The Leningrad Siege Study investigated the relationship between decreased maternal food intake and risk factors for coronary heart disease in adult life. The study screened 169 subjects exposed to intrauterine starvation during the Siege of Leningrad (now St Petersburg) 1941–4, 192 subjects born in Leningrad before the siege and 188 subjects born concurrently with these two groups but outside the area of the siege. No difference was found between the subjects exposed to starvation in utero and during infancy in glucose tolerance [in utero: 5.2 mmol/l (95% confidence interval 5.1 to 5.3; infancy: 5.3 (5.1 to 5.5), p = 0.94], insulin concentration, blood pressure, lipid concentration or coagulation factors. The intrauterine exposed group had evidence of endothelial dysfunction by higher concentrations of von Willebrand factor and a stronger interaction between adult obesity and blood pressure. Non-systematic differences in subscapular to triceps skinfold ratio, diastolic blood pressure and clotting factors were demonstrated compared to the non-exposed groups. In conclusion, this study did not find an association between intrauterine starvation and glucose intolerance, dyslipidaemia, hypertension or cardiovascular disease in adult life. These findings differ from studies of subjects exposed to maternal starvation during the Dutch Hunger Winter. However, the dissimilar effects of exposure to the two famines may contribute to our understanding of the mechanisms of the ‘thrifty phenotype’ and support the importance of catch-up growth during early childhood, a situation that occurred in the Netherlands but not in Leningrad.

People who were small at birth have been shown to have an increased risk of CHD and chronic bronchitis in later life. These findings have led to the fetal origins hypothesis that proposes that the fetus adapts to a limited supply of nutrients, and in doing so it permanently alters its physiology and metabolism, which could increase its risk of disease in later life. The Dutch famine — though a historical disaster — provides a unique opportunity to study effects of undernutrition during gestation in humans. People who had been exposed to famine in late or mid gestation had reduced glucose tolerance. Whereas people exposed to famine in early gestation had a more atherogenic lipid profile, somewhat higher fibrinogen concentrations and reduced plasma concentrations of factor VII, a higher BMI and they appeared to have a higher risk of CHD. Though the latter was based on small numbers, as could be expected from the relatively young age of the cohort. Nevertheless, this is the first evidence in humans that maternal undernutrition during gestation is linked with the risk of CHD in later life. Our findings broadly support the hypothesis that chronic diseases originate through adaptations made by the fetus in response to undernutrition. The long-term effects of intrauterine undernutrition, however, depend upon its timing during gestation and on the tissues and systems undergoing critical periods of development at that time. Furthermore, our findings suggest that maternal malnutrition during gestation may permanently affect adult health without affecting the size of the baby at birth. This gives the fetal origins hypothesis a new dimension. It may imply that adaptations that enable the fetus to continue to grow may nevertheless have adverse consequences for health in later life. CHD may be viewed as the price paid for successful adaptations to an adverse intra-uterine environment. It also implies that the long-term consequences of improved nutrition of pregnant women will be underestimated if these are solely based on the size of the baby at birth. We need to know more 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 a pregnancy. This should be exploited to improve the health of future generations.

Some, albeit not all studies on the relationship between intrauterine growth retardation (IUGR) and female pubertal development have found an earlier and rapidly progressing puberty as well as concomitant disorders of related functional systems such as polycystic ovary syndrome and short stature. These pubertal changes are part of a growing list of IUGR-related diseases, which includes non-insulin dependent diabetes mellitus and coronary heart disease. A pulsatile release of gonadotropin releasing hormone is thought to be a conditio-sinne-qua-non for the initiation of puberty. In the absence of prospective studies on gonadotropin releasing hormone pulse patterns in IUGR-children other markers of pubertal development such as age at menarche have been deployed. From these studies it is not clear, however, whether the findings of an earlier onset of puberty in IUGR-girls merely reflect a more rapid progression of puberty. Both the role for IUGR and the mechanisms behind the onset of puberty are still elusive. Assuming a connection between IUGR and pubertal development, parallels can be drawn between hypotheses on the longterm consequences of IUGR and hypotheses on the initiation of puberty. For example, the somatometer concept proposes a role for fat mass in the initiation of puberty, which is compatible with the hypothesis on non-skeletal catch-up growth after IUGR. The debate on the origins of puberty and the role of IUGR mainly focuses on nature and nurture. Judgmentally, studies in mono- and dizygotic twins discordant for birth weight may be of particular help.

