according to the magnitude of stressor-specific odds ratios, similar associations were observed. Cumulative stressor exposure did not account for the strong inverse association between age and gastroschisis risk.These findings show that gastroschisis risk appears to increase with accumulation of widely different types of exposures, consistent with the hypothesis that stress-induced inflammation might play an etiologic role.