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Hungry in the womb: What are the consequences? Lessons from the Dutch famine
Maturitas 70 (2011) 141–145
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Review
Hungry in the womb: What are the consequences? Lessons from the Dutch famine Tessa J. Roseboom ∗ , Rebecca C. Painter, Annet F.M. van Abeelen, Marjolein V.E. Veenendaal, Susanne R. de Rooij Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Department of Obstetrics and Gynaecology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 27 June 2011 Accepted 29 June 2011
Keywords: Dutch famine Prenatal undernutrition Cardiovascular disease Cognition Ageing
a b s t r a c t An increasing body of evidence suggests that poor nutrition at the very beginning of life – even before birth – leads to large and long term negative consequences for both mental and physical health. This paper reviews the evidence from studies on the Dutch famine, which investigated the effects of prenatal undernutrition on later health. The effects of famine appeared to depend on its timing during gestation, and the organs and tissues undergoing critical periods of development at that time. Early gestation appeared to be the most vulnerable period. People who were conceived during the famine were at increased risk of schizophrenia and depression, they had a more atherogenic plasma lipid profile, were more responsive to stress and had a doubled rate of coronary heart disease. Also, they performed worse on cognitive tasks which may be a sign of accelerated ageing. People exposed during any period of gestation had more type 2 diabetes. Future investigation will expand on the finding that the effects of prenatal famine exposure may reach down across generations, possibly through epigenetic mechanisms. Recent evidence suggests that similar effects of prenatal undernutrition are found in Africa, where many are undernourished. Hunger is a major problem worldwide with one in seven inhabitants of this planet suffering from lack of food. Adequately feeding women before and during pregnancy may be a promising strategy in preventing chronic diseases worldwide. © 2011 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Dutch famine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dutch famine studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Consequences of prenatal famine exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Developing countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Nausea and vomiting in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Diets of pregnant women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction There is an increasing body of evidence suggesting that those as yet unborn suffer large and long term negative consequences
∗ Corresponding author. E-mail address: [email protected] (T.J. Roseboom). 0378-5122/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2011.06.017
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of undernutrition. While famine is sadly not uncommon in many parts of the world, studying effects of undernutrition during specific periods of pregnancy is hampered by the fact that undernutrition is usually not restricted to pregnancy alone, and effects of chronic undernutrition and accompanying problems of infection complicate the situation. The Dutch famine has been used by various investigators as an equivalent to an experimental set-up to investigate the effects of prenatal undernutrition in humans. What is
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unusual about the Dutch famine is; that the famine was imposed on a previously well-nourished population; there was a sudden onset and relief from the famine; and, despite the adversities of the war, midwives and doctors continued to offer professional obstetric care and kept detailed records of the course of pregnancy, the delivery and the size and health of the baby at birth. Furthermore, detailed information is available on the weekly rations provided during the famine, and in several inflicted cities birth records were kept which allowed researchers to trace those born around the time of the famine and thus to study the long-term effects of prenatal famine exposure. Today the world faces a double burden of malnutrition that includes both under-nutrition and over-nutrition [1]. Never before in history have there been so many people with hunger worldwide. It is estimated that nearly 1 billion people worldwide go hungry each day. While at the same time more than one billion people are overweight or obese. Malnutrition – in any form – poses threats to health. Hunger and inadequate nutrition contribute to early deaths for mothers, infants and young children, and account for more losses of life than AIDS, malaria and tuberculosis combined (WHO nutrition facts). Among the key causes of hunger are natural disasters, conflict, poverty, poor agricultural infrastructure and over-exploitation of the environment. Recently, financial and economic crises have pushed more people into hunger. Most of the damage caused by malnutrition occurs in children before they reach their second birthday. The period from conception to 24 months of age is a crucial window of opportunity when the quality of a child’s diet has a profound, sustained impact on his or her health, and on his or her physical and mental development [1]. This review focuses on studies that investigated the effects of prenatal exposure to the Dutch famine on adult physical and mental health.
food came from the black market, central kitchens, church organisations and foraging trips to the countryside. The food situation quickly improved after the liberation of the Netherlands in early May 1945. One month later, the rations were above 2000 calories [2]. The famine had a profound effect on the general health of the population. In Amsterdam, the mortality rate in 1945 had more than doubled compared to 1939, and it is very likely that most of this increase in mortality was attributable to undernutrition [3]. But, even during this disastrous famine women conceived and gave birth to babies, and it is in these babies that the effects of maternal undernutrition during different periods of gestation on health in adult life can be studied. Because of its unique experimental characteristics, it is not surprising that people born around the time of the Dutch famine have been studied by many investigators.
