The much-investigated association between obstetric complications and schizophrenia has provided crucial support for developmental and nongenetic etiological models of the disorder. But does such an association really exist? This review outlines the history of the substantial literature examining this association and provides a quantitative synthesis of selected population-based studies. The limitations of the research methods that are currently used are discussed, and possible new lines of inquiry are suggested.

The first mention of an association between birth complications and schizophrenia occurred in the American Journal of Psychiatry in 1934. Rosanoff and colleagues published “The Etiology of So-Called Schizophrenic Psychoses,” based on detailed case reports of 142 pairs of twins concordant and discordant for schizophrenia. The authors concluded that schizophrenia could be regarded (at least in part) as a “decerebration syndrome which may result from birth trauma.” Somewhat surprisingly, nothing further was published on this topic until 1956 when Pasamanick and colleagues proposed their now-classic thesis of a “continuum of reproductive casualty,” whereby pregnancy and birth complications can lead to a gradient of injury extending from fetal and neonatal death through cerebral palsy, epilepsy, mental deficiency, and behavior disorder. The paper by Pasamanick and colleagues initially had its greatest impact on the field of child psychiatry. In the early 1960s, there were reports of significant associations between pregnancy complications (particularly toxemia, bleeding, and severe maternal illness) and childhood psychosis. However, diagnostic uncertainty about the classification of childhood psychosis seems to have halted research in this area. Even though a review in 1966 concluded that “the need for further research…is strongly indicated by these findings” , there was a gap of 10 years before a study by Torrey and colleagues reported an association between bleeding in pregnancy and childhood psychosis.

Research on Low Birth Weight (1966–1970)
In 1966 attention shifted to adult schizophrenia when Lane and Albee reported that the birth weights of 52 hospitalized schizophrenic adults were significantly lower than that of their siblings. Although the difference between the mean birth weights of the patients and their siblings was significant, it was quite small (in the region of 175 g), and few of the patients actually met the criteria for the “low birth weight” category (< 2500 g). Rather, there appeared to be a “shift in distribution” of birth weight within a population of cases compared with noncases. In 1967 Stabenau and Pollin published an analysis of birth histories of 100 pairs of monozygotic twins discordant for schizophrenia and reported that significantly more of the schizophrenic (index) twins had been the lighter of the two at birth and had experienced birth complications, particularly asphyxia. However, other investigators subsequently failed to find significant differences in birth weight between schizophrenic subjects and siblings or comparison subjects. It is likely that these studies were underpowered to find an effect, as the mean difference in birth weights between groups was actually very similar to that originally reported by Lane and Albee. The epidemiological concept of a “population shift” did not come to attention again until recent years.

Studies of High-Risk Groups (1970–1980)
The next phase of the literature was prompted by an analysis of obstetric complication data from the Copenhagen High-Risk Study. The “high-risk” design examined the characteristics of a group of offspring of schizophrenic parents who were at 10–15 times higher risk of developing schizophrenia than individuals from the general population. Mednick found that 70% of the “high-risk” children who were psychiatrically ill by their early 20s had suffered one or more serious pregnancy or birth complications, compared with 15% of the high-risk group who remained well and 33% of the comparison group (i.e., offspring of parents who did not suffer with schizophrenia). Mednick speculated that, given a subject’s genetic predisposition, schizophrenia would appear only if the hippocampus was selectively injured by anoxia at birth. Analyses of other high-risk study groups revealed an excess of unexplained fetal and neonatal deaths, bleeding and swelling during pregnancy, and neonatal problems. However the research strategy focusing on high-risk children was dealt a severe blow by a series a negative findings and, in particular, by two reports that failed to find any differences between the birth histories of schizophrenic women and those of women with other psychiatric disorders. A review concluded that there was little evidence for an excess of obstetric complications in births to parents with schizophrenia. Although this conclusion was later challenged, the era of research focused on high-risk offspring was effectively over by 1980. Indeed, only a handful of papers on the topic of obstetric complications and schizophrenia were published over the next few years, and interest in the topic seemed to have waned. The development of new brain imaging techniques provided the impetus for the next phase of the literature.

Population-Based Studies (1997–present)
This phase of the literature on obstetric complications and schizophrenia began in earnest in 1997 and continues to date. Studies are characterized by large samples drawn from population-based hospital or case registers, with comparison subjects drawn from the same population, and use of standardized, prospective obstetric data from birth records or registers. Investigators usually report odds ratios for individual obstetric complications and control for demographic confounders by matching or statistical adjustment.

