High blood pressure (BP) is highly prevalent and the main cause of premature death and disability worldwide [1–3]. Various genetic and environmental factors promote the development and persistence of high BP. Genome-Wide Association Studies of BP have shown statistically significant but small effects for independent BP genetic variants, which collectively can explain only 2% of the phenotypic variance for BP (1/20 of the expected genetic contribution) . About 50% of all new cases of high BP are attributable to excess weight (overweight and obesity), excessive salt intake (>4.5 g/day) explains 30% of cases, and low physical activity 16% . Other potential risk factors for hypertension have been identified, but it is still uncertain whether they have an independent effect on BP levels. These include socioeconomic position and low birth weight .
Among the proposed environmental early determinants of hypertension and other adult chronic conditions, undernutrition during pregnancy and infancy (‘critical periods’) has been postulated as a key driver [6–8].
Famines, though historical disasters, provide a unique opportunity to study the long-term impact of nutritional deprivation in early life on human development in general and cardiovascular conditions, including hypertension, in particular. Most previous studies on the famine effects during pregnancy were based on European cohorts experiencing famine during the Second World War, that is, the Dutch Hunger Winter and the Leningrad Siege [9,10]. The Dutch famine studies found significant association with adult hypertension at age 59 years but not at age 50 years . A recent study of the Leningrad siege found that those exposed to famine in childhood and the intrauterine period had a significantly higher prevalence of hypertension compared with the newborn/infant group .
More recently, the Chinese famine of 1959–1961, the largest in recent human history, is clearly worth examining as its duration (3 years) was longer than the Dutch Hunger (∼6 months) and the Leningrad famine (28 months), was not because of war, and affected most areas of such a big country like China. Thus, it provides an excellent setting to examine the effects of severe, early life undernutrition on adult chronic disease in a non-European population.
The Chinese famine has been attributed to the ‘Great Leap Forward’ campaign launched by Mao in 1958 and caused approximately 30 million excess deaths . Several studies have recently examined the association of famine exposure in early life and hypertension in the adult age in China [12–18], but findings were not always consistent.
The table shows the common and differing methodological characteristics of the main Chinese studies published so far. Critical issues in comparison among studies are the different definition of the windows of exposure to the famine, based on birth date, the definition of famine severity and the lack of a distinct nonfamine area. In fact, precise information on the dates of start and end of the famine was not available. Famine duration varied across regions, and the imprecise duration in the study areas may lead to the misclassification of the famine exposure periods and the difficulty to separate effects of fetal and infant famine. The famine affected all of China, but its timing and severity sharply varied from province to province, due to weather conditions, population density, and local policies on food shortage, affecting rural areas disproportionately.
Thus, for example, Li et al. defined the fetal development period as those adults born from October 1959 through September 1961 in areas of severe famine. However, under the exposure classification system by Wang's criteria , most of Li's study participants would have been classified as exposed during both fetal and infancy periods (January 1959–September 1961) . Interestingly, Li et al. and Yu et al.[13,18] excluded births from October 1958 to September 1959, and October 1961 to September 1962, from their national cohort given the imprecise, varying famine duration across mainland China, and Wang et al. considered that the famine duration in Guangdong province was from January 1959 to October 1961 based on local information, thus they considered exposure during ‘fetal period only’ in the period from October 1961 to June 1962. These specifics by area may help explain differences between studies. Also Li et al. found an increased risk of hypertension in severe famine areas, whereas Guandong was considered a less severely affected area [13,14]. Likewise, different birthdate ranges in infant periods among studies (e.g. Li vs Wang) [13,17] make seriously difficult comparisons. Also, prenatally exposed cohorts may also be exposed during infancy and early childhood due to the long and imprecise duration of the famine, thus making it difficult to separate effects only due to exposure during the prenatal period and the combined effects of fetal and infant periods [15,17]. Interestingly, Wang et al. defined infant cohort as those born from 1 January to 31 December 1958, thus assuring almost all participants in this group were exposed to famine in infanthood.
