Gestational Age and Growth Rate of Fetal Mass Are Inversely Associated with Systolic Blood Pressure in Young Adults: An Epidemiologic Study of 165,136 Swedish Men Aged 18 Years

David A. Leon1, Malin Johansson2 and Finn Rasmussen1

Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, London, United Kingdom.
Division of Epidemiology, Karolinska University Hospital, Stockholm, Sweden.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The objective of this study was to identify specific components of fetal growth that may underlie the observed association between birth weight and later blood pressure. A record linkage was made between the Swedish Medical Birth Registry, the Military Conscription Register, and censuses. For 165,136 men born in Sweden between 1973 and 1976 and conscripted from 1990 to 1996, systolic blood pressure was measured at age 18 years. Systolic pressure was independently inversely associated with birth weight for gestational age and with gestational age itself but not with birth length for gestational age. The difference in systolic pressure between the top and the bottom quintiles of birth weight for gestational age was -1.61 mmHg (95% confidence interval: -1.82 to -1.40) after adjustment for birth length for gestational age, height, and weight. The change in systolic pressure was -0.25 mmHg (-0.29 to -0.22) for a 1-week increase in gestational age. How far the inverse association of systolic pressure with length of gestation represents an independent effect of maturation is unclear. These findings help to refine the fetal origins hypothesis and provide further criteria against which potential biological mechanisms that link circumstances in utero to later blood pressure can be assessed. Am J Epidemiol 2000;152:597–604.

blood pressure; fetal development; gestational age

Abbreviations: CI: confidence interval; DBP, diastolic blood pressure; MBR, Medical Birth Registry; MSCR, Military Service Conscription Registry; SBP, systolic blood pressure.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Birth weight has been found to be inversely associated with blood pressure at most ages, including childhood (1GoGoGo–4Go). While some studies have failed to find the association in adolescents (5Go), recent longitudinal studies (6Go, 7Go) have found inverse associations of systolic blood pressure (SBP) with birth weight at all ages from 3 to 21 years. Although the pathophysiology underlying this association is unclear, undernourishment during a sensitive period of fetal life has been hypothesized to play an important role (8Go). This may or may not be determined by maternal characteristics, including diet (9Go), weight in pregnancy (10Go), or even the mother's own circumstances in utero, that are known to influence the birth weight of her offspring (11Go, 12Go).

Birth weight is a function of fetal growth rate and gestational age at delivery. Few studies of the association between blood pressure and size at birth have attempted to distinguish between these two components (3Go, 6Go). Moreover, how much later in life blood pressure is independently associated with other indicators of fetal growth, such as birth length, has not been adequately explored. In this paper, we address some of these unresolved issues by using a unique and very large routine data set from Sweden (13Go). We go beyond earlier published analyses of these data in that we attempt to identify the independent effects on SBP of birth weight, birth length, and gestational age (14Go).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The data were generated through a record linkage between the Swedish Medical Birth Registry (MBR), the Military Service Conscription Registry (MSCR) for men born from 1973 to 1976, and the Population and Housing Censuses of 1975 and 1990 for those born from 1975 to 1976. The linkage was achieved by using the unique personal identification code assigned to each person living in Sweden and was carried out with the permission of the Swedish Data Inspection Board and the Ethics Committee of the Karolinska Institute.

The MBR covers more than 99 percent of all children born in Sweden since 1973 and was used to collect data on birth weight, birth length, gestational age in days (from the first day of the last menstrual period), type of delivery, mother's age, and parity. In a special study of the quality of the MBR (15Go), the validity of all of these variables was assessed to be good.

SBP, weight, and height from the years 1990 to 1996 were obtained from the MSCR, which contains data from the medical conscription examination performed in most cases at age 18 in one of six centers throughout Sweden. The examination is compulsory for all except those with very severe chronic diseases or handicaps. Blood pressure was measured on the first day of the induction examination after 5–10 minutes rest in the supine position. If the SBP was 145 mmHg or below and the diastolic blood pressure (DBP) was between 50 and 85 mmHg, no further measurements were made. However, if the SBP and/or the DBP were found to be outside these limits, a second measurement was performed on the next day. In such cases, the result of the second measurement was entered into the register. Frequency tabulations of the data revealed clear evidence of "heaping" of DBP values, in particular, which appear to have been frequently rounded to the nearest 10 mmHg. This phenomenon was much less apparent for SBP, which was generally rounded to the nearest 2 mmHg. Because of the substantial rounding of DBP, our analyses focus on SBP alone.