2. The Dutch famine
4. Consequences of prenatal famine exposure
After the invasion of the Allied forces on the 6th of June 1944, a few weeks of heavy fights followed. Then, the Allied forces finally broke through German lines. Quickly, the Allied troops took possession of France, Luxembourg and Belgium. By the 4th of September 1944 the Allies had the strategic city of Antwerp in their hands, and on the 14th they entered the Netherlands. The Dutch expected that the German occupation would soon be over, and so did the commanders of the Allied forces. But the advance of the Allies to the north of the Netherlands came to a halt when operation “Market Garden” failed. The Dutch government in exile had called for a strike of the Dutch railways in order to support the Allied offensive. As a reprisal, the Germans banned all food transports. This embargo on food transports was lifted in early November 1944, when food transport across water was permitted again. But because most canals and waterways were frozen due to the early and extremely severe winter, it had become impossible to bring in food from the rural east to the urban west of the Netherlands. As a consequence, food stocks in the urban west of the Netherlands ran out rapidly. The official rations for the adult population fell abruptly to below 1000 calories per day at the end of November 1944. At the height of the famine from December 1944 to April 1945, the official daily rations varied between 400 and 800 calories. Infants under 1 year of age were relatively protected, because their official daily rations never fell below 1000 calories, and the specific nutrient components were always above the standards used by the Oxford Nutritional Survey [2]. Pregnant and lactating women were entitled to an extra amount of food, but at the peak of the famine these extra supplies could not be provided anymore. Also, extra
Studies on the long term consequences of prenatal exposure to famine on later health started with the landmark studies of Stein and Susser performed in the early seventies following the increasing awareness in the late 1960s that early nutritional deprivation might cause irreversible damage to the brain [5]. This study among military conscripts did not demonstrate any effect of starvation during pregnancy on the adult mental performance. However, men exposed to famine in early gestation were more likely to be obese, whereas those exposed in late gestation were less likely to be obese [6]. More recently, it has been shown that people conceived during the famine and thus exposed in early gestation had a two-fold increase in risk of schizophrenia [7] and anti-social personality disorder [8]. Prenatal famine exposure has also been associated with affective psychoses and depression, though not all studies replicated this finding. In their study of military conscripts Stein and Susser found no association between famine exposure and intelligence [9]. But more recently, two studies again investigated effects of prenatal famine exposure on cognition, now at age 58–59. In a study among men and women at age 59 from Rotterdam, Leiden and Amsterdam (The Dutch famine families study), no association was found between famine exposure and later cognitive performance [10]. In the Amsterdam study (the Dutch famine birth cohort study), however, there were indications that maternal malnutrition during fetal life may negatively influence aspects of cognitive function in later life as suggested by lower performance of men and women in utero during the famine on a Stroop-like task [11]. This may be an early manifestation of an accelerated cognitive ageing process, which will be further investigated by future examinations in that cohort.
3. Dutch famine studies The period of starvation ceased early in May 1945 immediately after the final surrender of the Germans. In addition to the immediate provision of food after the war, medical aid was a top priority for the Netherlands. Doctors from the UK and US were sent to survey medical needs. Clement Smith from Harvard Medical School was among the first to witness the effects of the famine on the health of the Dutch population. He immediately saw the opportunity to obtain information that would help resolve important questions on how poor maternal nutrition affects pregnancy and the development of the fetus before birth. Using obstetric records from Rotterdam and The Hague, he studied effects of prenatal exposure to famine on pregnancy and the fetus which he described in his paper: The effect of famine on pregnancy and its product [4]. He found that babies born during the famine (and thus exposed to famine in late gestation) were about 200 g lighter at birth.