The Chongqing study was the only one not reporting a significant association between any period of famine exposure and hypertension . However, data in this study were grouped by year rather than by month, and thus exposure periods were more imprecise, for example, study participants born in 1960 could have been exposed both prenatally and postnatally. Also, this study focused on fatty liver disease and only adjusted for sex and age.
To our knowledge, the first report of effects of the Chinese famine on hypertension was that by Huang et al.. They used robust analytical methods to measure more precisely intensity of the famine at the county level based on the sizes of birth year cohort, and also controlling for cohort effects (i.e.- age and time trends). However, they only studied young women, and they only found significant effects in rural areas probably due to small sample size in urban areas.
The study by Yu et al. published in this issue of the Journal, one of the latter studies on the study participants, used data from the large Dongfeng–Tongji cohort of retired motor manufacture workers in Shiyan, Hubei (China). Although mainly confirmatory, this study adds to the literature by examining individuals of an older age and in a different setting and geographical area than previous studies, and adjusted for a number of important covariates (Table 1). Although the authors used the same exposure definitions as Li et al., they found higher hypertension risk in fetal and infant periods, and Li found consistent association in only the fetal period. The older age of Yu's study participants due to longer follow-up makes plausible these findings. However, this study lacked adjustment for some important hypertension risk factors (e.g. salt consumption) and is prone to the healthy worker effect.
There is need for further discussion on different definitions and methods used to characterize the timing and intensity of the Chinese and other recent famines, and a systematic review of existing studies could be helpful. In addition, a cohort with individuals born during more specific intervals before, during, and after the famine could be helpful. Furthermore, in the absence of data on hypertension incidence, data on hypertension duration could be helpful for giving clues into critical periods of hypertension development.
Follow-up over time of people exposed to the famine or early-life undernutrition could obtain additional, potentially usable information on a variety of outcomes including heart disease, cancer, insulin resistance, diabetes, acceleration of the aging process , telomere shortening , decreased physical function in men and perhaps also frailty .
A life course approach might be a powerful strategy, but its value will depend on its success in elucidating new mechanisms and disease pathways as well as its ability to explain social, geographical, and temporal patterns of disease distribution . In fact, the mechanisms connecting undernutrition in early life with adult hypertension are still unclear. Two main hypotheses (fetal undernutrition and postnatal rich-nutrition environment) have been advanced , but much remains to be elucidated. The stronger association in Chinese study participants who were overweight or had a Western diet pattern as adults [13,17,18] suggests that the postnatal nutrition-rich environment does not match the fetal undernutrition environment, which may increase the risk of hypertension in later life. Some Chinese studies reported associations strongest among women , the reasons are not clear, and maybe boys had preferential treatment for food. Fortunately, women are especially receptive to advice about diet and lifestyle before and during a pregnancy, which should be exploited to improve the health of future generations .
Apart from the early exposure to famine, other environmental and socioeconomic conditions may be at work, and further research to identify specific components of maternal and child diet, and additional external factors [7,8,23], and joint effects of early and adult determinants is needed. Furthermore, the study of genetics, and interaction with environment factors, is promising especially thinking in terms of precision medicine. Epigenetic changes may also importantly contribute to heritability of hypertension [7,24].
Despite inconsistencies among studies and uncertainty, practically all the Chinese famine studies show that early life environment is critical for the risk of hypertension in adult life. To control the major diseases of adult life, together with our disturbing social inequalities in health, it may be necessary to improve not only the nutrition and environment of adults but also the nutrition and environment of pregnant mothers and small babies .
Famines in the modern era are the result more of human action than nature , and the Chinese famine was one of the largest social catastrophes in human history. Lessons should be learned from past experience and opportunities are open for further research that enriches knowledge derived from this tragedy for future generations.
Specific funding for this analysis was obtained from FIS grant PI13/02321 (Instituto de Salud Carlos III and FEDER/FSE).
Conflicts of interest
There are no conflicts of interest.
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