Other studies have attempted to relate the occurrence of influenza epidemics over extended time periods to the births of preschizophrenics. Significant associations were demonstrated between exposure to second trimester prenatal influenza and schizophrenia for birth cohorts in Denmark (Barr and others), and England and Wales (Sham and others; Adams and others).

However, not all investigators have found this association. Crow and colleagues reported no increased risk of schizophrenia in a study using individual rather than group data on a cohort that was in utero during the second trimester of the 1957 influenza epidemic. Yet, this study has been criticized, since exposure data were derived from maternal reports of influenza following delivery, which are subject to underreporting. Other negative studies include those by Torrey and others in 10 states of the United States, Susser and others in Holland 1994, and Erlenmeyer-Kimling and others in Croatia.

Thus, the question of prenatal influenza exposure as a risk factor for schizophrenia remains unresolved. We believe that the inherent limitations of the research designs used in these studies lie at the root of the uncertainty. First, most of these studies utilized data that applied to groups rather than to individuals (i.e., it was known whether a woman was in the second trimester of pregnancy during a month in a peak period of an influenza epidemic, but not whether the woman had influenza). Second, there was no serological documentation of influenza exposure among individual pregnancies. It is unlikely that this controversy will be resolved until advancements are made to more sophisticated methods.

Relationships between prenatal exposure to several other infectious agents, including measles, polio and varicella-zoster virus, have also been demonstrated (Torrey and others 1988), although few studies have been conducted.

Prenatal nutritional deprivation.

One of the best documented exposures with adverse developmental central nervous system effects is prenatal nutritional deficiency (Brown and colleagues; Butler and others). In the search for specific nutritional factors in schizophrenia, our attention has focused on micronutrient deficiencies, in part because they occur in both the developed and developing world (Little and Elwood), as does schizophrenia (Jablensky and others). The most well-known class of neurodevelopmental disorders caused by a micronutrient deficiency consists of neural tube defects (NTDs), which include spina bifida and anencephaly; these CNS malformations result from a failure of neural tube closure. Convincing evidence that folate supplementation in early gestation dramatically reduces the risk of NTDs (MRC Vitamin Research Study Group), suggesting that either a relative or absolute deficiency of prenatal folate.i.folate; is a cause of NTDs. As for micronutrient deficiencies, the prevalence of NTDs follows no simple gradient across rich and poor countries.

The Dutch Famine Study A series of investigations by our group on the effects of the Dutch Hunger Winter of 1944 to 1945 has demonstrated an association between severe prenatal nutritional deprivation and schizophrenia (Susser and Lin; Susser and others [submitted]; Brown and others). Toward the end of World War II, the Nazi blockade of occupied western Holland led to a severe famine in that area. Since the famine was both sudden and time- limited, and relatively complete data on health outcomes in the population were available, it was possible to relate the degree and timing of nutritional deprivation to a variety of reproductive indices and CNS anomalies (such as NTDs) (Stein and others) and, a generation later, to the occurrence of schizophrenia. We found a significant- greater than twofold- effect of severe famine exposure in early gestation on the risk of hospitalized schizophrenia in both male and female offspring. Moreover, we observed a remarkable concordance between the occurrence of schizophrenia and congenital neural defects (including spina bifida and anencephaly) following severe famine in early gestation, suggesting that prenatal folate deficiency should be further investigated as a potential causal factor in schizophrenia.