Accumulating Evidence for Prenatal Nutritional Origins of Mental Disorders

Abstract

THE STUDY BY ST CLAIR ET AL 1 IN THIS ISSUE OF JAMA reports an association between prenatal exposure to severe maternal nutritional deficiency and risk for schizophrenia in adulthood. Examination of this question was achieved through strategic use of the Chinese famine of 1959 through 1961 as the fulcrum of their study design. In so doing, these authors afford yet another excellent example, frequent among articles in the annual JAMA theme issue on violence and human rights, of epidemiologists extracting otherwise inaccessible scientific knowledge from the harsh soil of human catastrophe. Susser and Lin were the first to demonstrate this link between severe maternal nutritional deficiency and the offsprings’ risk for schizophrenia. That earlier study, which served as the scientific impetus and analytic model for the current investigation, examined the association between nutrition and schizophrenia using the unique circumstances created by the Dutch Hunger Winter of 1944-1945. In October 1944, the German Army blockaded food supplies to the Western Netherlands as punishment for Dutch involvement in the planned Allied invasion of Europe. Before the blockade, the food supply had been adequate; in May 1945, following the German retreat, it became quickly plentiful again. In the intervening months, however, the Dutch population, particularly in the larger cities, received increasingly meager food rations, a circumstance rendered especially difficult by an unusually harsh winter. Hence, Dutch women who were pregnant in October 1944 and others who conceived in the following months experienced declining food supplies at varying points in gestation. This wartime disaster, occurring in a previously wellnourished industrialized nation, created a natural experimental framework for examining the association of prenatal nutritional deficiency of varying intensity imposed at different points in intrauterine development with risk for postnatal psychiatric disorder in offspring. Analyses of rates of schizophrenia based on case data derived from the Dutch national psychiatric registry implicated early severe prenatal nutritional deficiency in a 2-fold increased risk of schizophrenia overall and in men and women offspring separately. Parallel studies, drawing on results from the medical examinations conducted on 18-year-old Dutch military recruits, documented a 2to 3-fold increased risk for schizoid personality disorder and for antisocial personality disorder, respectively, among persons exposed early in gestation to severe maternal nutritional deficiency. The schizophrenia findings from the Dutch and Chinese famine studies are in remarkable agreement, a consistency that enhances the validity of both investigations. St Clair et al also report a 2-fold increased risk for schizophrenia among individuals prenatally exposed to famine both overall and for each sex separately. Furthermore, the profile of both “epidemics” is entirely analogous although on vastly different temporal and population scales—an abrupt rate increase among individuals prenatally exposed to the famine followed by a rapid return to previous background rates at the close of the nutritional crisis. Of equal importance from the perspective of confidence in drawing causal inferences, the Chinese study successfully addresses several competing explanations for the Dutch findings, noted but not remediable in the studies on the Dutch famine. The nutritional interpretation of the Dutch famine findings was vulnerable to a variety of alternative explanations. Tulip bulbs, consumed at the height of the famine as a food substitute, could have exerted toxic effects on fetal brain development. Hormonal perturbations prompted by the physiological stress of the exceptionally cold winter, some unidentified aspect of urban life under German occupation toward the very end of the war, or the extremely rapid nutritional repletion starting in May 1945—each jointly or separately might have disturbed neuronal maturation. The Chinese replication of the Dutch findings, given the markedly different circumstances, culture, and ethnicity, renders these competing explanations moot or nearly so. During the Chinese famine, food substitutes comprised tree bark and the green algae chlorella, grown at home in vats of urine; the nutritional deprivation did not coincide with unusually harsh winters nor with military occupation by a foreign power.