American Journal of Epidemiology

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American Journal of Epidemiology Vol. 153, No. 8 : 779-782
Copyright © 2001 by The Johns Hopkins University School of Hygiene and Public Health

ORIGINAL CONTRIBUTIONS

Differences in Birth Weight and Blood Pressure at Age 7 Years among Twins

Jun Zhang, Ruth A. Brenner and Mark A. Klebanoff

From the Epidemiology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

	ABSTRACT

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Blood pressure later in life has been inversely associated with birth weight. However, concerns have been raised about whether this association merely reflects common environmental risk factors for both fetal growth restriction and high blood pressure or whether there is a genetic tendency to give birth to small babies and have high blood pressure. This study examined whether difference in birth weight of twins is associated with difference in blood pressure at age 7 years. The authors used data from the Collaborative Perinatal Project, United States, 1959–1966, which included 119 pairs of monozygotic and 86 pairs of same-sex dizygotic twins. The smaller twin in each pair had an average 300-g lower birth weight and was substantially thinner than the larger twin (p < 0.001). At age 7 years, body size and blood pressure were similar. Multiple linear regression was used to examine the association between difference in birth size and difference in blood pressure, adjusting for difference in body weight at age 7 years. None of the associations was statistically significant, and the direction of the associations was inconsistent. Further analyses stratified by birth weight, race, and sex revealed a similar, inconsistent pattern. The authors' findings fail to support the hypothesis that an unfavorable intrauterine environment adversely affects blood pressure in children.

birth weight; blood pressure; twins

Abbreviations: CI, confidence interval.

	INTRODUCTION

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Numerous studies have reported that blood pressure later in life is inversely associated with birth weight (1). Some researchers consider birth weight a marker for fetal nutrition. Barker (2) has proposed that undernutrition during a critical fetal stage may predispose a person to a higher risk of hypertension and other cardiovascular diseases. However, concerns have been raised that both birth weight and blood pressure are affected by genetic, environmental, nutritional, and behavioral factors (3). It is open to debate whether the association between birth weight and blood pressure merely reflects common risk factors for both fetal growth restriction and hypertension later in life (e.g., low socioeconomic status or smoking shared by mother and child), whether there is a genetic tendency to give birth to small babies and have high blood pressure, or whether an unfavorable intrauterine environment leads to a high risk of cardiovascular diseases. Lack of information on intrauterine exposures and an inability to separate environmental from genetic factors have seriously hampered efforts to address this issue adequately.

Fortunately, twins, especially monozygotic twins, provide a unique opportunity for this endeavor because they have an identical genetic background, have a similar intrauterine exposure, and are usually raised in the same environment. Yet, twins often have discordant birth weights because of discrepancies in the microintrauterine environment (e.g., different placentation and blood perfusion). Thus, any association between birth weight and blood pressure in monozygotic twins would presumably be attributable to intrauterine environment. In two recent twin studies, paired analysis of monozygotic twins showed that a decrease of 1 kg in birth weight was associated with a 6.5-mmHg increase in systolic blood pressure at age 8 years (n = 16 pairs, 95 percent confidence interval (CI): -9.4, 22.5) (4) and a 4.9-mmHg increase at age 54 years (n = 167 pairs, 95 percent CI: -3.9, 13.7) (5).

The purpose of the current study in a large US cohort was to examine whether differences in birth weight between twins are associated with differences in blood pressure at age 7 years. We hypothesized that if an unfavorable intrauterine environment causes higher blood pressure, the smaller twin at birth would have a higher blood pressure later in life than the larger twin of each pair.

	MATERIALS AND METHODS

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We used data from the Collaborative Perinatal Project, a large, prospective cohort study (6). Briefly, from 1959 to 1966, women who received prenatal care at 12 hospitals in the United States were invited to participate in this observational study. At entry, detailed demographic, socioeconomic, and behavioral information was collected by in-person interview. A medical history, physical examination, and blood sample were also obtained. At each prenatal visit, women were interviewed and physical findings were recorded. Extensive neonatal physical and neurologic measures, including birth weight, crown-heel length, and head circumference, were carefully taken by specially trained staff who used approved, standardized measuring instruments. The children were followed at 4, 8, and 12 months of age and at 4 and 7 years of age. However, blood pressure was measured at only the last follow-up visit.

When the children were between age 7 and 7.5 years, their parents were asked to bring them to the research center for a pediatric-neurologic examination and a battery of psychological tests. Weight, height, and head circumference were taken in a standardized manner. Trained nurses at each center obtained blood pressure from each child's right arm by using a standard mercury manometer, with the child at rest in a recumbent position. The cuff used was wide enough (at least 4 inches (10.16 cm)) for the child's arm. A total of 95 percent of twin pairs had their blood pressures taken at the same center on the same day. Both phase IV (muffling) and phase V (disappearance) were used to determine diastolic blood pressure. One measurement for each child was recorded. Twin zygosity was established by comparing nine red blood cell markers and by pathologic examination of the placenta (7).

