Lipid profiles in middle-aged men and women after famine exposure during gestation: the Dutch Hunger Winter Families Study.
ABSTRACT Many studies in humans have related birth weight to lipid profiles in adulthood. Fewer have estimated associations directly attributable to maternal nutrition during pregnancy.
Our objective was to determine whether famine exposure during gestation is associated with a more atherogenic profile in adult offspring.
In 2003-2005, we studied 1) 359 singleton men and women born between January 1945 and March 1946 in clinics in Amsterdam, Rotterdam, and Leiden whose mothers were exposed to the famine during pregnancy; 2) 299 singletons born in the same 3 institutions during 1943 or 1947; and 3) 313 unexposed same-sex siblings of the above individuals. A lipid profile was obtained after an overnight fast.
Female offspring with prenatal famine exposure had a dyslipidemic pattern characterized by elevated total cholesterol (0.26 mmol/L; 95% CI: 0.07, 0.46; P = 0.007), triglycerides (0.17 mmol/L; 95% CI: 0.03, 0.31; P = 0.02), and LDL cholesterol (0.17 mmol/L; 95% CI: -0.01, 0.36; P = 0.06) compared with unexposed offspring. This pattern was not seen in men. The increases in total cholesterol and LDL cholesterol were independent of body mass index, waist circumference, and midthigh circumference. The increase in triglycerides was independent of midthigh circumference but was attenuated with control for either body mass index or waist circumference. There was no evidence for associations within specific gestational windows. No association was observed between prenatal famine exposure and HDL cholesterol in either sex.
In women, but not in men, aged approximately 58 y, we observed an association between prenatal undernutrition and elevated total cholesterol concentrations and triglycerides.
- SourceAvailable from: Hein Putter[Show abstract] [Hide abstract]
ABSTRACT: Periconceptional diet may persistently influence DNA methylation levels with phenotypic consequences. However, a comprehensive assessment of the characteristics of prenatal malnutrition-associated differentially methylated regions (P-DMRs) is lacking in humans. Here we report on a genome-scale analysis of differential DNA methylation in whole blood after periconceptional exposure to famine during the Dutch Hunger Winter. We show that P-DMRs preferentially occur at regulatory regions, are characterized by intermediate levels of DNA methylation and map to genes enriched for differential expression during early development. Validation and further exploratory analysis of six P-DMRs highlight the critical role of gestational timing. Interestingly, differential methylation of the P-DMRs extends along pathways related to growth and metabolism. P-DMRs located in INSR and CPT1A have enhancer activity in vitro and differential methylation is associated with birth weight and serum LDL cholesterol. Epigenetic modulation of pathways by prenatal malnutrition may promote an adverse metabolic phenotype in later life.Nature Communications 11/2014; 5:5592. · 10.74 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Traditional studies focused on DNA as the heritable information carrier that passes the phenotype from parents to offspring. However, increasing evidence suggests that information, that is independent of the DNA sequence, termed epigenetic information, can be inherited between generations. Recently, in our lab, we found that prediabetes in fathers increases the susceptibility to diabetes in offspring through gametic cytosine methylation changes. Paternal prediabetes changed overall methylation patterns in sperm, and a large portion of differentially methylated loci can be transmitted to pancreatic islets of offspring up to the second generation. In this review, we survey the extensive examples of environmentally induced epigenetic inheritance in various species, ranging from Caenorhabditis elegans to humans. We focus mainly on elucidating the molecular basis of environmental epigenetic inheritance through gametes, which is an emerging theme and has important implications for explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases, which is also important for understanding the influence of environmental exposures on reproductive and overall health in offspring. For this review, we included relevant data and information obtained through a PubMed database search for all English language articles published up to August 2014 which included the term 'environmental epigenetic inheritance' and 'transgenerational epigenetic inheritance'. We focused on research papers using animal models including Drosophila, C. elegans, mouse and rat. Human data were also included. Evidence from animal models suggests that environmental epigenetic inheritance through gametes exists in various species. Extensive molecular evidence suggests that epigenetic information carriers including DNA methylation, non-coding RNAs and chromatin proteins in gametes play important roles in the transmission of phenotypes from parents to offspring. Given the large number of experimental evidence from various organisms, it is clear that parental environmental alterations can affect the phenotypes of offspring through gametic epigenetic alterations. This more recent thinking based on new data may have implications in explaining the prevalence of obesity, type 2 diabetes and other chronic non-genetic diseases. This also implies that, in the near future, epigenetic factors which are heritable should be regarded important in determining the risk of certain diseases. Moreover, identification of epigenetic markers in gametes (polar body or sperm) may hold great promise for predicting susceptibility to and preventing certain non-genetic diseases in offspring, as well as providing indications on parental environmental exposures. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: firstname.lastname@example.org.Human Reproduction Update 11/2014; · 8.66 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Type II diabetes mellitus (T2DM) is a widespread metabolic disorder characterized by insulin resistance precipitating abnormally high blood glucose levels. While the onset of T2DM is known to be the consequence of a multifactorial interplay with a strong genetic component, emerging research has demonstrated the additional role of a variety of epigenetic mechanisms in the development of this disorder. Heritable epigenetic modifications, such as DNA methylation and histone modifications, play a vital role in many important cellular processes, including pancreatic cellular differentiation and maintenance of normal β-cell function. Recent studies have found possible epigenetic mechanisms to explain observed risk factors, such as altered atherogenic lipid profiles, elevated body mass index (BMI), and impaired glucose tolerance (IGT), for later development of T2DM in children born to mothers experiencing both famine and hyperglycemic conditions. It is suggested that these epigenetic influences happen early during gestation and are less susceptible to the effects of postnatal environmental modification as was previously thought, highlighting the importance of early preventative measures in minimizing the global burden of T2DM.Frontiers in Cell and Developmental Biology 05/2014; 2:15.