Although a book outlining a standard examination protocol was issued, there is evidence of practice variation. It is apparent that there were systematic biases between centers, with two of the six centers recording mean SBPs 4–6 mmHg above the remainder. This appears to be partially explained by differences in rounding practices and the ways in which SBP above 145 mmHg have been dealt with. The extent of rounding and systematic differences between centers tended to vary across the years of observation. To deal with this potential confounding effect, all analyses are adjusted for conscription center and age and year of examination.

A total of 211,627 singleton male livebirths delivered in Sweden from 1973 to 1976 were identified in the MBR. For 174,425 (82 percent) of these, data were available on SBP, height, and weight from the induction examinations. The analyses were restricted to men born between 35 and 44 completed gestational weeks, in part because for more extreme gestations there was evidence of misclassification (16Go). Further exclusions were based on extreme values for other variables that were considered biologically implausible for a Swedish population (17Go, 18Go). Finally, we restricted analyses to men aged 17–19 years at conscription examination. In total, we included in the analyses 165,136 men, comprising 95 percent of those for whom information from birth and at military conscription was available.

For birth weight and birth length, z scores were calculated within each individual week of gestation from 35 to 44 weeks using the study population as a whole as the reference standard. These were used in analyses to examine the effect of growth rate on outcomes of interest. By definition, these z scores are uncorrelated with gestational age in weeks. Multiple linear regression analysis was conducted using the STATA statistical package (19Go).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The means, standard deviations, and ranges of the variables included in the analyses are given in table 1. The males were born from 1973 to 1976, fulfilling the same perinatal criteria as the study subjects, but excluded from the analyses mainly due to missing data on weight, height, or SBP at age 18 years, had means of birth weight, birth length, and gestational age of 3,516 g, 50.7 cm, and 39.7 weeks, respectively. According to the Population and Housing Census of 1990, 24 percent of the fathers of the included men aged 18 years had fewer than 9 years of school education compared with 27 percent of the individuals not included mainly due to missing data on height, weight, or SBP at age 18.


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TABLE 1. Means, standard deviations, and ranges of variables for 165,136 males born from 1973 to 1976 in Sweden

 
The association of SBP with size at birth and at age 18 years is shown in table 2. Blood pressure declined with increasing birth weight, birth length, and gestational age. In contrast, SBP increased with increasing weight and height at conscription examination. All of the associations showed statistically significant trends (p < 0.001). In summary, a 1-kg increase in birth weight was associated with a change in SBP of -0.60 mmHg (95 percent confidence interval (CI): -0.70, -0.50), a 1-cm increase in birth length was associated with a change of -0.07 mmHg (95 percent CI: -0.10, -0.05), and a 1-week increase in gestational age was associated with a change of -0.25 mmHg (95 percent CI: -0.28, -0.21).


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TABLE 2. Mean systolic blood pressure at conscription examination for 165,136 young males born between 1973 and 1976 in Sweden

 
Birth weight, birth length, gestational age, height, and weight at conscription examination were all correlated with each other to varying degrees (table 3). Adult weight at conscription examination was positively correlated with birth weight and birth length to an almost equal degree. However, the positive correlation of adult height at conscription examination with birth length was appreciably larger than that with birth weight. Adjustment for height and weight at conscription examination strengthened the effect of birth weight on SBP (-1.47 mmHg/kg, 95 percent CI: -1.57, -1.37) and of birth length on SBP (-0.28 mmHg/cm, 95 percent CI: -0.31, 0.26), while the effect of gestational age was unchanged.


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TABLE 3. Pairwise correlation coefficients for independent variables for 165,136 young males born between 1973 and 1976 in Sweden

 
Given the close correlation between gestational age and size at birth, how much were the unadjusted effects of gestational age due to confounding with birth weight and birth length? Adjustment for birth length and birth weight had little effect on the inverse association of gestational age with SBP (-0.22 mmHg/week, 95 percent CI: -0.25, -0.19). Adjustment for gestational age, however, reduced the strength of association of birth weight with SBP (-0.36 mmHg/kg, 95 percent CI: -0.47, -0.26) and eliminated the association of SBP with birth length (-0.01 mmHg/cm, 95 percent CI: -0.03, 0.02).

