Maternal Stress in Early Pregnancy Raises Schizophrenia Risk for Offspring

Caroline Cassels

August 29, 2008

August 29, 2008 — Acute maternal stress in the second month of pregnancy significantly increases the likelihood that the child will develop schizophrenia in later life, particularly if that child is female.

Investigators at the New York University School of Medicine, in New York City, found that acute maternal stress in the second month of pregnancy was associated with a 2.3-fold increased risk for schizophrenia in children; the risk was more than 4-fold among female children.

According to principal investigator Dolores Malaspina, MD, schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine, and major disasters, and recent evidence suggests that humans are most vulnerable in the first trimester of gestation.

"We showed that severe stress alone, in the absence of infection, malnutrition, or environmental changes, is related to later schizophrenia. Furthermore, we were able to pinpoint the timing of this risk, and showed there was sex specificity and that female offspring are at much greater risk than males," Dr. Malaspina told Medscape Psychiatry.

The study was published online August 21 in BMC Psychiatry.

Natural Experiment

Until recently, the evidence has been limited by low statistical power. The researchers note that it has been difficult to separate short-term psychic stressors from the long-term influence of disrupted environments, diets, or lifestyles that can act as chronic stressors during childhood. Furthermore, earlier research lacked specificity regarding the timing of stress and its character.

To examine the consequences of acute maternal stress in children, the investigators followed a cohort of offspring whose mothers were pregnant in June 1967, during the 6-day Arab–Israeli war.

This conflict, said Dr. Malaspina, was extremely severe but relatively short-lived and so provided investigators with "a natural experiment."

The researchers linked birth records with Israel's Psychiatric Registry and then analyzed data from the Jerusalem Perinatal Study, a population-based research cohort of 88,829 individuals born in Jerusalem between 1964 and 1976.

"We looked at the timing of the individuals' birth to narrow down, month by month, the exact point [in their gestational life] the insult took place, and then correlated that information with a diagnosis of schizophrenia in later life," said Dr. Malaspina.

Survival Effect?

A total of 637 people in this cohort of 88,829 were identified with schizophrenia-related diagnoses, and 676 were identified with other psychiatric disorders. According to the study, the raw data suggest a 2- to 3-fold excess of schizophrenia in the cohort born in January 1968, whose mothers would have been in their second month of pregnancy in June 1967.

The researchers found no unusual incidence of schizophrenia or other conditions among children conceived in the 3 months after the war or in those born in the 3 months before it.

Adjusted analyses revealed that the overall incidence of schizophrenia was more than double that for children who were in the second month of gestation in June 1967. In males alone, there was a 20% increased risk for the disorder; in females, the hazard ratio was 4.3.

The reason for the higher incidence of schizophrenia among females is not clear. But there are at least 2 potential hypotheses. The first is that males are less susceptible to schizophrenia, study coauthor Susan Harlap, MBBS, said in an interview.

However, she said, there is a second, and possibly more likely, explanation. Animal and clinical research shows that severely stressed females frequently spontaneously abort. In addition, epidemiologic studies show that male fetuses tend to be miscarried more frequently than females.

"There may be a survival effect at play, so it is not necessarily that female fetuses are more susceptible to schizophrenia due to maternal stress, but that they are less likely to be aborted in the presence of maternal stress," said Dr. Harlap.

Tip of the Iceberg?

According to Dr. Malaspina, the study's findings underscore the potential negative impact of maternal stress on the developing fetus.

"Severe stress may just be the tip of the iceberg. We must keep in mind that the brain doesn't develop from a blueprint, and stress during pregnancy can program genes for many medical conditions," she said.

Physicians need to advise women who are planning a family to reduce their stress levels well in advance of the actual pregnancy, she added.

"I believe there's very little information given to pregnant women about the need to reduce stress well before and during pregnancy. A certain amount of maternal stress is absolutely necessary for healthy fetal development, but women should be advised to, as much as they can, lead a healthy life that includes exercise, proper sleep, good nutrition, and reduced stress. We want all our patients to live a healthy lifestyle, and here's 1 more reason to," said Dr. Malaspina.

The researchers have disclosed no relevant financial relationships.

BMC Psychiatry. 2008; Published online before print August 21, 2008. Abstract

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