Video Abstract

Video Abstract

Close modal
CONTEXT:

Preterm birth is associated with incident heart failure in children and young adults.

OBJECTIVE:

To determine the effect size of preterm birth on cardiac remodeling from birth to young adulthood.

DATA SOURCES:

Data sources include Medline, Embase, Scopus, Cochrane databases, and clinical trial registries (inception to March 25, 2020).

STUDY SELECTION:

Studies in which cardiac phenotype was compared between preterm individuals born at <37 weeks’ gestation and age-matched term controls were included.

DATA EXTRACTION:

Random-effects models were used to calculate weighted mean differences with corresponding 95% confidence intervals.

RESULTS:

Thirty-two observational studies were included (preterm = 1471; term = 1665). All measures of left ventricular (LV) and right ventricular (RV) systolic function were lower in preterm neonates, including LV ejection fraction (P = .01). Preterm LV ejection fraction was similar from infancy, although LV stroke volume index was lower in young adulthood. Preterm LV peak early diastolic tissue velocity was lower throughout development, although preterm diastolic function worsened with higher estimated filling pressures from infancy. RV longitudinal strain was lower in preterm-born individuals of all ages, proportional to the degree of prematurity (R2 = 0.64; P = .002). Preterm-born individuals had persistently smaller LV internal dimensions, lower indexed LV end-diastolic volume in young adulthood, and an increase in indexed LV mass, compared with controls, of 0.71 g/m2 per year from childhood (P = .007).

LIMITATIONS:

The influence of preterm-related complications on cardiac phenotype could not be fully explored.

CONCLUSIONS:

Preterm-born individuals have morphologic and functional cardiac impairments across developmental stages. These changes may make the preterm heart more vulnerable to secondary insults, potentially underlying their increased risk of early heart failure.

The incidence of preterm birth is increasing and already affects >10% of live births worldwide.1,2  Gestational age at birth has a strong inverse association with cardiovascular mortality in young adulthood.3  Furthermore, population-based studies have demonstrated that preterm birth is a newly recognized risk factor for early heart failure and ischemic heart disease in young adulthood.4,5  Observational studies revealing impaired left ventricular (LV) systolic reserve with pump failure under physiologic stress,6  right ventricular (RV) dysfunction,7,8  and distinct ventricular morphology9  may help explain this increased risk. Nevertheless, there remains variability in published results, predominantly from small-sized cohorts, as well as insufficient characterization at different developmental stages. This hinders the identification of amenable targets and appropriate developmental windows for the adoption of primary prevention strategies.

We therefore performed a systematic review and meta-analysis, combining case-control published records from inception to March 25, 2020, with the aim to determine a more accurate effect size of prematurity on cardiac remodeling across developmental stages from birth to young adulthood. We hypothesized that many of the cardiac differences between preterm- and term-born individuals would emerge during infancy and persist during childhood and into young adulthood.

The meta-analysis design, performance, and reporting were made in accordance to MOOSE (Meta-analysis of Observational Studies in Epidemiology) group guidelines.10  The protocol was registered with PROSPERO International Prospective Register of Systematic Reviews (identifier CRD42016038650).

Search strategies were developed by a medical librarian (L.Y.) for the concepts of cardiac function, performance, and measures; echocardiography; cardiovascular magnetic resonance; and preterm- and term-born individuals. Search hedges combining standardized terms and key words were implemented in Embase (1947 to present), Ovid Medline (1946 to present), Scopus (1823 to present), Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov (2000 to present) (Supplemental Information). Authors’ data records and bibliographies were also screened. No language or date restrictions were applied. First and last authors of included studies published from 2000 to present and first and last authors of relevant conference abstracts published in the preceding 24 months were contacted. This resulted in the retrieval of unpublished data from 12 publications.1122  In addition, patient-level data and unpublished parameters were available from analyses of 692 individuals (cases = 302; controls = 390) from an additional 5 publications.6,7,9,23,24 

Searches were completed on March 25, 2020, resulting in 3057 citations after removal of duplicates, which were independently reviewed by 2 authors (F.T. and N.M.). Inclusion criteria were as follows: (1) concurrent evaluation of preterm-born cases (<37 weeks’ gestation) and term-born controls (≥37 weeks’ gestation), (2) reported relevant cardiac structure and/or function, and (3) evaluation performed after birth. For cases to represent individuals without significant neonatal and infant morbidity, studies were excluded by the presence of (1) cardiac malformation, (2) acute illness, or (3) specific stratification by intrauterine growth restriction (IUGR), small for gestational age (SGA), bronchopulmonary dysplasia (BPD), or patent ductus arteriosus. Results from these studies, with the exclusion of BPD, IUGR, SGA, and patent ductus arteriosus, for preterm infants were used when available.

