Birth Weight and Risk Factors for Atherosclerosis: A Retrospective Cohort Study in Japanese Workers

Introduction

An estimated 15%–20% of all births are diagnosed with low birth weight (birth weight < 2500 g), which is more than 20 million births per year globally [1]. Low birth weight is associated with neonatal morbidity and mortality [1]. In addition, low birth weight is associated with cardiovascular risk factors such as elevated blood pressure [2,3], lowered kidney function [4,5], dysregulation of lipid metabolism [6,7], and impaired glucose homeostasis [8,9] in later life.

B-type natriuretic peptide (BNP) is a hormone secreted mainly by cardiac ventricles [10], and it plays important roles in regulating volume homeostasis [11], cardiac fibrosis [12], vascular remodeling [13], and blood pressure [14]. Because it is increased in response to myocardial stretch and wall tension, plasma BNP is a strong biomarker for the diagnosis [15] and prognosis [16] of congestive heart failure. In a community-based population without heart failure, plasma BNP has been shown to predict risk of death and cardiovascular events [17].

We hypothesized that birth weight could be a useful clinical prognostic factor of plasma BNP level and therefore of cardiovascular events in the general population. However, the literature contains little information on the association between birth weight and plasma natriuretic peptide levels. A previous study has shown that young adults born with very low birth weight (birth weight < 1500 g) have a higher plasma level of N-terminal (NT) pro C-type natriuretic peptide (CNP), which regulates vascular tone and growth, than those born with normal weight; however, no difference in NT-proBNP level was observed [18].

Here, we examined the association between birth weight and risk factors for atherosclerosis, including plasma BNP level, in Japanese workers.

Patients and Methods

Study Design and Participants

This study was approved by the Keio University School of Medicine Ethics Committee (Approval No. 2018-0019-2) and was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.

This retrospective cohort study enrolled male and female Japanese workers, aged 40–70, who received an annual medical checkup performed by the Keio University Health Center (Japan) in 2018. Birth weight was obtained as continuous data and/or categorical data (<2500, 2500–2999, 3000–3499, 3500–3999, or >4000 g) via a self-administered questionnaire. Those who did not agree to be enrolled and those who did not complete the examinations or questionnaire were excluded from the study.

Anthropometric and Biochemical Measurements

Standing height and body weight were measured without shoes and outer clothing. Body mass index (BMI) was calculated as body weight divided by the square of the height (kg/m²).

Blood pressure (BP) was measured by a trained nurse using an electronic sphygmomanometer (BP-103i II; Omron Colin Co., Ltd., Tokyo, Japan) on the right arm in the seated position. When the measured BP was >130/85 mm Hg, the BP was re-measured, and the average of the two measurements was used for the analysis.

Plasma BNP was measured by chemiluminescent enzyme immunoassay. Peripheral blood cells were counted by flow cytometric assay. Total protein and albumin were measured by the Biuret method and the modified bromocresol purple method, respectively. Liver enzymes were assayed by using the Japanese Society of Clinical Chemistry standard method. Serum creatinine and triglycerides (TGs) were measured by enzymatic methods. Both high-density lipoprotein cholesterol (HDLC) and low-density lipoprotein cholesterol (LDLC) were measured by the direct method. Serum uric acid was determined by the uricase/peroxidase method. Fasting blood glucose (FBG) was assayed by ultraviolet absorption spectrophotometry. Hemoglobin A1c (HbA1c) was measured by the agglutination method.

Outcome Measures

We examined the association between birth weight and risk factors for atherosclerosis. The primary outcome measure was plasma BNP level, and the secondary outcome measures were BMI, BP, creatinine, uric acid, TGs, HDLC, LDLC, FBG and HbA1c.

Statistical Analyses

Baseline characteristics were summarized as means (SD) for continuous variables and as frequencies (proportions) for categorical variables.

To compare baseline characteristics by birth weight, participants were divided into three groups based on their birth weight (category 1, <2999 g; category 2, 3000–3499 g; category 3, >3500 g). The Jonckheere–Terpstra trend test was used to assess ordered differences among the birth weight categories.

To evaluate the clinical utility of birth weight for determining atherosclerotic risks, variables correlated with birth weight were assessed using a multivariable linear regression model. To avoid multicollinearity among the independent variables, correlation coefficients between pairs of variables were determined. Values were transformed to logarithmic scales when they were not normally distributed but had a log-normal distribution.

All statistical analyses were performed by using SPSS Statistics 25 (IBM Corporation, Armonk, NY). Statistical significance was defined as a P value less than 0.05 by using a two-sided test.

