Systematic Review and Meta-Analysis of Preterm Birth and Later Systolic Blood Pressure
Lower birth weight because of fetal growth restriction is associated with higher blood pressure later in life, but the extent to which preterm birth (<37 completed weeks' gestation) or very low birth weight (<1500 g) predicts higher blood pressure is less clear. We performed a systematic review of 27 observational studies that compared the resting or ambulatory systolic blood pressure or diagnosis of hypertension among children, adolescents, and adults born preterm or very low birth weight with those born at term. We performed a meta-analysis with the subset of 10 studies that reported the resting systolic blood pressure difference in millimeters of mercury with 95% CIs or SEs. We assessed methodologic quality with a modified Newcastle-Ottawa Scale. The 10 studies were composed of 1342 preterm or very low birth weight and 1738 term participants from 8 countries. The mean gestational age at birth of the preterm participants was 30.2 weeks (range: 28.8–34.1 weeks), birth weight was 1280 g (range: 1098–1958 g), and age at systolic blood pressure measurement was 17.8 years (range: 6.3–22.4 years). Former preterm or very low birth weight infants had higher systolic blood pressure than term infants (pooled estimate: 2.5 mm Hg [95% CI: 1.7–3.3 mm Hg]). For the 5 highest quality studies, the systolic blood pressure difference was slightly greater, at 3.8 mm Hg (95% CI: 2.6–5.0 mm Hg). We conclude that infants who are born preterm or very low birth weight have modestly higher systolic blood pressure later in life and may be at increased risk for developing hypertension and its sequelae.
See Editorial Commentary, pp 189–190
More than 12% of infants in the United States are born preterm (at <37 completed weeks' gestation),1 and the majority now survives to adulthood.2 Although researchers have focused considerable attention on the adverse neurodevelopmental consequences of preterm birth, particularly for those infants born very low birth weight (VLBW; <1500 g),3,4 relatively little is known about other aspects of later childhood and adult health that may also be associated with preterm and VLBW birth.
Lower birth weight is associated with higher blood pressure (BP) later in life.5 Other authors have implicated prenatal programming of BP by impaired fetal growth and its determinants, such as poor maternal nutrition,6 hypertensive disorders,7,8 and smoking,9 during pregnancy. Few, however, have examined the role of shortened gestation. Evidence is now emerging that lower birth weight resulting from preterm birth may also be associated with higher BP later in life,10 but most studies have been relatively small and/or included participants born at a single center.
It is important to gain a clear understanding of the extent to which preterm birth predicts higher BP later in life, to inform medical and preventive care for survivors of preterm birth as they reach adulthood, and to increase scientific understanding of mechanisms underlying the fetal and postnatal programming of BP. The aim of this study was to perform a systematic review of the literature and meta-analysis to test the hypothesis that children, adolescents, and adults who were born preterm or VLBW have higher systolic BP (SBP) and hypertension prevalence, as compared with those born at term.
We followed the Meta-Analysis of Observational Studies in Epidemiology11 guidelines regarding the design, implementation, analysis, and reporting of this study. We searched for all of the observational studies that compared the resting and/or ambulatory BP or the hypertension prevalence of former preterm or VLBW children (>2 years old), adolescents, or adults with those born at term, published from January 1946 through June 2011. We included studies of preterm and VLBW children because virtually all of the VLBW children are preterm. We included the following databases in our search: PubMed, Excerpta Medica Database, ISI Web of Knowledge, and Cumulative Index to Nursing and Allied Health Literature and used the following medical subject headings and key words: “preterm birth” OR “prematurity” OR “very low birth weight” OR “low birth weight” AND “blood pressure” OR “hypertension” OR “cardiovascular risk factors” OR “cardiovascular disease.” To identify additional pertinent articles, we used the “related citations” function in PubMed and hand-searched bibliographies of all of the articles that met our inclusion criteria, as well as review articles.
Selection of Articles
Of the 1979 identified articles, we excluded 1856 based on a review of the title and abstract conducted by 1 author (Figure 1). Two authors reviewed the full text of the remaining 123 articles to determine inclusion or exclusion. Any differences were resolved through discussion, resulting in agreement for all of the included and excluded articles. We excluded 96 articles for the following reasons: (1) no comparison group of term infants (22 articles); (2) age at measurement ≤2 years old (20 articles); (3) lack of data about birth weight or gestational age (16 articles); (4) review articles (13 articles); and (5) randomized trials (6 articles). We excluded 19 articles that reported results also reported in another article. If an article reported duplicate results from the same cohort or a subset of the cohort, we included the article with the largest sample size; in 1 case, identical results were published separately in English12 and French,13 so we included the article published in English. For studies that reported outcomes at different ages in separate articles, we included the article reporting results at the oldest age. Twenty-seven studies met inclusion criteria for the systematic review. For 1 article13,14 published in Hungarian, a neonatologist who is a fluent speaker assisted with reviewing the article for inclusion criteria and extracting the data.