Data were extracted into a customized database containing predefined measures of LV and RV structure, systolic function, and diastolic function based on recommendations by the American Society of Echocardiography, European Association of Echocardiography, and Society of Cardiovascular Magnetic Resonance guidelines (Supplemental Information).2528  Results were stratified by developmental ages: (1) neonates <28 days, (2) infants ≥28 days to ≤1 year, (3) children >1 to ≤14 years, (4) adolescents >14 to <18 years, and (5) young adults ≥18 to 35 years.

Primary and secondary LV and RV outcomes were determined on the basis of clinical utility and validity of the measures.2528  LV primary outcomes were as follows: LV ejection fraction (LVEF), LV longitudinal strain, LV peak systolic tissue velocity (LVs’) (mitral valve annulus) and LV peak early diastolic tissue velocity (LVe’) (mitral valve annulus), LV early Doppler inflow velocity/peak early diastolic tissue velocity ratio (E/e’) (estimated filling pressures), LV Doppler early/late diastolic mitral inflow velocity ratio (E/A), LV end-diastolic volume indexed to body surface area (LVEDVI), LV stroke volume indexed to body surface area (LVSVI), and LV mass indexed to body surface area (LVMI). RV primary outcomes were as follows: RV longitudinal strain and RV peak systolic tissue velocity (RVs’) (tricuspid valve annulus). Secondary outcomes were as follows: RV peak early diastolic tissue velocity (RVe’) (tricuspid valve annulus), mitral annular plane systolic excursion (MAPSE) and tricuspid annular plane systolic excursion (TAPSE), LV fractional shortening (LVFS), LV end-diastolic dimension (LVEDD), LV posterior wall thickness at end diastole (LVPWd), and LV length. Descriptions of the interpretation of these measures are provided in the Supplemental Information.

Detailed patient demographics and study characteristics were extracted for quality assessment. Two authors (F.T. and N.M.) independently verified the completed database against the original publications and resolved discrepancies through discussion.

In addition to result stratification by developmental ages, pooled analyses of cardiac function in children and young adults were performed, as appropriate, to elucidate potential contributors to their increased heart failure risk.4  Stratification at each developmental stage according to the degree of prematurity was made when sufficient data were available, with the cutoff of <32 weeks’ gestation selected on the basis of heart failure risk stratification.4 

Meta-analyses were performed by using Review Manager version 5.3 (The Cochrane Collaboration, Copenhagen, Denmark). Nonstandardized mean differences were weighted by the inverse variance and pooled by using random-effects models to estimate the weighted mean differences (WMDs). WMDs have also been expressed as percentages of age-based normal data derived from the weighted pooled mean for term-born individuals (percentage weighted mean difference [%WMD]). For instance, if the weighted pooled mean for term-born individuals for a given measure was 10 and the WMD was 2, then the %WMD would be 20%. The χ2 test of homogeneity (Cochran Q test; P < .1) and I2 statistic (>50%) were calculated to assess statistical significance and the degree of heterogeneity, respectively. On the basis of thresholds defined in the Cochrane Handbook of Systematic Reviews, studies with I2 <30% were considered to have low heterogeneity, whereas those >75% were considered to have high heterogeneity.29  We planned to evaluate publication bias visually with funnel plots and statistically with the test from Egger et al30  for pooled analyses containing ≥10 studies; however, because only 1 of the pooled analyses reached that threshold, supplemental publication bias testing was done for analyses containing ≥7 studies (Supplemental Figs 2126). Forest plots were depicted for visual interpretation of the individual study-specific and pooled estimates with respective 95% confidence intervals (CIs). Although some of the variation across studies may be due to methodologic diversity, it may also be due to differences in the characteristics of the study populations. Random-effects meta-regressions were therefore completed with Wilson’s SPSS macro by using IBM SPSS Statistics version 25 (IBM SPSS Statistics, IBM Corporation) to determine which covariates or study-level factors drive the measures of effect. In models, the influence of gestational age and birth weight was primarily explored and, secondarily, the influence of age, sex, IUGR or SGA, and BPD.

Quality assessment was performed independently by 2 authors (F.T. and N.M.) using a modified score system specific to preterm health for quality assessment of observational studies31  according to study design, matching of cases and controls, preterm group stratification, incidence of IUGR or SGA and BPD, completeness of participant demographics, cohort size, blinding of assessors, and reproducibility of reported results. A scale points system from 0 to 2 for each parameter was summed and adjusted to a percentage score, with high or moderate quality assigned to studies with a score >65% or 50%, respectively (Supplemental Table 1). Overall quality scores for meta-analyses were calculated as the sum of individual study quality scores weighted according to random-effects inverse variance.

