Evidence of Famine From Birth Rates and Mortality Rates
provides the birth and death rate for Liuzhou and its 18 surrounding districts that were served by Longquanshan psychiatric hospital, Liuzhou, for the years before, during, and after the famine. Fertility or birth rate decline, which is an accurate indicator of starvation in the periconceptional period or during early gestation, showed a modest (13%) drop in 1959, followed by 38% and 45% drops in 1960 and 1961, respectively. A rebound increase in fertility occurred in 1962 after the famine was over. The death rate doubled in 1959, tripled in 1960, but was only 50% above its prefamine level by 1961. This clearly indicates that severe famine started in 1959, peaked in 1960, and fell off rapidly in 1961.This is consistent with the historical records which report that severe famine conditions started to appear in Guangxi AR in the summer of 1959 and were relieved in early 1961. Birth rates decreased by around 50% for the years 1960 and 1961 in the rural areas. In Liuzhou city, the birth rate decrease was substantially less and occurred predominantly in 1961. Mortality was also considerably higher in the countryside than in the city. By 1962, fertility was above prefamine levels in town and countryside. These data provide conclusive evidence of famine in Liuzhou area most severe in the years 1959 and 1960.
Number of Births, Birth Rates, and Death Rates for Years 1956 Through 1965 in Liuzhou City and 18 Surrounding Counties of Liuzhou Prefecture
Is the Countryside Risk Similar for Han Chinese and Ethnic Minorities?
We do not have separate birth rates for Han Chinese and minority Chinese so only exploratory analyses could be performed. We used the total birth rates of each year (from 1956 to 1965) and made the assumption that the ratio of Han vs minority births would remain essentially unchanged from year to year. We divided the number of Han Chinese cases and the number of minority Chinese cases who were born in each year by total number of births and then compared rates in exposed birth cohorts 1960 and 1961 with rates in the reference years separately for Han Chinese and minority Chinese. Increased RR was present in both Han Chinese and ethnic minorities, with RR in Han Chinese slightly higher than in the ethnic minorities. Han Chinese: RR
1.88 (95% CI = 1.54–2.29) (1960) and RR
2.36 (95% CI = 1.97–2.86) (1961) and Ethnic minorities RR
1.55 (95% CI = 1.30–1.84) (1960) and RR
2.17 (95% CI = 1.87–2.51) (1961). Chi square and P
values are 25.05 and 5.578 × 10−7
and 107.56 and 3.354 × 10−25
for 1960 and 1961, respectively, for ethnic minorities.
It should be noted however that these are crude estimates because separate birth rates for Han Chinese and ethnic minorities were unavailable.
We saw no age of first treatment effects, and there was no change in proportion cases reporting a positive family history in those born in the years 1960 and 1961.
Epidemiological investigations of the effect of prenatal famine on human populations are rare. It is highly unusual to have reliable clinical and demographic information. Although the 1959−1961 Chinese famine took place in a developing country undergoing a major political and economic upheaval, the information currently available is unexpectedly good. Longquanshan psychiatric hospital is one of the largest psychiatric hospitals in China and is the single referral hospital for Liuzhou city and 18 surrounding counties. A smaller number of cases are also referred from other parts of Guangxi AR, but during 1971−2001, virtually all patients from Liuzhou and surrounding counties, if referred, were referred to Longquanshan hospital. We included in our sample only patients born in Guangxi and resident in Liuzhou and the surrounding 18 counties at the time of first treatment. The sample size was roughly double our previous study in Anhui. We were able to stratify into urban and rural. The psychiatric case records were excellent with more or less complete data on age of onset, ethnicity, and gender.
