Maternal–fetal blood incompatibility and the risk of schizophrenia in offspring
Introduction
Mounting empirical evidence for a neurodevelopmental origin of schizophrenia is fostering research on the possible prenatal contribution to the risk of schizophrenia (Weinberger, 1987, Susser et al., 1999, Murray and Fearon, 1999, McGrath et al., 2003). While epidemiologic findings for individual prenatal risk factors are not definitive, the evidence collectively suggests that prenatal insults are of etiological significance in schizophrenia.
In the present study, we hypothesized that offspring of a maternal–fetal blood incompatible pregnancy are at increased risk for schizophrenia, based on biological plausibility and prior reports (see below). In maternal–fetal blood incompatibility, an elevated risk of schizophrenia in the offspring is postulated to arise from a maternal immune response to the paternally inherited foreign fetal red blood cell antigens. Disruption of fetal neurodevelopment may evolve from multiple immunologic pathways leading to several pathological states including hemolytic induced chronic fetal hypoxia (Mollison et al., 1993), the accumulation of neurotoxic bilirubin within the developing brain (Cashore, 1990), as well as more speculative pathological processes involving the cross-reaction of maternal IgG antibodies with fetal brain antigens (Laing et al., 1995), and the breakdown of maternal immune tolerance of the fetus (van Gent et al., 1997).
Rh and ABO maternal–fetal blood incompatibility both can induce the production of maternal IgG antibodies against the fetal red blood cell antigens. The IgG antibodies can in turn transverse the placenta, enter the fetal circulation and attack fetal red blood cells (Bowman, 1999), and also gain access to the developing brain due to the immaturity and the permeability of the blood brain barrier (Adinolfi, 1985). A significant maternal antibody response can provoke hemolytic disease of the fetus. An Rh-negative woman requires a sensitizing exposure to Rh-positive cells. As a result, firstborn Rh incompatible offspring rarely experience hemolytic disease, while second and later Rh incompatible offspring are more likely to suffer its immunological sequalae. In contrast, since most group O women have anti-A and anti-B antibodies predating pregnancy, ABO hemolytic disease can occur in first pregnancies (Rawson and Abelson, 1960, Ozolek et al., 1994). ABO and Rh incompatibility are the two most common causes of hemolytic disease of the fetus. Rh disease is associated with serious morbidity and mortality while ABO disease is consistently milder.
Rh incompatibility, but not ABO incompatibility, has been examined as a risk factor for schizophrenia in several studies. A historical cohort study, conducted by Hollister et al. (1996) within a Danish sample born between 1959 and 1961, was the first study to explore the hypothesis. The authors restricted the analyses to males due to the small number of females diagnosed with schizophrenia within the cohort. They found that among the men, the rate of schizophrenia was significantly greater in the Rh incompatible group than in the Rh compatible group (RR = 2.78, 95% confidence interval = 1.2– 6.6). The risk was confined to second and later-born offspring from the Rh incompatible pregnancies. The study had some limitations: the restriction to male subjects, the use of hospital registry diagnoses for schizophrenia, and subject eligibility that was contingent on neonatal blood typing, which was not a routine procedure at that time. To further explore this association, Palmer et al. (2002) conducted a family-based candidate-gene study using patient–parent(s) pairs and trios comprising the youngest affected male or female sibling and at least one biological parent. The families were drawn from a Finnish sample born prior to the widespread use of anti-Rh (D) prophylaxis. Their estimated relative risk for Rh maternal–fetal genotype incompatibility was 2.6 (90% CI = 1.1, 6.0). Kraft et al. (2004) extended the work of Palmer et al. (2002) using the same Finnish sample and included all affected siblings within a family. They reported a relative risk of 1.7 (90% CI = 1.1, 2.5) in second and later born Rh incompatible offspring, based on the assumption that firstborn incompatibles were not at increased risk. While the sample of Palmer et al. (2002) and Kraft et al. (2004) appeared to contain a sufficient sample of females (respectively 38% and 42% of the entire sample), the effect estimates were not differentially reported by sex of affected offspring.