Several common adult diseases appear to be related to impaired fetal growth and this may be caused either by nutritional inadequacies at particular stages of pregnancy or by variation in alleles at specific growth loci. Little is known about the genes involved in the underlying mechanism. This review proposes that at least some of the effects have their origins at imprinted loci, genes that are unusual because they are expressed from only one parental allele. Many imprinted genes are crucial for fetal growth and determine birthweight. They can be disrupted in the early embryo by environmental influences and these disruptions can be inherited through many cell cycles into adult tissues. Their disruption can affect specific organs during fetal development and disruption could affect adult disease in a variety of direct and indirect means. Imprinted genes may be particularly vulnerable to disruption as they are functionally haploid and their expression is regulated by different means from the rest of the genome. Thus many imprinted genes provide plausible candidates for programming adult disease and warrant further study in this context.

Three recent studies reported that early depletion of the primordial follicle pool is likely to be an independent risk factor for Down's syndrome pregnancies. The size of the primordial follicle pool at birth is determined by oogenesis and by the rate of follicle atresia during the intra uterine period. Since intra uterine growth retardation was reported to be associated with a significantly reduced primordial follicle pool at birth, we investigated the possibility of a relation between low birth weight for gestational age and the risk of a Down's syndrome pregnancy. In a case control study, 95 women with a history of a Down's syndrome pregnancy and 85 controls provided information on their own birth weight and length of gestation. Birth weight standard deviation scores, indicating the difference in birth weight from a reference group, were significantly lower in Down's syndrome mothers than in controls. These findings illustrate that the risk of a Down's syndrome pregnancy is related to a low birth weight corrected for gestational age, possibly by a causal relation between intra uterine growth retardation and the size of the primordial follicle pool

Twin studies have a contribution to make to the debate concerning the foetal origins of adult disease. Twins are growth retarded compared to singletons and experience post-natal catch-up growth. However, there is no evidence that twins are at increased risk of cardiovascular disease. Studying whether discordance in size at birth within monozygotic twin pairs is predictive of discordance in later life disease should help resolve whether the association between size at birth and later disease is due to common genetic factors. Results from studies of blood pressure in childhood and adult life looking at these within twin effects are far from conclusive. There are, however, methodological problems in the interpretation of these results, not least of which is the relatively small numbers of twin pairs studied. Studies exploring the effect of zygosity and chorion type on later disease provide may provide a useful extension of the research agenda. In summary, twin studies to date have raised more questions about the foetal origins hypothesis than they have resolved.

Although there is substantial evidence from studies of singletons that small size at birth is linked with long-term adverse health effects, until recently little was known as to whether these associations extend to twins. A review of published studies suggests that at present there is little consistent evidence that birthsize in twins is associated with increased morbidity or morality. While, these findings may reflect methodological limitations, it is also argued that they arise as a consequence of the substantially different biology of fetal growth in twins.

In this study we examine the hypothesis that monozygotic (MZ) twins in historical databases are less discordant for birth weight due to negative selection of severely discordant MZ twins. Furthermore, we test the hypothesis that MZ twins are less discordant for birth weight when comparing a volunteer based twin registry with a population based twin registry, due to selective registration. Data were available on 3927 twin pairs from the volunteer Australian Twin Registry born before 1964, 3059 volunteer twin pairs from the Netherlands Twin Register born 1987–1989 and 454 Belgian twin pairs from The East Flanders Prospective Twin Survey born 1987–1989. Intrapair relative birth weight differences (RBWD) were computed for MZ and dizygotic (DZ) twins from each twin registry. Comparing birth weight differences between MZ and DZ twins provides support for the hypothesis that MZ twins are subject to a negative selection in historical databases. Furthermore, Australian MZ twins have a lower RBWD compared to Dutch MZ twins when corrected for the RBWD of Australian and Dutch DZ twins, indicating circumstances which only affect MZ twins. Our hypothesis that MZ twins are less discordant for birth weight in a volunteer based twin registry compared to a population based twin registry had to be rejected. We suggest that investigators using historical databases to test the fetal origins hypothesis should be aware of this increased likelihood of selective exclusion of individuals with extreme morphometric parameters at time of birth.