Results

Characteristics of the Participants

A total of 3384 Japanese workers aged 40–70 attended an annual medical checkup at Keio University Health Center, of which 1180 agreed to be enrolled in the present study. Continuous and/or categorical birth-weight data were available for 1109 of these 1180 participants (94%). The characteristics of the final study cohort are shown in Table 1. The mean age of the cohort was 50.3 years (48.4 years for men and 51.8 years for women), 53.4% of the subjects were female, and 5.0% of the subjects (3.9% of men and 5.9% of women) were diagnosed with low birth weight (<2500 g). Mean plasma BNP was 14.1 pg/μL for men and 22.4 pg/μL for women.

The results of the Jonckheere–Terpstra trend test for the characteristics of the participants according to birth-weight category and sex are shown in Table 2. In men, birth weight was significantly associated with HbA1c, whereas in women, it was significantly associated with diastolic BP and alkaline phosphatase (ALP). BNP level was not significantly associated with birth weight category for either sex.

Association Between Birth Weight and Risk Factors for Atherosclerosis

Next, we examined the association between birth weight and risk factors for atherosclerosis by using the Pearson correlation coefficient test using continuous birth-weight data (n = 212 for males, 359 for females). In men, birth weight was significantly negatively correlated with FBG (−0.135, 95% CI [−0.270, −0.001]) and HbA1c (−0.217, [−0.350, −0.084]). In women, birth weight was significantly negatively correlated with diastolic BP (−0.091, [−0.195, 0.000]).

The association among birth weight and risk factors for atherosclerosis was also examined by using categorical birth-weight data and Spearman’s rank correlation coefficient test (n = 517 for men, 592 for women). Birth weight category was significantly correlated with HbA1c in men (−0.124, [−0.210, −0.038]), and with diastolic BP in women (−0.091, [−0.174, −0.016]).

Log-transformed BNP level was not significantly correlated with birth weight, irrespective of whether continuous or categorical data was used (Pearson correlation coefficient using continuous birth-weight data: −0.006, [−0.130, 0.142] in men and −0.047, [−0.152, 0.057] in women; Spearman’s rank correlation coefficient using categorical birth-weight data: −0.030, [−0.116, 0.056] in men and −0.070, [−0.150, 0.011] in women).

Multiple Linear Regression for the Relationship Between Birth Weight and Risk Factors for Atherosclerosis

A multiple linear regression with HbA1c as the dependent variable was conducted in men. Age, birth weight (continuous data), BMI, systolic BP, white blood cell (WBC), hemoglobin, platelets, log(AST), log(ALT), log(ALP), log(gGTP), creatinine, uric acid, log(TGs), HDLC, LDLC, and log(BNP) were permitted to enter the regression model. HbA1c was significantly correlated with BMI, ALT, birth weight, creatinine, hemoglobin, WBC, and platelets (R² = 0.278) (Table 3).

A similar multiple linear regression with diastolic BP as the dependent variable was conducted in women. Diastolic BP was significantly correlated with gGTP, BMI, and hemoglobin (R² = 0.131); however, no correlation was observed with birth weight (Table 4).

Discussion

Here, we examined the association between birth weight and risk factors for atherosclerosis, especially plasma BNP level, in Japanese workers. We expected to find an association between birth weight and BNP, which is a predictor of cardiovascular events in the healthy general population [17]; however, no association was observed.

In the only study in the current literature in which the association between birth weight and natriuretic peptides was examined [18], plasma NT-proCNP level was higher in young adults diagnosed with very low birth weight (<1500 g) than in those born at normal birth weight, whereas no difference in NT-proBNP level was observed [18], which is consistent with the present results. One explanation for why an association was found between birth weight and CNP, but not NT-proBNP, may be that CNP is produced in response to vascular stress and predicts vascular risks more sensitively than does NT-proBNP [19]. This suggests that it may have been better to examine the association between birth weight and CNP.

In the present study, a sex difference was observed in the association between birth weight and risk factors for atherosclerosis; that is, birth weight was negatively correlated with HbA1c level in men but with diastolic BP in women. Low birth weight is known to be related to the development of impaired glucose tolerance and type 2 diabetes in adulthood [20]. It has been reported from a large population-based study conducted in Australia that the age and sex–adjusted odds ratio for high HbA1c level (>90th percentile) was 0.81 for a 1-kg increase in birth weight, and that an association between birth weight and high HbA1c was seen in the female, but not the male subgroup [21]. Other previous studies have also shown a strong association between low birth weight and adult-onset diabetes in women but not in men [22,23]. These sex differences may be partially explained by greater survival of females exposed to under-nutrition in utero [24] or by sexual dimorphism in susceptibility to develop diabetes [25]. However, in contrast to these previous findings, we found an association between birth weight and HbA1c not in women but in men. Although the reason for this contradictory finding is unknown, race- or ethnicity-based differences in the study participants between our and the previous study cohorts may be an important factor because the prevalence of diabetes mellitus is much lower in Japanese women compared with Western women [26]. Further studies are needed to clarify the underlying cause of these inconsistent findings.