The Rh incompatibility–schizophrenia association has also been tangentially included in epidemiologic studies that investigated the etiologic contribution of obstetric complications. Two meta-analyses (Geddes et al., 1999, Cannon et al., 2002) examined the association within mixed-sex samples, in which both excluded the study of Hollister et al. (1996). Assembling ten studies, Geddes et al. (1999) calculated a summary odds ratio of 1.40 (95% CI = 0.54– 3.63) for Rh incompatibility and Cannon et al. (2002), aggregating three other studies, derived a summary odds ratio of 2.00 (95% CI = 1.01– 3.96) for the effect of their Rhesus variable. (The studies evaluated different Rhesus related factor. Sacker et al. (1995), Kendell et al. (2000), and Byrne et al. (2000) estimated respectively the effect of maternal Rh negativity, Rh antibodies, and Rh incompatibility).
The epidemiologic literature on schizophrenia has consistently shown that males and females differ in terms of premorbid functioning, age at onset, symptomatology, treatment response, and course (Goldstein, 1997). Similarly, male infants are more severely affected by Rh hemolytic disease and kernicterus than their female counterparts (Walker and Mollison, 1957, Ulm et al., 1998). Based on these observations and from the study of Hollister et al. (1996), we posited that sex of the offspring would modify the effect of maternal–fetal blood incompatibility on the risk of schizophrenia.
We examined the effect of Rh and ABO incompatibility in offspring from the Prenatal Determinants of Schizophrenia (PDS) study (Susser et al., 2000), a prospective study drawn from a large birth cohort born before the availability of anti-Rh (D) prophylaxis. The PDS study featured comprehensive measures of prenatal and perinatal exposures, including the blood types of mother and infant, and implemented rigorous diagnostic assessments of adult schizophrenia outcome in the offspring. In addition, the cohort had an appreciable number of female offspring, which enabled us to examine interaction between Rh and ABO incompatibility and sex of offspring on the risk of schizophrenia.
Section snippets
Description of the cohort
The analytic sample was derived from the Prenatal Determinants of Schizophrenia (PDS); which has been described in detail elsewhere (Susser et al., 2000). The PDS study originated from the Child Health and Development Study, (CHDS), a birth cohort implemented to investigate associations between pregnancy events and offspring development (van den Berg, 1979, van den Berg et al., 1988). From 1959 to 1967, the CHDS assembled 19 044 live births of women who received prenatal care from Kaiser
Rh Sample characteristics
The Rh compatible group contained 5201 offspring and the Rh incompatible group had 350 offspring. The Rh incompatible offspring in the PDS study were similar to the Rh compatible offspring, except that Rh incompatible offspring were more likely to be offspring of Caucasian women than offspring of African-American and other minority ethnic women (see Table 2).
The effects of Rh incompatibility
The unadjusted rate ratio for strict Rh incompatibility and SSD was 1.63 (95% CI = 0.65–4.12) (Table 3). Adjusting for maternal age and
Discussion
The study has extended the line of evidence that Rh incompatibility may be a risk factor for schizophrenia. We found that strict Rh incompatibility was associated with a two-fold elevated rate of schizophrenia spectrum disorder and the effect was limited to male offspring. We also explored the effect of ABO incompatibility and observed a weaker effect, also limited to male offspring. When Rh and ABO incompatibility were analyzed separately, statistical significance was not achieved. However,
Conclusion
Maternal–fetal blood incompatibility is a unique prenatal exposure that incorporates genetics, the discordant maternal and fetal blood genotypes, and the intra-uterine environment, ensuing from the maternal immunologic responsiveness and fetal compensatory mechanisms. We observed that the most pronounced effect on later schizophrenia was exhibited among male offspring who were products of second and later Rh incompatible pregnancies, but the findings raise the possibility that other blood group
Acknowledgements
This manuscript was supported by the following grants: NIMH 1R01MH 63264-01A1 (A.S.B.), NIMH 1K02MH65422-01 (A.S.B.), NICHD NO1-HD-1-3334 (B. Cohn), NICHD NO1-HD-6-3258 (B. Cohn).
We also wish to acknowledge the following individuals for their contributions to this work: Barbara van den Berg, M.D., Barbara Cohn, Ph.D., and the late Jacob Yerushalmy, M.D. We also wish to thank the Lieber Center for Schizophrenia Research, the National Institute for Child Health and Development, and the Public
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