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In the early nineties, the Dutch famine was first used as a model to test the newly formulated ‘fetal origins’ hypothesis which was put forward by David Barker in 1989 when he observed associations between small size at birth and increased rates of cardiovascular and metabolic disease in later life [12]. In general, the Dutch famine studies have provided support for the fetal origins hypothesis. Studies in different cohorts and with different set-ups have shown that those who had been exposed to the Dutch famine during any stage of gestation were found to have raised glucose levels as adults [13–15], which may be due to an insulin secretion defect [16]. Whereas those exposed to famine in early gestation had more atherogenic lipid profiles [17,18] and disturbed blood coagulation [19]. Women who had been exposed to famine in early gestation appeared to be more centrally obese than those who had not been exposed to famine prenatally [20,21]. One study found an association between prenatal exposure to famine and later hypertension [22]. While another study found that exposure to famine during early gestation was associated with an increased blood pressure response to stress [23], and a striking increase in coronary heart disease in later life [24]. Those exposed to famine in early gestation had doubled rates of CHD. People conceived in famine not only had a higher cumulative incidence of CHD, but the disease occurred at an earlier age [25]. One study also reported that women who were conceived during the famine had an almost five times increased risk of breast cancer [26], but this was based on small numbers and needs further replication. The Dutch famine birth cohort study has found that exposure to famine in mid gestation was linked to a 3.2 fold increase in occurrence of microalbuminurea in adulthood and a 10% decrease in creatinine clearance, neither of which can be explained by cardiovascular confounders [27]. It may be that mid gestational exposure to famine – the period of rapid increase in nephron numbermay prevent formation of sufficient glomeruli and thus increase the risk for microalbuminurea and deteriorated renal function in adulthood. This supports the concept that intrauterine conditions during distinct, organ-specific periods of sensitivity may permanently determine health outcome in later life. Another example of this phenomenon is the finding in the same study that people who had been exposed to famine in mid gestation had an increased prevalence of obstructive airways disease [28]. These observations were not paralleled by reduced lung function or increased serum concentrations of IgE. This suggests that the increased prevalence of symptoms and disease may be attributable to increased bronchial reactivity rather than to irreversible airflow obstruction or atopic disease. Because the bronchial tree grows most rapidly in mid gestation, our findings support the hypothesis that fetal undernutrition permanently affects the structure and physiology of the airways during ‘critical periods’ of development that coincide with periods of rapid growth. Women who were exposed to famine prenatally had more children, more twins, were less likely to remain childless and started reproducing at a younger age when compared with unexposed women [29,30]. The constellation of adaptations the fetus made to undernutrition may be part of a thrifty phenotype. After the war Holland provided a postnatal environment with food abundance, which was unlike the conditions in the womb. This disadaptation of a thrifty phenotype may be important in the later susceptibility to chronic degenerative disease. People exposed to famine during gestation have increased rates of chronic degenerative diseases such as cardiovascular disease, metabolic disease, breast cancer and obesity. These findings are consistent with the theory of ‘life history regulation’ which proposes that the traits of fertility and body maintenance are mutually balanced, and that increased investments in one, are traded off by reduction in investment in the other. These findings may suggest that the balance in phenotypic traits
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underpinning life history regulation may be set by the conditions during life in the womb. The Dutch famine birth cohort study also assessed transgenerational effects of famine exposure. Grandmaternal exposure to famine for a brief period during gestation did not affect birth weight nor rates of cardiovascular or metabolic disease [31]. It was, however, associated with increased neonatal adiposity and poorer health among offspring of women who themselves had been exposed to famine in utero. These findings may suggest that the detrimental effects of poor maternal nutrition during gestation on health in later life pass down to subsequent generations. The Dutch famine families study provided the first direct evidence for epigenetic programming through prenatal famine exposure. Men and women who had been exposed to the famine periconceptionally had less methylation of the IGF2 gene compared with their unexposed same-sex siblings [32]. These findings may suggest that early undernutrition can cause epigenetic changes that persist throughout life. Further studies suggested that the effects of famine exposure on methylation are specific – i.e. are present in some genes but absent in others – and are generally small [33]. The findings provide a strong rationale to further investigate how early exposure to famine may affect later health. 5. Conclusions The findings from the Dutch famine studies have shown that maternal undernutrition during gestation has lasting negative consequences for the offspring’s health. Many chronic diseases that plague our society may originate in the womb. The effects seem to be large and depend on the timing during gestation and the organs and tissues developing at that time. Also, the effects are independent of the size of the baby at birth. Most notably, those exposed to famine in early gestation did not have lower birth weights than those who were not exposed to famine prenatally, but did have worst health outcomes as adults. This may imply that adaptations that enable the fetus to continue to grow may nevertheless have adverse consequences for health in later life. Chronic degenerative disease may be viewed as the price paid for adaptations made to an adverse intra-uterine environment. Findings from the Dutch famine studies – despite slight differences in individual findings between the different studies – in general, suggest that maternal nutrition before and during pregnancy play an important role in later disease susceptibility. This suggestion is in line with evidence from animal experiments that identified maternal diet during pregnancy – even before implantation – as important or the offspring’s adult health [34–36]. 5.1. Developing countries A recent study in Nigeria showed that prenatal undernutrition also affects later health in African populations [37]. People who had been exposed to the Biafran famine during the Nigerian civil war (1967–1970) in utero were found that have increased rates of hypertension and type 2 diabetes at the age of 40 compared to those who had not been exposed to the Biafran famine in utero. In contrast to the observations in the Dutch famine studies, those in the Biafran study suggest that the effects are more pronounced and emerge at an earlier age. The implications are important. On a population level, a 3.3 mmHg increase in systolic blood pressure and a 2 mmHg increase in diastolic blood pressure can be translated into an estimated increase in cardiovascular deaths by 25% and stroke by 32%. Given the combination of large blood pressure effects and increased rate of glucose intolerance resting on a basis of obesity before middle age, which is characteristic for Nigeria today (and possibly other Sub-Saharan countries), it is not surprising
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that disability and deaths from stroke and coronary heart disease are rapidly increasing. The Biafran study shows that fetal-infant undernutrition contributes significantly to the increasing prevalence of hypertension and glucose intolerance. This is probably also true for other sub-Saharan countries. Therefore, prevention of fetal and infant undernutrition should be given high priority in national health, education and economic agendas to limit the increase of non-communicable diseases in many African countries.