It is important also to consider the limitations of the data. Almost all records had data on presence or absence of family history. However, this was not systematically recorded, with details of family structure and size; it was little more than presence or absence of schizophrenia or other psychosis in a first-degree relative. Comprehensive records of births and deaths in the Liuzhou prefecture for the years before, during, and after the famine were also available for analysis. The birth rates for the present study were derived from the same official source of population statistics, compiled by Department of Police as in the Anhui study. In this respect, the 2 studies are directly comparable. We think that these records are the most accurate available as a source of information on births and deaths for the years of interest. They are internally consistent, eg, patterns of changes in births and deaths were similar when examined at level of prefecture, region, and province: they were also compatible with population age structure for Liuzhou prefecture as documented in the 1982 and 1988 census.15,16
These latter data are not directly comparable; however, because the census figures are for fiscal (June 30−June 30) years, whereas calendar years were used for the statistics of births and deaths. The figures are generally reliable but are not free of occasional errors. Absolute numbers for Liuzhou city were small and more vulnerable to the effects of inward and outward migration. Nonetheless, for consistency, the figures for all births used in the Anhui and Guangxi studies come from the same statistical sources.
shows that the decline in births was paralleled by an increased risk of schizophrenia in adults born during this period. The RRs were 1.50 (95% CI = 1.35−1.68) (1960) and RR
2.05 (95% CI = 1.87−2.27) (1961). Increased RRs are highly statistically significant for both 1960 and 1961 when analysed separately and would be even more so if analysis was performed on the 2 years combined (data not shown). Both years witnessed around a 50% decrease in the birth rate compared with prefamine years. Decline in fertility/births is an accurate proxy indicator of starvation and is an excellent method for timing the exposures. Although birth rates can be affected by events at any point until term, the further a pregnancy advances the less likely this is to abort. For this reason, dramatic declines in populations are normally associated with starvation around conception or during early gestation. These data fully concord with and extend the conclusions drawn from our previous Dutch and Chinese studies. See for comparison of the 2 Chinese studies. The peak RRs of around 2 are remarkably similar across the 3 studies in spite of differences in diet, ethnicity, and severity of the famines. Our data suggest that individuals most at risk of schizophrenia were those who were conceived or in early gestation in the second half of 1959 and through 1960, namely the time when the famine was at its height. Because they are born 6−9 months later, if our predictions are correct, we should observe elevated relative rates in the years 1960 and 1961. This is precisely what we observe. Although we cannot rule out an effect in late gestation, this seems unlikely. In this latter case, because the severe famine was evident by summer 1959 and ended early 1961, one might expect to observe increased risk beginning in 1959, peaking in 1960 and showing only a modest increase in 1961.This is not the pattern observed in either of the Chinese studies. The authors appreciate however that these analyses are based on data grouped by year rather than by monthly birth cohorts as in the Dutch study, and this is a limitation of the data. It is also true given the length of the famine that individuals born in 1960 could have been exposed both prenatally and postnatally to the effects of famine.
a. Adjusted Risk of Schizophrenia Vs Birth Rate for Years 1956–1964 in Rural Liuzhou Prefecture. b. Adjusted risk of schizophrenia vs birth rates for 1956–1964. Wuhu Prefecture, Anhui.
shows that in the Liuzhou prefecture the increased risk of schizophrenia comes almost exclusively from the countryside. Indeed, the city population shows no increased RR at all for any of the famine years. This lack of increased risk is consistent with the much less pronounced drop in birth rates observed in Liuzhou city (and even absence of drop in 1960) and the very modest increase in death rate compared with the countryside. The apparent drop in risk for the year 1960 in the city is probably a statistical artifact due to the anomalous lack of drop in birth rate. A similar pattern of no increase in risk has now also been observed in Wuhu city in Anhui (Yongyong Shi personal communication). The disparity in the extent of famine between the city and countryside may partly be explained by poor transport and communications in rural Guangxi at the time of the famine, but another factor was the division of China's people introduced in the early 1950s into separate urban and rural populations. Urban or rural status was determined at birth and movement between countryside and city was restricted and controlled by an internal passport system. The state undertook to provide those living in the cities with food from state grain stores. They had legal rights to a certain amount of food. For those in the countryside, entitlements were poorly defined that essentially meant they were allowed to retain residual grain after they had delivered government-imposed quotas. These latter arrangements are classic circumstances, according to Amartya Sen, in which famine can arise.6,15
The gulf between city and countryside was commented on at the time. Many city dwellers in China were barely aware that people were dying from famine in the countryside. Food availability and the proportion of the population with defined entitlements in the affected provinces were the 2 main determinants of mortality rates during the famine years.6
The absolute rates of schizophrenia for all years were substantially higher in Liuzhou city than in the surrounding counties. This may be partially accounted for by the well-documented increased rates of schizophrenia associated with urbanization that is observed in both developed and developing countries.16
A second contributor may be the reduced level of provision and access to psychiatric services in contemporary rural as compared with urban China.17
On the other hand, there is nothing to suggest that rural referral patterns would differ between those born before, during, or after the famine years. This cannot account for the elevated relative rates of schizophrenia among those conceived during the exposed years.
