Natural Experiments

The strongest evidence linking prenatal starvation to schizophrenia derives from natural experiments. Natural experiments are perhaps best known in the context of genetic epidemiology where twin and adoption studies are classic examples. However, natural experiments of a different kind can be built around circumscribed historical events. Sometimes these are tragic events such as famines, as in the examples described below, but a beneficial event can also be the basis for a natural experiment. The various kinds of natural experiment share 2 defining features.[2] First, unlike an ordinary observational study, people are selected into an exposed or unexposed group by an event largely outside of their control. Second, unlike an ordinary experiment, this event is not under the control of the investigator. As a result of these features, the design tends to be stronger than an ordinary observational study though not as strong as an ordinary experiment.

The first direct test of an association between prenatal starvation and schizophrenia arose as a result of the Dutch Hunger Winter of 1944-1945, one of the tragic events of World War II.[3] The famine was precipitated by a Nazi blockade of occupied Holland in October 1944, in retaliation for the support by the Dutch resistance to the Allied command. Already compromised by food shortages at the onset of the blockade, the food situation worsened further due to an unusually severe winter, which froze the canals used to transport food. The famine grew steadily worse until it ended with liberation in May 1945. During the height of the famine in the 2-3 months prior to liberation, the daily food ration was mainly bread and potatoes (by April 1945 the ration provided less than 500 calories daily), supplemental food was scarce, and the population was nutritionally depleted. Mortality was more than double, and fertility (reflected in births 9 months later) was less than half that of the previous year. Most affected were the 6 cities of western Holland.

Although tragic, the famine has provided a unique opportunity to examine health effects throughout life of starvation during specific periods of gestation.[4] This was made possible by the fact that the height of the famine was brief, clearly circumscribed in time, and afflicted a population that maintained excellent records on both food rations during the famine and on health outcomes for several decades hence. An early neurodevelopmental finding from the Dutch famine studies was an increase in congenital neural defects, especially neural tube defects including spina bifida and anencephaly, among a birth cohort conceived during the height of the famine.[3,5] This finding of an effect on neurodevelopment bolstered the plausibility of prenatal famine as a cause of later schizophrenia. It also provided a key component of the rationale for the analytic design of the Dutch famine study of schizophrenia.

In the schizophrenia study, we examined whether the birth cohort with excess central nervous system (CNS) anomalies also had an increased risk of schizophrenia. The exposed cohort was defined by birth in the famine cities during October 15-December 31, 1945; the height of the famine corresponded to the periconceptional period or early gestation for this cohort. The Dutch psychiatric registry was used to compare psychiatric outcomes in adulthood for exposed and unexposed birth cohorts. The primary outcome was a diagnosis of narrowly defined schizophrenia by International Classification of Diseases, Eighth/Ninth Revision, criteria (295.1, 2, 3, 6), as categorized in the Dutch National Psychiatric Registry for the years 1970-1992, during which time the subjects were aged 24-48 years. The study found a significant, 2-fold increase in the cumulative risk of schizophrenia in the exposed birth cohort.[5,6]

Moreover, a subsequent study showed a 2-fold increased risk of schizoid personality disorder in the same exposed birth cohort.[7] In this instance, the outcome data were obtained from military induction examinations conducted on all males when they reached age 18. Unlike the schizophrenia result, which was based on the psychiatric registry data, this finding was not limited to treated cases. It provides further evidence of an effect on schizophrenia spectrum disorders (SSDs) from an independent data source.

Inspection of the disease risks for successive birth cohorts of 1944-1946 revealed striking peaks in the incidence of schizophrenia, schizoid personality, and congenital neural defects in this same birth cohort.[8] This occurred in the context of an otherwise stable incidence of these disorders among cohorts exposed to famine during other periods of gestation and cohorts who were completely unexposed to famine during pregnancy.

It proved difficult to identify a second natural experiment along the same lines in which the Dutch result could be replicated or refuted. While famine is not uncommon in the world, it is usually not clearly demarcated in time, and the resources for assessing health outcomes are not available. In a recent study, however, the relation of prenatal famine to risk of schizophrenia was successfully examined in a cohort in the Wuhu region of Anhui Province, China.[9] In the late 1950s, a massive famine was precipitated in China by the marked social and economic upheaval known as the Great Leap Forward, which involved agricultural collectivization, use of flawed agricultural practices, and diversion of agricultural labor to other purposes. By some estimates, the famine caused 30-40 million deaths.[10] Anhui Province was one of the most affected.

In the Chinese study, monthly data on caloric rations were not available. Nonetheless, the authors, based on the Dutch results, could examine whether the risk of schizophrenia was increased in the birth cohorts conceived during the height of this famine. Accordingly, the Wuhu birth cohorts of 1960 and 1961 were defined as the exposed group. These cohorts were conceived in the period of most severe famine for this region, as documented in historical records, and as reflected in birth rates for 1960 and 1961 that were less than one-third the average for 1956-1959.

Thus, the authors compared the cumulative risk of schizophrenia among the birth cohorts of 1960 and 1961 with that of birth cohorts prior to and subsequent to the famine. The schizophrenia outcomes were obtained from systematic review of the records of the sole psychiatric hospital in the Wuhu region over the period 1971-2001. The increased risk—approximately 2-fold—was similar to that of the Dutch famine. A key advantage of the study was its much larger sample size. Replication in a population of very distinct ethnicity and culture from the Netherlands is consistent with a biological causation hypothesis.[11]

Several limitations of these studies need to be considered. We first consider the Dutch famine. First, as in all observational studies, there is the possibility that the results may have been confounded by certain known and unknown factors. One possible confounder that needs to be considered is prenatal stress. The exposed population was likely to have already been under severe stress due to the combination of the famine, war, and many other hardships, and prenatal stress has been associated with schizophrenia in some though not all studies, and there have been several limitations to this work.[12,13,14] However, it is worth noting that other areas of the Netherlands, which were also exposed to war and moderate levels of starvation, did not evidence an increased risk of schizophrenia.[15] A second potential confounder is social class of origin. We consider confounding by this factor to be unlikely because no associations have been demonstrated between schizophrenia and social class of origin in the Netherlands. Moreover, because the exposed cohort was weighted toward the upper classes due to greater fertility, this would tend to reduce the observed association between prenatal famine and schizophrenia.[5] Other limitations of the study included group data to define exposure and the inability to tease apart the effects of different types of nutritional deficiencies or of other substances that may have been ingested that might have toxic potential. With regard to the former limitation, it should be emphasized that the exposure was documented in detail and was pervasive in the population.

While the Chinese famine study offered several strengths, one weakness is that famine exposure data were not available by month; hence, the precision of the periods of famine cannot be as accurately estimated as in the Dutch famine study. However, the pattern of increased risk of schizophrenia by birth year is consistent with an early gestational effect; this is discussed in more detail in St Clair et al.[9]