Maternal–fetal blood incompatibility and the risk of schizophrenia in offspring

Abstract

Objective

Predicated on a maternal immune response to paternally inherited foreign fetal blood antigens, we hypothesized that maternal–fetal blood incompatibility increases susceptibility to schizophrenia in the offspring. The relation between schizophrenia and maternal–fetal blood incompatibility, arising from the D antigen of the Rhesus (Rh) and the ABO blood group antigens, was examined in a cohort of live-births.

Method

The data were drawn from the Prenatal Determinants of Schizophrenia Study, a cohort of births occurring between 1959 and 1967 to women enrolled in a Kaiser Permanente Plan-Northern California Region (KP). Adult offspring belonging to the KP from 1981 to 1997 were followed for the incidence of schizophrenia spectrum disorder (SSD). Cox proportional hazards regression was the primary analytic technique.

Results

Among second and later born offspring, the adjusted incidence rate ratio (RR_adj) of SSD was 1.80 (95% CI = 0.71–4.58) for the Rh incompatible offspring compared with the Rh compatible offspring; with the males exhibiting higher rate ratio (RR_adj = 2.37; 95% CI = 0.82–6.86) than the females (RR_adj = 0.93 95% CI = 0.12–7.01). Among all offspring, the RR_adj for ABO incompatibility was lower and the elevated rate ratio was similarly limited to the males (RR_adj = 1.68; 95% CI = 0.76–3.70). For Rh and/or ABO incompatibility, the RR_adj was 1.57 (95% CI = 0.87–2.82). A statistically significant result was detected only for the male offspring (RR_adj = 2.22; 95% CI = 1.10–4.47).

Conclusion

Although the results should be interpreted with caution given the few events of SSD, the findings extend the line of evidence that maternal–fetal blood incompatibility is a risk factor for schizophrenia spectrum disorder; with the strongest evidence to date implicating that the susceptibility pertains only to male 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.