Epidemiological studies have consistently shown a positive association between size at birth (i.e. birth weight or birth length) and height in children, adolescents and adults. To examine whether this association is explained by genetic or nongenetic (intra-uterine) factors, we investigated birth weight, birth length and height in 60 dizygotic and 68 monozygotic adolescent twin pairs still living with their parents. Birth weight of the twins was obtained from their mothers. Height was measured in a standardised way. The mean age was 17±1.7 years for the dizygotic twins and 16±1.8 years for the monozygotic twins. Both dizygotic and monozygotic twins with the lowest birth weight from each pair had a height that was lower compared to their co-twins with the highest birth weight (dizygotic twins: 172.2±7.9 vs. 173.8±9.4 cm [p = 0.05]; monozygotic twins: 171.1±9.4 vs. 171.8±9.5 cm [p = 0.01]). Similarly, both dizygotic and monozygotic twins with the shortest birth length from each pair had a height that was lower compared to their co-twins with the longest birth length (dizygotic twins: 172.3±7.9 vs. 174.9±9.7 cm [p < 0.05]; monozygotic twins: 168.9±10.6 vs. 169.9±10.2 cm [p < 0.01]). In addition, intra-pair differences in birth weight and birth length were significantly associated with differences in height in both dizygotic twins (regression coefficient: 4.3 cm/kg [95% confidence interval: 1.0 to 7.5] and 0.96 cm/cm [0.17 to 1.74], respectively) and monozygotic twins (2.8 cm/kg [1.4 to 4.1] and 0.73 cm/cm [0.40 to 1.06], respectively). These associations were stronger in dizygotic than in monozygotic twins, but this difference was not statistically significant (for birth weight p = 0.4; and for birth length p = 0.6). However, genetic model fitting indicated that models incorporating a genetic source of the covariance gave a better description of the observed association of birth weight and length with height in later life than models not incorporating this genetic source. The results were similar for data on adult height after 12 years of follow-up in a subgroup of these twin pairs. These data suggest that the association between size at birth and height in later life is influenced by non-genetic intra-uterine and by genetic factors.

The intrauterine growth patterns for twins are characterized by normal development during the first two trimesters and reduced growth during the third trimester. According to the fetal origins hypothesis this growth pattern is associated with risk factors for cardiovascular morbidity and mortality. We studied cause-specific mortality of 19,986 Danish twin individuals from the birth cohorts 1870–1930 followed from 1952 through 1993. Despite the large sample size and follow-up period we were not able to detect any difference between twins and the general population with regard to all-cause mortality or cardiovascular mortality. Hence, the intrauterine growth retardation experienced by twins does not result in any “fetal programming” of cardiovascular diseases. There is still an important role for twins (and other sibs) to play in the testing of the fetal origins hypothesis, namely in studies of intra-pair differences, which can assess the role of genetic confounding in the association between fetal growth and later health outcome.

Several epidemiological and metabolic studies have demonstrated an impact of the intrauterine environment on the development of disease in adult life, including Type 2 diabetes and glucose intolerance. Our finding of lower birth weights among monozygotic diabetic twins compared to their non-diabetic genetically identical co-twins confirms this association and, furthermore, eliminates the possibility that the association could be explained solely by common genes leading to both impaired intrauterine growth and increased risk of Type 2 diabetes. Due to an often shared placenta monozygotic twins may experience a more adverse intrauterine environment compared to dizygotic twins and may therefore be more prone to develop various metabolic abnormalities. Our findings of a higher glucose and insulin profile after oral glucose ingestion, and recently lower insulin-stimulated glucose uptake — indicating glucose intolerance and insulin resistance — among monozygotic compared to dizygotic twins may to some extent question the validity of classical twin studies in diabetes research where equal environmental influences in monozygotic and dizygotic twins is assumed. The potential role of an adverse intrauterine environment in causing Type 2 diabetes in humans, may to some degree alter our conception of the twin model in diabetes research including the interpretation of aetiological conclusions reached in previous classical twin studies of diabetes. However, our present knowledge is far too insufficient to discard the results from classical twin studies concerning the relative role of genes versus environment for the development of diabetes and its metabolic effects.

