The theory of developmental programming postulates early developmental events (such as intrauterine malnutrition) have a profound impact on the risk of future diseases during adulthood. Early life is a specific developmental period when an organism is highly “sensitive” to its environment. For example, the adaptations in response to fetal malnutrition1 that lead to metabolic and structural changes are beneficial for early survival, but might increase the risk of adult chronic diseases, such as type 2 diabetes and coronary heart disease.2
The structural and neuroendocrine development of the hypothalamic-pituitary-gonadal axis during the fetal stage plays a critical role in adulthood reproductive health and fertility.3,4 Natural menopause is a milestone of ovarian aging in a woman's life, resulting in the end of a women's reproductive years.5 The current knowledge about the impact of fetal development on adulthood reproductive health, including menarche and menopause is mainly based on a few Dutch famine studies with limited sample sizes, and the findings are inconclusive.6-8
A widespread and severe famine took place in China during 1959 to 1961, and it caused tens of millions of famine-related casualties.9 A few studies had investigated the association between Chinese famine exposure in early life and risk of metabolic diseases in adulthood,5,17,18 but no data were available for reproductive aging.
In the current study, we examined the association of early life exposure to famine with reproductive aging outcomes, indicated by early menopause and premature ovarian failure (POF), among Chinese women who were born around the Chinese famine period (1956-1964).
This retrospective cohort study was conducted between June 2011 and January 2012 in three communities from southeast China, including two from Shanghai and one from Fujian province. Participants in each study site were randomly selected using a clustered sampling technique with probabilities proportionate to the size of the city population.10 Among the 20,888 randomly selected women, 12,922 agreed to participate in the study. Eligible women born between 1956 and 1964 were further selected following the exclusion criteria: (1) a hysterectomy or bilateral oophorectomy, or exogenous hormone use, (2) implausible information on age at menarche or age at menopause, (3) born between October 1, 1958, and September 30, 1959, or between October 1, 1961, and September 30, 1962. The last exclusion criterion was to minimize misclassification of the exposure periods, because the exact dates of the start and the end of the Chinese famine were not the same across regions. Overall, 2,868 women were included in the final analysis (Fig. 1).11,12 Each participant completed a structured questionnaire with 19 questions about age, sex, personal and family medical history, education, occupation, age at menarche, age at menopause, information on reproductive history, parity, smoking and drinking habits, and physical activity. Written informed consent was obtained from each participant, and the study was approved by the Institutional Review Board of Fujian Provincial Hospital.
For the primary analyses, the participants were divided into three categories by their status of famine exposure: childhood-exposed group (born between October 1, 1956, and September 30, 1958), fetal-exposed group (born between October 1, 1959, and September 30, 1961), and nonexposed group (born between October 1, 1962, and September 30, 1964).13 In consideration of the fetal origins of adult disease14 and the particular importance of the fetal stage, the fetal-exposed group was further compared with the other two groups combined (namely, the fetal nonexposed group).
The primary outcome of the current study was female reproductive aging, indicated by early menopause and POF. Menopause was defined as lack of menstrual bleeding for at least 12 months, and the age at menopause was ascertained by the questionnaire with a question about the date of the final menstrual period. Early menopause was defined as the age of menopause is younger than 45 years old, and POF as the age of menopause is younger than 40 years old.
Secondary outcomes included other reproductive function variables, including nulliparity and spontaneous abortion. Nulliparity was defined as the failure to achieve a clinical pregnancy after 12 months or more of marriage. Spontaneous abortion referred to termination of pregnancy less than 28 weeks with fetal weight less than 1,000 g. Weight, height, and waist circumference were measured without shoes and in light clothing by experienced nurses. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared (kg/m2). Waist circumference was measured at the midpoint between the costal margin and iliac crests.
Data were double-entered, compared and corrected using EpiData software (EpiData 3.0 for Windows; The EpiData Association, Odense, Denmark). Baseline characteristics were presented as mean (±standard error) for the continuous variables and numbers (and percentages) for the categorical variables. Characteristics of different exposure groups were compared using student t test or chi-square test.
