Cardiovascular Risk Factors in Adolescents Born Preterm Marika Sipola-Leppänen, Marja Vääräsmäki, Marjaana Tikanmäki, Petteri Hovi, Satu Miettola, Aimo Ruokonen, Anneli Pouta, Marjo-Riitta Järvelin and Eero Kajantie Pediatrics 2014;134;e1072; originally published online September 1, 2014; DOI: 10.1542/peds.2013-4186

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/134/4/e1072.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Cardiovascular Risk Factors in Adolescents Born Preterm WHAT’S KNOWN ON THIS SUBJECT: Adolescents and adults born early preterm have higher blood pressure and altered glucose metabolism compared with their term born peers. Evidence of an atherogenic lipid profile is inconsistent. Whether these risks apply to those born less preterm is not known. WHAT THIS STUDY ADDS: In adolescence, girls have higher blood pressure and boys a more atherogenic lipid profile than their term born peers. Overall, our results are consistent with a dose-response relationship between shorter length of gestation and increasing levels of cardiovascular risk factors.

abstract BACKGROUND: Adolescents and adults born as small preterm infants show more pronounced risk factors of cardiovascular disease. Whether similar risks apply across all degrees of preterm birth is poorly known. METHODS: We studied the association between preterm birth and cardiovascular risk factors in 6642 16-year-old adolescents of the populationbased Northern Finland Birth Cohort 1986. Of these, 79 (1.2%) were born at ,34 gestational weeks (early preterm), 238 (3.6%) at 34 to 36 weeks (late preterm), and 6325 at term (controls). RESULTS: Girls born early preterm had 6.7 mm Hg (95% confidence interval: 3.1–10.2) higher systolic blood pressure (BP) and 3.5 mm Hg (1.1–5.8) higher diastolic BP, but no difference in serum lipid levels compared with control girls. Boys showed no differences in BP, but boys born early preterm had 6.7% (0.2%–13.7%) higher total cholesterol, 11.7% (2.1%–22.3%) higher low-density lipoprotein cholesterol, and 12.3% (3.1%–22.4%) higher apolipoprotein B concentrations. The differences were similar (BP) or stronger (lipids) when adjusted for maternal smoking, birth weight SD score, parental education, pubertal stage, BMI, and lifestyle. There were similar associations with length of gestation as a continuous variable. Accordingly, mean differences between late preterm and controls were in the same direction but weaker, although most were not statistically significant. CONCLUSIONS: Preterm birth was associated with elevated BP in adolescent girls and an atherogenic lipid profile in boys. Because these associations were strongest among those born early preterm, our findings are consistent with a dose-response relationship between shorter length of gestation and cardiovascular risk factors. Pediatrics 2014;134: e1072–e1081

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AUTHORS: Marika Sipola-Leppänen, MD,a,b,c Marja Vääräsmäki, MD, PhD,d,e Marjaana Tikanmäki, MD,a,b Petteri Hovi, MD, PhD,a,f Satu Miettola, MD,a,d Aimo Ruokonen, MD, PhD,g,h Anneli Pouta, MD, PhD,d,e Marjo-Riitta Järvelin, MD, PhD,b,e,i,j,k and Eero Kajantie, MD, PhDa,d,f Departments of aChronic Disease Prevention, Diabetes Prevention Unit and eChildren, Young People and Families, National Institute for Health and Welfare, Oulu, Finland; hDepartment of Clinical Chemistry, bInstitute of Health Sciences, and jBiocenter Oulu, University of Oulu, Oulu, Finland; cDepartment of Pediatrics and Adolescence, kUnit of Primary Care, and gNordLab Oulu, Oulu University Hospital, Oulu, Finland; dDepartment of Obstetrics and Gynecology, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland; fHospital for Children and Adolescents, Helsinki University Central Hospital, Helsinki, Finland; and iDepartment of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom KEY WORDS premature birth, blood pressure, hypertension, dyslipidemias, glucose metabolism ABBREVIATIONS ApoA1—apolipoprotein A1 ApoB—apolipoprotein B BP—blood pressure CI—confidence interval HDL-C—high-density lipoprotein cholesterol HOMA-IR—homeostasis model assessment values for insulin resistance LDL-C—low-density lipoprotein cholesterol METh—metabolic equivalent hour SGA—small for gestational age TC—total cholesterol TG—triglyceride VLBW—very low birth weight Dr Sipola-Leppänen carried out initial analyses and drafted the initial manuscript; Drs Vääräsmäki and Kajantie carried out initial analyses, reviewed and revised the manuscript, and supervised the writing process; Drs Tikanmäki, Hovi, and Miettola reviewed and revised the manuscript; Drs Ruokonen, Pouta, and Järvelin coordinated and supervised data collection and critically reviewed the manuscript; and all authors approved the final manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2013-4186 doi:10.1542/peds.2013-4186 Accepted for publication Jul 8, 2014 (Continued on last page)