Similar limitations on interpreting the findings from Guangxi apply as in the Anhui study. The figures for population at risk ignore the effects of emigration or death after 1988. However, the population in the region of Guangxi has, until recently, been static, and, in any case, there is no reason to expect more than a very modest bias for effects of emigration among those born before, during, or after the famine years. There are no reliable data on coincident factors, such as epidemics occurring in the Liuzhou region during the famine years. Ingestion of food substitutes such as bark from trees was common, and some may have been toxic. However, all these factors are unlikely to account for the fact that 3 separate studies have now demonstrated the same phenomenon, with different food substitutes in all 3.
Only a minority of schizophrenia cases were admitted to hospital for initial assessment. However, the clinical notes were well-documented, and reliability of diagnosis was good as our validation study described above demonstrates. We observed no difference in sex, age of onset, or proportion of cases with a first-degree relative with major mental illness (familial) between those conceived in the exposed vs nonexposed years. These findings are similar to the Anhui study.
The data on familiality are subject to the same limitations as the previous study of lack of specificity of diagnosis and no systematic data on family size. None the less the apparent lack of reduction in familiality in the exposed cohorts in both the Anhui and Guangxi studies suggests that a simple explanation that famine acts as an independent cause of schizophrenia, regardless of genetic liability to schizophrenia is less likely. If it was independent, half of the cases of schizophrenia among individuals born during the famine would be representative of the general population in terms of liability. This would result in a reduction in rate of positive family history among the exposed birth cohorts. This was not observed. However, in view of the limitations of the data, any conclusions must be provisional.
It could be also be argued that in view of the differing severity of famine conditions reported in the 3 studies one might expect that the RRs of schizophrenia would show a wider range of outcomes than we observe with perhaps the severer the famine the higher the RR. This is not the case. A possible explanation is that there is a threshold and ceiling effect; a drop to 2000 calories per day is required for the effect to occur. Any more severe starvation and there is failure of menstruation/ conception/gestation and/or live term births.
The mechanisms by which prenatal nutritional stress could produce increased risk of schizophrenia have been discussed in detail elsewhere.5,18,19
Although prenatal nutritional deficiency is the most likely explanation, preconceptual effects on sperm cannot be ruled out. Psychogenic effects of experiencing famine, only indirectly related to nutritional stress, are also possible. Alternatively it is possible that those with schizophrenia risk alleles have an advantage in times of famine so that more individuals at risk conceive, implant, come to term, and survive postnatally. Nutritional deficiency, especially of micronutrients involved in the folate pathway, may either directly affect growth of the developing fetal brain or indirectly affect it by interfering with DNA stability and/or epigenetic regulation of genes critical for brain development.20,21
The folate pathway has a key role in DNA synthesis, methylation, and repair. Nutritional stress can also alter molecular regulatory mechanisms and release previously accumulated but unexpressed variation.22,23
Both heat shock proteins 70 and 90 are elevated in vertebrates in response to starvation during early development.24
Prenatal nutritional stress could therefore shift the threshold for phenotypic expressivity of a trait such as schizophrenia. These potential psychological, physiologic, and molecular responses to prenatal nutritional stress are of course not mutually exclusive. All 3 studies have associated strengths and weaknesses; the Chinese studies are particularly vulnerable to the reliability of statistics collected half a century ago in a large, poor country in a time of chaos. However, the clinical epidemiological findings from all 3 famine studies show a remarkable consistency that makes a compelling case that our observations are in essence correct.
What remain unknown are the mechanisms. Famines are rare even in developing countries. However, micronutrient deficiencies are common. Large strides have been made in reducing fetal iodine deficiency−related disorders and neural tube defects by iodine and folate supplementation. It is possible that a similar strategy could also impact on rates of schizophrenia.