Lipid profiles in middle-aged men and women after famine exposure
during gestation: the Dutch Hunger Winter Families Study1–4
LH Lumey, Aryeh D Stein, Henry S Kahn, and JA Romijn
Background: Many studies in humans have related birth weight to
lipid profiles in adulthood. Fewer have estimated associations di-
rectly attributable to maternal nutrition during pregnancy.
Objective: Our objective was to determine whether famine expo-
sure during gestation is associated with a more atherogenic profile
in adult offspring.
Design: In 2003–2005, we studied 1) 359 singleton men and women
born between January 1945 and March 1946 in clinics in Amster-
dam, Rotterdam, and Leiden whose mothers were exposed to the
famine during pregnancy; 2) 299 singletons born in the same 3
institutions during 1943 or 1947; and 3) 313 unexposed same-sex
siblings of the above individuals. A lipid profile was obtained after
an overnight fast.
Results: Female offspring with prenatal famine exposure had a dys-
lipidemic pattern characterized by elevated total cholesterol (0.26
mmol/L; 95% CI: 0.07, 0.46; P ¼ 0.007), triglycerides (0.17 mmol/L;
95% CI: 0.03, 0.31; P ¼ 0.02), and LDL cholesterol (0.17 mmol/L;
95% CI: 20.01, 0.36; P ¼ 0.06) compared with unexposed offspring.
This pattern was not seen in men. The increases in total cholesterol
and LDL cholesterol were independent of body mass index, waist
circumference, and midthigh circumference. The increase in trigly-
cerides was independent of midthigh circumference but was attenu-
ated with control for either body mass index or waist circumference.
There was no evidence for associations within specific gestational
windows. No association was observed between prenatal famine ex-
posure and HDL cholesterol in either sex.
Conclusion: In women, but not in men, aged ’58 y, we observed
an association between prenatal undernutrition and elevated total
cholesterol concentrations and triglycerides.
Am J Clin Nutr
Elevated plasma or serum concentrations of total or LDL
cholesterol, an elevated ratio of total cholesterol (TC) to HDL
cholesterol (TC:HDL cholesterol), and elevated triglyceride
concentrations, especially with low HDL-cholesterol concen-
trations, all increase cardiovascular disease risk (1–5). Positive
reports on associations between reduced birth weight and adult
lipoprotein profiles (6–11) have been interpreted to support the
hypothesis that poor prenatal nutrition increases the risk of
cardiovascular disease later in life (12); these associations with
reduced birth weight have not been confirmed in all studies (13–
Although animal models have shown that maternal nutrition in
gestation affects cholesterol concentrations (16–19), human data
are sparse. Birth weight is a suboptimal indicator of early pre-
natal nutrition (20–23), and more direct measures of maternal
and fetal nutrition are therefore needed. The Dutch 1944–1945
famine provides a unique opportunity to study the effects of
maternal undernutrition at different stages of gestation on adult
health. The famine was clearly defined in place (limited to the
western Netherlands) and time (October 1944–May 1945) and
occurred in a society with a well-developed administrative struc-
ture. It resulted from a transport embargo on food imposed by
the German occupying forces in early October 1944. The se-
verity and widespread nature of the famine have been fully
documented (24–26). Despite the war, nutrition in the Netherlands
had generally been adequate before October 1944 (27). Official
rations, which eventually consisted of little more than bread and
potatoes, fell below 900 kcal/d by 26 November 1944 and were
as low as 500 kcal/d by April 1945. The famine ceased at lib-
eration in May 1945, after which time Allied food supplies were
rapidly distributed across the country. The famine affected
mortality, especially in the youngest and oldest age categories,
fertility, pregnancy weight gain, and infant size at birth (20, 26,
Three prior studies of the association between maternal
wartime nutritional experiences (in England, Leningrad, and
34). Their participants had attained ?50–55 y of age, and the
results were inconclusive. The present study was undertaken to
examine this association in an independent study population and
to extend follow-up through age ’58 y.
1From the Mailman School of Public Health, Columbia University, New
York, NY (LHL); the Hubert Department of Global Health, Emory Univer-
sity, Atlanta GA (ADS); the Centers for Disease Control and Prevention,
Atlanta, GA (HSK); and the Leiden University Medical Center, Leiden,
2The contents of this paper are solely the responsibility of the authors and
do not necessarily represent the official views of the Centers for Disease
Control and Prevention.
3Supported by the National Heart, Lung, and Blood Institute, NIH (R01
HL-067914; principal investigator: LHL).
4Address correspondence to LH Lumey, Columbia University, Depart-
ment of Epidemiology, Mailman School of Public Health, 722 West 168th
Street, New York NY 10032. E-mail: email@example.com.
Received September 29, 2008. Accepted for publication March 15, 2009.
First published online April 22, 2009; doi: 10.3945/ajcn.2008.27038.
Am J Clin Nutr 2009;89:1737–43. Printed in USA. ? 2009 American Society for Nutrition
SUBJECTS AND METHODS
As described in greater detail elsewhere (35), we identified
a birth cohort of 3307 live-born singleton births at 3 institutions
in famine-exposed cities (the midwifery training schools in
Amsterdam and Rotterdam and the university hospital in Lei-
den). We selected all 2417 births between 1 February 1945 and
31 March 1946 (infants whose mothers were exposed to the
famine during or immediately preceding that pregnancy) and
a sample of 890 births from 1943 and 1947 whom we designated
as hospital time controls (infants whose mothers were not ex-
posed to famine during this pregnancy). The sample of controls
included an equal number of births for each month, allocated
across the 3 institutions according to their size.