Multivariate logistic regression analyses accounting for the clustered sampling design (adjusting 2 dummy variables for 3 communities) were used to estimate the association between early life famine exposure and adulthood reproductive function. Multivariable model 1 adjusted for community (2 dummy variables), lifestyle factors including smoking status (yes or no) and alcohol consumption (yes or no), and socioeconomic factors, such as educational level and occupation status; multivariable model 2 further adjusted for BMI (kg/m2), which could be a mediator in the association of early famine exposure with adulthood reproductive aging. In a sensitivity analysis, waist circumference was used instead of BMI as a covariate to acknowledge the role of abdominal adiposity in the estimated association. Results of the logistic regression models were reported as odds ratios (ORs) and 95% confidence intervals (95% CIs).
All data analyses were performed with SPSS 19.0 statistical software package (SPSS, Chicago, IL). All P values were based on two-sided tests, with statistical significance set at P <0.05.
The characteristics of the participants are summarized in Table 1. Among the 2,868 women who participated in our study, 751 (26.2%) were in the fetal-exposed group, 1,029 (35.9%) in the childhood-exposed group, and 1,088 (37.9%) in the nonexposed group. Compared with women in the nonexposed group, those in the fetal-exposed group were more likely to have early menopause (P = 0.03). The other characteristics were comparable across famine exposure groups.
Table 2 presents the association of early life exposure to famine with reproductive aging variables. In the crude model, fetal-exposure was associated with higher odds of early menopause, but not POF; childhood exposure was not associated with either early menopause or POF. In multivariable model 1 with adjustment of lifestyle and socioeconomic factors, compared with women with nonexposure to famine, those who had fetal-exposure were more likely to developing menopause before 45 years old (adjusted OR of early menopause, 1.56 [95% CI, 1.06-2.31]), and showed a nonsignificant trend of higher risk of developing menopause before 40 years old (adjusted OR of POF, 1.93 [95% CI, 0.93-4.00]). As expected, compared with fetal-composure to famine, childhood-exposure had a weaker and statistically nonsignificant association in our analysis. Further adjustment of adiposity measurement BMI (adjusted OR of early menopause for the fetal-exposed group, 1.59 [95% CI, 1.07-2.36]) or waist circumference (adjusted OR of early menopause for the fetal-exposed group, 1.52 [95% CI, 1.21-2.27]) did not substantially change the results.
Based on the above results and the importance of fetal stage on development, the fetal-exposed group was further compared with the fetal-non-exposed groups combined, and the associations of this secondary analysis are presented in Table 3. Compared with the women in the fetal-nonexposed group, women in the fetal-exposed group had a significantly higher risk of POF (OR: 2.07, 95% CI: 1.08-3.87), and showed a borderline significant higher risk of early menopause (OR: 1.37, 95% CI: 0.98-1.91), independent of traditional risk factors including BMI. Adjustment of waist circumference instead of BMI did not substantially change the results (data not shown).
The associations between famine exposure and other adulthood reproductive function variables, such as nulliparity and spontaneous abortion did not reach statistical significance (Table 4).
In a large sample of Chinese women who were born around the Chinese Famine period (1956-1964), we demonstrated that prenatal exposure to famine was associated with ovarian aging, and such an association was independent of traditional risk factors including obesity. We found no evidence of an association between early life famine exposure and adulthood reproductive history, including nulliparity and spontaneous abortion. Our findings support the theory of fetal origins of adulthood reproductive aging.
Our study is among the first to report that prenatal exposure to famine may increase the risk of early reproductive aging, and such findings in Chinese women are in line with the one prior study of this kind (to our knowledge) from the Dutch population. In a study of 593 Dutch women, Yarde et al6 reported women exposed to prenatal famine were 24% more likely to experience natural menopause at any age using survival analyses. Other studies only provided indirect evidence studying famine exposure in childhood or using birth weight as a surrogate variable of fetal nutrition status. Elias et al15 reported that childhood-exposure to famine was related to earlier age of natural menopause among Dutch women. Among US and Puerto Rican women, Steiner et al16 reported a weak and nonsignificant association between low birth weight and younger age at menopause (hazard ratio 1.09; 95% CI: 0.99-1.20).