Of the 27 studies included in the systematic review, for the meta-analysis we included the 10 studies that reported the resting SBP difference in millimeters of mercury with 95% CI or SEs. We could not perform a meta-analysis for hypertension prevalence or ambulatory BP because of the small number of studies, heterogeneity of methodology, and lack of reported 95% CIs and SEs.
From the 27 included articles, 2 authors independently extracted the following information: (1) birth year(s); (2) location of cohort; (3) selection criteria for preterm or VLBW group; (4) sample size; (5) proportions of men and women; (6) prevalence of small for gestational age (SGA); (7) mean birth weight, gestational age, and age at BP measurement; (8) method of BP measurement and number of measurements; (9) hypertension definition; (10) SBP difference in millimeters of mercury between preterm and term participants for resting or ambulatory BP; (11) relative risk of hypertension; (12) 95% CI or SE around the effect estimates; and (13) P value. We focused on SBP because it is at least as good a predictor of later cardiovascular risk as diastolic BP and is measured with more accuracy in youth.15 The 2 authors compared extracted data and resolved any differences by discussion.
Because some articles reported >1 multivariable model and different studies adjusted for different sets of covariates, from each article we recorded estimates from the models adjusted for the fewest and most covariates. We categorized each model as having the following: (1) no adjustment apart from age and sex; (2) adjustment for any measure of socioeconomic status; (3) adjustment for any measure of fetal growth; and (4) adjustment for participant size at the time of BP measurement. If studies reported models adjusted separately for >1 measure of participant size, we used the height-adjusted estimate; if not reported, we used the body mass index–adjusted estimate, and, if that was not reported, we used the weight-adjusted estimate.
For studies that did not report an unadjusted (or only age- and sex-adjusted) estimate of SBP difference, we calculated the unadjusted SBP difference as the mean SBP of the preterm or VLBW participants minus the mean of the term participants. One study16 reported unadjusted SBP differences stratified by sex, so we calculated a weighted average SBP difference for the men and women combined. Similarly, for studies that did not report the relative risk or odds ratio of hypertension, we calculated the unadjusted relative risk as the percentage of preterm or VLBW participants with hypertension divided by the percentage of term participants with hypertension. For studies that reported the SE but not the 95% CI, we calculated the 95% CI as the estimated SBP difference ±1.96 times the SE. For studies that separately analyzed >1 term group (eg, SGA and appropriate for gestational age), we used the appropriate for gestational age term group for comparison. For studies that only reported results separately for SGA and appropriate for gestational age preterm or VLBW participants, we extracted both estimates. We did not attempt to contact authors regarding missing data.
Assessment of Methodologic Quality
We used a modified version of the Newcastle-Ottawa Scale17 to assess the methodologic quality of each study (Figure 2). We awarded studies a maximum of 7 stars, summed from up to 3 stars for selection and 2 each for comparability and outcome assessment, with more stars indicating better quality. Some studies reported >1 outcome (resting SBP, hypertension diagnosis, and ambulatory BP), so we rated the quality of those studies separately for each outcome. Two authors independently assessed the quality of each study. Initial agreement between the 2 authors on the quality score was 91%. All of the differences were resolved by discussion.
For the meta-analysis of resting SBP difference, to calculate effect estimates, we used random-effects models,18 which allow for sampling variability within and between studies. To assess the proportion of total variability in the effect estimate attributable to between-study heterogeneity, we calculated the I2 statistic and associated P value. We also created funnel plots and tested for asymmetry using the method of Egger et al.19 Funnel plot asymmetry may reflect selective publication of positive studies or lower methodologic quality of individual studies.20 When we identified significant heterogeneity (P<0.05) or funnel plot asymmetry, we performed an influence analysis in which we omitted the results of one study at a time and recalculated the pooled effect estimate.
For the primary meta-analysis, we used the least and most fully covariate-adjusted estimates from each study with 95% CIs. We also analyzed separately the estimates that were adjusted for any measure of socioeconomic status and later size. We could not perform a separate meta-analysis with estimates adjusted for fetal growth because there were only 2 studies with this information. We performed one set of secondary analyses restricted to studies of VLBW or very preterm (≤32 weeks' gestation) participants, because that group is at highest risk for long-term sequelae of preterm birth. We also stratified by year of birth (<1990 versus ≥1990) and performed a separate meta-analysis for the 5 studies with a quality score of 7 (highest quality). We used Stata 10.0 (Stata Corp LP, College Station, TX) for all of the analyses.