Adult systolic BP has been shown to be inversely related to birth weight [27]. The present study indicated that birth weight was associated with diastolic BP only in the female subgroup. Previous studies have demonstrated that the association between birth weight and adult BP in women was greater than [28] or equal to [29] that in men. BP is affected by cigarette smoking [30,31], alcohol intake [32,33], and obesity [34], which are less common in Japanese women than in men [35], suggesting the possibility of a high influence of birth weight on future blood pressure in women in the present study.

In the present study, we found that birth weight was significantly associated with diastolic, but not systolic, BP. It has been reported that diastolic BP is a more sensitive marker of vascular endothelial dysfunction compared with systolic BP [36,37], and that low birth weight is associated with decreased endothelial progenitor cell numbers and nitric oxide levels [38]. Therefore, it may be that low birth weight is a risk factor for vascular endothelial dysfunction, consequently diastolic BP could be an early marker of endothelial dysfunction.

The present study has some limitations. First, the population was restricted to middle-aged and elderly Japanese workers; therefore, our findings may not be generalizable to younger populations or other ethnicities. Second, 67% of the target population (2275 people) declined to participate in the study or were excluded due to missing data, which may have resulted in selection bias. Third, the study relies on self-reported measures of birth weight. Fourth, the lack of information concerning factors related to BNP levels, such as the levels of other natriuretic peptides, the proportion of smokers and the results of electrocardiography and echocardiography examinations, may have masked the association between birth weight and BNP. Fifth, the population in the present study is healthy enough to work so that the prevalence of atherosclerotic risk factors is low and BNP levels are within almost normal range. This might lead to miss the association of birth weight with atherosclerotic risk factors and with BNP levels. In the future, a prospective study including a different race and using non-self-reported birth weight data will be necessary to further improve our understanding of the association between birth weight and atherosclerotic risk factors.

Conclusion

In the present study, we found no association between birth weight and plasma BNP level, although an inverse relationship between birth weight and HbA1c in male, and diastolic BP in female, Japanese workers aged 40–70 years was observed. Although this study included some limitations and some findings were inconsistent with those of previous studies, our findings suggest that birth weight may partially predict the future risk factors for atherosclerosis, including BP and HbA1c.

BMI: Body mass index; BP: blood pressure; WBC: white blood cell; RBC: red blood cell; HDL: high-density lipoprotein cholesterol; LDL: low-density lipoprotein cholesterol; FBG: fasting blood glucose; BNP: B-type natriuretic peptide

Table 1: Characteristics of the study participants.

BNP: B-type natriuretic peptide, BMI: Body mass index; BP: blood pressure; WBC: white blood cell; RBC: red blood cell; HDLC: high-density lipoprotein cholesterol; LDLC: low-density lipoprotein cholesterol; FBG: fasting blood glucose

Table 2: Results of the Jonckheere–Terpstra trend test for the characteristics of the participants according to birth-weight category and sex.

BMI: Body mass index; WBC: white blood cell; HDLC: high-density lipoprotein cholesterol; BP: blood pressure; BNP: B-type natriuretic peptide

Table 3: Results of the multiple linear regression analysis with hemoglobin A1c as the dependent variable in the male participants.

BMI: Body mass index; WBC: white blood cell; BP: blood pressure; BNP: B-type natriuretic peptide; LDLC: low-density lipoprotein cholesterol; HDLC: high-density lipoprotein cholesterol

Table 4: Results of the multiple linear regression analysis with diastolic blood pressure as the dependent variable in the female participants.

Acknowledgements

This work was supported partly by Astellas Academic Support.

Conflicts of Interest

The authors declare no conflicts of interest associated with this manuscript.

