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American Journal of Clinical Nutrition, doi:10.3945/ajcn.2008.26140
Vol. 88, No. 6, 1648-1652, December 2008
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© 2008 American Society for Clinical Nutrition

Nutritional epidemiology and public health

Prenatal exposure to the Dutch famine is associated with a preference for fatty foods and a more atherogenic lipid profile 1,2,3

Federico Lussana, Rebecca C Painter, Marga C Ocke, Harry R Buller, Patrick M Bossuyt and Tessa J Roseboom

1 From the Departments of Vascular Medicine (FL and HRB) and Clinical Epidemiology, Biostatistics, and Bioinformatics (RCP, PMB, and TJR), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; the Unit of Hematology and Thrombosis, Department of Medicine, Surgery, and Dentistry, Ospedale San Paolo, University of Milano, Milano, Italy (FL); the Department of Gynaecology and Obstetrics, Medical Centre Alkmaar, The Netherlands (RCP); and the National Institute for Public Health and the Environment, Bilthoven, the Netherlands (MCO)

2 Supported by the Netherlands Heart Foundation.

3 Reprints not available. Address correspondence to TJ Roseboom, Clinical Epidemiology Biostatistics and Bioinformatics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: t.j.roseboom{at}amc.uva.nl.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Epidemiologic studies have shown that small size at birth is associated with an increased risk of cardiovascular disease and its biological risk factors, including type 2 diabetes, hypertension, hypercholesterolemia, and coronary artery disease (1-5). Animal studies show that undernutrition during gestation leads to diabetes (6), obesity (7), hypertension (8), hypercholesterolemia (9), and shortened life span (10).

Animal models have shown that maternal undernutrition during gestation can lead to modified cholesterol synthesis and elevated plasma cholesterol concentrations (11, 12). Recently, it was suggested that maternal undernutrition during gestation may increase the offspring's plasma cholesterol concentration by inducing a preference for high-fat food (13) and a reduction in physical activity (14). These observations in animal models indicate that fetal undernutrition could predispose to hypercholesterolemia and metabolic disorders directly through an interaction with cholesterol metabolism and indirectly by influencing lifestyle choices. Whether prenatal undernutrition may modify lifestyle choices has not been evaluated in humans.

The Dutch famine was a period of extreme food shortage in the west of the Netherlands that occurred during the last 5–6 mo of World War II. The Dutch famine cohort is unique because it is clearly delineated in time and allows the study of the effects of undernutrition restricted to pregnancy alone and to different periods of gestation. Studies in this cohort suggest that exposure to maternal undernutrition in early gestation is associated with changes in lipid profile (15), to increased amounts of abdominal obesity in women (16), and to an increased prevalence of coronary artery disease (17). Moreover, persons exposed at any stage of gestation had impaired glucose tolerance, probably because of an insulin secretion defect (18, 19). To investigate the role of fetal undernutrition on adult lifestyle choices, we assessed dietary and sedentary behavior with the use of validated questionnaires in the Dutch Famine Birth Cohort (20-22).


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participants
The Dutch Famine Birth Cohort consists of 2414 men and women born as singletons between 1 November 1943 and 28 February 1947 in the Wilhelmina Gasthuis in Amsterdam, Netherlands. The selection procedures of the cohort, which includes persons potentially exposed to famine during gestation and random sample of persons conceived in the year before and after that period, were described in detail earlier (15). Of the group of 1423 eligible persons, 810 (57%) agreed to participate (Figure 1Go). Informed consent was obtained from all participants. The institutional Medical Ethics Committee approved the study protocol.


Figure 1
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  		FIGURE 1.. Flow chart.

 
Exposure to famine
We defined the famine period according to the daily official food rations for the general population >21 y. We considered a fetus to be exposed to famine if the average daily rations of the mother during any 13-wk period of gestation were <4200 kJ. Persons born between 7 January 1945 and 8 December 1945 were considered exposed prenatally to famine. We defined periods of 16 wk to differentiate between persons who were exposed in late gestation (born between 7 January and 28 April 1945), in mid-gestation (born between 29 April and 18 August 1945), and in early gestation (born between 19 August and 8 December 1945). Persons born before 7 January 1945 and persons conceived after 8 December 1945 were considered as unexposed to famine in utero and were used as the control group.