Description of Studies Included in the Systematic Review
We identified 27 observational studies, published from 1998 to 2011, describing 25 unique cohorts from 13 countries, although 2 studies21,22 sampled from a common database and likely had some overlap of participants. Twenty three of the cohorts were from the United States, Europe, Australia, or New Zealand. The other 2 were from China23,24 and Brazil.23,24 Of the 24 articles, 22 reported resting SBP (Table 1 and Table S1, available in the online Data Supplement at http://hyper.ahajournals.org), 8 reported hypertension diagnosis (Table S2), and 5 reported ambulatory BP (Table S3).
|First Author, Year Published, Country, Year Born||Selection of Preterm/VLBW||Sample Size, Preterm/VLBW Term, %SGA (of Preterm/VLBW)||Age, y, Mean±SD, Range||% Follow-Up, Preterm/VLBW, Term||BP Method (No. of Measurements)||Multivariable Adjustment||Least Adjusted SBP Difference, mm Hg (Preterm/VLBW–Term) 95% CI, P||Most Adjusted SBP Difference, mm Hg (Preterm/VLBW–Term) 95% CI, P|
|Chan26||<1500 g or ≤ 32 wk||39||NR||NR||Manual||No||Yes||Yes||AGA preterm vs term:||−1.0 mm Hg†|
|2010||32||NR||NR||(2×)||−2 mm Hg*||95% CI−3.6–1.5|
|SGA preterm vs term:|
|4 mm Hg*|
|Bracewell et al27||<26 wk||214||6.3±NR||78%||Manual||No||No||No||−2.3 mm Hg†||−2.3 mm Hg†|
|2008||158||5.2–7.3||NR||(NR)||95% CI−4.6 to−0.1||95% CI−4.6 to−0.1|
|United Kingdom and Ireland||P=0.04||P=0.04|
|Rotteveel et al28||<32 wk and/or||57||20.7±NR||65%||Automated||No||No||Yes||AGA preterm vs term:||AGA preterm vs term:|
|2008||<1500 g||30||NR||(3×)||14.0 mm Hg†||15.0 mm Hg†|
|Netherlands||95% CI: 7.5–20.5||95% CI: 8.8–21.2|
|SGA preterm vs term:||SGA preterm vs term:|
|8.8 mm Hg†||12.8 mm Hg†|
|95% CI: 2.2–15.4||95% CI: 6.2–19.4|
|Hovi et al29||<1500 g||166||22.4±NR||65%||Automated||Yes||No||Yes||4.0 mm Hg†||4.8 mm Hg†|
|2007||172||18.5–27.1||55%||(2×)||95% CI: 1.5–6.5||95% CI: 2.1–7.4|
|Bonamy et al30||≤30 wk||39||9.1±1.7||63% (preterm+term)||Automated||No||No||Yes||−7.0 mm Hg*||2.6 mm Hg†|
|2007||21||7–12||(6×)||NR||95% CI: 0.6–4.6|
|Dalziel et al25||<37 wk||311||30±NR||51%||Automated||No||Yes||Yes||3.5 mm Hg†||3.3 mm Hg†|
|2007||147||NR||44%||(2×)||95% CI: 1.0–6.0||95% CI: 0.9–5.7|
|Hack et al16||<1500 g||195||20.2±NR||68%||Manual||Yes||No||Yes||2.3 mm Hg*||3.5 mm Hg†|
|2005||208||NR||57%||(2×)||NR||95% CI: 1.4–5.6|
|Doyle et al31||<1500 g and <37 wk||156||18.6±NR||74%||Manual||No||No||Yes||8.6 mm Hg†||10.6 mm Hg†|
|2003||38||NR||63%||(3×)||95% CI: 3.4–13.9||95% CI: 5.8–15.5|
|Barros and Victora23||<37 wk||37||NR±NR||62%||Manual||Yes||No||Yes||0.2 mm Hg†||1.1 mm Hg†|
|1999||811||14–15||76%||(2×)||95% CI: −3.2–3.5||95% CI: −2.0–4.2|
|Pharoah et al32||<1500 g||128||15±NR||74%||Automated||No||No||Yes||3.2 mm Hg†||4.4 mm Hg†|
|1998||128||NR||NR||(3×)||95% CI: 0.4–6.0||95% CI: 1.8–7.0|
Of the 22 studies that reported resting SBP, for the meta-analysis we included the 10 studies16,23,25–32 that reported estimates with CIs or SEs, composed of 1342 preterm or VLBW and 1738 term participants from 8 countries (Table 1). Of studies reporting these data, the mean gestational age of the preterm participants was 30.2 weeks (range: 28.8–34.1 weeks), and birth weight was 1280 g (range: 1098–1958 g). Studies used different definitions of SGA status, for example, birth weight for gestational age SD score less than −228 or birth weight <10th percentile for gestational age.25 The SGA proportion ranged from 15% to 51%. The mean age at BP measurement was 17.8 years (range: 6.3–22.4 years). Details of the 12 studies excluded from the meta-analysis are listed in Table S1.