Potential mechanisms underlie the observed associations. First, fetal exposure to malnutrition might affect the development of organs responsible for reproductive function or cause hypothalamic dysfunction, to affect menstruation and fertility.7 Early-life malnutrition may reduce the number of a woman's oocytes which are formed in utero, and therefore result in a higher risk of an early depleted oocyte pool, that is, early menopause. Second, malnutrition at the fetal stage could lead to epigenetic changes. Previous studies showed that famine exposure might persistently change hypothalamic gene expression, which is important to the development of reproductive function.17-19 In animal studies, rodent offspring that were exposed to nutrition deprivation at the fetal stage, carried epigenomic changes, such as those in DNA methylation during adulthood.20-24 In our analysis, adjustment of lifestyle and socioeconomic factors in adulthood had little impact on the observed association, indicating that poor nutrition in utero may lead to persistent changes in ovary aging in adults. Third, prenatal famine exposure may contribute to malfunction of the hypothalamic-pituitary-gonadal axis. Girls who experienced prenatally restricted growth had higher levels of basal gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, and estradiol compared with girls born healthily.8,25,26 In addition, the experimental studies using mice models with fetal malnutrition and intrauterine growth inhibition, found that the gonadal hormone level of the intrauterine growth inhibition mice was lower than the mice with normal growth.26-28
In our study, fetal exposure to famine was not related to other reproductive function such as nulliparity or spontaneous abortion. Residual confounding factors such as family plan, family economic situation, national policy, especially the one-family-one-child policy in China, may contribute to the null association. So future observational studies and animal experiments are warranted to explore the associations further.
Our study has several strengths. Our study is the first human cohort study in Asians to report the long-term association between prenatal famine exposure and reproductive aging. Our study sample is relatively large compared with Dutch Famine studies.6 The participants were selected from the general population using a clustered sampling method, and our results may have relatively broad generalizability to Chinese women born around the Chinese famine period. Nevertheless, the findings of the current study should be implicated in consideration of its limitations. First, this study is limited by its use of retrospectively self-reported data on exposures and outcomes, and information bias is inevitable. For example, the average recall time, that is, the time between survey date and the final menstrual period, was 4.7 years, and recall bias should be taken into consideration. Second, we did not include women who died before the conduct of the study, and these women could have the worst fetal exposure to famine if it is related to premature death. Such selection bias could lead to an underestimate of the real association between fetal nutritional status and reproductive-related outcomes. Third, the ages of participants between the exposure group and the control group, which were highly tied to exposure, were obviously different. The included participants were restricted within a narrow age range (8 years) to weaken cohort effects and potential information bias. Fourth, our findings should be interpreted with caution that the case numbers (in particular the cases with premature ovary failure) were relatively small, and this partially resulted in a limited precision of findings.
In conclusion, our study indicated that prenatal exposure to famine might increase the risk of early reproductive aging among Chinese women. Our finding underscores the importance of adequate nutrition during early-life stages to avoid adverse effects on adulthood reproductive health.
