Fetal exposure, heredity and risk indicators for cardiovascular disease in a Swedish welfare cohort

Ingrid Mogrena,b, Ulf Högberga,b, Birgitta Stegmayrc, Bernt Lindahld and Hans Stenlundb

a Department of Clinical Science, Obstetrics and Gynecology,
b Department of Public Health and Clinical Medicine, Epidemiology,
c Department of Public Health and Clinical Medicine, Medicine and
d Department of Public Health and Clinical Medicine, Behavioural Medicine, Umeå University, S-90185 Umeå, Sweden.

Abstract

Background The overall aim was to test whether low birthweight (LBW) in newborns is associated with the risk indicators for cardiovascular disease in early middle age, even in a welfare society. Further, a possible interaction of LBW and heredity for myocardial infarction or stroke was investigated.

Methods Overall, subjects were identified as newborns in a local birth register, and as adult participants, in the Västerbotten Intervention Program (n = 7876). Outcome measures such as systolic (SBP) and diastolic blood pressures (DBP), body mass index (BMI), cholesterol, triglycerides and anthropometrics were investigated (at age 29–41 years) in relation to LBW.

Results Low birthweight was associated with increased SBP and DBP. Triglycerides were elevated among women with LBW and total cholesterol was elevated in men with LBW. Heredity for myocardial infarction or stroke interacted with LBW, and indicated a synergistic effect on the level of SBP. The BMI did not differ between LBW and normal birthweight subjects.

Conclusions Our interpretation is that the ‘fetal origins’ hypothesis' is valid for middle-age subjects who grow up in a welfare society. The population attributable proportions that result from different exposures to LBW were relatively small overall; from a public health perspective, heredity was more important than LBW for elevated SBP.

Keywords Low birthweight, prenatal-exposure delayed effects, hypertension, cholesterol, triglycerides

Accepted 21 December 2000

As early as 1934 Kermack et al. published a paper which drew attention to the relation between infant mortality and future adult mortality rates, and indicated ‘their possible significance in interpreting the past and predicting the future’.1 In 1977 Forsdahl reported a close concordance between infant mortality rates in different Norwegian regions and life expectancy of adults in the same areas 50–60 years later.2 Barker et al. further explored what today is called the ‘Barker theory’ or the ‘fetal origins’ hypothesis', which states that physiological or metabolic ‘programming’ occurs at critical periods of early development and substantially determines the occurrence of pathological phenomena in later life.3 Several studies have tested the programming hypothesis, suggesting that fetal and early childhood growth causally determine the occurrence of adult chronic diseases such as coronary heart disease, stroke, hypertension and diabetes mellitus, among others.38 The early events enhance the risk of these chronic diseases, implying that both fetal and childhood effects, as well as adult lifestyles, contribute to these conditions.9 Children who in utero responded to a limited nutrient supply by reducing their fetal growth rates may be less able to adapt to modern Western lifestyles.9 Barker et al. have also proposed an alternative explanation for the relation between adverse fetal outcome and the risk for cardiovascular disease in later adult life: genetic influences that first show themselves in early life as growth failure are revealed in later adult life as degenerative disease.10

The main critiques of the methodologies of previous studies concern selection bias, inconsistencies within and across studies and socioeconomic confounding.7,1113 The interpretation of the observed associations in the ecological studies have been questioned because of possible considerable confounding by persisting geographical differentials in social and economic conditions.7,11,14,15 However, recent Swedish findings support the association of failure to realise growth potential in utero with blood pressure (later in life) and mortality from ischaemic heart disease.1618 The discussion today more focuses on how important this probable association is in terms of public health impact.19

The overall aim of the study was to test whether low birthweight (LBW) was associated with risk indicators for cardiovascular disease later in life, even in a welfare society. The specific aim was to examine the association of variations of length and weight at birth with risk indicators for cardiovascular disease in early middle age. Further, the aim was to address the still unsettled question of whether heredity is the common denominator in the association between adverse intrauterine environment and later adult disease.