Author Contributions

Tatsuhiko Azegami: Conception, Formal analysis, Investigation, Writing – Original Draft, Supervision, Project administration

Ayano Murai-Takeda: Supervision

Yasunori Sato: Formal analysis, Supervision

Hiroshi Itoh: Supervision

Masaaki Mori: Supervision, Funding acquisition

References

1. World Health Organization. Global Nutrition Targets 2025: Low Birth Weight Policy Brief (WHO/NMH/NHD/14.5). Geneva: World Health Organization; 2014
2. Ferrer M, Fernandez-Britto JE, Bacallao J and Perez H. Development of hypertension in a cohort of Cuban adolescents. MEDICC Rev 17 (2015): 41-47.
3. Jarvelin MR, Sovio U, King V, Lauren L, Xu B, McCarthy MI, Hartikainen AL, Laitinen J, Zitting P, Rantakallio P and Elliott P. Early life factors and blood pressure at age 31 years in the 1966 northern Finland birth cohort. Hypertension 44 (2004): 838-846.
4. Silverwood RJ, Pierce M, Hardy R, Sattar N, Whincup P, Ferro C, Savage C, Kuh D and Nitsch D. Low birth weight, later renal function, and the roles of adulthood blood pressure, diabetes, and obesity in a British birth cohort. Kidney Int 84 (2013): 1262-1270.
5. Kanda T, Takeda A, Hirose H, Abe T, Urai H, Inokuchi M, Wakino S, Tokumura M, Itoh H and Kawabe H. Temporal trends in renal function and birthweight in Japanese adolescent males (1998-2015). Nephrol Dial Transplant 33 (2018): 304-310.
6. Kawabe H, Shibata H, Hirose H, Tsujioka M, Saito I and Saruta T: Sexual differences in relationships between birth weight or current body weight and blood pressure or cholesterol in young Japanese students. Hypertens Res 22 (1999): 169-172.
7. Cooper R and Power C. Sex differences in the associations between birthweight and lipid levels in middle-age: findings from the 1958 British birth cohort. Atherosclerosis 200 (2008): 141-149.
8. Pilgaard K, Faerch K, Carstensen B, Poulsen P, Pisinger C, Pedersen O, Witte DR, Hansen T, Jorgensen T and Vaag A. Low birthweight and premature birth are both associated with type 2 diabetes in a random sample of middle-aged Danes. Diabetologia 53 (2010): 2526-2530.
9. Olaiya MT, Wedekind LE, Hanson RL, Sinha M, Kobes S, Nelson RG, Baier LJ and Knowler WC. Birthweight and early-onset type 2 diabetes in American Indians: differential effects in adolescents and young adults and additive effects of genotype, BMI and maternal diabetes. Diabetologia 62 (2019): 1628-1637.
10. Saito Y, Nakao K, Itoh H, Yamada T, Mukoyama M, Arai H, Hosoda K, Shirakami G, Suga S, Minamino N et al. Brain natriuretic peptide is a novel cardiac hormone. Biochem Biophys Res Commun 158 (1989): 360-368.
11. Sudoh T, Kangawa K, Minamino N and Matsuo H. A new natriuretic peptide in porcine brain. Nature 332 (1988): 78-81.
12. Tamura N, Ogawa Y, Chusho H, Nakamura K, Nakao K, Suda M, Kasahara M, Hashimoto R, Katsuura G, Mukoyama M, Itoh H, Saito Y, Tanaka I, Otani H and Katsuki M. Cardiac fibrosis in mice lacking brain natriuretic peptide. Proc Natl Acad Sci U S A 97 (2000): 4239-4244.
13. Yamahara K, Itoh H, Chun TH, Ogawa Y, Yamashita J, Sawada N, Fukunaga Y, Sone M, Yurugi-Kobayashi T, Miyashita K, Tsujimoto H, Kook H, Feil R, Garbers DL, Hofmann F and Nakao K. Significance and therapeutic potential of the natriuretic peptides/cGMP/cGMP-dependent protein kinase pathway in vascular regeneration. Proc Natl Acad Sci U S A 100 (2003): 3404-3409.
14. Ogawa Y, Itoh H, Tamura N, Suga S, Yoshimasa T, Uehira M, Matsuda S, Shiono S, Nishimoto H and Nakao K. Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene. J Clin Invest 93 (1994): 1911-1921.
15. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA and Breathing Not Properly Multinational Study I. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med, 347 (2002): 161-167.
16. Tsutamoto T, Wada A, Maeda K, Hisanaga T, Maeda Y, Fukai D, Ohnishi M, Sugimoto Y and Kinoshita M. Attenuation of compensation of endogenous cardiac natriuretic peptide system in chronic heart failure: prognostic role of plasma brain natriuretic peptide concentration in patients with chronic symptomatic left ventricular dysfunction. Circulation 96 (1997): 509-516.
17. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA and Vasan RS. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 350 (2004): 655-663.
