Anny H Xiang1, Xinhui Wang1, Mayra P Martinez1, Johanna C Walthall2, Edward S Curry3, Kathleen Page4, Thomas A Buchanan5, Karen J Coleman1, Darios Getahun6. 1. Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena. 2. Department of Psychiatry, Kaiser Permanente Southern California, Pasadena. 3. Department of Pediatrics, Kaiser Permanente Southern California, Pasadena. 4. Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, Los Angeles. 5. Division of Endocrinology and Diabetes, Keck School of Medicine, University of Southern California, Los Angeles5Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles. 6. Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena6Department of Obstetrics and Gynecology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey.
Abstract
IMPORTANCE: Information about the association of maternal diabetes and autism spectrum disorders (ASDs) in offspring is limited, with no report on the importance of timing of exposure during gestation. OBJECTIVE: To assess ASD risk associated with intrauterine exposure to preexisting type 2 diabetes and gestational diabetes mellitus (GDM) by gestational age at GDM diagnosis. DESIGN, SETTING, AND PATIENTS: Retrospective longitudinal cohort study including 322 323 singleton children born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC health plan membership, death due to any cause, or December 31, 2012. Relative risks of ASD were estimated by hazard ratios (HRs) using Cox regression models adjusted for birth year. EXPOSURES: Maternal preexisting type 2 diabetes (n = 6496), GDM diagnosed at 26 weeks' gestation or earlier (n = 7456) or after 26 weeks' gestation (n = 17 579), or no diabetes (n = 290 792) during the index pregnancy. MAIN OUTCOMES AND MEASURES: Clinical diagnosis of ASD in offspring. RESULTS: During follow-up, 3388 children were diagnosed as having ASD (115 exposed to preexisting type 2 diabetes, 130 exposed to GDM at ≤26 weeks, 180 exposed to GDM at >26 weeks, and 2963 unexposed). Unadjusted annual ASD incidences were 3.26, 3.02, 1.77, and 1.77 per 1000 among children of mothers with preexisting type 2 diabetes, GDM diagnosed at 26 weeks or earlier, GDM diagnosed after 26 weeks, and no diabetes, respectively. The birth year-adjusted HRs were 1.59 (95% CI, 1.29-1.95) for preexisting type 2 diabetes, 1.63 (95% CI, 1.35-1.97) for GDM diagnosed at 26 weeks or earlier, and 0.98 (95% CI, 0.84-1.15) for GDM diagnosed after 26 weeks relative to no exposure. After adjustment for maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, maternal preexisting type 2 diabetes was not significantly associated with risk of ASD in offspring (HR, 1.21; 95% CI, 0.97-1.52), but GDM diagnosed at 26 weeks or earlier remained so (HR, 1.42; 95% CI, 1.15-1.74). Antidiabetic medication exposure was not independently associated with ASD risk. Adjustment for a mother or older sibling with ASD in the full cohort and for maternal smoking, prepregnancy body mass index, and gestational weight gain in the subset with available data (n = 68 512) did not affect the results. CONCLUSIONS AND RELEVANCE: In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks' gestation, exposure to maternal GDM diagnosed by 26 weeks' gestation was associated with risk of ASD in offspring.
IMPORTANCE: Information about the association of maternal diabetes and autism spectrum disorders (ASDs) in offspring is limited, with no report on the importance of timing of exposure during gestation. OBJECTIVE: To assess ASD risk associated with intrauterine exposure to preexisting type 2 diabetes and gestational diabetes mellitus (GDM) by gestational age at GDM diagnosis. DESIGN, SETTING, AND PATIENTS: Retrospective longitudinal cohort study including 322 323 singleton children born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC health plan membership, death due to any cause, or December 31, 2012. Relative risks of ASD were estimated by hazard ratios (HRs) using Cox regression models adjusted for birth year. EXPOSURES: Maternal preexisting type 2 diabetes (n = 6496), GDM diagnosed at 26 weeks' gestation or earlier (n = 7456) or after 26 weeks' gestation (n = 17 579), or no diabetes (n = 290 792) during the index pregnancy. MAIN OUTCOMES AND MEASURES: Clinical diagnosis of ASD in offspring. RESULTS: During follow-up, 3388 children were diagnosed as having ASD (115 exposed to preexisting type 2 diabetes, 130 exposed to GDM at ≤26 weeks, 180 exposed to GDM at >26 weeks, and 2963 unexposed). Unadjusted annual ASD incidences were 3.26, 3.02, 1.77, and 1.77 per 1000 among children of mothers with preexisting type 2 diabetes, GDM diagnosed at 26 weeks or earlier, GDM diagnosed after 26 weeks, and no diabetes, respectively. The birth year-adjusted HRs were 1.59 (95% CI, 1.29-1.95) for preexisting type 2 diabetes, 1.63 (95% CI, 1.35-1.97) for GDM diagnosed at 26 weeks or earlier, and 0.98 (95% CI, 0.84-1.15) for GDM diagnosed after 26 weeks relative to no exposure. After adjustment for maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, maternal preexisting type 2 diabetes was not significantly associated with risk of ASD in offspring (HR, 1.21; 95% CI, 0.97-1.52), but GDM diagnosed at 26 weeks or earlier remained so (HR, 1.42; 95% CI, 1.15-1.74). Antidiabetic medication exposure was not independently associated with ASD risk. Adjustment for a mother or older sibling with ASD in the full cohort and for maternal smoking, prepregnancy body mass index, and gestational weight gain in the subset with available data (n = 68 512) did not affect the results. CONCLUSIONS AND RELEVANCE: In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks' gestation, exposure to maternal GDM diagnosed by 26 weeks' gestation was associated with risk of ASD in offspring.
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