Gestational Influenza Increases Risk for Bipolar Disorder

Kathleen Louden

May 08, 2013

If a woman has influenza during pregnancy, her child has a nearly 4-fold increased risk of having bipolar disorder later in life, new research shows.

"We now have evidence that maternal influenza is related to increased risk of bipolar disorder in the offspring," study coinvestigator Alan Brown, MD, told Medscape Medical News. "This suggests that prevention of influenza during pregnancy could reduce the risk of bipolar disorder."

Dr. Brown, a professor of clinical psychiatry and epidemiology at Columbia University Medical Center, New York City, conducted the study with researchers from the New York State Psychiatric Institute, also in New York City; Kaiser Permanente, in Oakland, California; and the University of KwaZulu-Natal, in Durban, South Africa.

The findings were published online May 8 in JAMA Psychiatry.

These results lend further support to the possibility of a viral cause of certain psychiatric disorders. Dr. Brown and his collaborators earlier found that the risk for schizophrenia increases with fetal exposure to maternal influenza virus ( Arch Gen Psychiatry 2004;61:774-780).

Prospective Diagnosis of Influenza

The new research was a nested case-control study that evaluated a population-based birth cohort from the Child Health and Development Studies, performed from 1959 to 1966 in pregnant women receiving obstetric care from Kaiser Permanente Health Plan's Northern California region.

The women's medical records were searched for physician-diagnosed influenza from before the last menstrual cycle to the time of delivery.

From among the women's live-born offspring, the researchers determined those with a potential diagnosis of bipolar disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision).

They obtained that information through the sons' and daughters' medical records at Kaiser Permanente and at a county behavioral healthcare facility as well as through a mailing to the mothers and adult offspring in the birth cohort.

The investigators confirmed the diagnosis of bipolar disorder through interviews of 214 individuals and found 72 cases of the disorder. They found another 23 interview-confirmed cases of bipolar disorder from an earlier study, the Prenatal Determinants of Schizophrenia Study, which also had asked individuals about bipolar disorder. Of the 95 case patients, 3 were excluded because of missing influenza data or because the patient was the sibling of a case patient, leaving 92 participants in the final study sample.

Matched control participants (n = 722) were selected from the same birth cohort; these individuals did not have a psychiatric disorder, according to Dr. Brown. There were no significant differences in demographic characteristics between affected case patients and unaffected control participants, the article showed.

Bipolar disorder had 3.82 times the odds of developing in offspring whose mother had influenza any time during pregnancy than in those who were not exposed to the influenza virus in the womb (95% confidence interval [CI], 1.58 - 9.24; P = .003), the authors reported. The association reportedly remained significant after adjustment for maternal age, race, education, and psychiatric disorders as well as gestational age.

In addition, a secondary analysis showed no association between bipolar disorder and maternal respiratory tract viruses other than influenza, as stated in the article.

When the researchers performed statistical analyses by each pregnancy trimester, only the third trimester showed a significant association between bipolar disorder and gestational influenza exposure (odds ratio [OR], 4.72; 95% CI, 1.13 - 19.76; P = .03).

However, Dr. Brown pointed out that the sample size was small, inasmuch as only 8 of the 92 case patients with bipolar disorder and 19 of the 722 control participants had in utero exposure to influenza. Therefore, he said, it is unclear when the potential insult might occur during pregnancy.

The authors did note that women who had influenza during pregnancy were significantly more likely to have a history of a psychiatric disorder (P = .04). However, after they adjusted for that potential confounder, the association between maternal influenza and adult offspring's increased risk for bipolar disorder remained, Dr. Brown said.

Strengths of the study, said Dr. Brown, included the prospectively documented diagnoses of influenza during pregnancy and the follow-up of all offspring through the years during which bipolar disorder most often has its onset. The youngest offspring in the cohort were 45 years old at study completion in 2011, he stated.

Limitations include the fact that the researchers have not yet analyzed archived maternal serum samples, he said.

Prevention Possible?

As with any observational study, Dr. Brown recommended more studies in other populations to try to replicate the findings. If prenatal influenza exposure is a cause of bipolar disorder, the authors suggest preventive measures for women of childbearing age, such as receiving prepregnancy vaccination against influenza and avoiding people with a respiratory tract infection during pregnancy.

The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommends that pregnant women receive routine immunization with the influenza injection, which contains killed virus.

Dr. Brown said his team did not recommend immunization during pregnancy because vaccination stimulates the immune response, and they theorize that an immune response in influenza triggers a chain of events leading to altered fetal brain development and bipolar disorder.

"I believe there's more benefit than potential harm to influenza vaccination during pregnancy, and there is no evidence in the literature of harm [to the fetus], but we can't rule out the possibility of harm," he said.

Cause Not Clear

Asked by Medscape Medical News to comment on this study, Robert Yolken, MD, a virologist and professor of pediatrics at Johns Hopkins Children's Center in Baltimore, Maryland, said the article was very good.

"It certainly adds to the growing body of evidence that some problems of early neurodevelopment are related to infection exposure in pregnancy," he said.

Although Dr. Yolken did not participate in the study, he does conduct research into how exposure to infectious agents, particularly during pregnancy, might be involved in the development of psychiatric disorders.

"These kinds of prospective studies are critical...and are the best way of answering these questions," he said.

Although Dr. Yolken agreed that an immune reaction is one possible explanation for the risk the authors observed from gestational influenza exposure, he said the cause could be the flu virus itself. Regardless, he said that study results published so far show that the immune response caused by the killed influenza vaccine is not the same as that for the virus.

More research is needed, he said, to understand why "many people get influenza before and during pregnancy, and only a small number of their infants later develop bipolar disorder."

This study was funded by the National Institute of Mental Health and the National Institute of Child Health and Development. Dr. Brown and his coauthors have reported no relevant financial relationships. Dr. Yolken has reported no relevant financial relationships.

JAMA Psychiatry. Published online May 8, 2013. Abstract

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