Contributors TR wrote the paper, RP, AvA, MV and SR commented on earlier versions of the paper and helped in revising the manuscript. Conflict of interests All authors have seen and approved of the final version of this manuscript. None have any conflict of interest to disclose.
5.2. Nausea and vomiting in pregnancy Provenance and peer review Although overnutrition is a bigger problem in developed countries than undernutrition is, the findings may also have implications for the developed world. The nutritional experience of babies who were exposed to famine in early gestation may resemble that of babies whose mothers suffer from severe morning sickness. Morning sickness is common in the first trimester, and severe morning sickness is associated with metabolic changes in the mother which are similar to those seen during starvation. Since the results of our study consistently show that the effects of undernutrition are independent of size at birth, the assumption that the longterm consequences of hyperemesis gravidarum will be limited because of the normal size of the babies at birth no longer holds. Recently, the first preliminary evidence was published suggesting that prenatal exposure to hyperemesis gravidarum is associated with negative adverse health influences [38]. Children born to mothers who suffered from hyperemesis gravidarum were found to have more psychological as well as behavioural problems in adulthood. Whether prenatal exposure to hyperemesis gravidarum is also associated with an increased risk of chronic degenerative diseases associated with prenatal famine exposure still needs to be investigated. 5.3. Diets of pregnant women The findings may also be relevant for other situations in which maternal diet is inadequate during pregnancy. A recent study in Southampton showed that very few women succeed in complying with the nutrition and lifestyle recommendations for planning a pregnancy; less than 3% complied fully with the recommendations on alcohol and folic acid intake in the three months before becoming pregnant [39]. Less than half the women who became pregnant within the three months of being interviewed were taking any folic acid supplements at the time of the interview and ate fruit and vegetables every day. This suggests that also in developed countries big improvements can be made to the diets of women of reproductive age, with potentially beneficial consequences for their offspring’s health. Also, it may be relevant for the increasing number of women in Japan who are thin by choice, despite sufficient availability of food. The mean BMI of Japanese women of reproductive age has rapidly decreased. One in four women in their twenties have BMIs below 18.5, and most of them have a strong desire to be thin [40]. There is concern that increasing numbers of young Japanese children may also have experienced a limited supply of food during their intrauterine development, with possible negative consequences for their later health. Indeed, the numbers of neonates born small is increasing at the same rate in Japan [41]. In general, adequately feeding women before and during pregnancy worldwide may be a promising strategy in preventing chronic diseases in future generations. Little is known about what an adequate diet for pregnant women might be. In general, women are especially receptive to advice about diet and lifestyle before and during pregnancy. This should be exploited to improve the health of future generations
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T.J. Roseboom et al. / Maturitas 70 (2011) 141–145 [24] Roseboom TJ, van der Meulen JHP, Osmond C, et al. Coronary heart disease after prenatal exposure to the Dutch famine 1944–45. Heart 2000;84(6):595–8. [25] Painter RC, de Rooij SR, Roseboom TJ, et al. OP Bleker Early onset of coronary heart disease after prenatal exposure to the Dutch famine. American. Journal of Clinical Nutrition 2006;84:322–7. [26] Painter RC, de Rooij SR, Roseboom TJ, et al. Breast cancer after prenatal exposure to the Dutch famine. American Journal of Human Biology 2006;18:853–6. [27] Painter RC, Roseboom TJ, van Montfrans GA, Bossuyt PMM, Krediet RT, Osmond Co, Barker DJ, Bleker OP. Microalbuminurea in adults after prenatal exposure to the Dutch famine. Journal of the American Society of Nephrology 2005;16(1):189–94. [28] Lopuhaä CE, Roseboom TJ, Osmond C, et al. Meulen Atopy, lung function and obstructive airways disease after prenatal exposure to famine. Thorax 2000;55:555–61. [29] Painter RC, Westendorp RG, de Rooij SR, Osmond C, Barker DJ, Roseboom TJ. Increased reproductive success of women after prenatal undernutrition. Human Reproduction 2008;23:2591–5. [30] Lumey LH, Stein AD. In utero exposure to famine and subsequent fertility: the Dutch Famine Birth Cohort Study. American Journal of Public Health 1997 Dec;87(12):1962–6. [31] Painter RC, Osmond C, Gluckman P, Hanson M, Phillips DI, Roseboom TJ. Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. International Journal of Obstetrics and Gynaecology 2008;115:1243–9. [32] Heijmans BT, Tobi EW, Stein AD, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proceedings of the National Academy of Sciences of the United States of America 2008;105: 17046–9.
