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Abstract

  1. Top of page
  2. Abstract
  3. Critical Review
  4. Discussion
  5. ACKNOWLEDGMENTS
  6. DISCLOSURE
  7. References

In countries undergoing nutrition transition and historically poor minority groups in wealthy countries, obesity tends to be more common in women than men. A potential contributor to this female excess of obesity is a mismatch between perinatal nutritional restriction and a later calorie-rich environment. Several epidemiologic and quasi-experimental studies support a gender-differential effect of early nutritional deprivation on adult obesity. The quasi-experimental studies are of particular interest because results of quasi-experimental studies are typically less vulnerable to confounding bias than observational studies. Four quasi-experimental studies—exploiting 20th century famines that occurred in Europe, Africa, and Asia—provide evidence that perinatal nutritional restriction followed by relative caloric abundance may increase adult obesity risk to a greater extent in women than men. If the findings are accurate and generalizable to contemporary food environments, they suggest that the female offspring of poor, or otherwise nutritionally restricted, women in rapidly developing and wealthy countries may be at particularly high risk of adult obesity. Research into gender-specific effects of early life nutritional deprivation and its interactions with later environmental exposures may provide insight into global gender differences in obesity prevalence.

In the United States, obesity prevalence is similar in women vs. men (1). However, black and Hispanic women have greater obesity prevalence than their male counterparts: 49.6% vs. 37.3% in blacks and 43.0% vs. 34.3% in Hispanics (1). This gender gap—an excess burden of obesity in women vs. men—is somewhat anomalous in a US context. However, globally, the phenomenon of higher obesity in women is common (2). A potential contributor to the gender gaps observed in US minority populations and globally could be a mismatch between a restricted in utero or perinatal nutritional environment and a later calorie-rich one.

Restricted nutrition in utero or during infancy could increase risk of obesity as an adult via a mismatch between an offspring's early life predictive adaptive response and a later calorically rich environment (3). There is limited experimental evidence that a nutritional mismatch could especially increase obesity risk in females (3). If true, this mismatch mechanism could be particularly relevant for understanding gender patterns of obesity in countries experiencing rapid economic development and historically poor populations in economically developed countries.

In moderately developed countries whose economies have rapidly expanded in recent decades, obesity prevalence tends to be higher in women than in men (4). For example, obesity prevalence in Brazil is 8.8% in men and 13.0% in women (5). The same is true of some historically poor subgroups in high-development countries (4). For instance, among aboriginal Canadians, obesity is 10% points higher in women (41.6% vs. 31.2%). In contrast, among nonaboriginal (mostly white) Canadians, the prevalence of obesity is similar between women and men (22.4% of women obese, 22.8% of men) (6). These settings may be characterized by a rapid nutrition transition, in which individuals may experience, within the same life time, deficits of calories or nutrients at critical developmental periods followed by later abundance of calories, sugars, and fats.

Critical Review

  1. Top of page
  2. Abstract
  3. Critical Review
  4. Discussion
  5. ACKNOWLEDGMENTS
  6. DISCLOSURE
  7. References

Evidence from observational epidemiology

An observational study in an urban South African township found that extreme childhood poverty, particularly that involving frequent hunger, was associated with increased obesity risk in women but not in men (7). While >75% of the women in the 2004–2005 household survey were overweight or obese, only 30% of men were. Decomposition analysis indicated that childhood hunger accounted for 11% of the disparity in obesity prevalence between women and men (7). Extreme childhood hunger likely correlates with fetal and infant nutritional deficits.

A US observational study found that the female-male gap in black young adult obesity prevalence was largest in adults whose parents had low educational attainment (8). Low parental education is a proxy for low childhood socioeconomic status (SES).

In the United States, low-SES populations are at especially high risk for low-birth weight (9) and early nutritional deficiencies coupled with high caloric and fat intake in adolescence and adulthood (10). Other social factors, such as family structure and household size, only weakly modified the gender gap (8). The specificity of parental education as a modifier of the gender gap lends credibility to the hypothesis that in utero or infant exposures related to low-SES heighten long-term adult susceptibility to obesity in a sex-specific manner. Further, the finding was generalizable to other race groups. A gender disparity was also found among the small subgroup of Whites with low-SES childhood backgrounds.