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Approximately 11% of all live-born infants worldwide are born preterm1–4 (ie, before 37 weeks of gestation). At least those born smallest and most immature show as children and adults more pronounced cardiovascular risk factors, for example increased blood pressure (BP),5–17 reduced glucose tolerance,7,11 and increased insulin resistance,7,8,18 compared with those born at term. As to plasma lipids, the results are mixed.7,8,12,17,19,20 Some associations between preterm birth and cardiovascular risk factors have been suggested to differ in men and women. For example, the difference in BP between those born with very low birth weight (VLBW; ,1500 g) and those born at term may be greater in women than in men.6,10,17 Few studies have been carried out to assess the long-term health of late/ moderately preterm infants, although they constitute the great majority of preterminfants.Forexample,intheUnited States, up to 74% of preterm infants are born late preterm (34–36 weeks of gestation),21,22 and in Europe over 80% are moderately preterm (32–36 weeks).22,23 Results of the few existing studies suggest a dose-response relationship between the degree of prematurity and higher BP in young adults.13,24 Alarmingly, studies in older adults born preterm suggest higher rates of disease, including type 2 diabetes25–27 and stroke.28 These risks are likely to be largely attributable to late/moderately preterm births. The underlying mechanisms and preceding risk factors are, however, poorly known. We hypothesized that adolescents born preterm (within the whole range of prematurity) have higher BP, impaired glucose regulation, and a more atherogenic lipid profile than full-term controls. We also hypothesized that the association between preterm birth and these outcomes may be different in boys and girls. In contrast to most previous studies concerning the later outcomes of

preterm birth, we tested these hypotheses in a birth cohort study based on an unselected population born within a defined geographical area.

METHODS The Original Birth Cohort The Northern Finland Birth Cohort 1986 is longitudinal cohort of all births in the 2 northernmost provinces of Finland with expected delivery date between July 1, 1985, and June 30, 1986. The data are prospectively collected from the first antenatal clinic visit onwards. Perinatal data came from health care records and questionnaires. Because length of gestation is a key predictive variable, we made a special effort to determine it as accurately as possible, as described in the Supplemental Methods. Definitions of hypertensive disorders of pregnancy, gestational diabetes, and maternal smoking have been described.29–31 Birth weight SD score was calculated on the basis of Finnish standards32; small for gestational age (SGA) was defined as more than 2 SD below the mean. Study Participants The latest clinical examination of the offspring was conducted in 2001–2002,

in which 74% (n = 6798) of 16-year-old cohort members residing in Finland participated (Fig 1). In our analysis, we included those 6642 subjects with data on length of gestation and at least 1 of the following variables: BMI, waist circumference, BP, serum lipid levels, and plasma glucose and serum insulin concentrations. In total, 79 (1.2%) of the study subjects were born before 34 weeks of gestation (early preterm), 238 (3.6%) at 34 to 36 weeks inclusive (late preterm), and 6325 (95.2%; controls) were born at 37 weeks or later. We compared those included in analyses with the members of the original cohort not included. In those not included, the mean length of gestation was 0.27 weeks shorter (P , .001), the proportion of individuals born preterm larger (P , .001; Fig 1), birth weight 77 g lower (P , .001), birth weight SD score 0.1 SD lower (P , .001), and the proportion of those born SGA higher (P = .006). Clinical Examination at 16 Years of Age The clinical examination has been described.29 Briefly, systolic and diastolic BPs (mm Hg) were measured from the

FIGURE 1 Participants in the study. GA, gestational age.

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right arm after 15 minutes of rest with the subject sitting, using an automated oscillometric device (Omron 705CP, Omron Corporation, Shiokoji, Horikawa, Kyoto, Japan) or, if this failed, a mercury sphygmomanometer. The mean of 2 measurements taken 2 minutes apart was calculated. Prehypertension was classified as BP $120/80 mm Hg and hypertension as $140/90 mm Hg.33

and 5 METhs per week for moderateto-vigorous physical activity. Pubertal stage was self-assessed with the help of drawings representing different stages of Tanner’s classification.37 All subjects and their guardians provided written informed consent, and the Ethics Committee of the University of Oulu approved the study.