Subjects and Methods

The Local Birth Register
Data from ledgers at delivery units in the counties of Västerbotten and Västernorrland for deliveries occurring from 1955 to 1972 were retrospectively collected by a unit connected to Umeå University. This register includes 123 819 births and is currently managed by the National Board of Health and Welfare (NBHW) in Sweden. Information was available on maternal age, parity, maternal diagnoses during pregnancy and delivery, diagnoses of the child, and birthweight >=2500 g or <2500 g.

The Västerbotten Intervention Program (VIP)
Since 1985 in the county of Västerbotten in Northern Sweden, there has been an ongoing community intervention programme on cardiovascular disease and diabetes: the Västerbotten Intervention Program. As a part of this programme all men and women are invited to a health survey at the age of 30, 40, 50 and 60 years. The methodologies used to collect data are described in detail elsewhere.2022

The sample
Figure 1Go shows that the individuals participating in the VIP were identified in the local registry of births from 1955 to 1972 in Västerbotten county. Subjects included in the sample were born 1955–1966 and each subject was aged 29–41 years when examined in the VIP during 1985–1997. Of the 7876 subjects identified, 3932 were males and 3944 were females (Figure 1Go). Age at examination is shown in Figure 2Go. The available information is presented in Table 1Go.



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Figure 1 Local Birth Register—Västerbotten Intervention Program sample

 


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Figure 2 Age at examination in the Västerbotten Intervention Program n = 7876

 

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Table 1 Available information
 
A subsample was constructed by extracting information on birthweight (g) and birth length (cm) from birth records in the archives of the University Hospital of Umeå. Data on birthweight was available for 2661 subjects: 1326 males and 1335 females. Birth length was available for 2479 subjects: 1240 males and 1239 females. Information on both birthweight and birth length was available for 2478 subjects. Information on gestational age was only available for 521 subjects.

Definitions
Low birthweight (LBW) was defined as birthweight <2500 g.

Normal birthweight (NBW) was defined as birthweight >=2500 g.

Systolic blood pressure (SBP) was categorized as high at >=160 mmHg in accordance with WHO criteria, and moderately elevated SBP was categorized as >=140 mmHg.

Diastolic blood pressure (DBP) was categorized as high at >=95mmHg in accordance with WHO criteria, and moderately elevated DBP was categorized as >=90 mmHg.

Total cholesterol was categorized as high total cholesterol (>=7.8 mmol/l) and moderately elevated total cholesterol (>=6.5 mmol/l).

Body mass index (BMI) was defined as weight (kg)/height (m2) and categorized as obesity (>=30.0 kg/m2) or overweight (>=25.0 kg/m2).

Heredity for myocardial infarction or stroke was defined as having a parent or sibling with an event of myocardial infarction or stroke before the age 60 years.

Pre-eclampsia or hypertension during pregnancy was defined according to the International Classification of Diseases (ICD-8 codes: 637.00, 637.01, 637.02, 637.03, 637.04, 637.09, 637.10, 637.99, 639.01, 639.09, 661.2).

Education was categorized as either education at university level or lower than university.

High attained height was defined as height >=179 centimetres for male subjects and height >=166 cm for female subjects. The cut-off point corresponded approximately to the mean height among the subjects and was further considered to represent an expressed potential of growth post-partum.17

Statistical methods
Non-parametric two-independent-samples testing was used to test the difference between groups. Odds ratios and their corresponding 95% CI were calculated by using logistic regression in univariate and multivariate analyses.

Interaction was estimated through calculation of synergy index (SI) (SI = RRAB – 1/[RRAb – 1] + [RRaB – 1]), as proposed by Rothman,23 and etiological fraction for synergy (EFSI = [SI – 1/SI] x [RRAB – 1/RRAB]). A corresponding 95% CI was estimated for synergy index.