Evidence from quasi-experimental studies

The previous evidence is from observational research and assumes that Americans who were low-SES as children and black South Africans who reported frequent hunger as children experienced an environmental mismatch between their early life and adult nutritional environments. Stronger causal evidence that in utero or perinatal nutritional deprivation influences gender differences in obesity susceptibility comes from quasi-experimental studies. In observational studies, the relationship between an exposure—such as fetal nutritional deprivation—and an outcome may be confounded by many other risk factors. Therefore, it is difficult to tease apart the effect of the exposure from the effects of other risk factors. In quasi-experimental studies, however, the exposure of interest is exogenous to, or statistically independent of, most other risk factors.

Perhaps the most well-known quasi-experimental study exploring the influence of fetal deprivation on later health is the Dutch famine study. The Dutch famine study is a quasi-experimental retrospective cohort of adults who were in utero in the Netherlands before, during, and after a World War II-era siege and ration cut (11). Exploiting the quasi-random nature of a 5-month ration cut, contemporary researchers examined 59-year-old adults who were exposed to the ration cut at different stages of gestation (160 males, 190 females) and nonexposed controls sampled from same-sex siblings (180 males, 180 females) and births at the same hospitals as the cases 2 years before or after the ration cut (137 males, 159 females). During the 5-month exposure period, rationed calories for adults ranged from 900 kcal/day down to 500 kcal/day, consisting almost entirely of bread and potatoes by the end. The nutritional deprivation ceased within weeks of liberation in spring 1945; residents were accorded abundant nutrition. Female—but not male—offspring who were in gestation during the ration cut had higher BMIs and waist circumferences in late middle age than controls, who did not gestate during the ration cut (11).

A Nigerian study had similar findings (12). From 1967–1970, during a civil war, Nigerian military forces pushed 7 million Biafrans, a minority group who had declared independence from Nigeria, into a small enclave and cut off food supplies to the people segregated there (12). An estimated 1–3 million people died, mostly of starvation. In 2009, researchers surveyed 1,339 adults at marketplaces in the former capital of the breakaway state of Biafra. Adults born between 1965 and 1967 were categorized as exposed to famine in early childhood (246 males, 142 females). Adults born between 1968 and January 1970 were categorized as exposed to famine in fetal life and infancy (189 males, 103 females). Those born between 1971 and 1973 were classified as unexposed (353 males, 133 females). In women, obesity (BMI ≥30 kg/m2) and overweight (25.0 kg/m2 ≤ BMI < 30.0 kg/m2) were more common in those exposed to the famine in the fetal and infant period compared to those born after the famine. No effects were observed in men.

A third investigation was designed to exploit deprivation caused by the Great Famine in China (1959–1961) (13). Using data from the nationally representative 2002 Chinese Nutrition and Health Survey (CNHS), the researchers divided rural respondents into those born during the 1959–1961 famine (1,997 men, 2,366 women) and a control group born in 1964, after the famine (1,220 men, 1,473 women). In men, there were no differences between the famine—exposed and control groups in mean BMI nor prevalence of study-defined overweight (24 ≤ BMI ≤ 27.9 kg/m2) or obesity (BMI ≥ 28 kg/m2). Women born in famine years, however, had higher BMI, greater prevalence of overweight, and greater prevalence of obesity than control women born in the same regions.

A final quasi-experimental study found no sex differences in effects of early life famine on later BMI, waist-to-hip ratio, or subscapular triceps skinfold ratio (14). A German blockade of Leningrad (present-day St Petersburg) between September 1941 and January 1944 included an especially severe period of starvation between November 1941 and May 1942. During this period, the average daily ration was around 300 cal, almost entirely of bread. Using a regularly updated record of all people living in or born in the city of Leningrad during the siege, the study assembled a group exposed to the blockade in utero (born November 1941 to June 1942; 37 males, 132 females) and a group exposed in infancy (born January 1941 to June 1941; 62 males, 130 females). A control group born in the same province but outside the besieged area between January 1941 and June 1942 were recruited as adults from hospital clinics and six local workplaces (50 males, 138 females). Diabetics were excluded from all analyses. The study found no differences among the intrauterine, infant, and control groups, in overall or sex-stratified analyses.

