Hypothyroidism in Pregnancy a Schizophrenia Risk Factor?
By Liam Davenport
Medscape Medical News
The offspring of women with hypothyroidism during pregnancy appear to have a substantially increased risk of developing schizophrenia, offering a potentially modifiable risk factor for the disease, new research shows.
Investigators found that children born to women with hypothyroxinemia during pregnancy had a 75% increased risk of developing schizophrenia, which remained significant after taking into account known risk factors for the disease.
Lead author David Gyllenberg, MD, PhD, department of child psychiatry, University of Helsinki and Helsinki University Central Hospital, Finland, said in a press release that the findings link to "an extensive literature on maternal hypothyroxinemia during gestation altering offspring brain development."
"I hope this paper can inform future animal studies examining molecular and cellular deviations that are relevant to schizophrenia," he added.
The research was published in the June issue of Biological Psychiatry.
Possible Mechanisms
Previous research has indicated that thyroid deficiency in early gestation alters brain development and that schizophrenia is associated with prenatal brain insults. The investigators examined whether maternal thyroid deficiency during early to mid-gestation is associated with schizophrenia in offspring.
They used data from the Finnish Prenatal Study of Schizophrenia, a nested case-control study with archived maternal sera drawn during the first or second trimester from more than 1 million pregnancies in Finland since 1983. The researchers also used the Finnish Hospital and Outpatient Discharge Register to identify cases of schizophrenia or schizoaffective disorder diagnosed before 2009, at a maximum patient age of 29 years.
From this, 903 pairs of schizophrenia cases and healthy controls were identified for which assays of both free thyroxine (fT4) and thyroid-stimulating hormone (TSH) were available.
Analysis revealed the proportion of participants with maternal hypothyroxinemia, defined as fT4 < 10th percentile and normal TSH, was 11.8% among schizophrenia cases vs 8.6% among controls, at an odds ratio (OR) of 1.75 (P = .002).
When redefining hypothyroxinemia as fT4 < 5th percentile and normal TSH, the proportion of individuals with maternal hypothyroxinemia was 6.6% among cases and 5.0% among controls, with an OR of 1.62 (P = .055).
Examining maternal fT4 levels as a continuous variable, researchers found that the risk of schizophrenia significantly decreased for each log-unit increase in maternal fT4, at an OR of 0.54 (P = .028). No such relationship was seen with TSH.
The association between maternal hypothyroxinemia and schizophrenia in offspring remained significant after adjusting for maternal psychiatric history, province of birth, and maternal smoking during pregnancy, at an OR of 1.70 (P = .010).
"One potential explanation for the association between maternal hypothyroxinemia and schizophrenia is that hypothyroxinemia contributes to altered fetal gene expression, which adversely affects fetal brain development," the researchers write.
"Another possible explanation for the finding is mediation by preterm birth or low birth weight."
While highlighting that they considered preterm and low birth weight potential mediators, rather than confounders, the researchers note that "low birth weight was not related to schizophrenia, fT4 under the median, and hypothyroxinemia, suggesting that it did not mediate the association."
Novel, Intriguing
In an accompanying commentary, Henning Tiemeier, MD, PhD, and Tim I. M. Korevaar, MD, Erasmus Medical Center, Rotterdam, the Netherlands, described the study as "elegant," adding that the authors have "identified a novel, intriguing and potentially modifiable risk factor for schizophrenia."
Nevertheless, they note that, although randomized trials have been advocated to determine whether screening and treatment for hypothyroxinemia in pregnancy can improve neurodevelopmental outcomes, "neither the choice of the thyroid parameter nor the neurodevelopmental outcome is trivial."
Dr Tiemeier and Dr Korevaar also point out that the current analysis, alongside previous studies, did not assess "one major presumed cause of hypothyroxinemia": iodine. "We need more studies from different countries to show the extent to which iodine underlies, or modifies, the effects of hypothyroxinemia in pregnant women — and preferably neurodevelopmental outcomes," they write.
Also commenting on the study, John H. Krystal, MD, chairman, department of psychiatry, Yale University School of Medicine and Chief of Psychiatry, Yale-New Haven Hospital and editor of Biological Psychiatry believes that the findings show the schizophrenia risk in the offspring of mothers with low thyroxine levels could be reduced.
"This study identifies a preventable potential contributor to the risk for schizophrenia. Maternal hypothyroidism can be easily diagnosed and effectively treated," he said in a press release.
The research was supported by National Institute of Mental Health Grants, the Sigrid Juselius Foundation, Foundation for Pediatric Research in Finland, and Finnish Medical Foundation.
The authors have reported no relevant financial relationships.
Biol Psychiatry. 2016;79:950-951, 962-970.