1. Baschat AA. Fetal growth restriction—from observation to intervention. J Perinat Med
2. Liu L, Wang W, Sun J, Pang Z. Association of famine exposure during early life with the risk of type 2 diabetes in adulthood: a meta-analysis. Eur J Nutr
3. Da Silva-Buttkus P, Van den Hurk R, Te Velde ER, Taverne MA. Ovarian development in intrauterine growth-retarded and normally developed piglets originating from the same litter. Reproduction
4. Da Silva P, Aitken RP, Rhind SM, Racey PA, Wallace JM. Impact of maternal nutrition during pregnancy on pituitary gonadotrophin gene expression and ovarian development in growth-restricted and normally grown late gestation sheep fetuses. Reproduction
5. Feng Y, Hong X, Wilker E, et al. Effects of age at menarche, reproductive years, and menopause on metabolic risk factors for cardiovascular diseases. Atherosclerosis
6. Yarde F, Broekmans FJ, Van der Pal-de Bruin KM, et al. Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study. Hum Reprod
7. Lumey LH, Stein AD. In utero exposure to famine and subsequent fertility: the Dutch Famine Birth Cohort Study. Am J Public Health
8. Verkauskiene R, Petraitiene I, Albertsson Wikland K. Puberty in children born small for gestational age. Horm Res Paediatr
9. 2006; Luo ZMR, Zhang X. Famine and overweight in China. Review of agricultural economics. 28:296–304.
10. Ning G. Risk Evaluation of cAncers in Chinese diabeTic Individuals: a lONgitudinal (REACTION) study. J Diabetes
11. Qiu C, Chen H, Wen J, et al. Associations between age at menarche and menopause with cardiovascular disease, diabetes, and osteoporosis in Chinese women. J Clin Endocrinol Metab
12. Pokoradi AJ, Iversen L, Hannaford PC. Factors associated with age of onset and type of menopause in a cohort of UK women. Am J Obstet Gynecol
13. Li Y, He Y, Qi L, et al. Exposure to the Chinese famine in early life and the risk of hyperglycemia and type 2 diabetes in adulthood. Diabetes
14. Barker DJ, Gluckman PD, Godfrey KM, Harding JE, Owens JA, Robinson JS. Fetal nutrition and cardiovascular disease in adult life. Lancet
15. Elias SG, Van Noord PA, Peeters PH, Den Tonkelaar I, Grobbee DE. Caloric restriction reduces age at menopause: the effect of the 1944-1945 Dutch famine. Menopause
16. Steiner AZ, D’Aloisio AA, DeRoo LA, Sandler DP, Baird DD. Association of intrauterine and early-life exposures with age at menopause in the Sister Study. Am J Epidemiol
17. Heijmans BT, Tobi EW, Stein AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci U S A
18. Cianfarani S. Foetal origins of adult diseases: just a matter of stem cell number? Med Hypotheses
19. Hanson MA, Gluckman PD. Developmental origins of health and disease: new insights. Basic Clin Pharmacol Toxicol
20. Lillycrop KA, Phillips ES, Torrens C, Hanson MA, Jackson AA, Burdge GC. Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr
21. Burdge GC, Lillycrop KA. Nutrition, epigenetics, and developmental plasticity: implications for understanding human disease. Annu Rev Nutr
22. Hoile SP, Lillycrop KA, Thomas NA, Hanson MA, Burdge GC. Dietary protein restriction during F0 pregnancy in rats induces transgenerational changes in the hepatic transcriptome in female offspring. PLoS One
23. Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci U S A
24. Anderson OS, Nahar MS, Faulk C, et al. Epigenetic responses following maternal dietary exposure to physiologically relevant levels of bisphenol A. Environ Mol Mutagen
25. Hernandez MI, Mericq V. Pubertal development in girls born small for gestational age. J Pediatr Endocrinol Metab
26. Hernandez MI, Martinez A, Capurro T, et al. Comparison of clinical, ultrasonographic, and biochemical differences at the beginning of puberty in healthy girls born either small for gestational age or appropriate for gestational age: preliminary results. J Clin Endocrinol Metab
27. Iwasa T, Matsuzaki T, Murakami M, et al. Effects of intrauterine undernutrition on hypothalamic Kiss1 expression and the timing of puberty in female rats. J Physiol
2010; 588 (pt 5):821–829.
28. Iwasa T, Matsuzaki T, Tungalagsuvd A, et al. LH and testosterone production are more sensitive to the suppressive effects of food deprivation in prenatally undernourished male rats. Int J Dev Neurosci