Blood samples were collected between 8:00 AM and 11:00 AM after an overnight fast. Samples of serum for insulin measurement were stored at 220°C and analyzed by radioimmunoassay with commercial reagents (Pharmacia Diagnostics, Uppsala, Sweden) within 7 days. Plasma glucose (enzymatic reference method with hexokinase), and serum total cholesterol (TC), high-density and low-density lipoprotein cholesterol (HDL-C and LDL-C), triglycerides (TGs; enzymatic, colorimetric method), and apolipoprotein A1 and B (ApoA1 and ApoB; immunoturbidimetric method) concentrations were analyzed within 24 hours of sampling at Oulu University Hospital laboratory by using a Cobas Integra 700 automatic analyzer (Roche Diagnostics, Basel, Switzerland).29,34 Homeostasis model assessment values for insulin resistance (HOMA-IR) were calculated from paired fasting glucose and insulin levels by using the validated calculator program available at www.dtu.ox.ac.uk.35

Statistical Methods

The participants and their parents completed questionnaires on medical history, smoking (“Have you ever smoked regularly?”), physical activity, and childhood socioeconomic status, for which we used educational attainment of the more educated parent (categorized into 4 levels). Physical activity was assessed on the basis of questions on daily time spent in commuting and weekly time in light or moderate-to-vigorous physical activity36 and transformed to total metabolic equivalent hours (METhs) per week, assuming 3 METhs per week for light, 4 METhs per week for commuting, e1074

Our main predictive variable was length of gestation, categorized into 3 groups: (1) 33weeks6days orlesscorresponding to “early preterm,” (2) 34 weeks 0 days to 36 weeks 6 days, corresponding to “late preterm” as defined in an American Academy of Pediatrics Clinical Report,38 and (3) a control group, subjects born at 37 weeks 0 days or later. We refer to this group as “term,” even though the group includes 250 subjects technically born postterm (at 42 weeks 1 day or later). In addition, we report the analyses with length of gestation as a continuous variable. All main outcome variables except BPs were logarithmically transformed to normalize their distributions. Descriptive data were compared by using Student’s t test or the x 2 test. Group means of outcome variables were compared by linear regression. The full regression model included age, BMI, height, birth weight SD score, maternal smoking during pregnancy, educational attainment of the more educated parent (dummy coded, with a separate category of those with missing data), smoking of the subject, physical activity, and Tanner pubertal stage. We performed analyses separately in boys and girls, because of statistically significant interactions between early preterm birth and gender as regards LDL-C (P = .02), ApoB (P = .03), and systolic BP levels (P = .009), and between late preterm birth and gender as regards HOMA-IR (P = .036). All P values are 2-tailed.

RESULTS Clinical Characteristics The pre- and neonatal characteristics of the groups are presented in Table 1 and characteristics at a mean age of 16.0 years (range, 14.6–17.0) are presented in Supplemental Table 4. Subjects born preterm were 0.1 years older than controls. Parents of early preterm subjects were less educated. Weight, height, BMI, waist circumference, and waist-hip ratio were similar in the individual genders in the preterm groups and their controls (Supplemental Table 4), even when adjusted for birth weight SD score, age, parental education, smoking, and physical activity. Girls born preterm were at an earlier pubertal stage than controls. Among boys, timing of puberty was similar between the groups. Blood Pressure Girls born early preterm had higher systolic and diastolic BPs than control girls (Table 2; Fig 2). The difference was similar after full adjustment. They were also more likely to have prehypertension or hypertension (Supplemental Table 4): odds ratio, 2.7 (95% confidence interval [CI]: 1.4–5.2) when adjusted as in the full model. Among boys, there were no differences in mean BP (Table 3; Fig 2). We also used length of gestation as a continuous variable; among girls, 1 week of gestation longer corresponded to 0.5 mm Hg (95% CI: 0.3–0.8) lower systolic BP, and 0.2 mm Hg (95% CI: 0.0–0.3) lower diastolic BP (Supplemental Table 5). There was no quadratic relationship between length of gestation and BP in either gender (all P . .1). Lipid Profile Among girls, lipid profiles were similar in all study groups (Table 2; Fig 2). As for boys, those born early preterm had higher mean TC, LDL-C, and ApoB concentrations than their controls. Boys

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TABLE 1 Pre- and Neonatal Characteristics of the Participants Early Preterm, n = 79