The Collaborative Perinatal Project recruited 58,760 pregnant women, 616 of whose pregnancies were twin gestations (1 percent). For 1,232 individual twins, there were 102 fetal losses, 136 infant deaths, 3 child deaths, and 4 losses to follow-up, yielding 987 individual twins eligible for follow-up at age 7 years. A total of 803 individual twins (81 percent) had a physical examination at age 7 years; of these, 361 pairs (722 individual twins) had complete information necessary for the current study. Thus, our study included 73 percent of all twins. For comparison, our crude analysis also included 39,673 liveborn singletons whose blood pressures were measured at age 7 years. The main focus of this study was twins, however.

Associations between the differences in birth weight, length, head circumference, and ponderal index between paired twins versus differences in blood pressure at age 7 years were examined in both unadjusted and adjusted analyses. We used the paired t test in the unadjusted analysis. Multiple linear regression was used to examine the association between birth weight and blood pressure, adjusting for current body weight in log transformation. Least-squares means of differences in blood pressure were calculated in the general linear model by adjusting for within-pair differences in current body weight. Since whether current body weight should be controlled as a confounder is under dispute (8), this paper presents both crude and adjusted results.

	RESULTS

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Among the 361 pairs of twins, 43 percent were White, 54 percent were Black, and 3 percent were of other race/ethnicity; 102 were male/male pairs, 126 were female/female pairs, and 133 were male/female pairs. Mean gestational age was 37 weeks (standard deviation, 3.1), and mean birth weight was 2,438 g (standard deviation, 508) (range, 964–4,111 g). Zygosity was classified as follows: 119 were monozygotic, 86 were same-sex dizygotic, 133 were opposite-sex dizygotic, and 23 were of indeterminate zygosity.

The vast majority of previous findings on the relation between birth weight and blood pressure were based on singleton births. To examine comparability between our twin data and data from previous studies, we first examined the relation between birth weight and systolic blood pressure in twins considered individually. After control for current body weight and sex, we found that a 1,000-g decrease in birth weight was associated with a 1.1-mmHg increase in systolic blood pressure (95 percent CI: -1.1, 3.2) among first twins (determined by order of delivery) (unadjusted value, -0.4). Similarly, a 1-kg decrease in birth weight was associated with a 1.3-mmHg increase in systolic blood pressure (95 percent CI: -0.9, 3.4) among second twins (unadjusted value, -0.6).

Table 1 presents basic characteristics of the twins as well as singletons. For both monozygotic and dizygotic twins, the smaller twin not only had a lower birth weight but also was significantly thinner in relation to length. On average, the smaller twins were 300 g lighter than the larger twins. The mean birth weight of all twins (2,438 g) was 750 g lower than that of the singletons. However, at age 7 years, the difference in body size was much smaller, and twins and singletons had similar blood pressures. After we adjusted for current weight, race, and sex, the mean systolic blood pressures of twins and singletons were identical at 102 mmHg.

View this table: [in this window] [in a new window]   TABLE 1. Characteristics of monozygotic and same-sex dizygotic twins at birth and at age 7 years, Collaborative Perinatal Project, United States, 1959–1966

 
We then used multiple linear regression to examine the association between the difference in birth size and the difference in blood pressure among twins, adjusting for the difference in current body weight. Table 2 shows that none of the associations was statistically significant and that the direction of the associations was inconsistent. We further stratified the difference in birth weight and the mean difference in blood pressure, adjusting for the difference in current body weight (table 3). Again, no consistent pattern was observed. Further analyses stratified by race (Black, White) and sex (male, female) revealed a similar inconsistent pattern (data not shown).

View this table: [in this window] [in a new window]   TABLE 2. Difference in size at birth and change in systolic and diastolic blood pressures* (mmHg) at age 7 years, based on multiple linear regression analysis, among twins in the Collaborative Perinatal Project, United States, 1959–1966

 

View this table: [in this window] [in a new window]   TABLE 3. Reduction in birth weight and mean difference in systolic and diastolic blood pressures* (mmHg) at age 7 years among twins in the Collaborative Perinatal Project, United States, 1959–1966

 