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[33] Tobi EW, Lumey LH, Talens RP, et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Human Molecular Genetics 2009;18:4046–53. [34] Fleming TP, Kwong WY, Prter R, et al. The embryo and its future. Biology of Reproduction 2004;71:1046–54. [35] Gardner DS, Pearce S, Dandrea J, et al. Peri-implantation undernutrition programs blunted angiotensin II evoked baroreflex responses in young adult sheep. Hypertension 2004;43:1290–6. [36] Edwards LJ, McMillen IC. Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology 2002;283: R669–79. [37] Hult M, Tornhammar P, Ueda P, et al. Hypertension, diabetes and overweight: looming legacies of the Biafran Famine. PLOS One 2010;5(10): e13582. [38] Mullin PM, Bray A, Schoenberg F, et al. Prenatal exposure to hyperemesis gravidarum linked to increased risk of psychological and behavioral disorders in adulthood. Journal Of Developmental Origins of Health and Disease 2011;2:200–4. [39] Inskip HM, Crozier SR, Godfrey KM, Borland SE, Cooper C, Robinson SM, Southampton Women’s Survey Study Group. Women’s compliance with nutrition and lifestyle recommendations before pregnancy: general population cohort study. British Medical Journal 2009;338(February):b481. [40] Hayashi F, Takimoto H, Yoshita K, Yoshiike N. Perceived body size and desire for thinness of young Japanese women: a population-based survey. British Journal of Nutrition 2006;96:1154–62. [41] Mother’s & Children’s Health & Welfare Association. Maternal and child health statistics of Japan. Tokyo: Toshihide Ei; 2008, p.44–46 [Japanese].
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Review
Hungry in the womb: What are the consequences? Lessons from the Dutch famine Tessa J. Roseboom ∗ , Rebecca C. Painter, Annet F.M. van Abeelen, Marjolein V.E. Veenendaal, Susanne R. de Rooij Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Department of Obstetrics and Gynaecology, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 27 June 2011 Accepted 29 June 2011
Keywords: Dutch famine Prenatal undernutrition Cardiovascular disease Cognition Ageing
a b s t r a c t An increasing body of evidence suggests that poor nutrition at the very beginning of life – even before birth – leads to large and long term negative consequences for both mental and physical health. This paper reviews the evidence from studies on the Dutch famine, which investigated the effects of prenatal undernutrition on later health. The effects of famine appeared to depend on its timing during gestation, and the organs and tissues undergoing critical periods of development at that time. Early gestation appeared to be the most vulnerable period. People who were conceived during the famine were at increased risk of schizophrenia and depression, they had a more atherogenic plasma lipid profile, were more responsive to stress and had a doubled rate of coronary heart disease. Also, they performed worse on cognitive tasks which may be a sign of accelerated ageing. People exposed during any period of gestation had more type 2 diabetes. Future investigation will expand on the finding that the effects of prenatal famine exposure may reach down across generations, possibly through epigenetic mechanisms. Recent evidence suggests that similar effects of prenatal undernutrition are found in Africa, where many are undernourished. Hunger is a major problem worldwide with one in seven inhabitants of this planet suffering from lack of food. Adequately feeding women before and during pregnancy may be a promising strategy in preventing chronic diseases worldwide. © 2011 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Dutch famine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dutch famine studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Consequences of prenatal famine exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Developing countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2. Nausea and vomiting in pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Diets of pregnant women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Provenance and peer review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction There is an increasing body of evidence suggesting that those as yet unborn suffer large and long term negative consequences
∗ Corresponding author. E-mail address: [email protected] (T.J. Roseboom). 0378-5122/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2011.06.017
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of undernutrition. While famine is sadly not uncommon in many parts of the world, studying effects of undernutrition during specific periods of pregnancy is hampered by the fact that undernutrition is usually not restricted to pregnancy alone, and effects of chronic undernutrition and accompanying problems of infection complicate the situation. The Dutch famine has been used by various investigators as an equivalent to an experimental set-up to investigate the effects of prenatal undernutrition in humans. What is
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unusual about the Dutch famine is; that the famine was imposed on a previously well-nourished population; there was a sudden onset and relief from the famine; and, despite the adversities of the war, midwives and doctors continued to offer professional obstetric care and kept detailed records of the course of pregnancy, the delivery and the size and health of the baby at birth. Furthermore, detailed information is available on the weekly rations provided during the famine, and in several inflicted cities birth records were kept which allowed researchers to trace those born around the time of the famine and thus to study the long-term effects of prenatal famine exposure. Today the world faces a double burden of malnutrition that includes both under-nutrition and over-nutrition [1]. Never before in history have there been so many people with hunger worldwide. It is estimated that nearly 1 billion people worldwide go hungry each day. While at the same time more than one billion people are overweight or obese. Malnutrition – in any form – poses threats to health. Hunger and inadequate nutrition contribute to early deaths for mothers, infants and young children, and account for more losses of life than AIDS, malaria and tuberculosis combined (WHO nutrition facts). Among the key causes of hunger are natural disasters, conflict, poverty, poor agricultural infrastructure and over-exploitation of the environment. Recently, financial and economic crises have pushed more people into hunger. Most of the damage caused by malnutrition occurs in children before they reach their second birthday. The period from conception to 24 months of age is a crucial window of opportunity when the quality of a child’s diet has a profound, sustained impact on his or her health, and on his or her physical and mental development [1]. This review focuses on studies that investigated the effects of prenatal exposure to the Dutch famine on adult physical and mental health.