Late Preterm, n = 238

Boys, n (%) 33 (41.8) 131 (55.0) Multiple births, n (%) 22 (27.8)*** 43 (18.1)*** Maternal smoking during pregnancy, n (%) 19 (24.0) 64 (26.9)** Gestational diabetes, n (%) 2 (2.5) 5 (2.1) Gestational hypertension, n (%) 17 (21.5)** 34 (14.3)* Preeclampsia, n (%) 12 (15.2)*** 24 (10.1)*** Length of gestation, weeks 32.0 (1.6)*** 36.0 (0.8)*** Length of gestation determined bya: Last menstrual period, n (%) 37 (46.8) 131 (55.0) Ultrasound, n (%) 41 (51.9) 104 (43.7) Method equivocal, n (%) 1 (1.3) 3 (1.3) Birth weight, g 1788 (461)*** 2696 (494)*** Birth weight SD score 20.82 (1.4)*** 20.65 (1.2)*** SGA, n (%) 15 (19.0)*** 21 (8.8)*** Supplementary oxygen, n (%) 59 (74.7)*** 79 (33.2)*** CPAP, n (%) 45 (57.0)*** 38 (16.0)*** Respirator treatment, n (%) 31 (39.2)*** 17 (7.1)*** Length of neonatal hospital stay, days 41.4 (47.6)*** 13.7 (31.5)***

Controls, n = 6325

Data Missing

3105 (49.1) 86 (1.4) 1203 (19.0) 83 (1.3) 653 (10.3) 289 (4.6) 40.0 (1.2)

0/0/0 0/0/0 1/2/34 27/59/476 0/11/110 0/11/110 0/0/0

3673 (58.1) 2560 (40.5) 92 (1.5) 3619 (476) 0.08 (1.0) 114 (1.8) 179 (2.8) 74 (1.2) 25 (0.4) 6.7 (4.8)

0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0 0/0/0

Numbers are mean (SD) or n (%).CPAP, continuous positive airway pressure. a See Supplemental Methods for further description. P value for difference compared with controls: * P , .05; ** P , .01; *** P , .001.

born preterm also had higher TG levels, but the difference reached statistical significance only in late preterm boys. Concentrations of HDL-C and ApoA1 were similar between groups (Fig 2). The value of P for interaction between early preterm birth and gender as regards LDL-C was 0.02, and for ApoB it was 0.03. Among boys, 1 week of gestation longer corresponded to 0.5% (95% CI: 0.1%–0.9%) lower TC, 1.0% (0.4%–1.6%) lower LDL-C, and 1.0% (0.4%–1.5%) lower ApoB, adjusted by variables in the full model (Supplemental Table 5). There were no quadratic relationships between the length of gestation and lipid concentrations (all P . .1). Glucose Metabolism Boys born late preterm had higher insulin levels and HOMA-IR values than boys born at term. There were no other differences in glucose or insulin concentrations in either gender (Table 3; Fig 2). Perinatal Factors Accompanying Preterm Birth We reran comparisons of the preterm groups with controls after excluding

subjects (1) born postterm and (2) with uncertain length of gestation (n = 221, as described in Methods). The results remained similar. We further reran the comparisons after excluding those born SGA. The differences in the main outcomes strengthened; adjusted for variables in the full model, systolic BP was 8.2 mm Hg (95% CI: 4.3 to 12.3) and diastolic BP 4.1 mm Hg (1.5 to 6.7) higher in girls born early preterm than in their controls. Among boys born early preterm, levels of TC were 10.4% (95% CI: 2.7% to 18.6%) higher, those of LDL-C 19.3% (7.7% to 32.2%), and those of ApoB 18.0% (7.2% to 29.9%) higher than in their controls. There was no difference between subjects born preterm SGA and the remaining subjects born preterm (P . .09). In addition, we reran the analysis with adjustment only for birth weight SD score to assess the effect of birth weight separately from the effect of other covariates; in girls born early preterm, BPs were 7.1 mm Hg (3.6 to 10.7)/3.6 mm Hg (1.2 to 6.0) higher than in controls. In boys born early preterm, TC was 5.4% (21.0% to 12.2%) higher, LDL-C was 10.3% (0.9% to

20.6%) higher, ApoB was 8.7% (20.2% to 18.4%) higher, and TG 16.7% (0.1% to 35.9%) higher compared with controls. In boys born late preterm, TG was 12.8% (4.2% to 22.0%) higher, fasting insulin 13.2% (3.1% to 24.3%) higher, and HOMA-IR 12.6% (2.6% to 23.6%) higher than in controls. Furthermore, we reran the analyses after (1) excluding subjects exposed to maternal gestational diabetes and (2) excluding those exposed to maternal hypertension or preeclampsia, and the results remained similar. Moreover, after further adjustment of the full regression model for maternal gestational diabetes, preeclampsia, and gestational or chronic hypertension, the results again remained similar. Current Disability and Chronic Disease Of the subjects, 32 (2 early preterm and 30 controls) had cerebral palsy or mental or physical disability, and 19 had type 1 diabetes (1 late preterm and 18 controls). We reran the analysis after exclusion of all these subjects. The differences in BP among girls were attenuated being 6.0 mm Hg (95% CI: 2.5 to 9.4)/2.7 mm Hg (95% CI: 0.4 to 5.0) higher in the early preterm group and 1.4 mm Hg (95% CI: 20.9 to 3.6)/0.5 mm Hg (95% CI: 21.0 to 2.0) higher in the late preterm group compared with controls. Otherwise the differences remained similar.