Tracing to current address
Names and addresses at birth for the 3307 infants were pro-
vided to the Population Register in the municipality of birth with
a request for tracing to their current address. Three hundred
eight (9%) were reported to have died in the Netherlands, and
275 (8%) were reported to have emigrated. The Population
Register in Rotterdam declined to trace 130 individuals born out
of wedlock, and current address could not be located for 294
subjects (9%). Address information was therefore obtained for
2300 individuals (70% of the birth cohort).
Enrollments and examinations
These 2300 individuals were sent a letter of invitation signed
by the current director of the institution in which they were born,
a same-sex sibling were asked that they contact this sibling for
study enrollment. For siblings, no information from prenatal or
delivery records is available because they were not members of
the birth series in the 3 institutions and were generally delivered
elsewhere. Initially, our study design called for the recruitment of
same-sex sibling pairs only, and the lack of an available sibling
was a reason for ineligibility. Later, all individuals from the birth
series were recontacted and invited for study irrespective of
We received 1075 positive responses to our study invitations
for a telephone interview and a medical examination at the
Leiden University Medical Center. Most clinical examinations
were conducted within 6 wk of the telephone interview. All study
protocols were approved by the Human Subjects (Medical ethics)
committees of the participating institutions. All participants
written informed consent at the start of the clinical examination.
The telephone interview included questions on sociodemo-
graphic characteristics such as education, health history, health
behaviors such as smoking and drinking, and medications for
examinations were scheduled early in the morning and included
the measurement of height measured to the nearest 1 mm with
a portable stadiometer (Seca, Hamburg, Germany), weight was
measured to the nearest 100 g with the participant standing on
a portable scale (Seca), waist was measured at the level of the
iliac crest and intersection with the midaxillary line, and right
midthigh circumference (MTC) was measured supine with the
hip flexed at 45? between the lateral inguinal crease and proximal
patella (36). A single measurement was taken for height and
weight and 2 for waist and MTC, with the mean value of the
2 taken for analysis unless these were too far apart, in which
case a third and fourth measure were taken, and the 3 measures
closest together from the available 4 were averaged (36). Blood
pressure was measured with an automated sphygmomanometer
(HEM 705-CP; Omron Health Care, Bannockburn, IL). Three
readings were obtained with the automatic setting from the
nondominant arm after several minutes of rest. In analyses, the
mean of the 2 closest readings was used (37). Hypertension was
defined as having a systolic blood pressure of ?140 mm Hg or
a diastolic blood pressure of ?90 mm Hg or having a medical
diagnosis with antihypertensive medication. Participants were
told to fast overnight before the clinic visit.
Serum TC, HDL cholesterol, and triglycerides from venous
(38–40). For individuals with a triglyceride concentration ,400
mg/dL, we calculated LDL cholesterol from measured TC, tri-
glycerides, and HDL cholesterol with the Friedewald formula
(41). We used the classifications from the third report of the
National Cholesterol Education Program Expert Panel on De-
tection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (ATP) (42) to define elevated TC (ATP category high: TC
? 6.216 mmol/L; 240 mg/dL), low HDL cholesterol (ATP cate-
gory low: HDL , 1.036 mmol/L; 40 mg/dL), elevated LDL (ATP
categories high and very high: LDL ? 4.138 mmol/L; 160 mg/
dL), and elevated triglycerides (ATP categories borderline high,
high, and very high: TG ? 1.69 mmol/L; 150 mg/dL). We defined
dyslipidemia as TC:HDL cholesterol . 5.0 or use of cholesterol-
lowering medication (43).
Famine exposure during gestation
hospital records to define the start of gestation unless it was
date from relevant annotations on the birth record and estimated
gestational age from birth weight and date of birth, using cutoffs
from tables of sex-, parity-, and birth weight-specific gestational
ages from the combined birth records of the Amsterdam mid-
wives school (1948–1957) and the University of Amsterdam
Obstetrics Department (1931–1965) (44). For each infant the
most consistent and plausible estimate of gestation was selected
and used together with date of birth to infer the LMP date.
We characterized exposure to famine during gestation by
determining the gestational ages (in weeks after the LMP) during
mother exposed in gestational weeks 1–10, 11–20, 21–30, or 31
to delivery if these gestational time windows were entirely
LUMEY ET AL
included in this period. Thus, pregnancies with LMP between 26
November 1944 and 4 March 1945 were considered exposed in
weeks 1–10, between 18 September 1944 and 24 December 1944
exposed in weeks 11–20, between 10 July 1944 and 15 October
1944 exposed in weeks 21–30, and between 2 May 1944 and 24
August 1944 exposed in week 31 through delivery. By these
definitions, any participant could have been exposed to famine
during at most 2 adjacent 10-wk periods. Individuals exposed in
?1 of the 10-wk periods were considered to have had any
prenatal famine exposure.
