Gestational and neonatal risk factors for bipolar disorder? Researchers investigated these associations in a nationwide cohort with register-based data.
“Mr Smith” is a 58-year-old Caucasian male with a history of bipolar I disorder. His most recent episode involved depression without psychotic features. The onset of his illness was in his early 40s. After a second major depressive episode at age 52 years, he came to realize that he had been having episodes of mania over the past decade. He is currently stabilized on lithium.
Mr Smith reports that he has maternal half-siblings with a history of hospitalizations for depression, although has no other known relatives with bipolar disorder. His developmental history was significant for premature birth at approximately 29 to 30 weeks’ gestation, and his birth weight was just over 2000 grams. At an outpatient visit, he asks whether his developmental history contributed to his bipolar disorder. As his psychiatrist, how would you respond?
There is some evidence that pre- and perinatal factors are associated with risk of bipolar disorder, including preterm birth.1-3 However, findings for other factors—including elective caesarean birth, small-for-gestational age (SGA), and small head circumference—are mixed.3 The impact of pregnancy complications, such as gestational diabetes and preeclampsia, are similarly unclear. Previous studies have used obstetric complication scores,4,5 which does not permit inferences regarding specific individual risk factors.
The Current Study
Beer and colleagues6 used Swedish population registers to examine whether neonatal characteristics are related to risk of bipolar disorder in a nationwide cohort. They assessed whether specific underlying causes of preterm birth and SGA are associated with bipolar disorder in offspring. They also performed nested sibling-controlled comparisons to account for residual confounding by time-invariant shared familial (genetic and environmental) risk factors.
The authors conducted a population-based cohort study among live singleton children born at ≥ 22 gestational weeks between 1983 and 2004 in the Swedish Medical Birth Register. These data were lined with the National Patient Register, which includes hospital discharge diagnosis since 1987 and outpatient visits since 2001. Bipolar disorder was defined by ICD-9 or ICD-10 diagnosis at least twice on different occasions.
The primary neonatal characteristics of interest were gestational age at birth, birth weight for gestational age, head circumference for gestational age, and mode of delivery. Secondary pregnancy complications included gestational diabetes, preeclampsia, and placental abruption.
Gestational age was determined primarily by second trimester ultrasound (65%) or last menstrual period (32%). Births were classified as post-term (≥ 42 weeks), term (37 to 41 weeks), moderately preterm (32 to 36 weeks), very preterm (29 to 31 weeks), or extremely preterm (22 to 27 weeks). SGA was defined as a birth weight for gestational age < 3rd percentile.
Covariates included maternal age at delivery, maternal country of birth, maternal education, parity, maternal height, early-pregnancy body mass index (BMI), smoking, maternal infection, paternal age at delivery, parental bipolar disorder, and other parental psychiatric disorder.
Cohort members were followed starting at age 13 years until bipolar disorder diagnosis, emigration, death, or December 31, 2017. Risk of bipolar disorder by age 25 years was estimated using Cox proportional hazard models, adjusted for potential confounding factors. Full siblings in the cohort were identified using the Multigeneration Register. Sibling comparisons were analyzed using stratified Cox models in which each family was a stratum, adjusting for potential confounding factors.
The general cohort consisted of 2,059,578 children, with 14,998 diagnosed with bipolar disorder at a median age of 25 years (0.75%). Bipolar disorder risk increased with maternal and paternal age, BMI, smoking and infections during pregnancy, parental bipolar or other psychiatric disorder, and neonatal sepsis, and it decreased with maternal parity. The full sibling cohort consisted of 1,467,819 full siblings from 640,321 families and 10,008 cases of bipolar disorder.
In both cohorts, gestational diabetes, placental abruption, gestational age ≤ 31 weeks, SGA (hazard ratio [HR] 1.68 in the sibling cohort), preterm birth, and birth by caesarean section (HR 1.58 in the general cohort) were associated with increased risk of bipolar disorder. In the sibling cohort, compared with 37 weeks’ gestational age, the HRs for bipolar disorder at 31, 28, and 22 weeks’ gestation were 1.31, 2.09, and 5.74, respectively.
The authors concluded that in a nationwide cohort study of more than 2.1 million individuals, spontaneous preterm birth, caesarean section delivery, and SGA were associated with increased risk of bipolar disorder in offspring. By contrast, neither head circumference nor any pregnancy complications were associated with bipolar disorder.
Study strengths included use of a validated algorithm to define bipolar disorder,7 a population-based design with nationwide registers, and use of a sibling-controlled cohort. Study limitations included relative sociodemographic homogeneity of the Swedish population, potential bias in the sibling cohort, and absence of data on bipolar I versus bipolar II disorder.
The Bottom Line
Specific neonatal characteristics, including spontaneous preterm birth, caesarean section delivery, and SGA—but not gestational complications—are associated with risk of bipolar disorder in offspring. Findings are relevant to the role of neurodevelopment in the etiology of bipolar disorder.
Dr Miller is a professor in the Department of Psychiatry and Health Behavior at Augusta University in Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times®. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
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2. Øgendahl BK, Agerbo E, Byrne M, et al. Indicators of fetal growth and bipolar disorder: a Danish national register-based study. Psychol Med. 2006;36(9):1219-1224.
3. Chudal R, Sourander A, Polo-Kantola P, et al. Perinatal factors and the risk of bipolar disorder in Finland. J Affect Disord. 2014;155:75-80.
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5. Kinney DK, Yurgelun-Todd DA, Tohen M, Tramer S. Pre- and perinatal complications and risk for bipolar disorder: a retrospective study. J Affect Disord. 1998;50(2-3):117-124.
6. Beer RJ, Cnattingius S, Susser ES, Villamor E. Associations of pregnancy complications and neonatal characteristics with bipolar disorder in the offspring: nationwide cohort and sibling-controlled studies. Bipolar Disord. 2023;25(4):312-322.
7. Sellgren C, Landén M, Lichtenstein P, et al. Validity of bipolar disorder hospital discharge diagnoses: file review and multiple register linkage in Sweden. Acta Psychiatr Scand. 2011;124(6):447-453.