DISCUSSION There are 2 main findings in this study. First, our results suggest that in adolescence the association between preterm birth and cardiovascular risk factors seems to be different in girls and boys. Among girls, preterm birth conferred a risk of higher BP. Among boys, it was associated with an atherogenic lipid profile and reduced insulin sensitivity. Second, our findings are consistent with a dose-response

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TABLE 2 Means (SD) in Controls and Mean Differences in BP and Biochemical Characteristics in Girls Controls, Mean (SD)

Systolic BP, mm Hg

109.9 (10.7)

Diastolic BP, mm Hg

66.8 (7.2)

TC, mmol/L

4.4 (1.2)

LDL-C, mmol/L

2.2 (1.3)

TGs, mmol/L

0.77 (1.5)

ApoB, mmol/L

0.66 (1.3)

Insulin, mU/L

9.8 (1.5)

HOMA-IR

1.38 (0.74)

Modela

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Early Preterm

Late Preterm

N

Mean Differenceb

95% CI

Mean Differenceb

95% CI

6.8*** 6.7*** 6.8*** 6.4*** 6.4*** 3.5** 3.5** 3.5** 3.1** 3.1** 2.3 2.5 2.5 1.9 1.8 21.0 20.8 20.8 21.6 20.7 27.0 27.4 27.4 210.2 24.3 1.4 1.5 1.5 0.4 1.8 0.2 0.9 1.6 22.5 23.1 20.1 0.2 1.2 22.9 23.8

3.3 to 10.3 3.2 to 10.2 3.4 to 10.2 3.0 to 9.8 3.0 to 9.8 1.1 to 5.9 1.1 to 5.8 1.3 to 5.8 0.8 to 5.4 0.9 to 5.4 23.0 to 8.0 22.8 to 8.1 22.8 to 8.0 23.3 to 7.5 23.6 to 7.6 28.3 to 6.9 28.1 to 7.2 28.1 to 7.0 28.8 to 6.2 28.3 to 7.5 217.8 to 5.2 218.2 to 4.7 217.9 to 4.4 220.4 to 1.4 215.6 to 8.5 25.5 to 8.8 25.4 to 8.9 25.3 to 8.8 26.3 to 7.7 25.3 to 9.5 211.2 to 13.1 210.5 to 13.9 29.4 to 13.9 213.0 to 9.2 214.0 to 9.3 213.5 to 15.2 213.1 to 15.6 211.6 to 15.9 215.1 to 11.1 216.0 to 10.1

1.9 1.7 1.9 1.7 1.5 0.7 0.6 0.7 0.5 0.7 0.7 0.9 0.9 0.4 0.0 1.8 2.0 2.0 1.2 1.3 3.8 3.3 3.4 0.2 1.1 1.1 1.2 1.2 0.3 0.9 4.6 5.7 6.6 2.5 3.7 3.5 4.5 5.0 1.1 3.0

20.3 to 4.2 20.6 to 3.9 20.3 to 4.0 20.5 to 3.9 20.7 to 3.8 20.8 to 2.3 20.9 to 2.1 20.8 to 2.1 21.0 to 1.9 20.8 to 2.2 22.7 to 4.3 22.5 to 4.5 22.5 to 4.4 23.0 to 3.9 23.5 to 3.7 23.2 to 7.0 23.0 to 7.2 22.9 to 7.1 23.7 to 6.3 23.7 to 6.7 24.2 to 12.4 24.6 to 11.9 24.3 to 11.8 27.2 to 8.4 26.7 to 9.7 23.6 to 6.0 23.4 to 6.2 23.4 to 6.0 24.3 to 5.1 23.9 to 5.9 23.4 to 13.3 22.4 to 14.1 21.2 to 14.9 25.0 to 10.5 24.2 to 12.2 25.4 to 13.4 24.6 to 14.4 23.6 to 14.4 27.2 to 10.2 25.8 to 12.5

3295 3291 3279 3279 3049 3295 3291 3279 3279 3049 3122 3117 3106 3106 2877 3122 3117 3106 3106 2877 3122 3117 3106 3106 2877 3189 3182 3169 3169 2943 3140 3136 3124 3124 2897 2880 2876 2865 2865 2663

HOMA-IR, homeostasis model assessment for insulin resistance. a Models: 0, Unadjusted; 1, Age; 2, Model 1 + BMI and height; 3, Model 2 + SD for birth weight, maternal smoking during pregnancy, and educational level of more educated parent; 4, Model 3 + smoking of the subject, physical activity, and Tanner Pubertal Stage. b Mean difference as a percentage, except for systolic and diastolic BPs, where the difference is in mm Hg. P values for differences in preterm groups compared with full-term controls: * P , .05; ** P , .01; *** P , .001.