We computed means and SDs and categorical distributions for
population characteristics and study outcomes for different ex-
posure categories as appropriate. Some outcomes (eg, trigly-
cerides) were also analyzed after log-transformation to make the
distribution closer to normal. These transformations had little
effect on the overall study findings, and details are not further
reported. We examined the association of exposure in any of the
10-wkexposure categories, considered as a group or individually,
logistic (for discrete outcomes) regression analysis. Each out-
come variable was considered separately. As controls, we used
hospital births for subjects without exposure in that period
combined with all sibling controls. We examined heterogeneity
of associations by sex and conducted sex-specific analyses when
significant heterogeneity (at P , 0.05) was observed. In all
regression models we first adjusted for age at examination (with
the use of linear and quadratic terms) and the use of cholesterol-
lowering medications (statins). We also adjusted for sex in
models, including men and women. We then controlled for se-
lected body fat measures associated with adverse metabolic
outcomes such as body mass index (BMI; in kg/m2), waist cir-
cumference, or MTC (45, 46). We then also controlled for de-
mographic and health characteristics such as education, current
smoking habit, alcohol use, and prevalent hypertension. In
practice, additional control for anthropometry, demographic, or
health characteristics had little effect on the risk estimates;
therefore, we only show tabulated study results adjusted for age,
use of cholesterol medication, and (when appropriate) sex.
Statistical analyses were conducted with SPSS version 10 (SPSS
Inc, Chicago, IL) or STATA version 8 (StataCorp, College Sta-
tion, TX) with the xtreg and xtlogit commands for hierarchical
models to control for clustering within families.
A total of 971 study participants attended the clinic exami-
nation of whom 19 had not fasted overnight and 6 had a missing
blood sample. We therefore here present study results for the
(36%) had been exposed to famine at some period in gestation,
294 (31%) were hospital controls either born before or conceived
after the famine, and 308 (33%) were same-sex sibling controls.
No significant differences were observed in sex, education,
reported smoking and drinking habits, or the use of cholesterol-
lowering medication among these 3 groups (Table 1). Sibling
controls were on average 1.5 y younger than other study par-
ticipants. As reported before, famine exposed participants had
a higher prevalence of hypertension (37) and an increased BMI
and waist circumference (36).
Adult lipid profile measures by exposure status appear in
Table 2. The overall prevalence of dyslipidemia was higher
among men than among women [34% compared with 21%; odds
ratio (OR): 2.0; 95% CI: 1.5, 2.7] as was the prevalence of low
HDL cholesterol (15% compared with 2.5%; OR: 6.9; 95% CI:
3.6, 13.4), resulting in higher ratios of TC and LDL cholesterol
to HDL cholesterol among men than among women.
Continuous measures of lipid profile among men and women
with any exposure to famine compared with controls are con-
trasted in Table 3. Tests for heterogeneity were significant at P ,
0.05 for all measures except HDL cholesterol and triglycerides.
Men with prenatal famine exposure at any time in pregnancy
showed a decrease in LDL cholesterol of 0.18 mmol/L (95% CI:
20.35, 20.01 mmol/L; P ¼ 0.04) relative to unexposed men.
Exposed women showed a TC increase of 0.27 mmol/L (95% CI:
0.07, 0.46 mmol/L; P ¼ 0.007), a triglyceride increase of 0.17
mmol/L (95% CI: 0.03, 0.31 mmol/L; P ¼ 0.02), and a LDL cho-
lesterol increase of 0.17 mmol/L (95% CI: 20.01, 0.36 mmol/L;
P ¼ 0.06) compared with unexposed women (Table 3).
The estimated increases in TC in women were not affected by
additional adjustment for either current BMI (0.28 mmol/L; 95%
CI: 0.10, 0.48 mmol/L; P ¼ 0.004), waist circumference (0.27
mmol/L; 95% CI: 0.07, 0.46 mmol/L; P ¼ 0.007), or MTC (0.28
mmol/L; 95% CI: 0.09, 0.47 mmol/L; P ¼ 0.005), nor was the
increase in LDL cholesterol affected by additional adjustment
for BMI (0.18 mmol/L; 95% CI: 20.004, 0.36 mmol/L; P ¼
0.06), waist circumference (0.17 mmol/L; 95% CI: 20.0013,
0.35 mmol/L; P ¼ 0.07), or MTC (0.18 mmol/L; 95% CI:
20.001, 0.36 mmol/L; P ¼ 0.05).
The increase in triglycerides in women also remained after
mmol/L; P ¼ 0.03), but it was much diminished and no longer
statistically significant at P , 0.05 after additional adjustment
for either current BMI (0.11 mmol/L; 95% CI: 20.03 mmol/L,
0.25; P ¼ 0.13) or waist circumference (0.08 mmol/L; 95%
CI: 20.06, 0.22 mmol/L; P ¼ 0.3).
Heterogeneity by sex was observed in the associations of LDL
cholesterol and ratios of LDL to HDL (LDL:HDL cholesterol)
with famine exposure (tests for heterogeneity P , 0.01 for these
outcomes); the LDL cholesterol was 0.18 mmol/L (95% CI:
20.35, 20.013 mmol/L; P ¼ 0.04) lower in exposed men than
in unexposed men, and LDL:HDL cholesterol was 0.21 units
lower (95% CI: 20.40, 20.02; P ¼ 0.03) as a result. There were
no differences in triglycerides or HDL cholesterol when exposed
men and women were compared with controls (Table 3).When we
used an exposure definition based on date of birth (34), in-
dividuals exposed to famine in early gestation showed a decrease
in LDL:HDL cholesterol of 1% (95% CI: 211.0%, –9.9%)
Results for dichotomous outcomes for mean and women are
presented in Table 4. Heterogeneity by sex (P , 0.01) was seen
for elevated TC and LDL cholesterol. In sex-adjusted models,
the ORs for low HDL cholesterol, elevated triglycerides, the use
of cholesterol-lowering medication, and dyslipidemia were 0.89
(95% CI: 0.52, 1.50; P ¼ 0.65), 1.48 (95% CI: 1.06, 2.08; P ¼
0.02), 1.18 (95% CI: 0.79, 1.77; P ¼ 0.42), and 1.05 (95% CI:
0.72, 1.53; P ¼ 0.80), respectively.