Seven of the 10 studies reported the unadjusted or least-adjusted estimates. The pooled unadjusted estimate of SBP difference was 2.2 mm Hg (95% CI: 1.1–3.3 mm Hg) higher for preterm or VLBW versus term participants. Using the most-adjusted estimates from all 10 of the studies, the pooled estimate was similar, at 2.5 mm Hg (95% CI: 1.7–3.3 mm Hg; Figure 3A). Restricting to the 5 higher quality studies, the most-adjusted pooled SBP difference was 3.8 mm Hg (95% CI: 2.6–5.0 mm Hg), somewhat higher than for the analysis including all 10 of the studies (Figure 3B). Restricting to the 8 studies of former VLBW or very preterm infants, the pooled adjusted SBP difference was 2.5 mm Hg (95% CI: 1.6–3.4 mm Hg; Figure 3C). For the 7 studies of participants born before 1990, the pooled adjusted SBP difference was 4.2 mm Hg (95% CI: 3.2–5.3 mm Hg), higher than for the 3 studies of participants born in 1990 or later (0.0 mm Hg [95% CI: −1.2–1.3 mm Hg).
Nine studies16,23,25,26,28–32 reported an estimate adjusted for later size; the pooled estimate for those studies was 3.3 mm Hg (95% CI: 2.4–4.2 mm Hg; Figure 3D). Three studies16,23,29 reported an estimate adjusted for a measure of socioeconomic status; the pooled estimate was 2.7 mm Hg (95% CI: 1.2–4.1 mm Hg; Figure 3E). Only 2 studies25,26 adjusted for fetal growth, so a separate pooled estimate was not feasible. One study16 reported adjusted results stratified by sex; the estimated SBP difference was similar for men (3.2 mm Hg [95% CI: 0.1–6.2 mm Hg]) and women (3.8 mm Hg [95% CI: 0.8–6.8 mm Hg]).
Visual inspection of the funnel plot using the most adjusted estimates (Figure 4) revealed asymmetry, with relatively large, positive effect sizes seen for the 2 studies28,31 with the smallest sample size and greatest variability (largest SE). The Egger et al19 test P value was 0.06, suggesting possible undue influence of these small studies on the pooled effect. We also noted significant heterogeneity in that analysis (P<0.0001). However, an influence analysis omitting one at a time the 2 studies28,31 with unbalanced effects on the funnel plot revealed pooled SBP differences of 2.3 mm Hg (95% CI: 1.4–3.1 mm Hg) for each of the 2 analyses, minimally different from the analysis including all 10 studies. Removing each of the other studies one at a time also minimally changed the estimate (data not shown). A funnel plot of the 5 higher quality studies showed 1 study with an unbalanced effect, but the Egger et al19 test P=0.29 suggested no small study effects.
Of the 12 studies12,14,21,24,33–40 excluded from the meta-analysis, 633–35,37,39,40 reported that former preterm or VLBW infants had SBP that was statistically higher than the term control group, with the SBP difference ranging from 5.1 to 13.0 mm Hg (Table S1). Two studies24,36 reported a small, nonsignificant, positive SBP difference; 412,14,21,38 did not report statistical testing.
Eight studies21,22, 33,34, 41,42 examined hypertension prevalence (Table S2), all but 214,25 of which included only VLBW or very preterm participants or analyzed separately a very preterm subgroup. The sample size of former preterm or VLBW infants ranged from 37 to 28 220. Three studies25,33,34 reported the percentage of preterm or VLBW participants who were also SGA, which ranged from 10.8% to 38.0%. Seven of the 8 studies assessed hypertension in adolescence or adulthood; 114 assessed hypertension at a mean age of 9.2 years. Four studies directly measured BP and defined systolic hypertension either as >140 mm Hg21,34 or >95th percentile for age.14,33 One study41 measured ambulatory BP and used different cutoffs for 24-hour, daytime, and nighttime hypertension. One study43 used discharge diagnoses, 122 used prescriptions for antihypertensive medications, and 125 used self-report of hypertension diagnosis. Only 2 studies21,22 adjusted for potential confounders.
Of the 8 studies, 321,22,25 reported a statistically higher relative risk of hypertension in preterm or VLBW participants, ranging from 1.2 to 2.5 compared with term participants. In 1 study41 that examined ambulatory BP, 6% of preterm or VLBW participants had 24-hour, daytime, and nighttime systolic hypertension, as compared with none of the term participants for 24-hour and daytime BP and 5% for nighttime BP; statistical testing was not reported. One study42 reported that the difference in hypertension prevalence was not statistically significant; 414,33,34,41 did not report statistical testing. Only 3 studies21,22,42 reported CIs or SEs around the estimates.
Characteristics of the 5 studies that reported ambulatory SBP are listed in Table S3. Four31,40, 41,44 included only VLBW or very preterm participants. The proportion of preterm or VLBW participants who were also SGA ranged from 27% to 42%. All but 1 study45 measured BP in adolescence or young adulthood. One study40 included only female participants. All of the studies used SpaceLabs 90207 to measure ambulatory BP. Only 2 studies31,44 adjusted for potential confounders.
Results were reported as 24-hour BP, daytime or awake BP, and nighttime or asleep BP. Three of the 5 studies31,41,44 reported statistically higher 24-hour SBP, 131 reported higher awake BP, and 145 reported statistically higher nighttime SBP. Only 2 studies44,46 reported 95% CIs or SEs around the ambulatory BP differences.