Data collection
Medical birth records provided information about the mother, the course of gestation, and the size of the infant at birth (18). Socioeconomic status at birth was defined according to the occupation of the head of family. Height was measured with a fixed or portable stadiometer; weight was measured with Seca scales (Hamburg, Germany) or Tefal portable scales (Groupe SEB Nederland BV, Veenendaal, Netherlands). Body mass index (BMI; in kg/m2) was calculated. Blood was drawn after an overnight fast to measure concentrations of plasma total, LDL, and HDL cholesterol and triglycerides by standard enzymatic methods (15). All participants were interviewed about their medical history, lifestyle, and use of medication. Current socioeconomic status was coded with the use of the ISEI-92 (23) according to the participant's or their partner's occupation. Dietary intake was assessed with the use of a validated food-frequency questionnaire (20, 21). Energy and nutrient intake was calculated with the use of the Dutch food composition table 2001. Physical activity was assessed with the use of a validated questionnaire (22), it included questions about participation in sports; the kind of sports; the number of times a week a person does sports; other physical activity, including gardening; the number of stairs climbed daily; and a summary of self-perceived physical activity (very active, active, inactive). We dichotomized the self-perceived physical activity score into low (inactive) and high (active or very active) physical activity in the analyses.

Statistical methods
Values are expressed as mean ± SD. Differences between unexposed subjects and those exposed in late, mid, or early gestation were calculated for continuous variables (lipid profiles and dietary intake) and tested for statistical significance with the t test as well as in a multivariable linear regression analysis that adjusted for the potential confounders of sex and BMI and adult (current socioeconomic status, smoking, use of lipid-lowering medication) and maternal (age, parity, weight at last prenatal visit, socioeconomic status at birth) characteristics. Logarithmic transformations were applied to data that had skewed distributions. To detect a possible age-related progression in the lipid profile, we only included data of subjects participating both at age 50 y and at age 58 y and compared changes in plasma lipid concentrations between age 50 y and age 58 y according to timing of prenatal exposure to the Dutch famine. Dietary preference is presented as energy (in kcal/d) and percentage of macronutrient intake. The relative risk of consuming a high-carbohydrate or high-protein or high-fat diet associated with exposure to famine was assessed by dividing diet composition into quartiles and calculating the odds ratio for the fourth quartile, with the 3 lowest quartiles considered the reference. We tested the crude odds ratio for statistical significance by the chi-square test and adjusted for potential confounders in a logistic regression analysis. The difference in physical activity between exposed and unexposed was analyzed with the use of logistic regression analyses and adjusting for potential confounders (such as sex and BMI). P values < 0.05 were considered to indicate statistical significance. SPSS for WINDOWS (version 12.0; SPSS Inc, Chicago, IL) was used for analysis of data.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study population
The cohort consisted of 810 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. Eighty participants were excluded from the analysis because of missing data because of failure of venepuncture or nonadherence to fasting instructions. Of the 730 persons included in the study 294 (40%) were exposed to famine in utero. Compared with those unexposed, persons born after exposure to the famine in late and mid gestation were lighter and shorter and had smaller heads, and their mothers weighed less at the last prenatal visit (Table 1Go). No significant differences were observed between the exposed and unexposed groups in smoking habits and socioeconomic status. In this cohort of 730 participants, 599 had provided analyzable answers to the food-frequency questionnaire, and 491 had data available on lipid profile at the age of 50 y.


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  		TABLE 1. Demographic and laboratory variables of the study population1

 
Famine exposure and lipid profile
No significant differences were observed in cholesterol concentrations between participants exposed to famine and thoseunexposed, but the ratio of LDL to HDL (LDL:HDL) cholesterol tended to be higher in the exposed group. The number of participants using lipid-lowering medication, however, was higher among those exposed to famine in early gestation than among the unexposed participants (21% compared with 15%). As published previously (17), at the age of 50 y, we found that participants who were exposed in early gestation (n = 63) had a more atherogenic lipid profile than did participants who were not exposed (n = 436), showing higher plasma concentrations of total and LDL cholesterol and LDL:HDL cholesterol (Table 1Go).

Effects of age
We evaluated whether prenatal famine exposure leads to more rapid deterioration of lipid profile with aging and compared people who participated at age 50 y and at age 58 y. Unexpectedly, mean total cholesterol, LDL, and LDL:HDL had decreased, whereas only plasma triglycerides had increased between ages 50 and 58 y. As suggested in multivariable analysis, the main determinant in our results was the higher number of participants taking lipid-lowering medication at age 58 y than at age 50 y (15% and 3%, respectively). After exclusion of participants using lipid-lowering medication, the progression of hypercholesterolemia in the group of participants exposed to famine in early gestation was significantly more pronounced than for the other groups, confirming that this period of gestation is crucial in determining consequences on lipid metabolism. In this subgroup the age-related mean plasma increases of total and LDL cholesterol between age 50 y and age 58 y were 0.49 ± 0.04 mmol/L and 0.19 ± 0.03 mmol/L, respectively, compared with an increase of 0.12 mmol/L (P = 0.02) in total cholesterol and with a decrease of 0.13 ± 0.04 mmol/L (P = 0.04) in LDL cholesterol among participants who were unexposed. Finally, the increase in triglyceride concentrations was also larger in the early exposed group (0.40 ± –0.04 g/L) than in the unexposed group (0.11 ± –0.04 g/L; P = 0.006).