GESTATIONAL FAMINE AND LATER LIPID PROFILE
Only modest associations were observed between exposure to
examined (Table 5). Tests for sex-specific heterogeneity were
significant at the level of P , 0.05 only for TC:HDL cholesterol.
In this study of men and women born in Amsterdam, Rot-
terdam, and Leiden toward the end of World War II, we observed
that prenatal exposure to the 1944–1945 Dutch famine was as-
sociated with sex-specific differences in the pattern of athero-
was not associated with an increase in lipids. In women, we
observed elevated serum concentrations of TC (0.27 mmol/L;
P ¼ 0.007), LDL cholesterol (0.17 mmol/L; P ¼ 0.06), and
triglycerides (0.17 mmol/L; P ¼ 0.02) relative to unexposed
women. The differences in women represent 0.25 SD for TC and
0.20 SD for LDL cholesterol and triglycerides,. No significant
Selected characteristics of men and women exposed to the Dutch famine during gestation with hospital and sibling controls examined between 2003 and 2005
(n ¼ 294)
58.6 6 1.63
27.3 6 4.3
97.3 6 11.4
(n ¼ 308)
57.2 6 6.4
27.0 6 4.2
96.4 6 11.3
(n ¼ 344)
58.7 6 0.4
28.4 6 5.0
99.8 6 11.3
Education exceeding primary or lower vocational schooling (%)
Current smoker (%)
Alcohol ?1 drink/wk (%)
Prevalent hypertension (%)4
Waist circumference (cm)
Use of cholesterol-lowering medication (%)
Prevalent dyslipidemia (%)5
1Born in the same institutions as exposed individuals but before the famine or after the famine and not exposed to famine during gestation.
2Comparing the 3 exposure categories by ANOVA or chi-square test, as appropriate.
3Mean 6 SD (all such values).
4Systolic blood pressure ? 140 mm Hg or diastolic blood pressure ? 90 mm Hg or prior diagnosis with medication.
5Ratio of total cholesterol to HDL cholesterol . 5.0 or use of cholesterol-lowering medication.
Fasting lipid concentrations, indexes, and prevalences of lipid abnormalities in men and women exposed to the Dutch famine during gestation with hospital
and sibling controls examined between 2003 and 20051
(n ¼ 136)
5.50 6 0.932
(n ¼ 131)
5.46 6 0.97
(n ¼ 158)
5.38 6 1.03
(n ¼ 158)
5.88 6 0.95
(n ¼ 177)
5.70 6 1.12
(n ¼ 186)
6.08 6 1.13
Elevated TC ? 6.216 mmol/L;
240 mg/dL (%)
HDL cholesterol (mmol/L)
Low HDL cholesterol ,
1.036 mmol/L; 40 mg/dL (%)3
Elevated triglycerides ?
1.69 mmol/L; 150 mg/dL (%)
Non-HDL cholesterol (mmol/L)
LDL cholesterol (mmol/L)
Elevated LDL cholesterol ?
4.138 mmol/L; 160 mg/dL (%)
Prevalent dyslipidemia: TC:HDL
cholesterol ratio .5.0 or use of
cholesterol-lowering medication (%)4
1.35 6 0.37
1.39 6 0.36
1.40 6 0.38
1.79 6 0.50
1.70 6 0.421.72 6 0.45
1.68 6 0.94
1.63 6 0.93
1.80 6 1.69
1.42 6 0.79
1.32 6 0.71
1.57 6 0.84
4.15 6 0.96
3.41 6 0.86
4.08 6 0.99
3.36 6 0.89
3.98 6 1.03
3.21 6 0.83
4.09 6 1.01
3.47 6 0.89
4.00 6 1.18
3.42 6 1.04
4.36 6 1.16
3.65 6 1.02
4.34 6 1.28
2.71 6 1.03
4.19 6 1.27
2.59 6 0.99
4.15 6 2.01
2.43 6 0.86
3.51 6 1.04
2.12 6 0.84
3.59 6 1.26
2.18 6 1.01
3.75 6 1.14
2.27 6 0.92
1TC, total cholesterol. Number of missing observations combining men and women: 1 for HDL cholesterol, non-HDL cholesterol, and TC:HDL
cholesterol; 15 for triglycerides; and 26 for LDL cholesterol and LDL:HDL cholesterol.
2Mean 6 SD (all such values).
3Overall prevalence in men was 15% and in women 2.5% (odds ratio: 6.9; 95% CI: 3.6, 13.4).
4Overall prevalence in men was 34% and in women 21% (odds ratio: 2.0; 95% CI: 1.5, 2.7).
LUMEY ET AL
change was observed in HDL cholesterol concentrations in men
or women. In the absence of nutrition information at the in-
dividual level, all inferences are made at the group level by
category of exposure to the famine.