Table 2 and Table S4 show the assessment of methodologic quality for the 27 studies included in the systematic review. All of the studies received ≥2 of 3 possible points for selection and ≥1 of 2 possible points for assessment; however, 17 studies received 0 points for lack of statistical adjustment for important potential confounders. Total scores ranged from 3 to 7.
|Study||Modified Newcastle-Ottawa Scale|
|Selection (Maximum 3 ★)||Comparability (Maximum 2 ★)||Assessment of BP (Maximum 2 ★)||Total Score (Maximum 7 ★)|
|Chan et al26||★★||★★||★||★★★★★|
|Bracewell et al27||★★★||★||★★★★|
|Rotteveel et al28||★★||★||★||★★★★|
|Hovi et al29||★★★||★★||★★||★★★★★★★|
|Bonamy et al30||★★★||★||★★||★★★★★★|
|Dalziel et al25||★★★||★★||★★||★★★★★★★|
|Hack et al16||★★★||★★||★★||★★★★★★★|
|Doyle et al31||★★★||★★||★★||★★★★★★★|
|Barros and Victora23||★★★||★★||★★||★★★★★★★|
|Pharoah et al32||★★★||★||★||★★★★★|
The results of our systematic review and meta-analysis suggest that preterm and VLBW births are associated with higher resting SBP later in life than term birth. Estimates were not materially changed by adjustment for differences in socioeconomic factors or attained height or weight, suggesting that differences in these factors do not account for the higher SBP observed in participants born preterm or VLBW. In fact, the association was strengthened somewhat by adjustment for attained size.
In our meta-analysis, we found quantitative evidence for small study effects, which can be explained by publication bias and/or poor methodologic quality of individual studies.20 Although our influence analysis suggested only a minor effect on results by the small studies, we cannot rule out publication bias. The fact that only 2 studies reported lower SBP with preterm birth could suggest publication bias but may just be chance findings. Because all of the studies were observational rather than randomized trials for which trial registration is required, we could not identify unpublished studies.
Our meta-analysis restricted to the higher quality studies suggests that poor methodologic quality of smaller studies does not explain the observed SBP difference. In addition to the 10 studies that met criteria for our meta-analysis, we identified an additional 12 studies of resting SBP difference in our systematic review, but we were not able to quantify the potential effect of publication bias or poor methodologic quality, because those studies did not report CIs or SEs around the estimated SBP difference.
Although the observed resting SBP difference of 2.5 mm Hg is modest, even small differences in BP are important for the population with respect to prevention of cardiovascular disease.47 The SBP difference that we observed is similar to the SBP increase that is associated with excessive intake of dietary sodium,48 a recommended target for public health interventions aimed at reducing the incidence of cardiovascular disease in the general US population. Unfortunately, prevention of preterm birth as a means to reduce cardiovascular disease is not feasible, because no effective strategy currently exists.
Our systematic review revealed limited data on the prevalence of hypertension in former preterm or VLBW adults. Only 3 studies reported CIs or SEs, and study methodology including the definition of hypertension differed substantially across studies, making it impossible to calculate pooled estimates, which would have been important given the relatively low observed prevalence of hypertension. Similarly, data are limited on ambulatory BP, although 4 of the 5 studies reported higher 24-hour or nighttime ambulatory SBP in the preterm or VLBW participants.
The survival of preterm and VLBW infants increased markedly in the 1990s because of advances in obstetric and neonatal care. In our meta-analysis, the SBP difference was greater for participants born before 1990 versus in or after 1990. This discrepancy may be related to differences in gestational age or specific care practices but might also be explained by differences in age at SBP measurement, which occurred in adolescence or adulthood for those born before 1990 but at school age for those born in or after 1990. BP differences related to differences in birth weight are known to amplify with increasing age.49 As the population of preterm and VLBW children born in the modern era of neonatal intensive care reaches adulthood, additional study of hypertension and its sequelae, including coronary heart disease and stroke, will be informative. It will also be important to ascertain whether the effect of preterm birth on later BP is stronger for the smaller, sicker infants who now survive because of advanced neonatal intensive care and also whether specific practices that lead to better survival also impact the risk of hypertension later in life.
The mechanisms linking preterm birth with later, higher BP may involve both prenatal and postnatal factors. The risk of hypertension may be influenced through the process of fetal programming, which involves long-lasting adaptation to an adverse intrauterine environment during a critical period in development.50 An adverse intrauterine environment may prompt preterm birth, for example, in the setting of preeclampsia or fetal growth restriction, although existing evidence does not consistently support a link between those conditions and later BP in former preterm or VLBW infants.16,33,51 In our meta-analysis, we were not able to examine the extent to which fetal growth restriction modifies or confounds the association of shortened gestation with later BP, because only 2 studies adjusted for a measure of fetal growth.