relationship between shorter length of gestation and cardiovascular risk factors; the highest mean levels of these factors were seen among those born early preterm, whereas those born late preterm had intermediate levels that were not always significantly different from those in the group born at term. Accordingly, the associations were also present when length of gestation was used as a continuous variable. These e1076

findings were not explained by background factors such as maternal pregnancy disorders, fetal growth, family socioeconomic status, or maternal smoking during pregnancy, or by current age, pubertal stage, body size, smoking, or physical activity. Blood Pressure Our results on BP are partly consistent with those in previous studies showing

that adolescents and adults born preterm with VLBW have higher systolic and/or diastolic BP than those born at term.6,7,9,10,12,13,39,40 Some investigators have reported that this difference is greater among women than among men,6,10 which was confirmed in a recent meta-analysis.17 Although we found no difference among boys, it may become apparent later in life. The association between late preterm birth and

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FIGURE 2 Mean differences and 95% CIs (error bars) in preterm groups compared with term-born controls (zero line) adjusted for age, birth weight, BMI, height, maternal smoking during pregnancy, educational level of the more educated parent, smoking of the subject, physical activity, and pubertal stage.

later BP has been less well studied. In a cohort born in 1966 in the same geographical area as the present cohort, women born preterm had higher systolic BP than those born at term.24 This association was not seen among men. However, in a Swedish cohort study that included only young men, those born between 33 and 36 weeks of gestation had higher systolic BP than those born at term.13 Both studies revealed a doseresponse relationship, with increasing BP with decreasing gestational age at birth. Elevated BP is associated strongly with cardiovascular mortality 41 and

is currently the globally leading risk factor of death and disease.42 Based on population studies, the difference of 6.8 mm Hg in systolic BP we found between girls born early preterm and girls born at term translates to 16% higher mortality from coronary heart disease and 26% higher mortality from stroke.43 Lipid Profile We found that adolescent boys born early preterm have higher levels of serum TC, LDL-C, and ApoB than boys born at term. ApoB is the primary apolipoprotein component of LDL-C and an even more accurate indicator of

cardiovascular risk. Previous findings concerning later life serum lipid levels of those born preterm are inconsistent. Several investigators have found no relationship between preterm birth/lower gestational age and standard serum lipid measurements in adults.8,11,19,20,44 However, in a recent meta-analysis, it was concluded that adults born preterm have on average 0.15 mmol/L higher LDL-C concentrations than controls, although this result was driven by previously unpublished data from one of the cohorts.17 This compares to differences we found that correspond to 0.22 mmol/L in the crude and 0.35 mmol/L

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TABLE 3 Means (SD) in Controls and Mean Differences in BP and Biochemical Characteristics in Boys Controls, Mean (SD)

Systolic BP, mm Hg

121.0 (12.1)

Diastolic BP, mm Hg

68.6 (7.9)

TC, mmol/L

4.0 (1.2)

LDL-C, mmol/L

2.1 (1.3)

ApoB, mmol/L

0.63 (1.3)

TGs, mmol/L

0.73 (1.5)

Insulin, mU/L

9.6 (1.6)

HOMA-IR

1.42 (0.93)

Modela

0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4 0 1 2 3 4

Early Preterm

Late Preterm

N

Mean Differenceb

95% CI

Mean Differenceb

95% CI

0.8 0.7 2.1 1.3 0.5 0.4 20.1 0.8 0.3 20.1 5.7 6.7* 7.4* 7.4* 8.5* 10.7* 11.7* 13.1** 12.1** 16.6** 11.2* 12.3** 13.8** 12.2** 15.6** 17.9* 19.2* 22.4** 19.3* 12.9 3.0 5.5 9.5 6.1 22.6 9.1 14.1 18.0 14.3 4.3

27.3 to 5.8 24.8 to 5.8 22.7 to 7.0 23.5 to 6.1 25.4 to 6.3 23.1 to 3.8 23.6 to 3.4 22.5 to 4.0 23.0 to 3.6 24.0 to 3.8 20.7 to 12.4 0.2 to 13.7 1.0 to 14.1 0.7 to 13.8 1.1 to 16.4 1.2 to 21.0 2.1 to 22.3 3.8 to 23.3 2.8 to 22.3 5.4 to 28.9 2.3 to 21.0 3.1 to 22.4 4.9 to 23.5 3.5 to 21.8 5.2 to 27.0 1.3 to 37.3 2.1 to 39.1 5.8 to 41.6 3.1 to 38.0 24.6 to 33.6 212.5 to 21.1 210.6 to 24.5 25.9 to 27.4 28.8 to 23.5 218.1 to 15.7 211.5 to 34.5 28.0 to 41.5 23.1 to 43.6 26.2 to 39.1 218.6to 33.8

