Rebecca C. Painter

Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life

Objective  Maternal undernutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. We investigated whether these effects may persist in subsequent generations.

Hungry in the womb: what are the consequences? Lessons from the Dutch famine.

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.

Prenatal undernutrition and cognitive function in late adulthood

At the end of World War II, a severe 5-mo famine struck the cities in the western part of The Netherlands. At its peak, the rations dropped to as low as 400 calories per day. In 1972, cognitive performance in 19-y-old male conscripts was reported not to have been affected by exposure to the famine before birth. In the present study, we show that cognitive function in later life does seem affected by prenatal undernutrition. We found that at age 56 to 59, men and women exposed to famine during the early stage of gestation performed worse on a selective attention task, a cognitive ability that usually declines with increasing age. We hypothesize that this decline may be an early manifestation of an accelerated cognitive aging process.

Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine

We previously showed that maternal under‐nutrition during gestation is associated with increased metabolic and cardiovascular disease in the offspring. Also, we found increased neonatal adiposity among the grandchildren of women who had been undernourished during pregnancy. In the present study we investigated whether these transgenerational effects have led to altered body composition and poorer health in adulthood in the grandchildren.

Prenatal exposure to the Dutch famine is associated with a preference for fatty foods and a more atherogenic lipid profile

BACKGROUND Evidence from animal models suggests that fetal undernutrition can predispose to hypercholesterolemia and metabolic disorders directly by programming cholesterol metabolism and may indirectly influence lifestyle choices. We have shown that persons who were exposed to the Dutch famine in early gestation have a more atherogenic lipid profile. OBJECTIVE We now investigate whether the excess in hypercholesterolemia may be a result of a more atherogenic diet or a reduction in physical activity. DESIGN We measured lipid profiles, dietary intake, and physical activity in 730 men and women (aged 58 y) born in the Wilhelmina Gasthuis in Amsterdam, Netherlands, around the time of the Dutch famine, whose birth records have been kept. RESULTS No differences were observed in mean intake of total energy or percentage of protein, carbohydrate, and fat in the diet between the different exposure groups. However, persons exposed to famine in early gestation were twice as likely (odds ratio: 2.1; 95% CI: 1.2, 3.9) to consume a high-fat diet (defined as the highest quartile of percentage of fat in the diet: >39% of energy from fat). They also tended to be less physically active (45% did sports compared with 52% in the unexposed group), although this did not reach statistical significance. CONCLUSIONS This is the first direct evidence in humans that prenatal nutrition may affect dietary preferences and may contribute to more atherogenic lipid profiles in later life.

Microalbuminuria in Adults after Prenatal Exposure to the Dutch Famine

Maternal undernutrition during gestation is associated with an increase in cardiovascular risk factors in the offspring in adult life. The effect of famine exposure during different stages of gestation on adult microalbuminuria (MA) was studied. MA was measured in 724 people, aged 48 to 53, who were born as term singletons in a university hospital in Amsterdam, the Netherlands, around the time of the Dutch famine 1944 to 1945. Twelve percent of people who were exposed to famine in mid gestation had MA (defined as albumin/creatinine ratio >/=2.5) compared with 7% of those who were not prenatally exposed to famine (odds ratio 2.1; 95% confidence interval 1.0 to 4.3). Correcting for BP, diabetes, and other influences that affect MA did not attenuate this association (adjusted odds ratio 3.2; 95% confidence interval 1.4 to 7.7). The effect of famine was independent of size at birth. Midgestation is a period of rapid increase in nephron number, which is critical in determining nephron endowment at birth. Fetal undernutrition may lead to lower nephron endowment with consequent MA in adult life.