The population attributable proportion (PAP = p(RR – 1)/ [1 + p(RR – 1)], p = the proportion of people exposed in the population), which is the proportion of cases in the population that should not have occurred, had the incidence of the outcome among those who were exposed been the same as for those who were unexposed, was calculated when appropriate.

Bivariate correlation was investigated with Pearson's correlation coefficient.

The Statistical Package for Social Sciences, Version 8.0 (SPSS 1997), and EpiInfo, Version 6.04B (1997), were used for statistical calculations.

Results

The mean SBP and triglycerides were elevated in females with LBW in comparison with females with NBW. Total cholesterol was elevated in male subjects with LBW in comparison to NBW subjects. Mean adult weight and adult height were lower for subjects born with LBW (Table 2Go). In logistic regression, LBW for females was associated with increased risks for high and moderately elevated SBP, and male LBW was associated with increased high DBP (Tables 3a and 3bGoGo).


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Table 2 Test for difference between groups for specified outcome variables between birthweight >=2500 g or <2500 g for each sex
 

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Table 3a Male subjects. Odds ratio (OR) and its 95% CI for specified outcome variables in relation to birthweight <2500 g (low birthweight LBW). Birthweight >=2500 g used as the reference group. Population attributable proportiona (PAP, in %) calculated when appropriate
 

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Table 3b Female subjects. Odds ratio (OR) and its 95% CI for specified outcome variables in relation to birthweight <2500 g (low birthweight LBW). Birthweight >=2500 g used as the reference group. Population attributable proportiona (PAP, in %) calculated when appropriate
 
In NBW subjects, heredity for myocardial infarction or stroke increased the risk of elevated SBP and DBP, increased the odds ratios for elevated BMI and moderately elevated level of cholesterol, in comparison to NBW subjects without heredity for myocardial infarction or stroke (Table 4Go). In analyses of the interaction of LBW and heredity for myocardial infarction or stroke (both sexes included in analyses), there appeared to be a probable synergistic effect on SBP and probably on DBP (Tables 4 and 5GoGo).


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Table 4 Odds ratio (OR) and its 95% CI for specified risk category and outcome variable. Population attributable proportiona (PAP, in %) calculated when appropriate
 

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Table 5 Odds ratio (OR) and its 95% CI for specified risk categories in relation to systolic blood pressure >=140 mmHg. Population attributable proportion (PAP, in %) calculated when appropriate. Synergy index and etiological fraction for synergy are provided
 
The estimates and their CI generally differed only slightly—and in many cases the association was strengthened, when adjustment for educational level, BMI, age, pre-eclampsia or heredity for myocardial infarction or stroke was performed in bivariate and multivariate logistic regression (Tables 3a and 3bGoGo). Interaction between LBW and pre-eclampsia or hypertension during pregnancy (both sexes included in analyses) was analysed in logistic regression, where a probable synergistic effect was found on SBP >=160 mmHg (Table 6Go). The indicated association was further strengthened when adjusted for heredity for myocardial infarction or stroke (Table 7Go).


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Table 6 Odds ratio (OR) and its 95% CI for specified risk category and outcome variable. Population attributable proportiona (PAP, in %) calculated when appropriate
 

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Table 7 Odds ratio (OR) and its 95% CI for specified risk category in relation to systolic blood pressure >=160 mmHg with adjustment for heredity for myocardial infarction or stroke. Synergy index and etiological fraction for synergy are provided
 
In logistic regression, LBW and high attained height (>=179 cm) for male subjects demonstrated an increased odds ratio for SBP >=160 mmHg (OR = 5.54, 95% CI : 1.23–24.89) in comparison with NBW and high attained height. The risk for total cholesterol >=7.8 mmol/l was elevated for subjects with NBW and height <179 cm (OR = 1.69, 95% CI : 1.13–2.52) and was further increased for subjects with LBW and high attained height (OR = 2.80, 95% CI : 0.84–9.34). Female subjects with LBW and height <166 cm had an increased risk for SBP >=160 mmHg (OR = 8.91, 95% CI : 2.69–29.44), for SBP >=140 mmHg (OR = 3.02, 95% CI : 1.54–5.89) and for total cholesterol >=6.5 mmol/l (OR = 2.19, 95% CI : 1.18–4.03) in relation to NBW and high attained height.