The preterm infant is ex utero during the fetal developmental period from the time of preterm birth to term (40 weeks' postmenstrual age) and typically spends several weeks to months after birth in the NICU. Thus, adverse postnatal conditions could also influence later BP through fetal programming mechanisms. For example, preterm and VLBW infants often experience extrauterine growth restriction during the NICU hospitalization.52 However, to our knowledge, no study has linked extrauterine growth restriction in preterm infants with later higher BP. In addition, long-term follow-up of randomized trials53,54 of nutrient-enriched preterm infant formula suggest that more rapid early weight gain may lead to higher BP. After NICU discharge, preterm infants typically experience gains in weight and length resulting in catch-up to their term-born peers by school age.55 Some28,33,56 but not all56,57 studies in preterm populations suggest that more rapid postnatal weight gain after term may lead to higher BP later in life. Although it is possible that altering early nutrition to prevent excessive weight gain may prevent the higher BP seen in former preterm and VLBW infants, one must also consider the risks of such a strategy, such as to neurodevelopment.56,58
A strength of our study is that we conducted a thorough and systematic search of multiple databases, so it is likely that we identified all of the relevant publications, although we could not identify unpublished studies. Two authors independently reviewed articles for inclusion/exclusion and extracted the data, improving the validity of our results. We also performed a quality assessment. We identified studies from multiple countries, improving the generalizability of our findings, although they may not apply to settings with fewer resources. Although we identified 22 studies that examined resting SBP in former preterm or VLBW infants, fewer than half reported CIs or SEs around the BP differences, so we could not include all of them in the meta-analysis. We also could not perform a meta-analysis of hypertension prevalence or ambulatory BP because of heterogeneity of methodology and the small number of published studies with CIs or SEs.
Our results suggest that preterm and VLBW infants have higher SBP later in life than those born at term and may be at increased risk for developing hypertension and its sequelae. These findings should inform medical and preventive care for survivors of preterm birth as they reach adulthood and also increase scientific understanding of mechanisms underlying the fetal and postnatal programming of BP.
We thank Alison Clapp at Children's Hospital Boston for her assistance with developing our search strategy and Dr Adrienne Unger for her translation assistance.
Sources of Funding
This work was supported by the
Mathews TJ, Minino AM, Osterman MJ, Strobino DM, Guyer B. Annual summary of vital statistics: 2008. Pediatrics. 2011; 127:146–157.CrossrefGoogle Scholar
Behrman RE. Preterm Birth: Causes, Consequences, and Prevention.Washington, DC: National Academies Press; 2006.Google Scholar
Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ. Cognitive and behavioral outcomes of school-aged children who were born preterm: a meta-analysis. JAMA. 2002; 288:728–737.CrossrefMedlineGoogle Scholar
Hack M. Adult outcomes of preterm children. J Dev Behav Pediatr. 2009; 30:460–470.CrossrefMedlineGoogle Scholar
Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000; 18:815–831.CrossrefMedlineGoogle Scholar
Bagby SP. Maternal nutrition, low nephron number, and hypertension in later life: pathways of nutritional programming. J Nutr. 2007; 137:1066–1072.CrossrefMedlineGoogle Scholar
Mamun AA, Kinarivala MK, O'Callaghan M, Williams G, Najman J, Callaway L. Does hypertensive disorder of pregnancy predict offspring blood pressure at 21 years? Evidence from a birth cohort study.J Hum Hypertens.Epub ahead of print April 21, 2011.Google Scholar
Tenhola S, Rahiala E, Halonen P, Vanninen E, Voutilainen R. Maternal preeclampsia predicts elevated blood pressure in 12-year-old children: evaluation by ambulatory blood pressure monitoring. Pediatr Res. 2006; 59:320–324.CrossrefMedlineGoogle Scholar
Oken E, Huh SY, Taveras EM, Rich-Edwards JW, Gillman MW. Associations of maternal prenatal smoking with child adiposity and blood pressure. Obes Res. 2005; 13:2021–2028.CrossrefMedlineGoogle Scholar
Norman M. Preterm birth: an emerging risk factor for adult hypertension?Semin Perinatol. 2010; 34:183–187.CrossrefMedlineGoogle Scholar
Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D, Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting: Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000; 283:2008–2012.CrossrefMedlineGoogle Scholar
Rossi P, Tauzin L, Marchand E, Boussuges A, Gaudart J, Frances Y. Respective roles of preterm birth and fetal growth restriction in blood pressure and arterial stiffness in adolescence. J Adolesc Health. 2011; 48:520–522.CrossrefMedlineGoogle Scholar
Rossi P, Tauzin L, Marchand E, Simeoni U, Frances Y. Arterial blood pressure and arterial stiffness in adolescents are related to gestational age [in French]. Arch Mal Coeur Vaiss. 2006; 99:748–751.MedlineGoogle Scholar
Erhardt E, Molnar D, Storcz J, Markus A, Torok K. Role of intrauterine growth in later cardiovascular risk factors in children 6–10 years of age [in Hungarian]. Orv Hetil. 1999; 140:2563–2567.MedlineGoogle Scholar
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003; 42:1206–1252.LinkGoogle Scholar
Hack M, Schluchter M, Cartar L, Rahman M. Blood pressure among very low birth weight (<1.5 kg) young adults. Pediatr Res. 2005; 58:677–684.CrossrefMedlineGoogle Scholar
Deeks JJ, Dinnes J, D'Amico R, Sowden AJ, Sakarovitch C, Song F, Petticrew M, Altman DG. Evaluating non-randomised intervention studies. Health Technol Assess. 2003; 7:iii–x, 1-173.CrossrefMedlineGoogle Scholar
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177–188.CrossrefMedlineGoogle Scholar
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315:629–634.CrossrefMedlineGoogle Scholar
Sterne JAC, Harbord RM. Funnel plots in meta-analysis. Stata J. 2004; 4:127–141.CrossrefGoogle Scholar
Johansson S, Iliadou A, Bergvall N, Tuvemo T, Norman M, Cnattingius S. Risk of high blood pressure among young men increases with the degree of immaturity at birth. Circulation. 2005; 112:3430–3436.LinkGoogle Scholar
Crump C, Winkleby MA, Sundquist K, Sundquist J. Risk of hypertension among young adults who were born preterm: a Swedish national study of 636,000 births. Am J Epidemiol. 2011; 173:797–803.CrossrefMedlineGoogle Scholar
Barros FC, Victora CG. Increased blood pressure in adolescents who were small for gestational age at birth: a cohort study in Brazil. Int J Epidemiol. 1999; 28:676–681.CrossrefMedlineGoogle Scholar
Cheung YF, Wong KY, Lam BC, Tsoi NS. Relation of arterial stiffness with gestational age and birth weight. Arch Dis Child. 2004; 89:217–221.CrossrefMedlineGoogle Scholar
Dalziel SR, Parag V, Rodgers A, Harding JE. Cardiovascular risk factors at age 30 following pre-term birth. Int J Epidemiol. 2007; 36:907–915.CrossrefMedlineGoogle Scholar
Chan PY, Morris JM, Leslie GI, Kelly PJ, Gallery ED. The long-term effects of prematurity and intrauterine growth restriction on cardiovascular, renal, and metabolic function. Int J Pediatr. 2010; 2010:280402.CrossrefMedlineGoogle Scholar
Bracewell MA, Hennessy EM, Wolke D, Marlow N. The EPICure study: growth and blood pressure at 6 years of age following extremely preterm birth. Arch Dis Child Fetal Neonatal Ed. 2008; 93:F108–F114.CrossrefMedlineGoogle Scholar
Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-Van de Waal HA. Infant and childhood growth patterns, insulin sensitivity, and blood pressure in prematurely born young adults. Pediatrics. 2008; 122:313–321.CrossrefMedlineGoogle Scholar
Hovi P, Andersson S, Eriksson JG, Jarvenpaa AL, Strang-Karlsson S, Makitie O, Kajantie E. Glucose regulation in young adults with very low birth weight. N Engl J Med. 2007; 356:2053–2063.CrossrefMedlineGoogle Scholar
Bonamy AK, Martin H, Jorneskog G, Norman M. Lower skin capillary density, normal endothelial function and higher blood pressure in children born preterm. J Intern Med. 2007; 262:635–642.CrossrefMedlineGoogle Scholar
Doyle LW, Faber B, Callanan C, Morley R. Blood pressure in late adolescence and very low birth weight. Pediatrics. 2003; 111:252–257.CrossrefMedlineGoogle Scholar
Pharoah PO, Stevenson CJ, West CR. Association of blood pressure in adolescence with birthweight. Arch Dis Child Fetal Neonatal Ed. 1998; 79:F114–F118.CrossrefMedlineGoogle Scholar
Vohr BR, Allan W, Katz KH, Schneider KC, Ment LR. Early predictors of hypertension in prematurely born adolescents. Acta Paediatr. 2010; 99:1812–1818.CrossrefMedlineGoogle Scholar
Evensen KA, Steinshamn S, Tjonna AE, Stolen T, Hoydal MA, Wisloff U, Brubakk AM, Vik T. Effects of preterm birth and fetal growth retardation on cardiovascular risk factors in young adulthood. Early Hum Dev. 2009; 85:239–245.CrossrefMedlineGoogle Scholar