An adverse intra-uterine environment has been associated with abdominal fat distribution in singletons. Twins often have a low birth weight and a short gestation. Therefore, they may have an increased risk to develop abdominal obesity. Furthermore, monozygotic monochorionic twins (MZ MC) have a larger intra-pair birth weight difference compared to monozygotic dichorionic twins (MZ DC). If adult anthropometry is programmed in utero, this may affect the intra-pair correlations in adulthood and, consequently, also the results from the classic twin method to estimate genetic and environmental influences. In the present study, we compared the absolute values, the intra-pair differences, and the intra-pair correlations of body mass, height, BMI, and abdominal fat distribution of 424 MZ MC, MZ DC and dizygotic (DZ) twin pairs (aged 18–34 yrs). DZ, MZ DC and MZ MC twins did not differ for most anthropometric characteristics. Only MZ women tended (p = 0.03) to accumulate more abdominal fat compared to DZ twins. Overall, the contribution of zygosity and chorion type to adult anthropometry was rather low (≤ 1.7%). Although the intra-pair birth weight difference of MZ MC pairs (10.5% in men, 12.3% in women) was significantly larger compared to that of MZ DC pairs (6.9% and 9.2% resp.), the intra-pair differences in adult anthropometry were similar for both MZ twin types. Also the intra-pair correlations of MZ MC and MZ DC pairs were strikingly alike, suggesting no significant influence of the prenatal environment on adult concordance. In conclusion, the substantial difference in the prenatal environment of MZ MC and MZ DC twins did not result in a difference in intra-pair concordance of adult anthropometry and fat distribution. Therefore, we suggest that the chorion type of MZ twins does not bias the twin design and the estimation of the genetic contribution to adult anthropometry.

Birthweight affects neonatal mortality and morbidity and has been used as a marker of foetal undernutrition in studies of prenatal effects on adult characteristics. It is potentially influenced by genetic and environmental influences on the mother, and effects of foetal genotype, which is partially derived from the maternal genotype. Interpretations of variation in birthweight and associated characteristics as being due to prenatal environment ignore other possible modes of materno-foetal transmission. Subjects were adult twins recruited through the Australian Twin Registry, aged 17 to 87 years, and the sample comprised 1820 men and 4048 women. Twins reported their own birthweight as part of a health questionnaire. Body Mass Index (BMI) was calculated from self-reports of height and weight. Correlations between co-twins' birthweights were high for both monozygotic (r = 0.77) and dizygotic (r = 0.67) pairs, leading to substantial estimates of shared environmental effects (56% of variance) with significant additive genetic (23%) and non-shared environmental (21%) components. Adult BMI was mainly influenced by genetic factors, both additive (36% of variance) and nonadditive (35%). The correlation between birthweight and BMI was positive, in that heavier babies became on average more obese adults. A bivariate model of birthweight and adult BMI showed significant positive genetic (rg = 0.16, p = 0.005) and environmental (re = 0.08, p = 0.000011) correlations. Intra-uterine environmental or perinatal influences shared by cotwins exercise a strong influence on birthweight, but the factors which affect both birthweight and adult BMI are partly genetic and partly non-shared environmental.

Aclearer understanding of the early determinants of normal and abnormal vascular development is pivotal in order to identify those at increased risk of later vascular disease, and perhaps to prevent it by early intervention. Measurement of pulse wave velocity(PWV) has been used in the postnatal evaluation of the monochorionic(MC) twins. They are genetically identical and those with twin-twin transfusion syndrome(TTTS) provide an ideal natural model in whom to study the influence of differing haemodynamic stresses on the developing vascular tree. We investigated firstly whether surviving twin pairs with TTTS have altered arterial distensibility in childhood by comparing PWV in the radial arteries of surviving MC twin pairs with TTTS and in two control groups, one cohort of MC twins without TTTS and another dichorionic group (DC) Secondly, we tested a cohort of TTTS twin pair survivors treated with laser photocoagulation. The co-twin pairs in the group managed palliatively with amnioreduction showed increased PWV in the donor and reduced PWV in the recipient twins. This was neither seen in the laser-treated, nor in the control groups. Our studies suggest that a period of haemodynamic imbalance gives rise to changes in a muscular conduit artery that persist at least into infancy and it seems that by correcting the abnormal haemodynamics relatively soon after the disease process had begun, the alterations in elasticity are prevented. These studies are the first to demonstrate fetal programming of the vascular bed in humans, and prevention or reversal of this programming by an intervention in mid-gestation.