food came from the black market, central kitchens, church organisations and foraging trips to the countryside. The food situation quickly improved after the liberation of the Netherlands in early May 1945. One month later, the rations were above 2000 calories [2]. The famine had a profound effect on the general health of the population. In Amsterdam, the mortality rate in 1945 had more than doubled compared to 1939, and it is very likely that most of this increase in mortality was attributable to undernutrition [3]. But, even during this disastrous famine women conceived and gave birth to babies, and it is in these babies that the effects of maternal undernutrition during different periods of gestation on health in adult life can be studied. Because of its unique experimental characteristics, it is not surprising that people born around the time of the Dutch famine have been studied by many investigators.
2. The Dutch famine
4. Consequences of prenatal famine exposure
After the invasion of the Allied forces on the 6th of June 1944, a few weeks of heavy fights followed. Then, the Allied forces finally broke through German lines. Quickly, the Allied troops took possession of France, Luxembourg and Belgium. By the 4th of September 1944 the Allies had the strategic city of Antwerp in their hands, and on the 14th they entered the Netherlands. The Dutch expected that the German occupation would soon be over, and so did the commanders of the Allied forces. But the advance of the Allies to the north of the Netherlands came to a halt when operation “Market Garden” failed. The Dutch government in exile had called for a strike of the Dutch railways in order to support the Allied offensive. As a reprisal, the Germans banned all food transports. This embargo on food transports was lifted in early November 1944, when food transport across water was permitted again. But because most canals and waterways were frozen due to the early and extremely severe winter, it had become impossible to bring in food from the rural east to the urban west of the Netherlands. As a consequence, food stocks in the urban west of the Netherlands ran out rapidly. The official rations for the adult population fell abruptly to below 1000 calories per day at the end of November 1944. At the height of the famine from December 1944 to April 1945, the official daily rations varied between 400 and 800 calories. Infants under 1 year of age were relatively protected, because their official daily rations never fell below 1000 calories, and the specific nutrient components were always above the standards used by the Oxford Nutritional Survey [2]. Pregnant and lactating women were entitled to an extra amount of food, but at the peak of the famine these extra supplies could not be provided anymore. Also, extra
Studies on the long term consequences of prenatal exposure to famine on later health started with the landmark studies of Stein and Susser performed in the early seventies following the increasing awareness in the late 1960s that early nutritional deprivation might cause irreversible damage to the brain [5]. This study among military conscripts did not demonstrate any effect of starvation during pregnancy on the adult mental performance. However, men exposed to famine in early gestation were more likely to be obese, whereas those exposed in late gestation were less likely to be obese [6]. More recently, it has been shown that people conceived during the famine and thus exposed in early gestation had a two-fold increase in risk of schizophrenia [7] and anti-social personality disorder [8]. Prenatal famine exposure has also been associated with affective psychoses and depression, though not all studies replicated this finding. In their study of military conscripts Stein and Susser found no association between famine exposure and intelligence [9]. But more recently, two studies again investigated effects of prenatal famine exposure on cognition, now at age 58–59. In a study among men and women at age 59 from Rotterdam, Leiden and Amsterdam (The Dutch famine families study), no association was found between famine exposure and later cognitive performance [10]. In the Amsterdam study (the Dutch famine birth cohort study), however, there were indications that maternal malnutrition during fetal life may negatively influence aspects of cognitive function in later life as suggested by lower performance of men and women in utero during the famine on a Stroop-like task [11]. This may be an early manifestation of an accelerated cognitive ageing process, which will be further investigated by future examinations in that cohort.