Nineteen per cent of subjects with NBW were educated at university compared with 17.5% of LBW subjects.

In the subsample the mean birthweight was 3502 g (SD 531) for males and 3394 g (SD 506) for females. Correlations were seen between birthweight and adult weight (r = 0.171, P < 0.001), birthweight and height (r = 0.256, P < 0.001), birth length and adult weight (r = 0.213, P < 0.001), and birth length and height (r = 0.336, P < 0.001). Birth length was weakly, positively correlated to DBP (r = 0.048, P < 0.01).

Discussion

We found that LBW was associated with increased SBP and DBP in early middle age. The level of triglycerides was elevated among women with LBW and total cholesterol was elevated in men with LBW. Heredity for myocardial infarction or stroke exerted its own effect and interacted with LBW, demonstrating a probable synergistic effect on the level of SBP, and probably on DBP. Pre-eclampsia or hypertension during pregnancy also probably interacted with LBW and increased the risk for hypertension in early middle age.

A quality control assessment of the contents of the local birth register has been performed.24 The distribution of sex was almost the reverse quotient in relation to the original birth register, where there was a slight dominance of male subjects. It is well known that females more willingly participate in population surveys than do males; however, we do not consider there to be any major bias concerning this condition.

Subjects in the VIP represent a population-based cohort. The participation rate has varied from 55% to 60% of those eligible who were invited to participate during the course of the programme. The participants have been compared to the non-participants and no obvious social differences were found.22

Participants in the VIP are mainly born in the county of Västerbotten. However, migration into and out of Västerbotten county has obviously decreased the number of eligible subjects who could be identified in the local birth register based on the premise—born in the geographical area 1955–1972. The condition of migration would only induce bias if subjects with LBW at birth migrate in a manner different from that of NBW subjects. Although caution should be applied when assessing the effect of migration, we do not consider this to be a major source of bias.

The category of subjects with LBW includes both small-for-gestational age subjects (term and pre-term) and children born with appropriate weight for gestational age (term and pre-term). According to the Medical Birth Registry, the prevalence of small-for-gestational age was 30.6% among all Swedish liveborn children with LBW during 1982–1996; pre-term births constituted 65.2% of all children with LBW, and among the pre-term births small-for-gestational age accounted for 17.6% of the cases (personal communication—Centre for Epidemiology at the NBHW). Among all Swedish singleton births from 1973 to 1981, the overall prevalence of LBW was 3.8%: 3.5% for boys and 4.0% for girls.25 The overall prevalence of LBW was 3.5% (males 3.1%, females 4.0%).

Low birthweight has been found to be associated with elevated blood pressure in both childhood26 and adolescence,27 although studies of adolescents have been inconsistent.26 Few studies have been conducted on how birthweight is related to blood pressure, anthropometrics and lipids in early middle age.28 We found significant associations between LBW and elevated blood pressure, although mean age in the sample was only 32 years. A positive, synergistic effect of heredity for myocardial infarction or stroke and LBW on the risk of hypertension was indicated.

Heredity for myocardial infarction or stroke was defined as having a parent or sibling with an event of myocardial infarction or stroke before the age of 60 years. Apparently, the information extracted from the history may include different categories of exposure, such as genetic inheritance (e.g. hypertension, lipid disorders) and social stratification (e.g. lifestyle, diet) among other possible factors, and the findings must therefore be considered accordingly. Information on heredity was available for 6846 of 7876 eligible subjects (86.9%). We further evaluated the group of non-responders (subjects not answering the question on heredity). The male/female quotient was 0.97 for responders and 1.23 for non-responders. We found a significant higher age (mean age 32.23 versus 30.34 for males, 32.36 versus 30.34 for females) and a higher proportion of subjects with education at university (14.7% versus 2.0% among male subjects, 26.2% versus 8.6% among female subjects) among responders in comparison with non-responders. The distribution of LBW did not significantly differ between responders and non-responders. As a result of the similar LBW distribution and because educational level is strongly associated with the outcome variables, we do not consider the influence of heredity to be overestimated.