It has been proposed that low birth weight is associated with high levels of blood pressure in later life. The aim of this study was to assess the relationship of blood pressure to birth weight and current body size during growth and adulthood. A total of 711 female multiple births, with one group of 244 in their growth phase mean age 12.0 (2.3)(SD) years and the other of 467 adults (mean age 35.2 (12.6) years), had height, weight and both systolic (SBP) and diastolic (DBP) blood pressures measured, and self-reported their birth weight. Regression analyses were performed to assess the cross-sectional and within-pair associations of blood pressure to birth weight, with and without adjustments for current body size. Within-pair analysis was based on 296 twin pairs. Cross-sectionally, a reduction in birth weight of 1 kg was associated with 2 to 3 mm Hg higher age-adjusted SBP, which was of marginal significance and explained about 2% of the population variance. Adjustment for body mass index did not significantly change this association. Within-pair analyses found no association between birth weight and SBP or DBP, even after adjusting for current body size. After age, current body size was the strongest predictor of systolic BP. The weak association of blood pressure to birth weight cross-sectionally is of interest, but any within-pair effect of birth weight on blood pressure must be minimal compared with the effect of current body size.

The hypothesis was tested that monozygotic (MZ) and dizygotic (DZ) twins, with their lower average birth weight, have higher adult blood pressure than their singleton brothers or sisters. From the Netherlands Twin Registry, 261 twin families were recruited from a young adult and an older adult cohort with mean ages of 26.2 and 50.4 respectively. These families yielded 204 MZ twins with 71 singleton siblings and 271 DZ twins with 103 of their singleton siblings. Anti-hypertensive medication use of these 649 participants was assessed twice with a two-year interval. Resting blood pressure was measured thrice during a standardized laboratory protocol. In spite of a significant difference in birth weight (1036 gram), no differences were found in anti-hypertensive medication use at both time points between twins and singletons nor between their resting laboratory diastolic or systolic blood pressure. These results applied to each gender and to both age cohorts. Limiting the analyses to matched twin-sibling pairs of the same families and taking current weight and height into account did not change the results; no evidence was found for a twin-singleton difference. It was concluded that estimates of genetic and environmental contributions to blood pressure deriving from twin studies do not appear to be biased and may be generalized to singletons. Our results suggest that the lower birth weight in twins does not reflect the intrauterine disadvantage described by the Barker hypothesis.

Previous studies have suggested that perinatal factors influence the risk for asthma but population studies on perinatal factors and risk for hay fever are few. We studied the effect of perinatal factors on the risk for hay fever among adolescent twins by a questionnaire study involving five consecutive nation-wide birth cohorts of 16-year-old twins and their parents. The risk for parent-reported, doctor-diagnosed hay fever in the adolescents associated with several perinatal characteristics was assessed with logistic regression analysis among individuals and by a discordant pair analysis. In the univariate analysis of the birth factors, the risk for hay fever increased with increasing birth weight (p for trend = 0.048, OR for those ≥ 3000g 1.35, 95% CI 0.91–2.02 compared to those < 2000g) and gestational age (p for trend = 0.04, OR for those born after 40 weeks of gestation 2.24, 95% CI 1.03–4.86, compared to those born before 33 weeks of gestation) and was lower in those subjects hospitalised in the neonatal period (OR 0.74, 95% CI 0.58–0.93). Because of significant interactions between parental hay fever status and birth factors (ponderal index, p = 0.03 and maternal age p = 0.04), stratified analysis were performed. The positive association between birth weight and hay fever was most obvious among adolescents with no parental history of hay fever (p for trend = 0.03). Similar, though not significant, trends were found with other birth factors among these families, whereas no such trend was found among adolescents with parental hay fever, suggesting that gestational maturity increases the risk for hay fever in the absence of genetic predisposition. However, of the perinatal factors only neonatal hospitalisation (OR 0.75, 95% CI 0.59–0.96) remained a significant risk factor for the development of hay fever, when adjusted for non-perinatal factors.

Many studies have found an inverse association between fetal growth and cardiovascular disease related to the metabolic syndrome in adulthood. Nevertheless, the relative importance of genetics and the intrauterine environment remain unclear. The objective of the study was to test the fetal origins hypothesis and the fetal insulin resistance hypothesis by studying the impact of fetal growth on Body Mass Index (BMI) in young adulthood. In a nationwide cohort study, the Swedish Medical Birth Register for the years 1973–1979 was linked with the Military Service Conscription Register for 1990–1999. In 1998 a questionnaire was mailed to all male twins, included in the two registers, who were alive and still resident in Sweden. The study covers the 923 male twin pairs for which full data were available. Mixed linear models were used to estimate within-pair and between-pair differences in birthweight and their relations to BMI. A weak positive association was found among the monozygotic twins for the withinpair difference in birthweight and BMI. No significant association was found among the monozygotic for the between-pair difference in birthweight and BMI. No significant associations were found for dizygotic twins. These findings do not seem to support either the fetal programming hypothesis or the fetal insulin resistance hypothesis.