The clearest way to separate the association between gestational age and SBP from size at birth is to examine the association of SBP with a measure of growth rate such as birth weight for gestational age and birth length for gestational age. Table 4 shows the change in SBP for a quintile increase in birth weight and birth length for gestational age, unadjusted and adjusted for the effects of each other and of size at conscription examination. It should be noted that all of the estimates in this table were independent of gestational age as, by definition, the z scores were uncorrelated with gestational age.


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TABLE 4. Change in systolic blood pressure (mmHg) and 95% confidence intervals associated with a quintile change in birth weight for gestational age and birth length for gestational age z score for 165,136 males born from 1973 to 1976 in Sweden

 
In table 4, birth weight for gestational age shows a stronger association with SBP compared with birth length for gestational age. Moreover, when both variables were included in the model without adjustment for size at conscription examination, the effects of these two growth parameters were in opposite directions, with birth length for gestational age showing a significant positive association with SBP. However, when additionally adjusted for height and weight at conscription examination, the inverse association of birth weight for gestational age with SBP became larger, while that for birth length for gestational age was eliminated.

Birth length for gestational age was strongly positively associated with attained adult height, which, in turn, was positively associated with SBP. Men who were in the top quintile of birth length for gestational age were, on average, 6.2 cm (95 percent CI: 6.0, 6.3) taller at conscription examination than were men in the bottom quintile of birth length for gestational age, independent of birth weight for gestational age. The corresponding independent effect of birth weight for gestational age on height at conscription was much weaker, with an average difference of only 1.3 cm (95 percent CI: 1.2, 1.4) between the men in the top and bottom z score quintiles. Thus, when unadjusted for adult height (and weight), birth length for gestational age served as a proxy for adult height. However, once adult height and weight were put in the model, birth length for gestational age no longer had any effect on SBP independent of birth weight for gestational age.

These results are illustrated graphically in figures 1 and 2, which show the independent effect of gestational age and birth weight for gestational age z score on SBP and the absence of an independent effect of birth length for gestational age z score. In figure 1, differences in SBP (relative to a baseline of men in the lowest quintile of birth weight born at 35–37 weeks gestation) were plotted against gestational age in weeks for each quintile of birth weight for gestational age z score. Smooth and consistent declines of SBP with gestational age were evident for each quintile of birth weight for gestational age. In addition, the quintile lines run almost parallel, suggesting a constant effect of birth weight for gestational age on SBP, irrespective of gestational age at delivery. On the basis of the model used to plot figure 1, the average difference in SBP between the top and bottom quintiles of birth weight for gestational age was -1.61 mmHg (95 percent CI: -1.82, -1.40). In the same model, there was a change in SBP of -0.25 mmHg (95 percent CI: -0.29, -0.22) for a 1-week increase in gestational age. Figure 2 illustrates the absence of effect of birth length on SBP once birth weight for gestational age, gestational age, weight, and height at conscription examination were taken into account. While the same effect of gestation is apparent, as seen in figure 1, the quintile lines for birth length for gestational age are superimposed on one another, indicating that this dimension of fetal growth had no independent effect on SBP in young adulthood.



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FIGURE 1. Difference in SBP by gestational age and quintile of birth weight for gestational age (relative to quintile 1, 35–37 weeks), adjusted for birth length for gestational age and height, weight, age, and center of conscription examination for males born in Sweden between 1973 and 1976.

 


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FIGURE 2. Difference in SBP by gestational age and quintile of birth length for gestational age (relative to quintile 1, 35–37 weeks), adjusted for birth weight for gestational age and height, weight, age, and center of conscription examination for males born in Sweden between 1973 and 1976.

