Children whose parents who were together for less than 3 years before conception may be at higher risk of developing schizophrenia, new research suggests.
Investigators analyzed more than 90,000 offspring born between 1964 and 1976, separating out measures of paternal age, father's age at marriage, parental psychiatric diagnosis, and duration of marriage.
They found that offspring born to parents married for less than 2 years, which is equivalent to approximately 1 year of pre-pregnancy sexual contact, had a 50% higher risk for schizophrenia, and offspring in marriages lasting 2 to 4 years had a 30% increase in risk, compared with offspring of parents married 4 or more years.
Moreover, longer marriage duration appeared to confer protection against schizophrenia risk in offspring: for every additional 5 years of marriage, a 14% reduction in risk was predicted.
"The results of the study show that longer marriage periods before conception can offer some protective [benefit] against the risk for schizophrenia in the offspring," principal investigator Dolores Malaspina, MD, professor of psychiatry and neuroscience, genetics and genomic sciences, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News.
"The effect is independent of the risk that is related to a family psychiatric history and independent of the increasing risk for offspring schizophrenia that is associated with advancing paternal age," she said.
The study was published online March 8 in Schizophrenia Research.
Inflammatory Component
"Schizophrenia is increasingly understood as an inflammatory condition following an exposure that activated the immune system [and] we thought this short duration of sexual contact may be a source of inflammation to the fetus," Malaspina said.
"Many pregnancy conditions have been considered as sources of immune reactions in the fetus," she continued, "including infections, stress, and maternal medical conditions.
"Evidence from the obstetric literature shows that a short duration of sexual cohabitation by parents is a risk factor for abnormal blood flow in the placenta, [which] is thought to reflect maternal intolerance to the paternal genetic material, which diminished over a period of sexual contact."
To investigate the question, the researchers turned to data from the prospective, population-based Jerusalem Perinatal Cohort Schizophrenia Study (JPSS), a birth cohort study that recorded all births in a defined area of Jerusalem from 1964–1976.
This particular cohort was chosen because the researchers sought to quantify length of sexual contact between parents based on date of marriage (DoM). The researchers added, however, that DoM is an "insufficient proxy for the total length of sexual cohabitation by a couple currently, in almost all developed countries."
However, more than 97% of offspring in the JPSS study were born to married couples, as Israel had (and continues to have) among the lowest out-of-wedlock births of any country.
The duration of marriage at the time of each proband's birth can therefore be "reasonably considered to be the lower limit on the length of time that the mother was vaginally exposed to the sperm of the proband's father in this cohort," the authors write.
The researchers used stratified and continuous statistical models to analyze offspring risk for schizophrenia and separated interrelated measures of paternal age, father's age at marriage, parental psychiatric diagnoses, and DoM.
No "Schizophrenogenic" Fathers
Of the entire sample of probands (N = 90,079), almost all (97.4%) were born to married mothers, with the remainder born to divorced, widowed, or never-married women, and most were born to people with stable partnerships.
The age of fathers ranged from 16 to 80 years at the births (mean [SD] age 30.5 [±6.8] years, median 30 years). A total of 1704 probands (1.9%) were excluded due to missing information, leaving 89,823 births.
There were 552 probands (348 boys, 204 girls) diagnosed with schizophrenia.
The years representing paternal age, father's age at marriage, and the duration of the marriage were significantly interrelated (P < .001).
Longer DoM was found to confer protection against risk, with each 5 years predicting a 14% reduction in risk (relative risk [RR] = 0.86 [0.79–0.95]; P trend = .0015).
Paternal and maternal diagnoses of schizophrenia and "other psychiatric diagnoses" were respectively diagnosed in 1.2% and 2% of the fathers and in 1.2% and 1.6% of the mothers.
Offspring of fathers with a schizophrenia diagnosis had a fourfold increase in the risk for schizophrenia (RR = 4.30, 2.91–6.35, P < .0001), while offspring of fathers with other psychiatric conditions had twice the risk for schizophrenia (1.99, 1.30–3.04, P = .0015), compared with offspring of fathers without a mental illness.
Maternal diagnosis of schizophrenia and "other psychiatric conditions" conferred an even greater risk (RR = 6.16, 4.39–8.62; and RR = 2.61, 1.68–4.05, respectively, both Ps < .0001).
The risks were higher for maternal transmission than paternal transmission for schizophrenia and for other psychiatric diagnoses (43% and 31%, respectively), although the differences did not reach statistical significance.
However, accounting for parental diagnoses as covariates did not alter the RR for DoM.
When the researchers conducted stratified analyses, they found that the greatest RR risk for DoM less than 2 years was 1.53 (1.11–1.66) with lesser risk for 2 to 4 years (1.38 [1.05–1.81]) compared to more DoM of ≥10 years.
In these analyses, the effects were found to be independent of parental psychiatric diagnoses.
In unadjusted analyses, father's age at marriage was found to be significantly related to offspring schizophrenia risk (P trend < 0.04); however, the risk from later paternal age at marriage was eliminated by adjustment for the duration of the marriage (RR, 1.18 [0.82–1.70]).
However, apparent risk related to later fathers' age at marriage (1.27: P < 0.0001) was eliminated after accounting for DoM and later paternal age.
The final full model included duration of marriage, parental diagnoses, and paternal age. In this model, offspring born to couples with shorter marital duration had the highest RR (less than 2 years 1.53 [1.11–1.66]; 2–4 years 1.38 [1.05–1.81]; and 5–7 years 1.11 [0.87–1.42]), compared with offspring of parents married 10 or more years.
Alternatively, there was a decrease in risk for each 5 years of marriage (RR, 0.89 [0.82–0.97], P trend = 0.01.
The same protective effect of longer DoM was found when the model was stratified by paternal age (RR, 0.85 [0.84–0.97] P = .013).
Malaspina cited previous studies showing that men who married later in life had more offspring with schizophrenia, and that those studies suggested "that some social problem interfered with their coupling that was inherited as schizophrenia by their offspring."
However, she said, "we disproved this contention about late-marrying dads, showing the risk to their offspring was explained by their short marriage duration before conception and their paternal age, thus we did not find 'schizophrenogenic fathers.' "
Further studies "will investigate the biology of these pregnancies, but we propose that maternal immune intolerance of the paternal antigens plays a role, as this reaction decreases over a period of time with sexual exposure."
Thought-Provoking Hypothesis
Commenting on the study for Medscape Medical News, John McGrath, MBBS, MD, PhD, AM, professor at the National Centre for Register-based Research at Aarhus University, Denmark, said that Malaspina "has a track record of generating interesting new candidate risk factors for serious mental disorders, such as schizophrenia."
Malaspina's new studies "explore a novel hypothesis" — children who are born soon after marriage have an increased risk of schizophrenia. Malaspina and colleagues have "provided several potential mechanisms that may explain this — for example, maternal immune activation may be more prominent early after marriage," added McGrath, who was not involved with the current study.
He called this a "testable hypothesis," adding that he is sure "this new study will stimulate many follow-up studies [because] it is a very thought-provoking hypothesis."
Malaspina suggested the finding is "relevant to the increased risk for schizophrenia observed across first births, which has been described for many decades. In the absence of any other known risk factors, it may suggest schizophrenia as well as other inflammatory conditions in first-born offspring."
The study was supported in part by the National Institutes of Health and the G. Harold and Leila Y. Mathers Charitable Foundation. Malaspina, study coauthors, and McGrath have disclosed no relevant financial relationships.
Schizophr Res. Published online March 8, 2019. Abstract
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Cite this: Marriage Duration May Influence Kids' Schizophrenia Risk - Medscape - May 06, 2019.
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