Discussion

  1. Top of page
  2. Abstract
  3. Critical Review
  4. Discussion
  5. ACKNOWLEDGMENTS
  6. DISCLOSURE
  7. References

In three quasi-experimental studies, fetal or infant nutritional deprivation was associated with greater susceptibility to obesity in women but not men. The one study that did not find a sex difference was one with a less pronounced mismatch between the fetal and perinatal, and postnatal environments (13). In the Leningrad cohort, a poor nutritional environment persisted for years after the most severe period of starvation ended in spring 1942. In contrast, the nutritional environment changed abruptly after the end of the Dutch famine siege. The studies of the Biafran and Chinese famines did not describe to what degree the postnatal and later environments differed from the perinatal famine environments. However, the Chinese famine study restricted its sample to rural residents in order to minimize differences between the famine and post-famine environments among migrants to urban areas (13).

In all of the studies, the fetal and perinatal nutritional environments were measured at the ecological level and not well-defined for any given individual. Therefore, the exact timing and nature of nutritional exposures are ambiguous to varying degrees in each study. The studies with the best characterized exposures were the Dutch famine and Leningrad studies: defining exposure based on official government rations provided specificity about the timing and approximate magnitude of nutritional deprivation. The Chinese and Biafran studies defined exposure more crudely, by birth before or during multiyear famines.

Each of the quasi-experimental studies may be biased by selective mortality or low-response rates that may be differentially patterned by sex and adult weight status. Response rates in the Dutch famine and Leningrad cohorts were especially low, e.g., 25–35% in the Dutch famine study, and lower in men than women. The Biafran study had a very high response rate: >90%.

Finally, poor sampling methods could have caused bias in some studies. The Chinese famine study had the most valid sampling—from a national survey. In contrast, the Biafran study sampled from a gender-imbalanced marketplace, which is probably not representative of the target population. The Leningrad cohort had excellent methodology for sampling its exposed population; however its method of sampling controls was poor: controls were a mix of patients at an eye surgery clinic and several different local workplaces. Furthermore, diabetics (who are more likely to be obese) were excluded. The Dutch Famine's use of hospital births (a minority of babies born during the siege) was not optimal, but they attempted to minimize bias by assembling a control series defined by similar selection processes.

Gender differences in the response to perinatal nutrition restriction could occur through various mechanisms. Early nutritional deprivation may have long-term, sex-specific effects on appetite and weight regulation (7). Alternatively, gender differences could be mediated by greater “catch-up” growth in infant girls vs. boys (12). Additionally, experimental work in animals, such as the Agouti mouse, has generated a great interest in epigenetic mechanisms that may affect obesity in humans. Much of the experimental literature concerns maternal and perinatal social stress, which is an alternative mechanism by which famine and childhood poverty may affect later obesity risk (15). The experimental literature has identified several possible mechanisms mediating sex-specific responses to maternal stress and malnutrition: interference with sex hormone signaling; alteration of methylation patterns of genes, including insulin-like growth factor-2; and sex-dependent perturbations to the functioning of the placenta (15).

The extreme nutritional and social conditions experienced by the victims of famines are not generalizable to most contemporary populations. In fact, in many contemporary populations, early life hypernutrition is a competing developmental risk factor for later obesity (3). However, the studies reviewed suggest that the female offspring of poor, or otherwise nutritionally restricted, women in rapidly developing and wealthy countries may be at particularly high risk of obesity due to environmental mismatches between early and later life. This novel hypothesis of gender-specific effects of fetal or perinatal nutritional deprivation on later obesity risk is speculative. However, if true, gender-specific effects of in utero or perinatal nutritional deprivation and its interactions with later environmental exposures may provide insight into global gender differences in obesity prevalence.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. Critical Review
  4. Discussion
  5. ACKNOWLEDGMENTS
  6. DISCLOSURE
  7. References

This study was supported by the Robert Wood Johnson Foundation Health and Society Scholars Program.

DISCLOSURE

  1. Top of page
  2. Abstract
  3. Critical Review
  4. Discussion
  5. ACKNOWLEDGMENTS
  6. DISCLOSURE
  7. References

The author declared no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Critical Review
  4. Discussion
  5. ACKNOWLEDGMENTS
  6. DISCLOSURE
  7. References