18. Prickett TCR, Darlow BA, Troughton RW, Cameron VA, Elliott JM, Martin J, Horwood LJ and Espiner EA. New Insights into Cardiac and Vascular Natriuretic Peptides: Findings from Young Adults Born with Very Low Birth Weight. Clin Chem 64 (2018): 363-373.
19. Prickett TCR, Spittlehouse JK, Miller AL, Liau Y, Kennedy MA, Cameron VA, Pearson JF, Boden JM, Troughton RW and Espiner EA. Contrasting signals of cardiovascular health among natriuretic peptides in subjects without heart disease. Sci Rep 9 (2019): 12108.
20. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C and Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 303 (1991): 1019-1022.
21. Al Salmi I, Hoy WE, Kondalsamy-Chennakesavan S, Wang Z, Gobe GC, Barr EL and Shaw JE. Disorders of glucose regulation in adults and birth weight: results from the Australian Diabetes, Obesity and Lifestyle (AUSDIAB) Study. Diabetes Care 31(2008): 159-164.
22. Zimmermann E, Gamborg M, Sorensen TI and Baker JL. Sex Differences in the Association Between Birth Weight and Adult Type 2 Diabetes. Diabetes 64 (2015): 4220-4225.
23. Yarmolinsky J, Mueller NT, Duncan BB, Chor D, Bensenor IM, Griep RH, Appel LJ, Barreto SM and Schmidt MI. Sex-specific associations of low birth weight with adult-onset diabetes and measures of glucose homeostasis: Brazilian Longitudinal Study of Adult Health. Sci Rep 6 (2016): 37032.
24. Lee C. In utero exposure to the Korean War and its long-term effects on socioeconomic and health outcomes. J Health Econ 33 (2014): 76-93.
25. Kava RA, West DB, Lukasik VA and Greenwood MR. Sexual dimorphism of hyperglycemia and glucose tolerance in Wistar fatty rats. Diabetes 38 (1989): 159-163.
26. Spanakis EK and Golden SH. Race/ethnic difference in diabetes and diabetic complications. Curr Diab Rep 13 (2013): 814-823.
27. Barker DJ, Osmond C, Golding J, Kuh D and Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ 298 (1989): 564-567.
28. Singh GR and Hoy WE. The association between birthweight and current blood pressure: a cross-sectional study in an Australian Aboriginal community. Med J Aust 179 (2003): 532-535.
29. Lawlor DA, Ebrahim S and Davey Smith G: Is there a sex difference in the association between birth weight and systolic blood pressure in later life? Findings from a meta-regression analysis. Am J Epidemiol 156 (2002): 1100-1104.
30. Bowman TS, Gaziano JM, Buring JE and Sesso HD. A prospective study of cigarette smoking and risk of incident hypertension in women. J Am Coll Cardiol 50 (2007): 2085-2092.
31. Thuy AB, Blizzard L, Schmidt MD, Luc PH, Granger RH and Dwyer T. The association between smoking and hypertension in a population-based sample of Vietnamese men. J Hypertens 28 (2010): 245-250.
32. Klatsky AL, Friedman GD, Siegelaub AB and Gerard MJ. Alcohol consumption and blood pressure. Kaiser-Permanente Multiphasic Health Examination data. N Engl J Med 296 (1977): 1194-1200.
33. Marmot MG, Elliott P, Shipley MJ, Dyer AR, Ueshima H, Beevers DG, Stamler R, Kesteloot H, Rose G and Stamler J. Alcohol and blood pressure: the INTERSALT study. BMJ 308 (1994): 1263-1267.
34. Kannel WB, Brand N, Skinner JJ, Jr., Dawber TR and McNamara PM. The relation of adiposity to blood pressure and development of hypertension. The Framingham study. Ann Intern Med 67 (1967): 48-59.
35. Tsugane S: Alcohol, smoking, and obesity epidemiology in Japan. J Gastroenterol Hepatol 27 Suppl 2 (2012): 121-126.
36. Maggio AB, Farpour-Lambert NJ, Montecucco F, Pelli G, Marchand LM, Schwitzgebel V, Mach F, Aggoun Y and Beghetti M. Elevated E-selectin and diastolic blood pressure in diabetic children. Eur J Clin Invest 42 (2012): 303-309.
37. Bhandari SS, Davies JE, Struck J and Ng LL. Plasma C-terminal proEndothelin-1 (CTproET-1) is affected by age, renal function, left atrial size and diastolic blood pressure in healthy subjects. Peptides 52 (2014): 53-57.
38. Souza LV, De Meneck F, Oliveira V, Higa EM, Akamine EH and Franco MDC. Detrimental Impact of Low Birth Weight on Circulating Number and Functional Capacity of Endothelial Progenitor Cells in Healthy Children: Role of Angiogenic Factors. J Pediatr 206 (2019): 72-77 e71.