In an earlier study of this question carried out in women born
at the Amsterdam university hospital, Dutch adults exposed to
famine in early gestation based on date of birth were reported to
show an increase in LDL:HDL cholesterol of 13.9% (95% CI:
2.6%, 26.4%) at age 50 y compared with unexposed hospital
controls (34). Other lipid measures were not different from
controls. Outcomes in that study were not reported separately
for men and women. Our study finding is not consistent with the
above, because we observed a decrease in LDL:HDL cholesterol
of 1% (95% CI: 211.0%, 9.9%) with the use of the exposure
classification based on date of birth. In the same Amsterdam
population examined at age 58, LDL:HDL cholesterol was again
reported to be elevated in subjects exposed to famine in early
gestation (47). Some differences between study designs and
study populations might contribute to the observed differences
between these famine populations. For instance, the present
study also includes sibling controls in addition to unexposed
controls born in the same institutions as the exposed individuals,
and we expect these to be particularly effective in the control of
family-related variables. Differences between the 2 studies may
also reflect sampling variability inherent in the relatively small
Two additional studieshavefocused onmaternal energy intake
in wartime. Neither showed associations between pregnancy
nutrition and lipid profiles in adult offspring. The first study
included pregnant women in England who were examined in
1942–1944 to determine whether the wartime rations were suf-
ficient to prevent nutritional deficiencies and whose offspring
were later traced and examined (32). In the study from England,
pregnancy nutrition did not reach starvation levels, and exposure
was defined in terms of biochemical variables such as packed
cell volumes, erythrocyte counts, and protein and vitamin con-
centrations and not estimated caloric intake. The second study
included men and women born during the siege of Leningrad of
1941–1944 (33). The siege was extended (900 d) and caused
extreme nutritional deprivation. It is not clear whether the null
results reflect the true absence of long-term effects or whether
the study failed to detect existing long-term effects because of
Association of exposure to the Dutch famine at any period during gestation with fasting lipid concentrations or indexes
among men and women examined between 2003 and 20051
Famine-exposed men (n ¼ 158) Famine-exposed women (n ¼ 186)
Estimate 95% CIP Estimate95% CIP
HDL cholesterol (mmol/L)
Non-HDL cholesterol (mmol/L)
LDL cholesterol (mmol/L)
LDL cholesterol:HDL cholesterol
1TC, total cholesterol. Values represent differences relative to sex-specific unexposed control subjects (294 hospital
controls: 158 men and 136 women; 308 sibling controls: 177 men and 131 women) obtained by linear regression with
adjustment for age (linear and quadratic terms), cholesterol medication, and clustering within sibships. Tests for hetero-
geneity by sex as obtained from coefficients from interaction terms in regression models were significant at P , 0.05 for all
outcomes, except HDL cholesterol (P ¼ 0.37) and triglycerides (P ¼ 0.18).
Association of exposure to the Dutch famine at any period during gestation with the prevalence of fasting lipid abnormalities among men and women
examined between 2003 and 20051
Famine-exposed men (n ¼ 158) Famine-exposed women (n ¼ 186)
Odds ratio 95% CIP Odds ratio 95% CIP
Total cholesterol ? 6.216 mmol/L (240 mg/dL)
HDL cholesterol , 1.036 mmol/L (40 mg/dL)
LDL cholesterol . 4.138 mmol/L (160 mg/dL)
Triglycerides ? 1.69 mmol/L (150 mg/dL)
Use of cholesterol-lowering medication
Dyslipidemia (ratio of total cholesterol to HDL cholesterol
. 5.0 or use of cholesterol-lowering medication)
1Values represent odds ratios relative to sex-specific unexposed control subjects (294 hospital controls: 158 men and 136 women; 308 sibling controls: 177
men and 131 women) obtained by logistic regression with adjustment for age (linear and quadratic terms), cholesterol medication, and clustering within sibships.
Tests for heterogeneity by sex as obtained from coefficients from interaction terms in regression models were as follows: total cholesterol (P ¼ 0.01); HDL
cholesterol (P ¼ 0.87); LDL cholesterol (P ¼ 0.01); triglycerides (P ¼ 0.03); use of cholesterol-lowering medication (P ¼ 0.04), and dyslipidemia (P ¼ 0.06).
GESTATIONAL FAMINE AND LATER LIPID PROFILE
misclassification of famine exposure status, lack of study power,
or selective follow-up.
At first sight, our findings of a more atherogenic lipid profile in
women after prenatal famine exposure appear to be consistent
with previous findings in this population that body weight and
indexes of fat deposition at several tissue sites were increased in
women (36) and with the observation by others that excess body
weight worsens the degree of dyslipidemia (48). However, the
observed statistical increases in TC (and small increase in LDL
cholesterol) in women are independent of current BMI, waist
circumference, and MTC. The increases are also independent of
other factors associated with elevated lipid concentrations such
as the use of statins. Our findings suggest therefore that prenatal
exposure to famine may have separate (and sex-specific) effects
on body weight and fat distribution and on the programming
of cholesterol metabolism in later life through distinct path-
ways that need further exploration. It is unclear whether these
effects will ultimately translate into differences in cardiovas-
It is a potential limitation of this study that not all individuals
from the birth series participated in the follow-up examinations.
For bias to occur, loss to follow-up would have to be associated,
however, both with exposure and with outcome. No significant
differences were observed in birth characteristics (birth weight,
birth length, placental weight, maternal age at delivery, or birth
order) comparing the individuals who were traced from birth to
current address (70%) with those who were not traced because of
death(9%), migration(8%), or lossto follow-upfor otherreasons
(13%). These birth characteristics did not differ significantly
between study participants and traced individuals who chose not
to participate (35). In addition, study participation was not as-
sociated with prenatal famine exposure status. Furthermore, the
effect of potential bias from parental characteristics that may be
associated with offspring lipid profile was minimized by our
inclusion of same-sex siblings to control for genetic sources of
such variations. Family controls would also minimize potential
biases arising from the strong association between family so-
cioeconomic status and paternal occupational class and fertility
during the famine, with fertility declining most sharply among
lower class sectors (28).