	DISCUSSION

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Individual twins are usually smaller than singletons of comparable gestational age, particularly during the third trimester. Twins presumably suffer from relative intrauterine malnutrition. According to Barker's hypothesis (2), twins would naturally have higher blood pressures than singletons. Williams and Poulton (9) found that overall, twins actually had lower systolic blood pressures, by 5 mmHg, than singletons at age 9 years. However, the number of twins in that study was very small (n = 22), and no detailed analysis was conducted. We found that the large difference in birth weight between singletons and twins did not affect blood pressure at age 7 years. Furthermore, population-registry-based studies have demonstrated that compared with the general population, twins do not have a higher overall mortality rate (10) or mortality due to ischemic heart disease (11). Critics have argued that the fetal growth patterns of singletons and twins are so different that Barker's hypothesis does not apply to twins (12). Phillips and Osmond theorized that downregulation of growth rate early in gestation might protect against growth restriction induced by undernutrition in later gestation (12). This speculation was not supported by our findings; the smaller twins were not only smaller but also thinner, indicating that they were not immune to growth restriction in the third trimester. It is yet to be demonstrated whether fetal growth restriction due to suboptimal placentation or maternal smoking (usually starting before pregnancy) differs from that due to insults later in pregnancy and how these factors are associated with blood pressure later in life. The Williams and Poulton study suggested that maternal smoking rather than undernutrition might be the culprit for higher blood pressure in infants of lower birth weight.

The accuracy of blood pressure assessment is questioned frequently, particularly in studies reporting negative findings. Indeed, the major deficiency in the current study is that only one blood pressure measurement was recorded on the data form. It may be argued that the random error in blood pressure measurements might have drawn the results toward the null value. In the "Report of the Second Task Force on Blood Pressure Control in Children—1987" (13), nine studies carefully conducted in the United States and Great Britain and involving more than 70,000 White, Black, and Mexican-American children were used to establish standards for children's blood pressure. The coefficient of variation (standard deviation/mean) was 10.6 percent for systolic blood pressure at age 7 years. In the current study, the corresponding coefficient of variation was 10.1 percent for singletons and 9.9 percent for twins. These results suggest that the accuracy of the blood pressure assessment in our study was comparable to that in other studies. In addition, a comprehensive review by Law and Barker concluded that in general, systolic blood pressure in childhood rises by 1–2 mmHg for every kilogram decrease in birth weight (14). When we treated separate twins as if they were singletons, we found that a 1,000-g decrease in birth weight was associated with an increase in systolic blood pressure of about 1.2 mmHg for both first and second twins. That our results were within the reported range further suggests that gross dilution of an effect due to nondifferential misclassification of blood pressure was unlikely.

In summary, our study shows that after control for current weight, a difference in birth weight between well-matched twins is not associated with a difference in blood pressure at age 7 years. Our findings fail to support the hypothesis that an unfavorable intrauterine environment adversely affects blood pressure in children.

	NOTES

 
Reprint requests to Dr. Jun Zhang, Epidemiology Branch, National Institute of Child Health and Human Development, NIH Building 6100, Room 7B03, Bethesda, MD 20892 (e-mail: Jun_Zhang{at}nih.gov).

	REFERENCES

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1. Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens 1996;14:935–41.[ISI][Medline]
2. Barker DJP. Mothers, babies, and disease in later life. London, United Kingdom: BMJ Books, 1994.
3. Paneth N, Susser M. Early origin of coronary heart disease (the "Barker hypothesis"). BMJ 1995;310:411–12.[Free Full Text]
4. Dwyer T, Blizzard L, Morley R, et al. Within pair association between birth weight and blood pressure at age 8 in twins from a cohort study. BMJ 1999;319:1325–9.[Abstract/Free Full Text]
5. Poulter NR, Chang CL, MacGregor AJ, et al. Association between birth weight and adult blood pressure in twins: historical cohort study. BMJ 1999;319:1330–3.[Abstract/Free Full Text]
6. Niswander KR, Gordon M, eds. The Collaborative Perinatal Study of the National Institute of Neurological Diseases and Stroke: the women and their pregnancies. Philadelphia, PA: WB Saunders, 1972.
7. Myrianthopoulos NC. An epidemiologic survey of twins in a large, prospectively studied population. Am J Hum Genet 1970;22:611–29.[Medline]
8. Lucas A, Fewtrell MS, Cole TJ. Fetal origins of adult disease—the hypothesis revisited. BMJ 1999;319:245–9.[Free Full Text]
9. Williams S, Poulton R. Twins and maternal smoking: ordeals for the fetal origins hypothesis? A cohort study. BMJ 1999;318:897–900.[Abstract/Free Full Text]
10. Christensen K, Vaupel JW, Holm NV, et al. Mortality among twins after age 6: fetal origins hypothesis versus twin method. BMJ 1995;310:432–6.[Abstract/Free Full Text]
11. Vagero D, Leon D. Ischemic heart disease and low birth weight: a test of the fetal-origins hypothesis from the Swedish Twin Registry. Lancet 1994;343:260–3.[ISI][Medline]
12. Phillips DIW, Osmond C. Twins and the fetal origins hypothesis. (Letter). BMJ 1999;319:517.[Free Full Text]
13. Report of the Second Task Force on Blood Pressure Control in Children—1987. Pediatrics 1987;79:1–25.[Abstract/Free Full Text]
14. Law CM, Barker DJP. Fetal influences on blood pressure. J Hypertens 1994;12:1329–32.[ISI][Medline]

Received for publication March 22, 2000. Accepted for publication July 18, 2000.

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