November 15, 2004

Risk from pain killers?

Association between prenatal exposure to analgesics and risk of schizophrenia.

Sorensen HJ, Mortensen EL, Reinisch JM, Mednick SA.
Br J Psychiatry. 2004 Nov;185:366-71.

Background: Along with genes, there are many environmental factors that may increase risk for schizophrenia. Some studies have suggested there is greater risk for developing schizophrenia if an unborn child (prenatal) is exposed to viruses such as influenza. The disturbances in the brain and spinal cord that may occur prior to birth in a fetus may increase the risk for schizophrenia. However, this is still debated since there are researchers who have argued that it is still unclear whether prenatal exposure to influenza influences schizophrenia. The authors in this study wanted to further clarify this relationship, but in particular they were interested in the medications that a mother takes during pregnancy and its effects on the baby's later risk for developing schizophrenia. They were particularly interested in a group of medications known as analgesics which are used to reduce pain (e.g. Aspirin).

Method: This was a Danish study that used data that had already been collected in their Copenhagen Perinatal Cohort and the Danish Psychiatric Central Register. They had information about exposure to pain relieving medicines and psychiatric hospitalizations for 7999 individuals (4098 males and 3941 females). They collected mothers´┐Ż reported use of medication through prenatal and postnatal interviews for any medications taken for at least 5 days during pregnancy. They included both prescribed analgesics and pain relievers bought over the counter, but they were not able to separate medications used for treating fever from those used for treating pain. So a mixed group of pain relievers was used ranging from Aspirin to morphine. They made statistical adjustments for parental history of schizophrenia, second-trimester viral infections, other drug treatment during pregnancy, pregnancy complications, parental social status and parental age.

Results: They found that in a risk set of 7999 individuals, there were 1.5% cases of schizophrenia. Interestingly, prenatal exposure to pain killers in the second trimester was associated with an elevated risk. In other words, the estimate of the risk of schizophrenia was more than four times greater in babies who were exposed to pain medications in the second trimester (the association was slightly stronger in females than in males). This suggests that the second trimester is a time when the immature fetal brain is particularly sensitive to a range of environmental influences. However, only 6.9% of the total group with schizophrenia had been exposed to analgesics in the second trimester, so these findings need to be interpreted cautiously.

This study found an unusually high risk of schizophrenia (11.1% and 8.9%, respectively) in the small subgroup of children from mothers who were treated with morphine or opioid pain killers. This could be because of medication related effects, but since this was such a small subgroup of the overall group of mothers, we need to be careful when making generalizations about this morphine finding. Maternal intake of psychiatric drugs during the second trimester was also correlated with intake of pain medications in the same period. This suggests that the mothers may have had psychiatric diagnoses already, which was not explored and could explain the findings through a genetic mechanism.

Interpretations & Limitations: The authors suggest 3 different types of explanations for their results. First, chemical substances might have caused a change in the neurodevelopment of the fetus, which increased the risk for schizophrenia later on. Secondly, there may have been an effect for some somatic or medical condition in the mother for which she took the pain relievers during pregnancy. Thirdly, there could be some unidentified factors (which could not be fully controlled in the analysis) that influenced intake of pain medicines by the mother and later risk for developing schizophrenia.

While it is interesting to learn that there maybe something unique about the second trimester that increases vulnerability to environmental factors and possible risk for schizophrenia, there are many reasons to be cautious about the findings. On top of the limitations with reduced power to detect results for certain analyses, the authors did not look at the effects of the mother drinking alcohol or using illegal drugs pregnancy, which could have influenced the outcome. They were also not able to address the question of taking pain medications for viral infection in the second trimester since only 15 mothers were exposed to both viral infection and took pain killers. Another limitation is that the data on prenatal exposure to medication that they used dated back to the early 1960s and some of the drugs used at that time are now obsolete in most countries. Much more research is needed to clarify the nature of the relationship between medications taken during pregnancy and later risk for schizophrenia.

This study was supported by: Sygekassernes Helsefond (Health Insurance Foundation) grant to H.J.S., grants HD-17655 and HD-20263 from the National Institute of Child Health and Human Development to J.M.R., grant DA-05056 from the National Institute on Drug Abuse to J.M.R., grant 9700093 from the Danish Research Council to E.L.M., and grant 1400/2-4-1997 from the Danish National Board of Health to E.L.M.

Click here to find this article on PubMed

Author: Farzin Irani


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