title: Prenatal exposure to gestational diabetes mellitus as an independent risk factor for long-term neuropsychiatric morbidity of the offspring.
abstract: The reported rates of gestational diabetes mellitus are constantly escalating and little is known about long-term complications in the offspring. Evidence from the field of epigenetics strongly advocates the need for research on the neuropsychiatric complications in offspring prenatally exposed to gestational diabetes mellitus.
  
  
  
  We sought to assess whether in utero exposure to gestational diabetes mellitus increases the risk of long-term neuropsychiatric morbidity in the offspring.
  
  
  
  A population-based cohort study compared the incidence of hospitalizations due to neuropsychiatric disease between singletons exposed and unexposed to gestational diabetes mellitus. Deliveries occurred in the years 1991 through 2014 in a regional tertiary medical center. Perinatal deaths, multiple gestations, mothers with pregestational diabetes or lack of prenatal care, and children with congenital malformations were excluded from the study. A multivariate generalized estimating equation logistic regression model analysis was used to control for confounders and for maternal clusters.
  
  
  
  During the study period 231,271 deliveries met the inclusion criteria; 5.4% of the births were to mothers diagnosed with gestational diabetes mellitus (n = 12,642), of these 4.3% had gestational diabetes type A1 (n = 10,076) and 1.1% had gestational diabetes type A2 (n = 2566). During the follow-up period, a significant linear association was noted between the severity of the gestational diabetes (no gestational diabetes, gestational diabetes mellitus A1, gestational diabetes mellitus A2) and neuropsychiatric disease of the offspring (1.02% vs 1.36% vs 1.68%, respectively, P < .001). A Kaplan-Meier curve demonstrated that children born to women with gestational diabetes mellitus had higher cumulative incidence of neuropsychiatric morbidity. Using a generalized estimating equation multivariable logistic regression model, controlling for time-to-event, maternal age, gestational age at delivery, maternal obesity, maternal preeclampsia and fertility treatments, maternal gestational diabetes mellitus was found to be an independent risk factor for long-term neuropsychiatric disease of the offspring (gestational diabetes mellitus A1 [adjusted odds ratio, 1.83; 95% confidence interval, 1.53-2.19] and gestational diabetes mellitus A2 [adjusted odds ratio, 1.64; 95% confidence interval, 1.18-2.27]). Within the limits of our database, our findings also point to a possible association between in utero exposure to gestational diabetes mellitus and autistic spectrum disorder of the offspring (adjusted odds ratio, 4.44; 95% confidence interval, 1.55-12.69), which was found significant also after controlling for time-to-event, maternal age, gestational age at delivery, and offspring weight at birth.
  
  
  
  Exposure to maternal gestational diabetes mellitus is an independent risk factor for long-term neuropsychiatric morbidity in the offspring.
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Kira
authors.initials: K
authors.lastname: Nahum Sacks
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Friger
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Shoham-Vardi
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Hanaa
authors.initials: H
authors.lastname: Abokaf
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Spiegel
authors.affiliation: Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Sergienko
authors.affiliation: Department of Pediatrics, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Daniella
authors.initials: D
authors.lastname: Landau
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel. Electronic address: sheiner@bgu.ac.il.
authors.forename: Eyal
authors.initials: E
authors.lastname: Sheiner
mesh_terms: D000328:Adult; D000067877:Autism Spectrum Disorder / Q000453:epidemiology; D002547:Cerebral Palsy / Q000453:epidemiology; D015331:Cohort Studies; D016640:Diabetes, Gestational / Q000453:epidemiology; D004827:Epilepsy / Q000453:epidemiology; D001068:Feeding and Eating Disorders / Q000453:epidemiology; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007557:Israel / Q000453:epidemiology; D065886:Neurodevelopmental Disorders / Q000453:epidemiology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012307:Risk Factors; D020181:Sleep Apnea, Obstructive / Q000453:epidemiology
keywords: autistic disorder; gestational diabetes mellitus; long-term effects; neuropsychiatric disorders; offspring; prenatal exposure