Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study

Size at birth

Table 2 shows hazard ratios for coronary heart disease according to size at birth. The ratios fell with increasing birth weight, although this was not significant. Hazard ratios were not related to the length of gestation, but adjustment for gestation strengthened the association with birth weight. Hazard ratios fell more steeply with increasing length. The hazard ratio for developing coronary heart disease increased by 10.2% (95% confidence interval 4.3 to 15.7) for each cm decrease in length at birth, adjusted for gestation. There were no trends with head circumference or ponderal index.

Hazard ratios tended to rise with increasing placental weight, although this trend was not significant. There was, however, a significant rise with an increasing ratio of placental weight to birth weight (P=0.01, adjusted for gestation). In a simultaneous analysis with birth weight, placental weight, and gestational age the hazard ratios fell with increasing birth weight (P=0.007) but rose with increasing placental weight (P=0.03). There were stronger trends in a simultaneous analysis of birth length, placental weight, and gestational age, the hazard ratios falling with increasing birth length (P>0.0001) and rising with increasing placental weight (P=0.02). The hazard ratios increased by 13.8% (7.5 to 19.6) for each cm decrease in length at birth and increased by 14.8% (2.6 to 28.3) for each 100 g increase in placental weight. The trends with length and placental weight were similar for fatal and non-fatal disease.

Table 3 shows hazard ratios according to length and placental weight. Because the relative size of the body and placenta change during gestation we excluded preterm babies. Compared with women who were longest at birth but had the lowest placental weight, whose hazard ratio was set at 1.0, the highest ratio, 5.2, was in women who were short at birth but had heavy placentas.

Growth in childhood

At each age from 7 to 15 years the mean heights and weights of women who developed coronary heart disease were below those of all other women. At 7 years, for example, their height was 0.42 cm less and their weight 0.20 kg less. At no age, however, were the differences significant. At birth their length was 0.17 SD below average; while at 7 and 15 years their heights were only 0.08 SD and 0.02 SD below average, respectively. Therefore their heights and weights had largely “caught up” between birth and 15 years. Table 4 shows the combined effects of length at birth and height in childhood on hazard ratios for coronary heart disease. Height at 7 years is used but the findings with all other ages are similar. The hazard ratio for women who were longest at birth and tallest as children is set at 1.0. The fall in risk of coronary heart disease with increasing length at birth was steeper among women who were tallest as girls. This interaction between birth length and childhood height was significant (P=0.02). At no age in childhood was body mass index related to later coronary heart disease.

Maternal characteristics

The mothers' heights and their weights and body mass indices during pregnancy were unrelated to the occurrence of coronary heart disease in their daughters. When, however, we divided the mothers according to their height, using the median height of 1.58 metres as in our previous analysis, we found that the interactive effects of short length at birth and tallness in childhood on coronary heart disease was stronger among the daughters of taller women (P=0.006 for interaction between birth length and height at 7 years in daughters of tall women). As expected, taller mothers tended to have taller daughters, the correlation coefficient between mother's height and daughter's height at 7 years being 0.36.

Crowding in the home and social class during childhood

An examination of the average number of inhabitants and rooms in the homes where the girls grew up showed that 47% of them lived in homes with only one room (see table 1). We used the ratio of the number of inhabitants to the number of rooms as an index of crowding. Table 5 shows that families living in less crowded homes were of higher social class, and the daughters were taller at all ages. Coronary heart disease, however, was unrelated to the number of inhabitants, number of rooms, crowding, or social class in childhood.

Sex differences in fetal growth

In comparison with the men in the cohort the women had smaller head circumferences at birth (34.3 cm v 34.9 cm), shorter body lengths at birth (49.7 cm v 50.2 cm), and lower birth weights (3315 g v 3443 g). Mean placental weights, however, were similar (628 g v 634 g). During childhood the heights and weights of the men and women were similar until adolescence when, as expected, women became shorter and heavier. Table 6, which gives the percentage of girls among term babies according to length at birth and placental weight, shows that the small differences in average body size at birth between the sexes conceal large differences in proportionate size. Short body length in relation to high placental weight, the pattern which predicts coronary heart disease in women (table 3), is much more common among girls than boys (P>0.0001; table 6). In contrast, table 7 shows that thinness at birth in relation to a large head circumference is much more common among boys than girls (P>0.0001); and it is thinness at birth that predicts coronary heart disease in men.

