Complications of pregnancy, neonatal characteristics and bipolar disorder in offspring



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, he realized he had been having episodes of mania for 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 he has no other known relatives with bipolar disorder. His developmental history was significant for his premature birth at about 29-30 weeks gestation and his birth weight was just over 2000 grams. During an office visit, he asks if his developmental history has 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 for bipolar disorder, including being born preterm.1-3 However, findings for other factors, including elective cesarean delivery, reduced gestational age (SGA), and reduced head circumference, are mixed.3 Similarly, the impact of pregnancy complications, such as gestational diabetes and preeclampsia, is unclear. Previous studies have used obstetric complication scores,4.5 which does not allow inferences about specific individual risk factors.

The current study

Beer and colleagues6 used Swedish population registries to examine whether neonatal characteristics correlate with bipolar disorder risk in a national cohort. They evaluated whether specific underlying causes of preterm birth and SGA are associated with bipolar disorder in the offspring. They also performed sibling-controlled nested comparisons to account for residual confounding due to shared, time-invariant familial risk factors (genetic and environmental).

The authors conducted a population-based cohort study among live single infants born at 22 weeks’ gestation between 1983 and 2004 in the Swedish Medical Birth Registry. These data were aligned with the National Patient Register, which includes hospital discharge diagnoses since 1987 and outpatient visits since 2001. Bipolar disorder has been defined by ICD-9 or ICD-10 diagnosis at least twice on different occasions.

The main 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 mainly determined by second trimester ultrasound (65%) or last menstrual period (32%). Births were classified as postterm (42 weeks), full term (37 to 41 weeks), moderately preterm (32 to 36 weeks), very preterm (29 to 31 weeks), or extremely preterm (22 to 31 weeks). 27 weeks). SGA it was defined as 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, infection maternal, paternal age at delivery, parental bipolar disorder, and other parental psychiatric disorders.

Members of the cohort were followed up from age 13 until diagnosis of bipolar disorder, emigration, death, or December 31, 2017. Risk of bipolar disorder at age 25 was estimated using Cox proportional hazards models, adjusted for potential confounding factors. Full siblings in the cohort were identified using the multigenerational registry. Sibling comparisons were analyzed using stratified Cox models in which each family was a stratum, adjusting for potential confounding factors.

The overall cohort consisted of 2,059,578 children, with 14,998 diagnosed with bipolar disorder at a mean age of 25 years (0.75%). Bipolar disorder risk increased with maternal and paternal age, BMI, smoking and infections during pregnancy, parental bipolar disorder or other psychiatric disorders, and neonatal sepsis, and decreased with maternal parity. The sibling cohort consisted of 1,467,819 sibs from 640,321 families and 10,008 cases of bipolar disorder.

In both cohorts, gestational diabetes, placental abruption, gestational age 31 weeks, hazard ratio [HR] HR 1.68 in the sibling cohort), preterm delivery, and delivery by cesarean section (HR 1.58 in the overall cohort) were associated with an increased risk of bipolar disorder. In the sibling cohort, relative to 37 weeks’ gestational age, the HRs for bipolar disorder at 31, 28, and 22 weeks of gestation were 1.31, 2.09, and 5.74, respectively.

Study conclusions

The authors concluded that in a national cohort study of over 2.1 million individuals, spontaneous preterm delivery, cesarean delivery, and SGA were associated with an increased risk of bipolar disorder in offspring. In contrast, neither head circumference nor any pregnancy complications have been associated with bipolar disorder.

Study strengths included the use of a validated algorithm to define bipolar disorder,7 a population-based design with national registries and the use of a sibling controlled cohort. Limitations of the study included the relative sociodemographic homogeneity of the Swedish population, potential bias in the sibling cohort, and the absence of data on bipolar I disorder versus bipolar II disorder.

The bottom line

Specific neonatal characteristics, including spontaneous preterm delivery, cesarean delivery, and SGA, but not gestational complications, are associated with the risk of bipolar disorder in the offspring. The 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 sits on the editorial board and serves as section head for schizophrenia 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.


1. Nosarti C, Reichenberg A, Murray RM, et al. Preterm birth and psychiatric disorders in young adult life.Arch Gen Psychiatry. 2012;69(6):E1-E8.

2. gendahl BK, Agerbo E, Byrne M, et al. Fetal growth indicators and bipolar disorder: a study based on the Danish national register.Psychol Med. 2006;36(9):1219-1224.

3. Chudal R, Sourander A, Polo-Kantola P, et al. Perinatal factors and risk of bipolar disorder in Finland.J Affective disorder. 2014;155:75-80.

4. Kinney DK, Yurgelun-Todd DA, Levy DL, et al. Obstetrical complications in patients with bipolar disorder and their siblings.Psychiatry Res. 1993;48(1):47-56.

5. Kinney DK, Yurgelun-Todd DA, Tohen M, Tramer S. Pre- and perinatal complications and the risk of bipolar disorder: a retrospective study.J Affective disorder. 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 offspring: national cohort and sibling-controlled studies.Bipolar disorder. 2023;25(4):312-322 .

7. Sellgren C, Landn M, Lichtenstein P, et al. Validity of hospital discharge diagnoses of bipolar disorder: File review and linking of multiple registries in Sweden.Acta Psychiatr Scand. 2011;124(6):447-453.

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