Pregnancy, Influenza & Elevated Psychosis Risks In Adult Offspring

Photo Credit – CDC

 

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It’s been well documented that influenza and pregnancy are a bad combination - one that can endanger both the mother and unborn child’s life – and that women are more susceptible to influenza while (and just after) they are pregnant. It is for this reason that the CDC encourages all pregnant women to get the flu shot (see Pregnant Women & Influenza (Flu)).

 

These risks were well illustrated in an open access research article in the BMJ in 2011 (Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study) that found that pregnant women who were admitted to the hospital with an  H1N1 infection experienced a 3 to 4 times higher rate of preterm birth, 4 to 5 times greater risk of stillbirth, and a 4 to 6 times higher rate of neonatal death.

 

But over the past decade we’ve also seen evidence of a less obvious, and long-delayed, impact of these type of infections.  Namely, an increase in a variety of child, adolescent, and adult development disorders experienced by offspring who were exposed to the flu (or the mother’s immune response) while in the womb.

 

A few examples include:

• In a 2004 study (Serologic evidence of prenatal influenza in the etiology of schizophrenia  Brown et al.) found a 7-fold increase in the risk of developing schizophrenia when exposed to influenza during the first trimester. No increased risk was found for exposure during the second and third trimester.

• Another study from 2008 (Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8  Ellman et al.) suggested that it was prenatal exposure to a type of protein - (proinflammatory cytokines, specifically interleukin-8) – produced by the body during viral infections, that can lead (in rare cases) to brain abnormalities.

• In 2012 research by a team at UC Davis found that fever (from any cause) during pregnancy more than doubled the odds of having a child with autism or developmental delays (see  Is Maternal Influenza or Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study Zerbo et al.) 
• In November of  2012, in Of Pregnancy, Flu & Autism, we saw a study that found a twofold increase in autism among children with prenatal influenza exposure, and a threefold increase in autism among children with prolonged prenatal fever exposure
• And just last year (May, 2013) we looked at a JAMA Psychiatry report that linked bipolar disorder (BD) to influenza exposure while still in the womb  (see Pregnancy, Influenza, & Bipolar Disorder In Offspring).

 

These studies are admittedly small and less than conclusive, and while they suggest an increase in relative risk over pregnancies without fever or viral infection – in terms of absolute risk – the odds that a mother’s fever or viral infection during pregnancy would result in a developmentally challenged child remains low.

 

We’ve a new study, this time appearing in the American Journal of Psychiatry that adds to, and reinforces some of these earlier studies.  While not finding a statistically significant link between maternal pregnancy and bipolarity in offspring (odds ratio of 1.26), when they refined it to bipolar disorder with psychosis, they determined a nearly fivefold increased risk.

The authors explain:

 

“Since prenatal influenza has been previously associated with schizophrenia, a disorder characterized in large part by psychotic episodes such as hallucinations and delusions, our results support the hypothesis that maternal influenza exposure may preferentially increase the risk for psychosis apart from traditional diagnostic categories.”

 

Although more research is needed to validate these findings, the authors suggest that prevention of maternal influenza infection may decrease the incidence of bipolar disorder with psychotic features in the population.

 

Serological Documentation of Maternal Influenza Exposure and Bipolar Disorder in Adult Offspring

Sarah E. Canetta, Ph.D.; Yuanyuan Bao, M.S.; Mary Dawn T. Co, M.D.; Francis A. Ennis, M.D.; John Cruz, B.S.; Masanori Terajima, M.D., Ph.D.; Ling Shen, Ph.D.; Christoph Kellendonk, Ph.D.; Catherine A. Schaefer, Ph.D.; Alan S. Brown, M.D., M.P.H.

Abstract

Objective The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features.

Method The study used a nested case-control design in the Child Health and Development Study birth cohort. In all, 85 individuals with bipolar disorder were identified following extensive ascertainment and diagnostic assessment and matched to 170 comparison subjects in the analysis. Serological documentation of maternal exposure to influenza was determined using the hemagglutination inhibition assay.

Results No association was observed between serologically documented maternal exposure to influenza and bipolar disorder in offspring. However, maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features.

Conclusions The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis.

 

 

Obviously this is a major concern for expectant mothers, but we’ve also seen evidence that the influenza virus can be neurotropic - capable of infecting and damaging brain cells – in people of any age, not just those in the womb.

 

• see Revisiting The Influenza-Parkinson’s Link 
• see  Lancet: The Influenza - Guillain Barré Syndrome Connection
• see Stanford Study Finds Influenza – Narcolepsy Connection

 

When you consider the potential long-term health effects of influenza infection – rare or not – it makes sense to do whatever one can reasonably do to avoid infection. 

 

And that means getting the flu shot every year, avoiding people when they are obviously sick, and practicing good flu hygiene (covering coughs, washing hands, avoid touching face) year round.

Pregnancy, Influenza, & Bipolar Disorder In Offspring

Photo Credit – CDC

 

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While we await the next installment in the nCoV and H7N9 story, we’ve a new study that appeared yesterday in JAMA Psychiatry, that links bipolar disorder (BD) to influenza exposure while still in the womb.