1.0 1.3 1.1 0.6 0.5 20.2 20.4 20.5 20.7 20.4 2.0 2.2 1.9 1.8 1.4 4.3 4.4 4.0 3.6 3.2 4.9* 5.0* 4.5* 3.8 3.6 13.8** 13.2** 12.4** 10.4** 9.3* 13.7** 13.8** 12.7** 10.0* 8.6* 13.0* 13.2** 11.5* 9.3* 5.9

21.4 to 3.5 21.0 to 3.7 21.0 to 3.2 21.6 to 2.7 21.6 to 2.7 21.7 to 1.4 21.9 to 1.2 21.9 to 1.0 22.2 to 0.7 21.9 to 1.0 21.2 to 5.3 21.0 to 5.5 21.2 to 5.1 21.3 to 5.0 21.8 to 4.8 20.4 to 9.2 20.2 to 9.3 20.5 to 8.6 20.8 to 1.1 21.5 to 8.1 0.5 to 9.5 0.5 to 9.6 0.3 to 8.9 20.5 to 8.2 20.9 to 8.2 5.2 to 23.0 4.7 to 22.4 4.4 to 21.0 2.5 to 18.9 1.0 to 18.2 4.6 to 23.5 4.7 to 23.7 4.5 to 21.7 1.9 to 18.7 0.2 to 17.6 3.0 to 24.0 3.2 to 24.3 2.4 to 21.4 0.3 to 19.0 23.0 to 15.6

3174 3174 3160 3160 2781 3174 3171 3160 3160 2781 3100 3094 3081 3081 2710 3101 3095 3082 3082 2711 3159 3153 3140 3140 2767 3100 3094 3081 3081 2710 3116 3111 3098 3098 2730 2918 2914 2903 2903 2561

a Models: 0, Unadjusted; 1, Age; 2, Model 1 + BMI and height; 3, Model 2 + SD for birth weight, maternal smoking during pregnancy, and educational level of more educated parent; 4, Model 3 +

smoking of the subject, physical activity, and Tanner Pubertal Stage. Mean difference as a percentage, except for systolic and diastolic BPs, where the difference is in mm Hg. P values for differences in preterm groups compared with full-term controls: * P , .05; ** P , .01; *** P , .001.

b

in the adjusted model. Furthermore, studies involving measurement of lipids after a meal12,45 or detailed lipid profiling by metabolomics17 have indicated a more atherogenic lipid profile in adults born preterm. We believe that these differences among boys are a consequence of preterm birth rather than slow fetal growth, because the difference was stronger when boys born SGA were excluded. A male-specific association between e1078

low birth weight and serum LDL-C levels in Filipino adolescents,46 and TC in young Swedish adults47 suggests that slow fetal growth can have similar genderspecific associations as preterm birth as regards lipid profile later in life. The magnitude of these associations, 0.19 mmol/L for TC47 and 0.26 mmol/L for LDL-C46, is similar to corresponding differences we found between boys born early preterm versus controls (0.23 mmol/L for TC and 0.22 mmol/L for

LDL-C). In addition, among the general population, there is a weak but consistent association between low birth weight and serum TC among men (0.04 mmol/L per kg) that may not exist among women.48 The mechanisms behind these gender differences are not known. In this cohort, girls born at term had slightly higher TC, LDL-C, and ApoB concentrations than boys born at term; in other words, boys born early preterm approached the concentrations

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of girls. These concentrations increase with puberty. Earlier puberty, which has been observed in adolescents born preterm at VLBW,49 could in part explain the gender differences we found. However, in the current study, the self-reported Tanner stages did not suggest an earlier puberty in either gender. Glucose Metabolism Boys born late preterm had higher fasting insulin levels and HOMA-IR values than controls; otherwise we did not find any difference between adolescents born preterm and controls in outcomes used to assess glucose metabolism. Fasting insulin and HOMA-IR may, however, not be sufficiently sensitive indicators of insulin resistance. Studies in prepubertal children18 and young adults7,8,50 born preterm have shown insulin resistance that was clearly indicated by intravenous18,50 and oral glucose tolerance tests, and also higher fasting insulin levels.7 Our findings, together with the results of these studies, are consistent with the hypothesis that preterm birth is associated with impaired glucose regulation later in life.

