Prenatal Risk Factors in Schizophrenia

Significant research developments in the etiopathogenesis of schizophrenia have occurred during the past several years. One such advance is the "neurodevelopmental" hypothesis that events during early brain development, especially the prenatal and perinatal periods, may play an important causal role in at least some, and perhaps many, cases of schizophrenia. Consequently, the study of potential factors that could impair early brain development is likely to prove fruitful in identifying particular causes of this illness.

Converging lines of evidence in favor of the neurodevelopmental hypothesis of schizophrenia derive largely from three areas of schizophrenia research: brain imaging/neuro-pathology, premorbid abnormalities and minor physical anomalies.

Brain imaging and cytoarchitectonic studies have consistently demonstrated increased ventricular size and reduced volumes of medial temporal lobe structures, and abnormalities of neuronal number and organization in patients with schizophrenia (Waddington 1993a,b; Suddath and others; Bogerts and others; Akbarian and others). The fact that structural brain anomalies occur in "first episode" patients suggests that they are likely present before the onset of illness (Waddington 1993a). In addition, children destined to develop schizophrenia have increased neuromotor and psychosocial abnormalities, including social withdrawal, disruptive behavior and emotional lability (Walker and others; Jones and others). The third piece of evidence derives from studies of minor physical anomalies (MPAs), minor malformations of the head, eyes, ears, hands, mouth or feet that are ectodermal in origin, and that are thought to result from environmental or genetic insults in the first or second trimesters (Green and others). Investigations of MPAs are of relevance to schizophrenia, since ectodermal development closely parallels maturation of the fetal brain, and patients with schizophrenia, compared to controls, have an increased occurrence of MPAs (Green and others).

The study of monozygotic (MZ) twins; discordant for schizophrenia has provided a critically important strategy to differentiate the relative contribution of genes and environment to adverse neurodevelopmental events. Because identical twins share all of their genes, any between-twin differences are presumed to be environmental in origin. In a landmark MRI study of discordant MZ twins, Suddath and colleagues demonstrated that almost every affected twin had increased ventricular size and diminished volumes of temporolimbic structures, including the hippocampus, compared to his or her respective unaffected twin. Further studies of discordant MZ twins, including investigations using positron emission tomography (PET) and dermal ridge counts (Bracha and colleagues), have provided additional evidence supporting environmental etiologies.

Although many different types of prenatal exposures are potential risk factors for schizophrenia, we shall focus upon three of the best studied: prenatal infection, prenatal nutritional deficiency and obstetric complications.

Prenatal infection.

It is well-known that many infectious agents have detrimental effects on fetal brain development. These infectious teratogens include rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV) (Whitley and Stagno). With respect to developmental pathology, several concordant findings exist between congenital infection syndromes resulting from these viruses and schizophrenia, including brain and dermatoglyphic abnormalities.

Many epidemiologic studies support a potential role for prenatal viral insults in schizophrenia. One of the first major pieces of evidence is the consistent demonstration of a 5 percent to 15 percent excess of births in the winter and early spring among individuals destined to develop schizophrenia (Torrey and Kaufmann). These findings led to a flurry of investigations attempting to relate epidemics of specific viral agents to the births of preschizophrenic patients.

Since influenza epidemics typically occur periodically in the winter and affect a significant proportion of the population, most epidemiologic studies of prenatal infection and schizophrenia have focused on this virus. Several of these studies do suggest that prenatal influenza exposure is a risk factor for schizophrenia. The 1957 type A2 influenza .i.influenza; epidemic, the second most severe pandemic of this century, provided investigators with an excellent opportunity to examine this potential relationship. In 1988, the first such investigation, conducted in Finland, suggested a higher incidence of schizophrenia among cohorts that were in utero during the second trimester of gestation, compared to unexposed birth cohorts (Mednick and colleagues 1988). Subsequent investigations of cohorts exposed to the 1957 epidemic in Great Britain (OýCallaghan and colleagues), Ireland (Cannon and others), Japan (Kunugi and others) and Australia (McGrath and others) replicated the initial finding, and all but one showed second trimester specificity for the association.