Sex differences in fetal growth and coronary heart disease

In keeping with findings among women in the United Kingdom,1 Sweden,2 the American nurses' study,3 and India15 we found that coronary heart disease among women in the Helsinki cohort was associated with low birth weight (table 2). This trend was of only borderline significance, after adjustment for length of gestation, but it became strongly significant after adjustment for placental weight (table 3). Low birth weight therefore predicts coronary heart disease in both women and men. Our analysis of body proportions at birth, however, has shown that the paths of intrauterine growth that led to low birth weight and later coronary heart disease differed between the two sexes in the same cohort. The women were born short in length while the men were born thin; these associations being much stronger than those with birth weight. Stunting and thinness at birth may represent two different responses to fetal undernutrition, and published findings suggest that the long term consequences of these responses differ. While both have been found to be associated with raised blood pressure in later life,16 17 stunting is associated with persistent changes in liver function, including raised serum cholesterol concentration18 and plasma fibrinogen,19 while thinness is associated with features of the insulin resistance syndrome including impaired glucose tolerance and dyslipidaemia.20

We found that the paths of fetal growth among women and men in this cohort differed. The small sex differences in average body measurements at birth (table 1) concealed large differences in body proportions (tables 6 and 7). Girls tended to be short in relation to their placental size; boys tended to be thin in relation to their head circumference. As the girls and boys were born to the same group of mothers these differences in body proportions must reflect intrinsic differences between the sexes in their paths of growth at similar levels of maternal nutrition. The rate of fetal growth of girls and boys is known to differ from an early stage of gestation, even from before implantation. 10 11 21 Girls grow more slowly. Because different parts of the body grow at different phases of gestation, sex differences in growth rates could lead to differences in body proportions at birth. In animals the rate of intrauterine growth is known to modify the effects of a brief period of maternal undernutrition on the offspring's body composition at birth.2223

Sex differences in childhood growth and coronary heart disease

In both women and men the effects of reduced fetal growth on the risk of coronary heart disease were increased by accelerated or “catch up” growth. Among women the effect of being short at birth was greatest in those who were tall in childhood (table 4). Men who were thin at birth increased their risk by having an above average body mass index in childhood. The risk among women was not influenced by body mass in childhood, and risk among men was not influenced by height. In our previous report we discussed several possible reasons why catch up growth could be associated with adverse outcomes in later life.9 One speculation is based on the observation that restricted fetal growth leads to permanently reduced cell numbers in tissues such as kidney, in which there is no further cell replication after birth.24 Postnatal catch up growth could be deleterious either because overgrowth of a limited cell mass disrupts cell function or because large body size imposes an excessive metabolic demand on a limited cell mass.

The childhood heights of the women were related to their mothers' heights, and the interaction between short length at birth and tallness in childhood in increasing the risk of coronary heart disease was stronger in the daughters of taller mothers. This could reflect both nutritional and genetic influences, the nutritional benefits associated with a taller, heavier mother being either direct effects during lactation or better availability of food after weaning. We used the level of crowding in the home as an index of living conditions. Women who grew up in less crowded homes were taller at all ages. The level of crowding was not, however, related to later coronary heart disease (table 5). Our findings therefore suggest that it is good nutrition and genetic influences rather than living conditions and low rates of infection that lead to catch up growth in height and increased risk of later coronary heart disease in women. A similar suggestion came from our analyses of the men, among whom catch up in weight was associated with high maternal body mass.9 We conclude that coronary heart disease among both the women and men in our study reflected poor prenatal nutrition combined with improved postnatal nutrition.

Sex differences in coronary heart disease

We have found that coronary heart disease among women and men is associated with the body proportions at birth that distinguish the two sexes. Women who develop coronary heart disease were short at birth, particularly in relation to placental weight; the men were thin. It has been suggested that the growth of every human fetus is constrained by the mother through her limited capacity to deliver nutrients to it.25 In the light of this, coronary disease could represent the outcome of more severe constraint to which female and male fetuses respond differently because female fetuses grow more slowly. By the time of birth the girls have become short and the boys thin. The long term changes in physiology and metabolism associated with shortness and thinness at birth are different, and so too it seems are the adverse effects of catch up growth in height and weight during childhood. The lower rates of coronary heart disease among women may originate in their slower rates of growth in utero.