Famine exposure and dietary preference
The mean percentage of protein, carbohydrate, and fat in the diet did not differ among the exposure groups (Table 2Go). Participants exposed to famine in early gestation were more likely to consume a high-fat diet (Table 3Go). The relative risk of participants with early exposure to famine of consuming a high-fat diet, defined as the highest quartile of fat in the diet (>39% of energy from fat), was 2.0 (95% CI: 1.1, 3.7). The relative risk remained significantly higher after adjustment for sex, birth weight, BMI, and socioeconomic status (odds ratio: 2.1; 95% CI: 1.2, 3.9). The higher percentage of participants who consumed a high-fat diet in those exposed to famine in early gestation partially explained the effects of prenatal exposure to famine on total cholesterol concentrations (the effect of early exposure on total cholesterol changed from 0.40 (95% CI: 0.04, 0.0.76) to 0.12 (95% CI: –0.27, 0.51) after adjustment for fat intake (Table 4Go).


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  		TABLE 2. Food intake and physical activity according to timing of famine exposure

 

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  		TABLE 3. Fat intake (in percentiles) according to timing of famine exposure

 

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  		TABLE 4. Effect size of early exposure on lipid levels1

 
Famine exposure and physical activity
Participants exposed to famine in early gestation tended to be less physically active (45% compared with 52% of participants unexposed to famine who practiced sports; Table 2Go). In addition, they more often rated their physical activity level as low (37% of subjects exposed to famine in early gestation compared with 30% of subjects unexposed). None of these differences, however, reached statistical significance.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study shows that people exposed to famine in early gestation were twice as likely to consume a high-fat diet (defined as the highest quartile of percentage of fat in the diet: >39% of energy from fat), and they had a tendency to be less physically active. This may, in part, explain why persons exposed to famine in early gestation have a more atherogenic lipid profile.

One of the limitations of the present study is the validity of the questionnaires. Studies have shown, however, that the questionnaire is reliable enough to rank persons according to consumption (20-22). Although some items may be underreported, this will only have introduced bias if underreporting was unequally distributed across exposure groups, which seems unlikely. In addition, the selective participation of healthier people could have influenced our results. Yet, in the absence of a difference in response rates between those who were exposed and those who were unexposed, there is no reason to believe that selective participation affected the differences among the different exposure groups.

A significant number of participants were treated with lipid-lowering medication, and this might have led to an underestimation of the effect of exposure to undernutrition during early gestation on lipid profile. After exclusion of subjects treated for hypercholesterolemia, we observed a substantial age-related progression of atherogenic lipid profile, especially in participants with early exposure to famine. These findings nicely fit evidence from studies in both animals and humans showing that suboptimal fetal environment is associated with more rapid aging (17, 24-31).

Experiments in animals have shown that manipulations of the diets of pregnant animals can produce changes in the offspring's behavior and in the physiology of metabolic processes. Rats deprived of protein in utero were shown to have hyperphagia (4) and a preference for high-fat food (13). Another feature of these animals is also a decrease in locomotor activity (14, 32), exacerbated by postnatal hypercaloric nutrition. To our knowledge, this is the first report that undernutrition during fetal life can influence adult diet preference and sedentary behavior in humans. The combined analysis of the present data and animal models suggests that adult lifestyles and metabolic disorders might have a common prenatal origin. The current finding suggests that dietary preferences, rather than being a choice, may be established by physiologic programming in early life.

On the basis of animal models, it was suggested that the mechanisms underlying the effects of prenatal exposure to undernutrition might be mediated by the induction of leptin resistance (4, 33-35) and changes in hypothalamic development (32). We were not able to show any differences in hypothalamic-pituitary-adrenal axis activity in response to psychological or pharmacologic stress between exposure groups so far (36, 37). Leptin resistance, however, has not yet been studied in our cohort.

In conclusion, our findings suggest that adult lifestyles might be influenced by prenatal nutrition. An understanding of these biological processes may have important implications for public health; indeed, identifying the ideal content of the diet for women of reproductive age and their newborn might provide the opportunity for disease prevention and health-promoting effects in that of the offspring.


   ACKNOWLEDGMENTS
 
We thank all participants for their collaboration.

The author's responsibilities were as follows—FL: did the statistical analyses and wrote the first draft; MCO: performed the analyses of the food-frequency questionnaires; TJR: conceived and set up the study and wrote the final version of the manuscript; all authors commented on earlier versions of the manuscript and approved the final version. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication March 12, 2008. Accepted for publication August 31, 2008.




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