Increased placental vascular resistance assessed by umbilical Doppler velocimetry has been associated with intrauterine growth and hypertension in pregnancy.29 It has been shown that birthweight increases with increasing blood pressure until the hypertensive range is reached.30,31 Hypertensive pregnancies have been found to be characterized by lower birthweight and shorter gestational age, however, intrauterine growth retardation was not a general characteristic.32 Children born after hypertensive pregnancies have higher blood pressure compared to children born after normotensive pregnancies.33 This association could be confirmed among our subjects and further, a probable synergistic effect of pre-eclampsia or hypertension during pregnancy and LBW was found, even when the odds ratios were adjusted for heredity for myocardial infarction or stroke.

Population-based studies have revealed that a significant within-population variation in body composition can be explained by inherited differences.34 Body fat distribution is strongly associated with insulin resistance and the metabolic syndrome, where abdominal obesity probably constitutes a more severe aberration in metabolism.20 There was no difference in BMI among subjects with LBW and NBW. Normal BMI however, does not preclude abdominal adiposity. Increased risk for coronary heart disease among people with LBW has been found to be restricted to people with high BMI in adulthood.35

Female LBW subjects had significantly higher triglycerides and male LBW subjects had significantly higher total cholesterol, but no difference was found for HDL cholesterol.

Adult height has been found to be inversely associated with ischaemic heart disease mortality.36 A failure to realise growth potential in utero (as indicated by being light at birth but tall as an adult) has been found to be associated with raised adult blood pressure.17 Our findings support the work of Leon et al. as we found an increased risk for elevated SBP and increased levels of total cholesterol in male subjects with LBW and high attained height and further, elevated SBP among female subjects with LBW and high attained height.

Low socioeconomic status of the pregnant woman has been associated with adverse reproductive outcome such as LBW.37,38 Socioeconomic effects on reproductive outcome were concluded to be moderate in two Swedish studies.39,40 The father's class has been shown to be strongly associated with ischaemic heart disease risk in adult life,41 and the work of the Barker group have been criticised for not adequately adjusting for confounding factors like socioeconomic circumstances at birth.7,11 However, it was concluded that the strong inverse associations between birthweight and blood pressure among 50-year-old Swedish men were unlikely to be explained by confounding by socioeconomic circumstances at birth or in adult life.16 The LBW and NBW subjects had a similar distribution of education level. In calculations, educational level was used as an indicator of socioeconomic status.

In contrast to earlier studies, where the subjects were born during the first decades of the 20th century, our study describes subjects born during a welfare period.

Conclusions

Our findings mainly support the ‘fetal origins’ hypothesis' in that we have found indicators in early middle age associated with cardiovascular disease later in life. We have further demonstrated that heredity for myocardial infarction or stroke exerts its own effect and has a probable synergistic effect with LBW. The population attributable proportions that result from different exposures to LBW were relatively small overall and from a public health perspective, heredity was more important than LBW for elevated SBP.

Acknowledgments

This study was supported by grants from the Swedish Council for Social Science Research (No. 95–0043:1B), the Swedish Medical Research Council (No. 27P-12134 and 27X-13077), National Institute of Public Health, the Joint Committee of the Northern Sweden Health Care Region, the County Council of Västerbotten, and the Medical Faculty, Umeå University. Thanks to Åsa Ågren, Department of Public Health and Clinical Medicine, Nutritional Research, and Markku Peltonen, Department of Public Health and Clinical Medicine, Medicine, for data management. We also thank Professor Kjell Asplund, Department of Public Health and Clinical Medicine, Medicine, for valuable co-operation, and Erik Bergström, Department of Public Health and Clinical Medicine, Epidemiology, for inspiring comments.

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