Prenatal metabolic risks for offspring neurodevelopmental and psychiatric disorders

Prenatal metabolic disturbances have been reported to increase the risk for offspring adverse outcomes. However, the joint (i.e. combined) effects of several prenatal metabolic exposures on offspring neurodevelopmental and psychiatric disorders are less well documented, and few studies have investigated the associations between prenatal metabolic risks and offspring neurodevelopmental and psychiatric disorders other than attention-deficit/hyperactivity disorders (ADHD) and autism spectrum disorders (ASD). This thesis aims to explore if, and at what magnitude, prenatal metabolic risks are associated with adverse birth outcomes and offspring neurodevelopmental and psychiatric disorders.

Study I and II investigated the combined effects of maternal pre-gestational obesity and different types of diabetes on the risk for offspring neurodevelopmental and psychiatric disorders, using a population-based cohort. All live births in Finland between 2004 and 2014 (n=649 043) were included with a followed-up until 2014. Cox proportional hazards regression analyses with adjustment for possible maternal and birth-related confounders were used to estimate the effect of the exposures by maternal diabetes, stratified by categories of maternal body mass index (BMI), on the outcomes of offspring neurodevelopmental and psychiatric disorders and offspring prescription of psychotropic drugs. Study I found that the combination of maternal insulin-treated pre-gestational diabetes mellitus (PGDM) and severe obesity was associated with a markedly higher risk for any neurodevelopmental and psychiatric disorder in offspring (Hazard ratios [HR]=2.97; 95% CI, 2.23–3.96), than severe obesity (HR=1.45; 95% CI, 1.35–1.56) or PGDM (HR=1.17; 95% CI, 0.99–1.39) alone. Gestational diabetes mellitus (GDM) did not increase the risk for these disorders. Study II found that compared with normal-weight mothers without diabetes, pre-gestational type 2 diabetes (T2DM) without insulin treatment in severely obese mothers was associated with any neurodevelopmental and psychiatric disorders in offspring (HR=1.97; 95% CI, 1.64–2.37), although with a lower effect size than that for severely obese mothers with insulin-treated PGDM (HR=2.71; 95% CI, 2.03–3.61). GDM with severe obesity had a lower overall effect size (HR=1.61; 95% CI, 1.50–1.72).

Study III examined whether maternal polycystic ovary syndrome (PCOS) or anovulatory infertility is associated with an increased risk for offspring neurodevelopmental and psychiatric disorders up to 22 years of age, using a population-based Finnish cohort including all live births (n=1 105 997) between 1996 and 2014 with a follow-up until December 2018. Cox proportional hazards regression analyses and stratified analyses, with adjustment for possible maternal and birth-related confounders, were conducted. The role of PCOS, independently or jointly with maternal obesity, GDM, cesarean delivery, perinatal problems and use of fertility treatment, was studied. Results showed that maternal PCOS was associated with several neurodevelopmental and psychiatric disorders in offspring (HR for any diagnosis=1.32; 95% CI, 1.27–1.38). Compared to offspring to normal-weight mothers without PCOS, the risk for these offspring disorders was markedly higher in those to severely obese mothers with PCOS (HR=2.11; 95% CI, 1.76–2.53). GDM, cesarean delivery and perinatal problems could explain part of the effect sizes, but fertility treatment could not.

Study IV evaluated whether maternal preeclampsia, alone or jointly with perinatal problems (indicating severe preeclampsia), associated with the risk for offspring neurodevelopmental and psychiatric disorders using a Finnish population-based cohort of more than 1 million births between 1996 and 2014 with a follow-up until December 2018. Cox proportional hazards regression analyses and sibling pair analyses were used. This study found an increased risk of specific developmental disorders (adjusted HR=2.82; 95% CI, 2.60–3.05), attention-deficit/hyperactivity disorders and conduct disorders (adjusted HR=1.88; 95% CI, 1.65–2.14) in offspring of mother with severe preeclampsia, which were beyond those of perinatal problems or mild preeclampsia alone. The sibling pair analysis suggested that the associations detected between severe preeclampsia and offspring neurodevelopmental and psychiatric disorders were not explained by familial confounding.