Our study adds to the literature on the long-term consequences
of exposure to the Dutch famine. First, we collected adult health
outcomes among individuals from institutions not previously
studied. This allows for comparisons with earlier observations
and increases the overall size of Dutch famine populations that
have been located and followed for study. Second, our sibling
controls provide additional opportunities to compare study out-
comes among same-sex siblings discordant for prenatal famine
In conclusion, our findings suggest an association between
profile at age 58 in women. Follow-up studies will show if these
findings are also associated with an increased risk of cardio-
We thank the Vroedvrouwenscholen of Amsterdam and Rotterdam and the
Obstetrics Department of the Leiden University Medical Center in Leiden for
their help in accessing their archives. The clinical examinations were carried
out at the study centerof Gerontology and Geriatrics,LeidenUniversityMed-
ical Center, under the supervision of L de Man.
The authors’ responsibilities were as follows—LHL and ADS: developed
the study hypothesis, designed the study, developed study protocols, and co-
ordinated all data collection activities, and conducted data analysis; LHL:
obtained major funding and wrote initial drafts of the manuscript; and
HSK and JAR: provided advice and consultation. All authors participated
in data interpretation and reviewed and approved the final version of the man-
uscript. None of the authors declared a conflict of interest.
1. Kannel WB. The Framingham Study: its 50-year legacy and future
promise. J Atheroscler Thromb 2000;6:60–6.
2. Criqui MH, Golomb BA. Epidemiologic aspects of lipid abnormalities.
Am J Med 1998;105(suppl1A):48S–57S.
3. Lemieux I, Lamarche B, Couillard C, et al. Total cholesterol/HDL
cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of
ischemic heart disease risk in men: the Quebec Cardiovascular Study.
Arch Intern Med 2001;161:2685–92.
4. Ingelsson E, Schaefer EJ, Contois JH, et al. Clinical utility of different
lipid measures for prediction of coronary heart disease in men and
women. JAMA 2007;298:776–85.
5. Castelli WP. Lipids, risk factors and ischaemic heart disease. Athero-
6. Barker DJ, Martyn CN, Osmond C, Hales CN, Fall CH. Growth in utero
Association of exposure to the Dutch famine during specific 10-wk periods of gestation with adult lipid profile among fasting men and women examined
between 2003 and 20051
Exposed week 31 to
delivery (n ¼ 126)
Exposed weeks 21–30
(n ¼ 141)
Exposed weeks 11–20
(n ¼ 125)
Exposed weeks 1–10
(n ¼ 71)
Estimate 95% CI Estimate 95% CI Estimate95% CIEstimate95% CIP2
HDL cholesterol (mmol/L)
Non-HDL cholesterol (mmol/L)
LDL cholesterol (mmol/L)
1TC, total cholesterol. Values represent differences from unexposed control subjects (294 hospital controls and 308 sibling controls). Estimates were
obtained by linear regression with adjustment for individuals exposed in each specific 10-wk period, age (linear and quadratic terms), sex, cholesterol
medication, and clustering within sibships. Tests for heterogeneity by sex were P ¼ 0.03 for TC:HDL cholesterol and P ? 0.07 for all other outcomes.
2Overall test of association for the 4 periods of exposure considered as a group (Wald test, 4 df).
LUMEY ET AL
7. Ziegler B, Johnsen SP, Thulstrup AM, Engberg M, Lauritzen T, Sorensen
HT. Inverse association between birth weight, birth length and serum total
cholesterol in adulthood. Scand Cardiovasc J 2000;34:584–8.
8. Suzuki T, Minami J, Ohrui M, Ishimitsu T, Matsuoka H. Relationship
between birth weight and cardiovascular risk factors in Japanese young
adults. Am J Hypertens 2000;13:907–13.
9. Mi J, Law C, Zhang KL, Osmond C, Stein C, Barker D. Effects of infant
birthweight and maternal body mass index in pregnancy on components
of the insulin resistance syndrome in China. Ann Intern Med 2000;132:
10. Kawabe H, Shibata H, Hirose H, Tsujioka M, Saito I, Saruta T. Sexual
differences in relationships between birth weight or current body weight
and blood pressure or cholesterol in young Japanese students. Hypertens
11. Mogren I, Hogberg U, Stegmayr B, Lindahl B, Stenlund H. Fetal ex-
posure, heredity and risk indicators for cardiovascular disease in
a Swedish welfare cohort. Int J Epidemiol 2001;30:853–62.
12. Barker DJP. Mothers, babies and disease in later life. London, United
Kingdom: British Medical Journal, 1994.
13. Huxley R, Owen CG, Whincup PH, Cook DG, Colman S, Collins R.
Birth weight and subsequent cholesterol levels: exploration of the ‘‘fetal
origins’’ hypothesis. JAMA 2004;292:2755–64.
14. Fall CH, Barker DJ, Osmond C, Winter PD, Clark PM, Hales CN.
Relation of infant feeding to adult serum cholesterol concentration and
death from ischaemic heart disease. BMJ 1992;304:801–5.
15. Lawlor DA, Davey Smith G, Ebrahim S. Life course influences on in-
sulin resistance: findings from the British Women’s Heart and Health
Study. Diabetes Care 2003;26:97–103.
16. Innis SM. Influence of maternal cholestyramine treatment on cholesterol
and bile acid metabolism in adult offspring. J Nutr 1983;113:2464–70.
17. Naseem SM, Khan MA, Heald FP, Nair PP. The influence of cholesterol
and fat in maternal diet of rats on the development of hepatic cholesterol
metabolism in the offspring. Atherosclerosis 1980;36:1–8.
18. Lucas A, Baker BA, Desai M, Hales CN. Nutrition in pregnant or lac-
tating rats programs lipid metabolism in the offspring. Br J Nutr 1996;
19. Pennington JS, Pennington SN. Rat adult offspring serum lipoproteins
are altered by maternal consumption of a liquid diet. Lipids 2006;41:
20. Stein AD, Zybert PA, van de Bor M, Lumey LH. Intrauterine famine
exposure and body proportions at birth: the Dutch Hunger Winter. Int J
21. Gillman MW. Epidemiological challenges in studying the fetal origins
of adult chronic disease. Int J Epidemiol 2002;31:294–9.