 
For men born in 1975 and 1976, sociodemographic data about the parents at the time of the 1975 and 1990 Population and Housing Censuses were available (n = 76,208). For this subset of the population, the measures of effect were very similar to those reported in table 4 for the total study population. Educational level of the father from the 1990 Census (in four categories, from fewer than 9 years education to university educated) and maternal and paternal total income from the 1975 Census were all positively associated with their son's SBP at age 18 years, i.e., SBP increased as educational level and income increased. Adjustment for these factors slightly strengthened the size of the inverse association between birth weight for gestational age and SBP.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
This study is based on routine data from large, nationwide health data registers. Only 78 percent of all singleton men born from 1973 to 1976 were linked to conscript examination data and included in the analysis. However, the mean birth weight of the males born in 1973–1976 fulfilled the same perinatal criteria as study subjects, but was excluded due to missing data on weight, height, or SBP at age 18 years and was only 2 percent lower than the mean birth weight of the men age 18 years who were included in the study. Furthermore, the proportion of fathers with less than 9 years of school education in 1990 was only slightly lower (24 percent) among study participants then among those not included (27 percent). It is thus unlikely that the association between perinatal factors and later blood pressure could be explained by selection bias. The fact that adjustment for parental socioeconomic characteristics slightly strengthened the inverse associations of SBP with birth weight for gestational age suggests that these associations cannot be explained by socioeconomic confounding.

Measurement errors in key variables, including blood pressure at conscription examination, are likely to be larger than those in studies that use more standardized protocols. There is evidence of systematic differences in measurement of SBP between conscription examination centers, although any bias that might have been introduced should have been minimized because we took center and year of examination into account in the analyses. A lack of precision in the measurement of blood pressure will have led to an underestimation of the strength of effect. This type of error may explain in part the weaker association between birth weight and SBP seen in this study compared with some others (1Go). The very large size of the study, however, has provided us with an exceptional opportunity to separate out the effects on SBP in early adult life of gestational age and rate of linear fetal growth and of accretion of fetal mass. Our analyses of SBP in Swedish conscripts in relation to perinatal factors go beyond those previously published (14Go), which did not look at the effects on SBP of birth weight and length for gestational age.

It has been suggested (20Go) that, in adolescents and young adults, disturbances in tracking of blood pressure may obscure any association between size at birth and blood pressure. However, our finding of an inverse association between SBP and birth weight in men aged 18 years is consistent with the results of two other recent studies of young adults. Uiterwaal et al. (6Go), in their longitudinal study of those aged 5–37 years, found the strongest association between birth weight and SBP to be in the age group 15–19 years, in which a 1-kg increase in birth weight was associated with a change in SBP of -3.1 mmHg. A study of Israeli conscripts aged 17 years (21Go), similar in design to our study, reported an inverse association between birth weight and SBP in 6,700 male subjects, with a change in SBP of -0.94 mmHg per kg increase in birth weight after adjustment for adult weight and various maternal factors. The effect we have reported (-1.47 mmHg/kg) lies in between these two estimates.

Only a minority of other studies have included data on gestational age. These have generally found similar results, in that adjustment for length of gestation was reported to reduce the strength of the association between birth weight and SBP (3Go, 6Go, 22Go). We found that adjustment for gestational age slightly reduced the strength of association between birth weight and SBP, consistent with an independent, confounding effect of gestational age.

The independent effect of gestational age on SBP at age 18 years observed in this study, although not large, is strikingly smooth and consistent. Few other studies have presented results for gestational age that are adjusted for birth weight, with two studies (22Go, 23Go) finding that gestational age is inversely associated with SBP and another (24Go) finding a positive association. One interpretation of the inverse association observed is that factors associated with maturation in the last 6–8 weeks of pregnancy are involved in programming SBP later in life. However, it may be that gestational age at delivery is reduced in pregnancies with fetal growth impairment, and it is this impairment that leads to raised blood pressure in later life. There is evidence that hypertensive mothers have shorter-duration pregnancies (25Go, 26Go) and that their offspring, in turn, have raised blood pressures either as a result of inheritance or through impairment of fetal growth that is associated with raised maternal blood pressure (27Go). Further work needs to be done to establish how far the inverse association between gestational age and SBP may be explained by these alternative mechanisms.

Size at birth is a function of fetal growth rate as well as of length of gestation. Fetal growth rate is best measured directly by serial ultrasound. However, such data were not available, and we have used size at birth for gestational age z score instead. Our results suggest that it is the rate of accretion of fetal mass (measured as birth weight for gestational age) that is associated with later blood pressure. By definition, this effect is independent of gestational age. These results are consistent with those from the few other studies of fetal determinants of later blood pressure that have looked at birth weight for gestational age (28Go, 29Go). The Israeli conscript study (21Go) found that SBP in the top quintile of birth weight for gestational age was 117.7 mmHg and that SBP in the bottom quintile was 118.7 mmHg. This compares with a 1.6-mmHg difference between top and bottom quintiles in our study. Williams et al. (30Go) examined blood pressure at age 7 years in relation to intrauterine growth retardation, defined as a birth weight for gestational age in the 10th centile or below. SBP was higher in the small-for-gestational age group (n = 70) compared with those who were of normal birth weight for gestational age (11–89th centiles, n = 680). A smaller excess of SBP was observed at follow-up at age 18 years. These results, along with those from our analyses, parallel the conclusion of another recent Swedish study (31Go) that found mortality from coronary heart disease to be related to fetal growth rate rather than birth weight per se.