It was hoped (indeed expected!) that these large, methodologically robust studies would provide clear, consistent answers about the relationship between individual obstetric complications and schizophrenia, but this has not proved to be the case. As Table 1 shows, the findings from the population-based studies were mostly negative and surprisingly contradictory. Rather than dealing with each of these studies separately, we have elected to carry out a meta-analytic synthesis of the results. Possible reasons for the discrepancies between studies will be discussed after presentation of the findings from the meta-analysis. The standardized fashion of reporting results and the similarities in the methods of the population-based studies lend themselves to a meta-analytic approach. Meta-analysis provides a method for integrating quantitative data from multiple studies by using a weighted average of the results in which larger studies have more influence than smaller studies. It improves the estimates of effect size, increases the statistical power, and helps to make sense out of studies with conflicting conclusions.

The limitations of using a meta-analytic approach for observational studies should be mentioned. Observational studies may yield estimates of association that are influenced to a greater or lesser degree by confounding or bias, and meta-analysis in itself is no defense against such factors (“bias in equals bias out”). The population-based studies in this analysis were relatively free from bias, and the odds ratios were adjusted for confounders such as sex, hospital where the birth took place, and social class. However the samples were drawn from different populations, in terms of geography, age at illness onset, and cohort and period effects, and all these differences could provide sources of confounding factors. Obstetric practices and methods for recording information about different complications vary between countries and over time.

Complications of pregnancy
Bleeding and preeclampsia in pregnancy have been associated with psychosis since the earliest days of such research. Pasamanick and colleagues singled out the “anoxia-producing complications of pregnancy such as toxemia and bleeding” as most likely to be associated with behavior problems.

Preeclampsia came to particular attention in 1996 when Kendell and colleagues reported a very strong association between preeclampsia and later schizophrenia, but, in their attempt to extend the study group and replicate this finding, a flaw in the original study design was uncovered, and a retraction was published. The revised analysis found no significant effect for preeclampsia. However, in the largest single population-based study to date, preeclampsia was the only obstetric risk factor that remained significant after the analysis controlled for all potentially confounding factors . What could be the mechanism of action of this association? The most popular theory at present involves the mechanism of abnormal fetal blood flow resulting in chronic fetal hypoxia or malnutrition.

Bleeding during pregnancy has many causes. Implantation bleeding and abbreviated menses are common in the first month, and placenta praevia and premature separation of the placenta are frequent causes in the last month. The causes of mid-pregnancy bleeding are less well understood. In one study, two-thirds of the cases were found to be due to premature separation, placenta praevia, hydatiform moles, incompetent cervices, and other identifiable causes, while in one-third of the cases, the cause could not be determined. In severe cases of bleeding, the pathogenic effect on the fetus is thought to be anoxia, but, in many cases, the amount of bleeding may be slight, and anoxic brain damage is unlikely. Another explanation is that bleeding can represent a threatened spontaneous abortion. This is consistent with the striking and as yet unexplained findings of an excess of stillbirths and neonatal deaths among schizophrenic women . Rieder and colleagues hypothesized that bleeding was “the result of rather than the cause of injury. In other words the process of uterine rejection could have begun but been interrupted.” Genetic or autoimmune factors may play a part in such a process.

The association between diabetes in pregnancy and later schizophrenia, although strong, is based on only two studies in this analysis, neither of which provided information on the type of diabetes. Indirect support for the association comes from one report that high prepregnancy body mass increases the risk of schizophrenia in the offspring, since high maternal body mass index is associated with non-insulin-dependent diabetes and gestational diabetes. The effects on the developing brain of altered glucose metabolism are not well understood. Poorly controlled maternal diabetes is associated with an increased risk of congenital anomalies and impaired intellectual and psychomotor development in offspring. Insulin-dependent diabetes mellitus has been found to be more common among the first-degree relatives of patients with schizophrenia than among comparison subjects, indicating that an autoimmune process might be involved. Autoimmune mechanisms could also be implicated in the association between rhesus incompatibility and later schizophrenia. Rhesus hemolytic disease of the newborn is an illness with neurological consequences secondary to effects of a maternal antibody. Hemolytic disease can lead to early spontaneous abortion, chronic fetal hypoxia, neonatal asphyxia and pulmonary edema, and neonatal hyperbilirubinemia and kernicterus. The association has independent support from a cohort study that found a twofold increase in relative risk of schizophrenia among men from rhesus-incompatible pregnancies and a report that neonatal hyperbilirubinemia is a risk factor for later mental illness.

Mary Cannon, M.D., Ph.D., M.R.C.Psych., Peter B. Jones, M.D., Ph.D., M.R.C. Psych., and Robin M. Murray, M.D., D.Sc., F.R.C.Psych.

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Source: http://ajp.psychiatryonline.org/cgi/content/full/159/7/1080