Possible Mechanisms Although those born preterm had been more often exposed to maternal pregnancy disorders, maternal smoking, or were more often born SGA, these conditions did not in general explain their more pronounced cardiovascular risk factors compared with those born at term. The differences in plasma lipids in boys, however, attenuated slightly when adjusted for birth weight SD score. This suggests that the higher rates of slow fetal growth among those born preterm could in part underlie the higher plasma lipid concentrations in boys born preterm.

subjects born early preterm was too small for detailed subgroup analysis of maternal pregnancy disorders. In addition, missing values exist for some covariates. This may have resulted in less precise estimates. Pubertal stage was self-reported, which may further introduce inaccuracy. However, most, although not all,52,53 previous studies support the validity and reliability of self-assessment throughout pubertal development.54–57

CONCLUSIONS

Adolescents born preterm were less likely to participate in the study, and it is possible that subjects with impairments associated with preterm birth are underrepresented. This would, however, only be expected to result in more conservative estimates. The number of

We found that adolescents born early preterm have more pronounced risk factors of cardiovascular disease than adolescents born at term: girls have higher BP; boys have a more atherogenic lipid profile. Our findings are also consistent with a dose-response relationship between the degree of prematurity and these risk factors, although the specific magnitude of the risk factors in those born late preterm remains to be confirmed. The risk factors we found are modifiable. Therefore, our results prompt vigilance in the promotion of a healthy lifestyle and screening of hypertension and dyslipidemias in children and adults born preterm.

5. Pyhälä R, Räikkönen K, Feldt K, et al. Blood pressure responses to psychosocial stress in young adults with very low birth weight: Helsinki study of very low birth weight adults. Pediatrics. 2009;123(2):731–734 6. Hovi P, Andersson S, Räikkönen K, et al. Ambulatory blood pressure in young adults with very low birth weight. J Pediatr. 2010;156(1):54–59 7. Hovi P, Andersson S, Eriksson JG, et al. Glucose regulation in young adults with very low birth weight. N Engl J Med. 2007; 356(20):2053–2063 8. Dalziel SR, Parag V, Rodgers A, Harding JE. Cardiovascular risk factors at age 30 following pre-term birth. Int J Epidemiol. 2007;36(4):907–915 9. Evensen KA, Steinshamn S, Tjønna AE, et al. Effects of preterm birth and fetal growth

retardation on cardiovascular risk factors in young adulthood. Early Hum Dev. 2009;85 (4):239–245 Hack M, Schluchter M, Cartar L, Rahman M. Blood pressure among very low birth weight (,1.5 kg) young adults. Pediatr Res. 2005;58(4):677–684 Irving RJ, Belton NR, Elton RA, Walker BR. Adult cardiovascular risk factors in premature babies. Lancet. 2000;355(9221):2135–2136 Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-Van de Waal HA. Abnormal lipid profile and hyperinsulinaemia after a mixed meal: additional cardiovascular risk factors in young adults born preterm. Diabetologia. 2008;51(7):1269–1275 Johansson S, Iliadou A, Bergvall N, Tuvemo T, Norman M, Cnattingius S. Risk of high

The differences could also be explained by differences in adolescent lifestyle.51 However, physical activity, smoking, or socioeconomic status did not explain the difference in cardiovascular risk factors in our study. Study Limitations

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(Continued from first page) Address correspondence to Marika Sipola-Leppänen, Department of Chronic Disease Prevention, National Institute for Health and Welfare, PO Box 310, 90101 Oulu, Finland. E-mail: marika.sipola-leppanen@thl.fi PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2014 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Supported by the Academy of Finland (SALVE program for 2009–2012 and grants 127437, 129306, 130326, 134791 and 263924 to EK); the European Commission (Framework 5 award QLG1-CT-2000-001643); the Doctoral Programs of Public Health, University of Tampere (to MSL); the Yrjö Jahnsson Foundation (6201 to MSL); and the Sigrid Jusélius Foundation (to EK and MSL), the Finnish Foundation for Pediatric Research (to EK), Emil Aaltonen Foundation (to EK), Signe and Ane Gyllenberg Foundation (to EK), and Novo Nordisk Foundation (to EK). POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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Cardiovascular Risk Factors in Adolescents Born Preterm Marika Sipola-Leppänen, Marja Vääräsmäki, Marjaana Tikanmäki, Petteri Hovi, Satu Miettola, Aimo Ruokonen, Anneli Pouta, Marjo-Riitta Järvelin and Eero Kajantie Pediatrics 2014;134;e1072; originally published online September 1, 2014; DOI: 10.1542/peds.2013-4186 Updated Information & Services

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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Cardiovascular risk factors in adolescents born preterm.

Adolescents and adults born as small preterm infants show more pronounced risk factors of cardiovascular disease. Whether similar risks apply across a...
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