3. Dutch famine studies The period of starvation ceased early in May 1945 immediately after the final surrender of the Germans. In addition to the immediate provision of food after the war, medical aid was a top priority for the Netherlands. Doctors from the UK and US were sent to survey medical needs. Clement Smith from Harvard Medical School was among the first to witness the effects of the famine on the health of the Dutch population. He immediately saw the opportunity to obtain information that would help resolve important questions on how poor maternal nutrition affects pregnancy and the development of the fetus before birth. Using obstetric records from Rotterdam and The Hague, he studied effects of prenatal exposure to famine on pregnancy and the fetus which he described in his paper: The effect of famine on pregnancy and its product [4]. He found that babies born during the famine (and thus exposed to famine in late gestation) were about 200 g lighter at birth.
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In the early nineties, the Dutch famine was first used as a model to test the newly formulated ‘fetal origins’ hypothesis which was put forward by David Barker in 1989 when he observed associations between small size at birth and increased rates of cardiovascular and metabolic disease in later life [12]. In general, the Dutch famine studies have provided support for the fetal origins hypothesis. Studies in different cohorts and with different set-ups have shown that those who had been exposed to the Dutch famine during any stage of gestation were found to have raised glucose levels as adults [13–15], which may be due to an insulin secretion defect [16]. Whereas those exposed to famine in early gestation had more atherogenic lipid profiles [17,18] and disturbed blood coagulation [19]. Women who had been exposed to famine in early gestation appeared to be more centrally obese than those who had not been exposed to famine prenatally [20,21]. One study found an association between prenatal exposure to famine and later hypertension [22]. While another study found that exposure to famine during early gestation was associated with an increased blood pressure response to stress [23], and a striking increase in coronary heart disease in later life [24]. Those exposed to famine in early gestation had doubled rates of CHD. People conceived in famine not only had a higher cumulative incidence of CHD, but the disease occurred at an earlier age [25]. One study also reported that women who were conceived during the famine had an almost five times increased risk of breast cancer [26], but this was based on small numbers and needs further replication. The Dutch famine birth cohort study has found that exposure to famine in mid gestation was linked to a 3.2 fold increase in occurrence of microalbuminurea in adulthood and a 10% decrease in creatinine clearance, neither of which can be explained by cardiovascular confounders [27]. It may be that mid gestational exposure to famine – the period of rapid increase in nephron numbermay prevent formation of sufficient glomeruli and thus increase the risk for microalbuminurea and deteriorated renal function in adulthood. This supports the concept that intrauterine conditions during distinct, organ-specific periods of sensitivity may permanently determine health outcome in later life. Another example of this phenomenon is the finding in the same study that people who had been exposed to famine in mid gestation had an increased prevalence of obstructive airways disease [28]. These observations were not paralleled by reduced lung function or increased serum concentrations of IgE. This suggests that the increased prevalence of symptoms and disease may be attributable to increased bronchial reactivity rather than to irreversible airflow obstruction or atopic disease. Because the bronchial tree grows most rapidly in mid gestation, our findings support the hypothesis that fetal undernutrition permanently affects the structure and physiology of the airways during ‘critical periods’ of development that coincide with periods of rapid growth. Women who were exposed to famine prenatally had more children, more twins, were less likely to remain childless and started reproducing at a younger age when compared with unexposed women [29,30]. The constellation of adaptations the fetus made to undernutrition may be part of a thrifty phenotype. After the war Holland provided a postnatal environment with food abundance, which was unlike the conditions in the womb. This disadaptation of a thrifty phenotype may be important in the later susceptibility to chronic degenerative disease. People exposed to famine during gestation have increased rates of chronic degenerative diseases such as cardiovascular disease, metabolic disease, breast cancer and obesity. These findings are consistent with the theory of ‘life history regulation’ which proposes that the traits of fertility and body maintenance are mutually balanced, and that increased investments in one, are traded off by reduction in investment in the other. These findings may suggest that the balance in phenotypic traits
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underpinning life history regulation may be set by the conditions during life in the womb. The Dutch famine birth cohort study also assessed transgenerational effects of famine exposure. Grandmaternal exposure to famine for a brief period during gestation did not affect birth weight nor rates of cardiovascular or metabolic disease [31]. It was, however, associated with increased neonatal adiposity and poorer health among offspring of women who themselves had been exposed to famine in utero. These findings may suggest that the detrimental effects of poor maternal nutrition during gestation on health in later life pass down to subsequent generations. The Dutch famine families study provided the first direct evidence for epigenetic programming through prenatal famine exposure. Men and women who had been exposed to the famine periconceptionally had less methylation of the IGF2 gene compared with their unexposed same-sex siblings [32]. These findings may suggest that early undernutrition can cause epigenetic changes that persist throughout life. Further studies suggested that the effects of famine exposure on methylation are specific – i.e. are present in some genes but absent in others – and are generally small [33]. The findings provide a strong rationale to further investigate how early exposure to famine may affect later health. 