Maternal Metabolic Disease and Offspring Neurodevelopment—An Evolving Public Health Crisis | Cardiology | JAMA Network Open | JAMA Network
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Invited Commentary
October 14, 2021

Maternal Metabolic Disease and Offspring Neurodevelopment—An Evolving Public Health Crisis

Author Affiliations
  • 1Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston
  • 2Vincent Center for Reproductive Biology, Massachusetts General Hospital, Boston
JAMA Netw Open. 2021;4(10):e2129674. doi:10.1001/jamanetworkopen.2021.29674

As the prevalence of maternal metabolic morbidity, including diabetes, obesity, and hypertension, has increased, so too has the prevalence of neurodevelopmental disorders in children.1-3 Large maternal-child cohort studies have demonstrated consistent associations between maternal metabolic disease and offspring neurodevelopmental disorders and psychiatric illness, including an increased risk for autism spectrum disorder, attention-deficit/hyperactivity disorder, schizophrenia, intellectual disability, anxiety, and depression, with small to modest effect sizes ranging from adjusted odds ratios and hazard ratios of 1.2 to 2.0.4,5 Animal model studies represent an important mechanistic adjunct to these population-level data and have provided insights into the mechanisms underlying the potential impact of maternal diabetes and metabolic comorbidities on the developing fetal brain.4 Maternal-fetal hyperglycemia and consequent fetal hyperinsulinemia, chronic intrauterine tissue hypoxia, inflammation, and generation of reactive oxygen species by the developing brain; the mobilization of iron from the developing brain to maintain oxygen delivery to other tissues; and placental and brain lipotoxicity have all been demonstrated to play a role in abnormal fetal and offspring brain development in the setting of maternal diabetes and metabolic syndrome.4,6

In this population-based cohort study drawing from nationwide Danish birth registries spanning from 1978 to 2016, Noguiera Avelar e Silva and colleagues7 investigate associations between maternal pregestational and gestational diabetes and offspring risk for 10 types of psychiatric disorders over nearly 4 decades. After adjusting for numerous potential confounders, including maternal and paternal history of any psychiatric disorder, offspring sex, singleton vs multiple gestation, maternal parity, educational level, smoking, cohabitation during pregnancy, urban residence at birth, and age at delivery, the authors identified significant associations between maternal diabetes and increased offspring risk of schizophrenia, anxiety disorders, intellectual disabilities, neurodevelopmental disorders (language and scholastic deficits and autism spectrum disorders), and behavioral disorders (attention-deficit/hyperactivity disorder, conduct disorders, and emotional disorders), with hazard ratios ranging from 1.16 to 1.55. The largest effect sizes were noted for schizophrenia, intellectual disabilities, and anxiety disorders. Notably, after adjusting models further for maternal body mass index (BMI), they found that gestational diabetes remained significantly associated with schizophrenia, anxiety disorders, and behavioral disorders and that pregestational diabetes remained significantly associated with intellectual disabilities and developmental disorders. The BMI-adjusted vs BMI-unadjusted models demonstrate the difficulty in parsing the potential contributions of maternal prepregnancy obesity, gestational weight gain, and diabetes during pregnancy to adverse neurodevelopmental outcomes in offspring. These 3 maternal exposures are closely intertwined and have been found in large epidemiologic studies to be associated with an independent and sometimes synergistic risk for adverse offspring neurodevelopmental and psychiatric outcomes.4 As both obesity and diabetes increase among women of reproductive age,2,3 we can anticipate increasing rates of neurodevelopmental and psychiatric morbidity among children and young adults, portending a public health crisis of significant proportions.