22. Wells J. Commentary: games people play–birthweight. Int J Epidemiol
23. Lumey LH. Reproductive outcomes in women prenatally exposed to
undernutrition: a review of findings from the Dutch famine birth cohort.
Proc Nutr Soc 1998;57:129–35.
24. Stein ZA, Susser M, Saenger G, Marolla F. Famine and human de-
velopment: the Dutch Hunger Winter of 1944–1945. New York, NY:
Oxford University Press, 1975.
25. Burger GCE, Drummond JC, Sandstead HR. Malnutrition and starvation
in western Netherlands, September 1944 to July 1945, Parts I and II
’s-Gravenhage, Netherlands: Staatsuitgeverij, 1948.
26. Lumey LH, Van Poppel FW. The Dutch famine of 1944-45: mortality
and morbidity in past and present generations. Soc Hist Med 1994;7:
27. Trienekens G. The food supply in the Netherlands during the Second
World War. In: Smith DF, Phillips J, eds. Food, science, policy and
regulation in the twentieth century. International and comparative per-
spectives. London, United Kingdom: Routledge, 2000:117–33.
28. Stein Z, Susser M. Fertility, fecundity, famine: food rations in the Dutch
Famine 1944/45 have a causal relation to fertility, and probably to fe-
cundity. Hum Biol 1975;47:131–54.
29. Stein Z, Susser M. The Dutch famine, 1944–1945, and the reproductive
process. I. Effects or six indices at birth. Pediatr Res 1975;9:70–6.
30. Sindram IS. De invloed van ondervoeding op de groei van de vrucht.
½The influence of undernutrition on fetal growth.? Ned Tijdschr Verlosk
Gynaecol 1953;53:30–48 (in Dutch).
31. Stein AD, Ravelli AC, Lumey LH. Famine, third-trimester pregnancy
weight gain, and intrauterine growth: the Dutch Famine Birth Cohort
Study. Hum Biol 1995;67:135–50.
32. Huxley RR, Neil HA. Does maternal nutrition in pregnancy and birth
weight influence levels of CHD risk factors in adult life? Br J Nutr 2004;
33. Stanner SA, Bulmer K, Andres C, et al. Does malnutrition in utero
determine diabetes and coronary heart disease in adulthood? Results
from the Leningrad siege study, a cross sectional study. BMJ 1997;315:
34. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC,
Bleker OP. Plasma lipid profiles in adults after prenatal exposure to the
Dutch famine. Am J Clin Nutr 2000;72:1101–6.
35. Lumey LH, Stein AD, Kahn HS, et al. Cohort profile: the Dutch Hunger
Winter families study. Int J Epidemiol 2007;36:1196–204.
36. Stein AD, Kahn HS, Rundle A, Zybert PA, van der Pal-de Bruin K,
Lumey LH. Anthropometric measures in middle age after exposure to
famine during gestation: evidence from the Dutch famine. Am J Clin
37. Stein AD, Zybert PA, van der Pal-de Bruin K, Lumey LH. Exposure to
famine during gestation, size at birth, and blood pressure at age 59 y:
evidence from the Dutch Famine. Eur J Epidemiol 2006;21:759–65.
38. Stinshoff K, Weisshaar D, Staehler F, Hesse D, Gruber W, Steier E.
Relation between concentrations of free glycerol and triglycerides in
human sera. Clin Chem 1977;23:1029–32.
39. Rifai N, Cole TG, Iannotti E, et al. Assessment of interlaboratory per-
formance in external proficiency testing programs with a direct
HDL-cholesterol assay. Clin Chem 1998;44:1452–8.
40. Sugiuchi H, Uji Y, Okabe H, et al. Direct measurement of high-density
lipoprotein cholesterol in serum with polyethylene glycol-modified en-
zymes and sulfated alpha-cyclodextrin. Clin Chem 1995;41:717–23.
41. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concen-
tration of low-density lipoprotein cholesterol in plasma, without use of
the preparative ultracentrifuge. Clin Chem 1972;18:499–502.
42. Third Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection. EvaluationTreatment of High Blood Cho-
lesterol in Adults (Adult Treatment Panel III) final report. Circulation
43. Allison MA, Budoff MJ, Wong ND, Blumenthal RS, Schreiner PJ,
Criqui MH. Prevalence of and risk factors for subclinical cardiovascular
disease in selected US Hispanic ethnic groups: the Multi-Ethnic Study
of Atherosclerosis. Am J Epidemiol 2008;167:962–9.
44. Kloosterman GJ. On intrauterine growth. The significance of prenatal
care. Int J Gynaecol Obstet 1970;8:895–912.
45. Snijder MB, van Dam RM, Visser M, Seidell JC. What aspects of body
fat are particularly hazardous and how do we measure them? Int J Ep-
factor for unfavourable glucose and lipid levels, independently of high ab-
dominal fat. The Health ABC Study. Diabetologia 2005;48:301–8.
47. Lussana F, Painter RC, Ocke MC, Buller HR, Bossuyt PM, Roseboom
TJ. Prenatal exposure to the Dutch famine is associated with a prefer-
ence for fatty foods and a more atherogenic lipid profile. Am J Clin Nutr
48. Denke MA, Sempos CT, Grundy SM. Excess body weight. An under-
recognized contributor to dyslipidemia in white American women. Arch
Intern Med 1994;154:401–10.
GESTATIONAL FAMINE AND LATER LIPID PROFILE