Impaired insulin secretion after prenatal exposure to the Dutch famine

OBJECTIVE—We previously reported that people prenatally exposed to famine during the Dutch Hunger Winter of 1944–1945 have higher 2-h glucose concentrations after an oral glucose tolerance test in later life. We aimed to determine whether this association is mediated through alterations in insulin secretion, insulin sensitivity, or a combination of both. RESEARCH DESIGN AND METHODS—We performed a 15-sample intravenous glucose tolerance test in a subsample of 94 normoglycemic men and women from the Dutch Famine Birth Cohort. We used the disposition index, derived as the product of insulin sensitivity and the first-phase insulin response to glucose as a measure of the activity of the β-cells adjusted for insulin resistance. In all analyses, we adjusted for sex and BMI. RESULTS—Glucose tolerance was impaired in people who had been prenatally exposed to famine compared with people unexposed to famine (difference in intravenous glucose tolerance test Kg value −21% [95% CI −41 to −4]). People exposed to famine during midgestation had a significantly lower disposition index (−53% [−126 to −3]) compared with people unexposed to famine. Prenatal exposure to famine during early gestation was also associated with a lower disposition index, but this difference did not reach statistical significance. CONCLUSIONS—Impaired glucose tolerance after exposure to famine during mid-gestation and early gestation seems to be mediated through an insulin secretion defect.

Consequences of hyperemesis gravidarum for offspring: a systematic review and meta‐analysis

Please cite this paper as: Veenendaal M, van Abeelen A, Painter R, van der Post J, Roseboom T. Consequences of hyperemesis gravidarum for offspring: a systematic review and meta‐analysis. BJOG 2011;118:1302–1313.

Blood pressure response to psychological stressors in adults after prenatal exposure to the Dutch famine

Objective There is increasing evidence that restricted prenatal growth is associated with exaggerated blood pressure responses to stress. We investigated the effect of maternal undernutrition on the adult offsprings stress response. Design A historical cohort study. Methods We performed continuous blood pressure and heart rate measurements during a battery of three 5-min physiological stress tests (Stroop test, mirror-drawing test and a public speech task) in 721 men and women, aged 58 years, born as term singletons in Amsterdam at about the time of the Dutch 1944–1945 famine. Results During the stress tests, the systolic blood pressure (SBP) rose from baseline by 20 mmHg during the Stroop test, by 30 mmHg during the mirror-drawing test and by 47 mmHg during the public speech task. The SBP and diastolic blood pressure increase during stress was highest among individuals exposed to famine in early gestation compared with unexposed subjects (4 mmHg extra systolic increase, P = 0.04; 1 mmHg diastolic increase, P = 0.1, both adjusted for sex). Exposure during mid and late gestation was not associated with a stress-related increment of blood pressure (P adjusted for sex > 0.6). Correcting for confounders in a multivariable model did not attenuate the association between famine exposure in early gestation and the SBP increment. The heart rate increment was not related to famine exposure during any part of gestation. Conclusion We found a greater blood pressure increase during stress among individuals exposed to famine in early gestation. Increased stress responsiveness may underlie the known association between coronary heart disease and exposure to famine in early gestation.

Exposure to severe wartime conditions in early life is associated with an increased risk of irritable bowel syndrome: a population-based cohort study.

OBJECTIVES:Stressful events during early life have been suggested to play an important role in the development of the irritable bowel syndrome (IBS). In this study, we evaluate whether an exposure to severe wartime conditions during gestation and in early life are associated with an increased prevalence of IBS.METHODS:We assessed the prevalence of IBS using the Rome II questionnaire among 816 men and women (aged 58±1 years) who were born as term singletons in Wilhelmina Gasthuis, Amsterdam, The Netherlands around the time of World War II.RESULTS:Of a total of 816 participants, 9.6% (n=78, 52F) met the criteria for IBS. Exposure to severe wartime conditions in utero was not associated with the prevalence of IBS in adulthood (8.3%). Early-life exposure to severe wartime conditions was associated with an increased prevalence of IBS. The prevalence of IBS among individuals exposed up to 0.5 years of age, 1 year of age, and 1.5 years of age was 8.1%, 12.5%, and 15.3%, respectively. The increased IBS prevalence was not associated with an increased stress response.CONCLUSIONS:Our data indicate that exposure to severe wartime conditions in early life is associated with an increased risk of developing IBS. To what extent this is attributable to the stressful environment of war, to severe undernutrition, or to the increased prevalence of infectious diseases is, however, unclear.