5. Conclusions The findings from the Dutch famine studies have shown that maternal undernutrition during gestation has lasting negative consequences for the offspring’s health. Many chronic diseases that plague our society may originate in the womb. The effects seem to be large and depend on the timing during gestation and the organs and tissues developing at that time. Also, the effects are independent of the size of the baby at birth. Most notably, those exposed to famine in early gestation did not have lower birth weights than those who were not exposed to famine prenatally, but did have worst health outcomes as adults. This may imply that adaptations that enable the fetus to continue to grow may nevertheless have adverse consequences for health in later life. Chronic degenerative disease may be viewed as the price paid for adaptations made to an adverse intra-uterine environment. Findings from the Dutch famine studies – despite slight differences in individual findings between the different studies – in general, suggest that maternal nutrition before and during pregnancy play an important role in later disease susceptibility. This suggestion is in line with evidence from animal experiments that identified maternal diet during pregnancy – even before implantation – as important or the offspring’s adult health [34–36]. 5.1. Developing countries A recent study in Nigeria showed that prenatal undernutrition also affects later health in African populations [37]. People who had been exposed to the Biafran famine during the Nigerian civil war (1967–1970) in utero were found that have increased rates of hypertension and type 2 diabetes at the age of 40 compared to those who had not been exposed to the Biafran famine in utero. In contrast to the observations in the Dutch famine studies, those in the Biafran study suggest that the effects are more pronounced and emerge at an earlier age. The implications are important. On a population level, a 3.3 mmHg increase in systolic blood pressure and a 2 mmHg increase in diastolic blood pressure can be translated into an estimated increase in cardiovascular deaths by 25% and stroke by 32%. Given the combination of large blood pressure effects and increased rate of glucose intolerance resting on a basis of obesity before middle age, which is characteristic for Nigeria today (and possibly other Sub-Saharan countries), it is not surprising
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that disability and deaths from stroke and coronary heart disease are rapidly increasing. The Biafran study shows that fetal-infant undernutrition contributes significantly to the increasing prevalence of hypertension and glucose intolerance. This is probably also true for other sub-Saharan countries. Therefore, prevention of fetal and infant undernutrition should be given high priority in national health, education and economic agendas to limit the increase of non-communicable diseases in many African countries.
Contributors TR wrote the paper, RP, AvA, MV and SR commented on earlier versions of the paper and helped in revising the manuscript. Conflict of interests All authors have seen and approved of the final version of this manuscript. None have any conflict of interest to disclose.
5.2. Nausea and vomiting in pregnancy Provenance and peer review Although overnutrition is a bigger problem in developed countries than undernutrition is, the findings may also have implications for the developed world. The nutritional experience of babies who were exposed to famine in early gestation may resemble that of babies whose mothers suffer from severe morning sickness. Morning sickness is common in the first trimester, and severe morning sickness is associated with metabolic changes in the mother which are similar to those seen during starvation. Since the results of our study consistently show that the effects of undernutrition are independent of size at birth, the assumption that the longterm consequences of hyperemesis gravidarum will be limited because of the normal size of the babies at birth no longer holds. Recently, the first preliminary evidence was published suggesting that prenatal exposure to hyperemesis gravidarum is associated with negative adverse health influences [38]. Children born to mothers who suffered from hyperemesis gravidarum were found to have more psychological as well as behavioural problems in adulthood. Whether prenatal exposure to hyperemesis gravidarum is also associated with an increased risk of chronic degenerative diseases associated with prenatal famine exposure still needs to be investigated. 5.3. Diets of pregnant women The findings may also be relevant for other situations in which maternal diet is inadequate during pregnancy. A recent study in Southampton showed that very few women succeed in complying with the nutrition and lifestyle recommendations for planning a pregnancy; less than 3% complied fully with the recommendations on alcohol and folic acid intake in the three months before becoming pregnant [39]. Less than half the women who became pregnant within the three months of being interviewed were taking any folic acid supplements at the time of the interview and ate fruit and vegetables every day. This suggests that also in developed countries big improvements can be made to the diets of women of reproductive age, with potentially beneficial consequences for their offspring’s health. Also, it may be relevant for the increasing number of women in Japan who are thin by choice, despite sufficient availability of food. The mean BMI of Japanese women of reproductive age has rapidly decreased. One in four women in their twenties have BMIs below 18.5, and most of them have a strong desire to be thin [40]. There is concern that increasing numbers of young Japanese children may also have experienced a limited supply of food during their intrauterine development, with possible negative consequences for their later health. Indeed, the numbers of neonates born small is increasing at the same rate in Japan [41]. In general, adequately feeding women before and during pregnancy worldwide may be a promising strategy in preventing chronic diseases in future generations. Little is known about what an adequate diet for pregnant women might be. In general, women are especially receptive to advice about diet and lifestyle before and during pregnancy. This should be exploited to improve the health of future generations
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