 

Some background information on BD from the NIMH, that shows millions of Americans suffer to one degree or another from this disorder.

 

Bipolar Disorder Among Adults

Bipolar disorder, sometimes referred to as manic-depressive disorder, is characterized by dramatic shifts in mood, energy, and activity levels that affect a person’s ability to carry out day-to-day tasks. These shifts in mood and energy levels are more severe than the normal ups and downs that are experienced by everyone.

 

Additional information about bipolar disorder can be found on NIMH’s bipolar disorder page.

 

As you might imagine, it takes the review of decades of health data to link a viral exposure in the womb to the development of any adult-onset illness.  

 

And that’s exactly what researchers from Columbia University Medical Center, the New York State Psychiatric Institute, Kaiser Permanente, in Oakland, California; and the University of KwaZulu-Natal Durban, South Africa did.

 

Using data derived from Kaiser Permanente Health Plan's Northern California region, researchers checked for influenza diagnoses among pregnant women enrolled between 1959 and 1966, and then followed up on their offspring’s medical records for diagnoses consistent with bipolar disorder later in life.

 

Based on a relatively small, and geographically limited data set, researchers found a nearly 4-fold increase (3.82 times) in bipolar disorder among offspring whose mother had experienced an influenza infection during pregnancy, compared to offspring not exposed to the virus as a fetus.

 

First a link to the study (and some excerpts from the abstract), then I’ll return with more.

 

 

Gestational Influenza and Bipolar Disorder in Adult Offspring

Raveen Parboosing, MBChB, MMed, FCPath(SA)(Viro), MS; Yuanyuan Bao, MS; Ling Shen, PhD; Catherine A. Schaefer, PhD; Alan S. Brown, MD, MPH

JAMA Psychiatry. 2013;():1-8. doi:10.1001/jamapsychiatry.2013.896.

(EXCERPT)

Main Outcome and Measures  Bipolar I or II disorder, BD not otherwise specified, or BD with psychotic features.

Results  We found a significant, nearly 4-fold increase in the risk of BD (odds ratio, 3.82 [95% CI, 1.58-9.24; P = .003]) after exposure to maternal influenza at any time during pregnancy. The findings were not confounded by maternal age, race, educational level, gestational age at birth, and maternal psychiatric disorders.

Conclusions and Relevance  Maternal influenza may be a risk factor for BD. Although replication is required, the findings suggest that prevention of maternal influenza during pregnancy may reduce the risk of BD.

 

As with all observational studies, there are some weaknesses that must be considered, including: the relatively small cohort of patients studied, the lack of lab confirmation of maternal flu diagnosis, and difficulties in finding intact medical histories on offspring.  

 

That said, over the past decade we’ve seen a growing number of studies that have tentatively linked prenatal exposure to influenza (or an influenza-like-illness) to a variety of child, adolescent, and adult psychiatric and developmental disorders. 

 

A few examples include:

• In a 2004 study (Serologic evidence of prenatal influenza in the etiology of schizophrenia  Brown et al.) found a 7-fold increase in the risk of developing schizophrenia when exposed to influenza during the first trimester. No increased risk was found for exposure during the second and third trimester.
• Another study from 2008 (Structural brain alterations in schizophrenia following fetal exposure to the inflammatory cytokine interleukin-8  Ellman et al.) suggested that it was prenatal exposure to a type of protein - (proinflammatory cytokines, specifically interleukin-8) – produced by the body during viral infections, that can lead (in rare cases) to brain abnormalities.
• Last year, research by a team at UC Davis found that fever (from any cause) during pregnancy more than doubled the odds of having a child with autism or developmental delays (see  Is Maternal Influenza or Fever During Pregnancy Associated with Autism or Developmental Delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) Study Zerbo et al.) 
• In November of last year, in Of Pregnancy, Flu & Autism, we saw a study that found a twofold increase in autism among children with prenatal influenza exposure, and a threefold increase in autism among children with prolonged prenatal fever exposure

 

It should be noted that these studies looked at relative risk increases, and that the absolute risk of offspring developing these psychiatric or developmental disorders later in life – regardless of exposure in the womb - is still fairly low.

 

Debated also is whether these disorders might be caused by an immune response to infection by the mother, or fetal exposure to the virus itself.

 

While the jury is still out, we’ve seen evidence that the influenza virus can be neurotropic - capable of infecting and damaging brain cells. For a recent review of this supposed link, see Revisiting The Influenza-Parkinson’s Link.

 

For these, and other reasons, the CDC and many other public health entities continue to stress the importance of seasonal flu vaccination for pregnant women.

 

In October of 2011, in IDSA: Flu Vaccines In Pregnancy, we saw several studies presented at the 49th Annual Meeting of the Infectious Diseases Society of America (IDSA) reaffirming the benefits and safety of maternal vaccination.

 

The CDC has synopsized these studies in:

 

Pregnancy and Influenza Vaccine Safety

 

Vaccines are drugs, and there is no such thing as a 100% safe and 100% effective drug. Even taking over-the-counter medicines entail some risks.

 

But the safety profile of flu vaccines is excellent, and serious side effects are exceedingly rare.

 

The overwhelming evidence shows that the real risk comes from the virus, not from the shot.