Study V and VI examined associations of maternal diabetes and maternal BMI with offspring having abnormal birth weight and/or being preterm at birth including all live births in Finland from 2004 to 2014 (in Study V), and associations between prematurity and/or abnormal birth weight with offspring neurodevelopmental and psychiatric disorders including all live births in Finland from 1996 to 2014 (in Study VI). Study V showed that maternal insulin-treated PGDM was associated with markedly increased risks for large for gestational age (LGA) births (Adjusted odds ratio [OR]=43.80; 95% CI, 40.88–46.93) and preterm births (OR=11.17; 95% CI, 10.46–11.93) regardless of the maternal pre-pregnancy BMI, whereas obese mothers with T2DM had mild to moderately increased risks for LGA births (OR=12.44; 95% CI, 10.29–15.03) and prematurity (OR=2.14; 95% CI, 1.70–2.69). Further, Study VI found that preterm birth (moderately preterm: HR=1.43, 95% CI, 1.38–1.47; very preterm: HR=2.86, 95% CI, 2.67–3.07; and extremely preterm: HR=5.40, 95% CI, 4.95–5.89) and abnormal birth size (small for gestational age [SGA]: HR=1.53, 95% CI, 1.48–1.59; LGA: HR=1.14, 95% CI, 1.09–1.20) were each associated with the risk for offspring neurodevelopmental and psychiatric disorders with larger effect sizes for those born with both exposures (very preterm & SGA: HR=5.15, 95% CI, 4.56–5.81; moderately preterm & SGA: HR=1.92, 95% CI, 1.75–2.10). Sibling pair analyses indicated that these associations were not explained by unmeasured familial confounding.

Taken together these studies strongly suggest that prenatal and perinatal risk factors should be considered in relation to offspring neurodevelopmental and psychiatric disorders. It is proposed that future studies aimed at reducing such risk factors should be performed.

List of scientific papers

I. Linghua Kong, Gunnar Norstedt, Martin Schalling, Mika Gissler, Catharina Lavebratt. The Risk of Offspring Psychiatric Disorders in the Setting of Maternal Obesity and Diabetes. Pediatrics. 2018, 142(3): e20180776.
https://doi.org/10.1542/peds.2018-0776

II. Linghua Kong, Ida A. K. Nilsson, Kerstin Brismar, Mika Gissler, Catharina Lavebratt. Associations of Different Types of Maternal Diabetes and Body Mass Index with Offspring Psychiatric Disorders. JAMA Network Open. 2020, 3(2): e1920787.
https://doi.org/10.1001/jamanetworkopen.2019.20787

III. Xinxia Chen, Linghua Kong, Terhi T. Piltonen, Mika Gissler, Catharina Lavebratt. Association of Polycystic Ovary Syndrome or Anovulatory Infertility with Offspring Psychiatric and Mild Neurodevelopmental Disorders: a Finnish Population-based Cohort Study. Human Reproduction, 2020, 35(10): 2336-2347.
https://doi.org/10.1093/humrep/deaa192

IV. Linghua Kong, Xinxia Chen, Yajun Liang, Yvonne Forsell, Mika Gissler, Catharina Lavebratt. Association of Severe Preeclampsia with Offspring Neurodevelopmental and Psychiatric Disorders. [Submitted]

V. Linghua Kong, Ida A. K. Nilsson, Mika Gissler, Catharina Lavebratt. Associations of Maternal Diabetes and Body Mass Index with Offspring Birth Weight and Prematurity. JAMA Pediatrics. 2019, 173(4): 371-378.
https://doi.org/10.1001/jamapediatrics.2018.5541

VI. Linghua Kong, Xinxia Chen, Mika Gissler, Catharina Lavebratt. Association of Preterm Birth and Abnormal Birth Size with Neurodevelopmental and Psychiatric Disorders in Spontaneous Births. [Manuscript]