To our knowledge, our study is the first to systematically examine whether birth length has an effect on SBP that is independent of birth weight. We found that birth length for gestational age was not independently associated with SBP at age 18 years once birth weight for gestational age and height and weight at adult examination were taken into account. It should be considered whether the absence of an independent effect of linear fetal growth may be due to birth length being relatively poorly measured compared with birth weight. Theoretical work has demonstrated that differences in precision of measurement of two correlated explanatory variables can give rise to spurious conclusions concerning the true causal relation (32Go). However, it is striking that we observed adult height to be much more strongly associated with birth length for gestational age than it was with birth weight for gestational age, a result supported by other studies (33Go). This suggests that recorded birth length is informative in its own right and measures a dimension of fetal growth that is distinct from, and not reducible to, birth weight. Given these considerations, we conclude that linear fetal growth rate (measured by the birth length for gestational age z score) is implicated in fetal "programming" of later blood pressure.

The pattern of linear bone growth is different from that of weight (17Go, 34Go). In these data, at 35 weeks gestation average birth length is over 94 percent of length at 40 weeks, in contrast to birth weight, which at this stage is only 78 percent of weight at 40 weeks. Birth length is thus going to be less affected by impaired fetal nutrition in late gestation than is birth weight. Ultrasound studies (35Go) suggest that fetal fat and fat-free mass may be determined by different factors, with much of the last part of gestation involving accretion of fat mass in preparation for postnatal life. Further evidence that mechanisms determining rate of linear and soft-tissue growth are distinct comes from animal and human data showing maternal hyperinsulinemia to increase birth weight to a much greater proportional degree than birth length (36Go).

We have interpreted the associations between various perinatal characteristics and SBP at age 18 years as being consistent with the fetal programming hypothesis (8Go). It has been proposed that there is at least a prima facie case for considering the possibility that these sorts of associations could be due to a common underlying genetic component (37Go). It is likely that results of ongoing twin studies and transgenerational research will increase our knowledge about genetic factors, which may have an impact on birth weight as well as on blood pressure in adult age (38Go). The growing body of animal experimental evidence (39Go), in which manipulations of maternal and fetal nutrition have been demonstrated to affect blood pressure and other physiologic characteristics in offspring, provides strong evidence for the biologic plausibility of environmental programming in utero.

We therefore suggest that it is rate of accretion of fetal soft-tissue mass rather than of linear bone growth that is associated with programming of later blood pressure. This should help to refine the fetal origins hypothesis and provide further criteria against which potential biologic mechanisms can be assessed. For example, can the hypothesized pathway linking programming of the hypothalamic-pituitary-adrenal axis to impaired fetal growth and later blood pressure (40Go) be related to the specific features of fetal mass accretion we have identified? To answer this question is likely to require more basic investigation of the determinants of different dimensions of human fetal growth.

The absolute size of the effects we have reported are small. However, there is now good evidence that appreciably larger effects are apparent at older ages (2Go) and among those who are more obese than our 18-year-old Swedish conscripts (40Go, 41Go). Until more is understood about the underlying mechanisms and, in particular, how closely size at birth is a good or poor proxy measure of the pertinent disturbances in fetal growth and development, judgment of the clinical or public health importance of these associations remains highly speculative and uncertain.


    ACKNOWLEDGMENTS
 
The authors acknowledge comments made on earlier drafts of the paper by various colleagues, including Ilona Koupilová, Paul McKeigue, and Chris Power, that were most useful.


    NOTES
 
Reprint requests to Dr. Finn Rasmussen, Division of Epidemiology, The Norrbacka Building, Karolinska University Hospital, S-171 76 Stockholm, Sweden (e-mail: finn.rasmussen{at}imm.ki.se).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication March 16, 1999. Accepted for publication October 18, 1999.


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