This study was unique not only in its large size (capturing more than 2.4 million births) and long follow-up period (39 years of follow-up data; median follow-up of 19 years), but also in the comprehensive list of neurodevelopmental and psychiatric outcomes queried and the wide-ranging set of potential confounders adjusted for in the models. The sibship analyses also contributed to this study’s rigor, permitting an estimation of offspring risk attributable specifically to maternal diabetes. These analyses demonstrated that type 1 diabetes was associated with a 9% increase in the composite outcome of any psychiatric disorder and that type 2 diabetes was associated with a 28% increase in any psychiatric disorder, whereas gestational diabetes was not associated with any significant increase in the composite outcome. Although the generalizability of results from this cohort to more racially and ethnically diverse populations with a higher incidence of diabetes (approximately 15% of pregnancies are affected by maternal diabetes worldwide5,8 compared with the 2% incidence of exposed pregnancies in this cohort) remains an open question, the associations reported here represent a critical step toward understanding the potential relationship between maternal diabetes in pregnancy and adverse offspring neuropsychiatric outcomes. Future studies in this area should focus on the differential impact of maternal exposures on the developing fetal brain during critical developmental windows, including all trimesters of pregnancy and lactation. In addition, the “2-hit hypothesis” paradigm9 can be used to understand how underlying offspring genetic and environmental susceptibilities, as well as the additive or synergistic impact of other maternal pregnancy exposures, may coalesce to drive adverse neurodevelopmental outcomes in some but not all exposed offspring.

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Article Information

Published: October 14, 2021. doi:10.1001/jamanetworkopen.2021.29674

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Edlow AG. JAMA Network Open.

Corresponding Author: Andrea G. Edlow, MD, MSc, Vincent Center for Reproductive Biology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (

Conflict of Interest Disclosures: Dr Edlow is supported by grants R01HD100022, 3R01HD100022-S1, 3R01HD100022-S2, and 5U54MH118919 from the National Institutes of Health.

Zablotsky  B, Black  LI, Maenner  MJ,  et al.  Prevalence and trends of developmental disabilities among children in the United States: 2009-2017.   Pediatrics. 2019;144(4):e20190811. doi:10.1542/peds.2019-0811 PubMedGoogle Scholar
Deputy  NP, Kim  SY, Conrey  EJ, Bullard  KM.  Prevalence and changes in preexisting diabetes and gestational diabetes among women who had a live birth—United States, 2012-2016.   MMWR Morb Mortal Wkly Rep. 2018;67(43):1201-1207. doi:10.15585/mmwr.mm6743a2 PubMedGoogle ScholarCrossref
Hales  CM, Fryar  CD, Carroll  MD, Freedman  DS, Ogden  CL.  Trends in obesity and severe obesity prevalence in US youth and adults by sex and age, 2007-2008 to 2015-2016.   JAMA. 2018;319(16):1723-1725. doi:10.1001/jama.2018.3060 PubMedGoogle ScholarCrossref
Shook  LL, Kislal  S, Edlow  AG.  Fetal brain and placental programming in maternal obesity: a review of human and animal model studies.   Prenat Diagn. 2020;40(9):1126-1137. doi:10.1002/pd.5724 PubMedGoogle ScholarCrossref
Chen  S, Zhao  S, Dalman  C, Karlsson  H, Gardner  R.  Association of maternal diabetes with neurodevelopmental disorders: autism spectrum disorders, attention-deficit/hyperactivity disorder and intellectual disability.   Int J Epidemiol. 2021;50(2):459-474. doi:10.1093/ije/dyaa212 PubMedGoogle ScholarCrossref
Van Lieshout  RJ, Voruganti  LP.  Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms.   J Psychiatry Neurosci. 2008;33(5):395-404.PubMedGoogle Scholar
Nogueira Avelar e Silva  R, Yu Y, Liew Z, Vested A, Sørensen HT, Li J.  Associations of maternal diabetes during pregnancy with psychiatric disorders in offspring during the first 4 decades of life in a population-based Danish birth cohort.   JAMA Netw Open. 2021;4(10):e2128005. doi:10.1001/jamanetworkopen.2021.28005Google Scholar
Kong  L, Chen  X, Gissler  M, Lavebratt  C.  Relationship of prenatal maternal obesity and diabetes to offspring neurodevelopmental and psychiatric disorders: a narrative review.   Int J Obes (Lond). 2020;44(10):1981-2000. doi:10.1038/s41366-020-0609-4 PubMedGoogle ScholarCrossref
Maynard TM, Sikich L, Lieberman JA, LaMantia AS. Neural development, cell-cell signaling, and the "two-hit" hypothesis of schizophrenia.  Schizophr Bull. 2001;27(3):457-476. doi:10.1093/oxfordjournals.schbul.a006887
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