Statistical Power
The effect sizes for the relationship between obstetric risk factors and later schizophrenia are generally small, with odds ratios of less than 2. This is the sort of effect size reported for the relationship between passive smoking and lung cancer or the risk of breast cancer among users of the oral contraceptive pill. Such small effects are usually controversial and are some way from indicating strong causality. One may be dealing with proxy effects for some other lifestyle or socioeconomic factors or interactive effects with as-yet-unknown genetic or epigenetic factors. The study of individual obstetric risk factors for schizophrenia could be conceptualized as the search for rare risk factors for a rare disease and is therefore truly suitable neither for the classic cohort design nor for case-control designs. The power of even the largest population-based studies to detect odds ratios of 1.5 was less than 70% . Methods such as the “nested” case-control design are useful, but, even so, the lack of independence of individual obstetric complications (discussed earlier) and possible interactive effects further erode statistical power. Some studies have tried to overcome low statistical power by examining only one exposure on the basis of a prior hypothesis. This has proved a relatively fruitful endeavor, showing significant effects for the putative risk-increasing mechanism of hypoxic and ischemic damage, but each set of researchers has used different combinations of exposures, hindering replication and comparison or pooling of the results between studies.

Definition of Obstetric Complications
No one realized initially just how common the broadly defined Lewis-Murray obstetric complications are in the general population—about 25%–30% of births involve at least one Lewis-Murray complication. So many discrete exposures are wrapped up in the term “obstetric complication” that it is essentially meaningless to consider them as one risk factor. Before beginning to judge whether any association should be interpreted as causal, researchers must consider many distinct associations in terms of chance, bias, or confounding. If the field is to progress, advances are needed not only in population-based methods but also in sharpening the definitions of the exposures under scrutiny. A broad definition of obstetric complications should no longer be used as it will not improve our understanding of the field any further. More careful definition of exposures, such as prenatal measurement of maternal antibodies, and more extensive use of quantitative measures, including birth weight or head circumference, are likely to show larger and more consistent effects.

Information on the Prenatal Period
Birth records tend to include detailed information about the delivery and neonatal period, but information about the prenatal period is less reliable. Details about the course of the pregnancy are often recorded at the time of admission to the labor ward. Major pregnancy complications, such as preeclampsia, are usually mentioned, but there may be no record of problems such as prenatal stress or there may be insufficient detail about timing of infection or bleeding.

Nevertheless, the current meta-analysis shows that many prenatal factors (even with the less-than-optimal data available) are significantly associated with later schizophrenia. Even stronger effects may have been found if detailed, prospective data on the prenatal period were available. Ecological data, cunningly exploited, have provided clues of the existence of other prenatal risk factors for schizophrenia, including prenatal infection, prenatal malnutrition, and prenatal stress. Such exposures should ideally be incorporated into future studies of obstetric complications and schizophrenia. Another approach would be to follow up a cohort of individuals who have suffered definite specific prenatal (or perinatal) complications and assess a range of outcomes during development—a return to the position advocated by Pasamanick and colleagues many decades ago. This approach has already been useful in elucidating some rare prenatal exposures such as rubella infection and rhesus incompatibility and is currently being applied to follow-up studies of subjects with low birth weight and premature birth. This approach could also address the issue of specificity of obstetric risk factors for schizophrenia.

Interactive or Subgroup Effects
There has long been interest in whether the effect of obstetric complications may be confined to a subgroup of patients with schizophrenia, such as those with a family history, or male sex, or early onset, but most studies have not had sufficient power to examine this issue reliably. Verdoux and colleagues, in an individual-patient data meta-analysis, found a relationship between age at onset of schizophrenia and obstetric complications—the earlier the age at onset of schizophrenia, the more likely a history of obstetric complications—but found no relationship with family history of schizophrenia or gender. Cannon and colleagues also found a relationship between asphyxia and schizophrenia among patients with early-onset schizophrenia. However, in general, the recent population-based studies have tended not to examine subgroups within the population of patients with schizophrenia.

The study of gene-environment interactions is beginning to be applied to schizophrenia. There is increasing awareness that “hidden” genetic factors can have a substantial influence on the effect of environmental exposures, such as obstetric complications. An exposure that has a small effect on schizophrenia in general may have a large effect in those with a specific genetic make-up. In the coming decade we may see the first reports of studies that examine precisely measured genetic and environmental causes of schizophrenia in the same population . However, to adequately model interactive effects involving rare environmental risk factors (such as individual obstetric complications) and genes of small effect, sample sizes of tens of thousands will be required. We also have to take into account the dynamic interplay between genes and environment in utero.

Need for Collaborative Approaches
Current methods for studying the relationship between obstetric complications and schizophrenia merely allow us to report associations and, as a result, we have become stuck at the point of reporting risk factors of “vanishingly small effect” over and over again. Research in this area will need to move beyond the domain of epidemiology and involve other disciplines, such as developmental biology, neuropathology, and genetics. Innovative approaches include the use of animal models to study effects of prenatal infection and the analysis of large cohorts with detailed prenatal data and stored prenatal serum. As we enter what some researchers have called a new age of epidemiology for schizophrenia, the combination of larger cohorts, new paradigms, and modern statistical and molecular techniques provides the opportunity to discover how obstetric complications contribute to the causation of schizophrenia.

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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