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Although our understanding continues to evolve and grow, we know that some types of maternal infections (Cytomegalovirus (CMV), Rubella, Zika, etc.) can greatly increase the chances that a child developing in utero will be born with some type of (often profound) developmental or physical defect.
Less well understood are the potential long-term, and less obviously connected, neuropsychiatric illnesses (i.e. autism spectrum disorder, depression, suicide risk, etc) that may arise later in life as a result of these types of exposures.Over the past dozen years we've looked at a number of studies that have attempted to quantify the impact of influenza and other viral infections on both pregnant women and their offspring.
While some of these studies are more compelling than others, we've seen a wide range of sequelae linked to maternal flu infection, including:
- A 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 in 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).
More recently, in 2017's Molecular Psy.: Increased Autism Risk Linked To Prenatal Fever, we saw study that found maternal fever in the 2nd trimester was linked to a 40% increased risk of autism.Adding additional weight to these concerns, yesterday JAMA Psychiatry published an impressively large, multi-decade study, on the risk of developing neuropsychiatric disease that found (emphasis mine).
`. . . those people whose mothers had been hospitalized for any infection during pregnancy had a 79 percent higher risk of being diagnosed with autism and a 24 percent increased risk of being diagnosed with depression.'First some excerpts from the Abstract (follow the link to read it in its entirety), followed by some excerpts from a press release by the UW School of Medicine.
Original Investigation
March 6, 2019
Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero
Benjamin J. S. al-Haddad, MD, MSc, PhD1; Bo Jacobsson, MD, PhD2,3; Shilpi Chabra, MD1; et al Dominika Modzelewska, MS2; Erin M. Olson, PhD4,5; Raphael Bernier, PhD6; Daniel A. Enquobahrie, MD, PhD4; Henrik Hagberg, MD, PhD2,7; Svante Östling, MD, PhD8; Lakshmi Rajagopal, PhD1,9,10; Kristina M. Adams Waldorf, MD2,11; Verena Sengpiel, MD, PhD2
JAMA Psychiatry. Published online March 6, 2019. doi:10.1001/jamapsychiatry.2019.0029Key PointsAbstract
Question Does exposure to maternal infection during pregnancy increase the long-term risk for major psychiatric disorders in the child?
Findings In this Swedish population-based cohort study of children born between 1973 and 2014, exposure to infection in pregnancy significantly increased the risk for autism spectrum disorder and depression.
Meaning Maternal infection during pregnancy may be responsible for some portion of autism and depression in childhood and adulthood among the exposed offspring.
(EXCERPTS)
Design, Setting, and Participants A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries. Children were excluded if they were born too late to contribute person-time, died before being at risk for the outcome, or were missing particular model data. Infection and psychiatric diagnoses were derived using codes from hospitalizations. Directed acyclic graphs were developed from a systematic literature review to determine Cox proportional hazards regression models for risk of psychopathologic conditions in the children. Results were evaluated using probabilistic and simple bias analyses. Statistical analysis was conducted from February 10 to October 17, 2018.
(SNIP)
Results A total of 1 791 520 Swedish-born children (48.6% females and 51.4% males) were observed from birth up to age 41 years, with a total of 32 125 813 person-years. Within the directed acyclic graph framework of assumptions, fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism (hazard ratio [HR], 1.79; 95% CI, 1.34-2.40) or depression (HR, 1.24; 95% CI, 1.08-1.42). Effect estimates for autism and depression were similar following a severe maternal infection (autism: HR, 1.81; 95% CI, 1.18-2.78; depression: HR, 1.24; 95% CI, 0.88-1.73) or urinary tract infection (autism: HR, 1.89; 95% CI, 1.23-2.90; depression: HR, 1.30; 95% CI, 1.04-1.61) and were robust to moderate unknown confounding. Within the directed acyclic graph framework of assumptions, the relationship between infection and depression was vulnerable to bias from loss to follow-up, but separate data from the Swedish Death Registry demonstrated increased risk of suicide among individuals exposed to pregnancy infection. No evidence was found for increased risk of bipolar disorder or psychosis among children exposed to infection in utero.
Conclusions and Relevance These findings suggest that fetal exposure to a maternal infection while hospitalized increased the risk for autism and depression, but not bipolar or psychosis, during the child’s life. These results emphasize the importance of avoiding infections during pregnancy, which may impart subtle fetal brain injuries contributing to development of autism and depression.
(Continue . . . .)
From the press release.
March 6, 2019
For immediate release
Pregnancy infection increases a child’s autism, suicide risk
Study found increased risk for depression, suicide in children whose mothers were hospitalized during pregnancy.
Media Contact:
Barbara Clements, bac60@uw.edu, 206.221.6706
The increased risk was seen even when the mothers were treated for infections generally considered mild.
Children whose mothers were hospitalized with an infection during pregnancy may be at increased risk for autism, depression and suicide later in life, according to a new study by researchers at the University of Washington School of Medicine in Seattle, Washington, and the Sahlgrenska Academy in Gothenburg, Sweden.
Previous research has indicated that infections caused by specific pathogens, such as cytomegalovirus and the herpes virus, can cause fetal brain injury, abnormal brain development and an increased risk for certain psychiatric disorders.
The findings, published March 6 in JAMA Psychiatry, suggest that any infection in the mother during pregnancy—even those of microbes that do not invade the fetal brain—may increase a child’s risk of developing autism and depression.
“These findings suggest that preventing any infection in mothers during pregnancy may be important for the long-term health of their children,” said lead author Benjamin al-Haddad, who at the time of the study was a pediatric resident at the UW School of Medicine.
The researchers analyzed the hospital records of nearly 1.8 million people born in Sweden between 1973 and 2014, from birth to age 41. That people whose mothers had been hospitalized for any infection during pregnancy had a 79 percent higher risk of being diagnosed with autism and a 24 percent increased risk of being diagosed with depression. No increased risk was detected for two other disorders: psychosis, including schizophrenia, and bipolar disorder.
The increased risk was observed even when the mothers were treated for infections generally considered mild, such as those of the urinary tract.
It is unclear how an infection by a microbe that does not directly attack the fetal brain could nevertheless affect its development, said al-Haddad. Research has shown that exposure to inflammatory proteins released by the mother’s immune system to fight off infection may affect gene expression in fetal brain cells. Other research suggests that inflammation may increase the production of serotonin, a neurotransmitter, by the placenta, which may alter fetal brain development, he said.
The study was co-led by Kristina Adams Waldorf, a professor of obstetrics and gynecology at the UW School of Medicine, and Verena Sengpiel, an associate professor in obstetrics and gynecology at Sahlgrenska Academy.
(Continue . . . ).
While this study obviously includes other types of infection beyond influenza, the flu is a common cause of maternal hospitalization, and can have serious outcomes for both the mother and her unborn child (see Study: Outcomes Of Infants Born To Women With Influenza A(H1N1)pdm09).
Despite ample evidence of flu's harm to expectant mothers and their offspring - and numerous studies showing both the safety and benefits of influenza vaccination for pregnant women - uptake of the flu vaccine among pregnant women remains far lower than public health officials would like to see.