Willemsen RH, de Kort SW, van der Kaay DC, Hokken-Koelega AC. Independent effects of prematurity on metabolic and cardiovascular risk factors in short small-for-gestational-age children. J Clin Endocrinol Metab. 2008; 93:452–458.CrossrefMedlineGoogle Scholar
Menezes AM, Hallal PC, Horta BL, Araujo CL, Vieira Mde F, Neutzling M, Barros FC, Victora CG. Size at birth and blood pressure in early adolescence: a prospective birth cohort study. Am J Epidemiol. 2006; 165:611–616.CrossrefMedlineGoogle Scholar
Bonamy AK, Bendito A, Martin H, Andolf E, Sedin G, Norman M. Preterm birth contributes to increased vascular resistance and higher blood pressure in adolescent girls. Pediatr Res. 2005; 58:845–849.CrossrefMedlineGoogle Scholar
Singhal A, Kattenhorn M, Cole TJ, Deanfield J, Lucas A. Preterm birth, vascular function, and risk factors for atherosclerosis. Lancet. 2001; 358:1159–1160.CrossrefMedlineGoogle Scholar
Irving RJ, Belton NR, Elton RA, Walker BR. Adult cardiovascular risk factors in premature babies. Lancet. 2000; 355:2135–2136.CrossrefMedlineGoogle Scholar
Kistner A, Celsi G, Vanpee M, Jacobson SH. Increased blood pressure but normal renal function in adult women born preterm. Pediatr Nephrol. 2000; 15:215–220.CrossrefMedlineGoogle Scholar
Keijzer-Veen MG, Dulger A, Dekker FW, Nauta J, van der Heijden BJ. Very preterm birth is a risk factor for increased systolic blood pressure at a young adult age. Pediatr Nephrol. 2010; 25:509–516.CrossrefMedlineGoogle Scholar
Bonamy AK, Norman M, Kaijser M. Being born too small, too early, or both: does it matter for risk of hypertension in the elderly?Am J Hypertens. 2008; 21:1107–1110.CrossrefMedlineGoogle Scholar
Bonamy AK, Andolf E, Martin H, Norman M. Preterm birth and carotid diameter and stiffness in childhood. Acta Paediatr. 2008; 97:434–437.CrossrefMedlineGoogle Scholar
Hovi P, Andersson S, Raikkonen K, Strang-Karlsson S, Jarvenpaa AL, Eriksson JG, Pesonen AK, Heinonen K, Pyhala R, Kajantie E. Ambulatory blood pressure in young adults with very low birth weight. J Pediatr. 2010; 156:54–59, e51.CrossrefMedlineGoogle Scholar
Bayrakci US, Schaefer F, Duzova A, Yigit S, Bakkaloglu A. Abnormal circadian blood pressure regulation in children born preterm. J Pediatr. 2007; 151:399–403.CrossrefMedlineGoogle Scholar
Doyle LW, Roberts G, Anderson PJ. Outcomes at age 2 years of infants <28 weeks' gestational age born in Victoria in 2005.J Pediatr. 2010; 156:49–53., e41.CrossrefMedlineGoogle Scholar
Rose G. Strategy of prevention: lessons from cardiovascular disease. BMJ (Clin Res Ed). 1981; 282:1847–1851.CrossrefMedlineGoogle Scholar
Bibbins-Domingo K, Chertow GM, Coxson PG, Moran A, Lightwood JM, Pletcher MJ, Goldman L. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med. 2010; 362:590–599.CrossrefMedlineGoogle Scholar
Moore VM, Cockington RA, Ryan P, Robinson JS. The relationship between birth weight and blood pressure amplifies from childhood to adulthood. J Hypertens. 1999; 17:883–888.CrossrefMedlineGoogle Scholar
Barker DJ. The developmental origins of adult disease. J Am Coll Nutr. 2004; 23:588S–595S.CrossrefMedlineGoogle Scholar
Belfort MB, Gillman MW, McCormick MC. Prenatal and perinatal predictors of blood pressure at school age in former preterm, low birth weight infants.J Perinatol.Epub ahead of print July 7, 2011.Google Scholar
Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics. 2003; 111:986–990.CrossrefMedlineGoogle Scholar
Lucas A, Morley R, Cole TJ, Gore SM, Lucas PJ, Crowle P, Pearse R, Boon AJ, Powell R. Early diet in preterm babies and developmental status at 18 months. Lancet. 1990; 335:1477–1481.CrossrefMedlineGoogle Scholar
Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later blood pressure: two cohorts after randomised trials. Lancet. 2001; 357:413–419.CrossrefMedlineGoogle Scholar
Hack M, Schluchter M, Cartar L, Rahman M, Cuttler L, Borawski E. Growth of very low birth weight infants to age 20 years. Pediatrics. 2003; 112:e30–e38.CrossrefMedlineGoogle Scholar
Belfort MB, Martin CR, Smith VC, Gillman MW, McCormick MC. Infant weight gain and school-age blood pressure and cognition in former preterm infants. Pediatrics. 2010; 125:e1419–e1426.CrossrefMedlineGoogle Scholar
Keijzer-Veen MG, Finken MJ, Nauta J, Dekker FW, Hille ET, Frolich M, Wit JM, van der Heijden AJ. Is blood pressure increased 19 years after intrauterine growth restriction and preterm birth? A prospective follow-up study in The Netherlands.Pediatrics. 2005; 116:725–731.CrossrefMedlineGoogle Scholar
Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK. Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics. 2006; 117:1253–1261.CrossrefMedlineGoogle Scholar