Systematic review yielded 38 eligible publications of 32 unique observational studies comprising 3136 individuals (Fig 1) (preterm = 1471; term = 1665). All 38 of the included eligible publications were in English. Of these, 21 records revealed data in neonates (n = 1709; preterm = 742)13,15,1719,21,23,3245 ; 13, in infants (n = 940; preterm = 446)1316,21,23,24,38,39,41,42,46,47 ; 7, in children (n = 635; preterm = 348; mean ages: 6.7–11 years)11,20,46,4851 ; none, in adolescents; and 6, in young adults (n = 582; preterm = 301; mean ages: 18–25.1 years).6,7,9,12,22,52  All but 1 study provided analyses by echocardiography. A decision to include this cardiovascular magnetic resonance study7,9  was based on high-quality assessment and impact to the study field.

FIGURE 1

Flow diagram in which the screening and selection of studies for inclusion in the meta-analysis are described. Through database and manual searches, 3057 records were identified after removal of duplicates. These were systematically screened, resulting in the inclusion of 38 publications of 32 unique observational studies in this meta-analysis. CENTRAL, Cochrane Central Register of Controlled Trials.

FIGURE 1

Flow diagram in which the screening and selection of studies for inclusion in the meta-analysis are described. Through database and manual searches, 3057 records were identified after removal of duplicates. These were systematically screened, resulting in the inclusion of 38 publications of 32 unique observational studies in this meta-analysis. CENTRAL, Cochrane Central Register of Controlled Trials.

Close modal

Demographic characteristics for each study are presented in Supplemental Table 2. Cases and controls were matched for age in all studies. Cases with IUGR or SGA were completely excluded in 13 studies and unreported in 11 studies, whereas cases with BPD were excluded in 5 studies and unreported in 9 studies. The overall reported incidence of IUGR or SGA and BPD was low (<15%) in 63% and 66% of studies, respectively, and high (30%–50%) in 22% and 28% of studies, respectively. Two studies were excluded because of 100% IUGR53  or BPD54  stratification, and 2 studies were excluded because of >50% IUGR or SGA incidence together with a low-quality assessment secondary to pilot methodology and low cohort size (n = 30 and 25; cases = 15 and 13; controls = 15 and 12, respectively), unfavorable retrospective recruitment design, and very low birth weight preterm stratification.55,56 

As shown in Supplemental Table 3, meta-analyses were not possible at all developmental stages for all parameters. For instance, sufficient data for analyses of RVs’ and RVe’, as well as TAPSE and MAPSE, were only available for neonates; LVSVI analysis was only possible in children and young adults; and analyses of LV length and LVEDVI could only be done for young adults. Because researchers of only 6 studies investigated individuals born preterm at ≥32 mean weeks’ gestation in infancy,13,21,23,38,39,41  none in childhood, and only 1 in young adulthood,6  analyses stratified to ≥32 weeks’ gestation were only possible for E/A, LVFS, LVMI, and LVPWd in infants and were not possible in children or young adults. Participant-level values were used to stratify data from 3 studies6,13,23  for <32 and ≥32 weeks’ gestation subanalyses. Summaries for primary outcomes are presented in Table 1, and summaries for secondary outcomes are presented in Supplemental Table 4.

TABLE 1

Summary of Meta-analyses for Primary Outcomes of Cardiac Structure and Function in Preterm-Born Individuals Compared With Term-Born Controls

Neonates, WMD (95% CI)Infants, WMD (95% CI)Children, WMD (95% CI)Young Adults, WMD (95% CI)Pooled Children and Young Adults, WMD (95% CI)
LVEF, %      
 PT versus T −2.89 (−5.18 to −0.61)* −1.58 (−3.60 to 0.44) 1.67 (−0.48 to 3.82) 0.66 (−0.16 to 1.48) 0.79 (0.02 to 1.55)* 
 <32 wk versus T −2.48 (−5.78 to 0.82) −1.97 (−4.38 to 0.44) 1.67 (−0.48 to 3.82) 1.08 (0.18 to 1.98)* 1.15 (0.35 to 1.95)** 
 ≥32 wk versus T −4.54 (−6.69 to −2.40)*** — — — — 
LVs’, cm/s      
 PT versus T −0.81 (−1.13 to −0.49)*** 0.13 (−0.52 to 0.78) −0.73 (−1.05 to −0.41)*** 0.03 (−0.74 to 0.80) −0.34 (−0.83 to 0.14) 
 <32 wk versus T −0.93 (−1.15 to −0.71)*** −0.10 (−0.60 to 0.40) −0.73 (−1.05 to −0.41)*** −0.32 (−0.82 to 0.18) −0.61 (−0.88 to −0.34)*** 
 ≥32 wk versus T −0.45 (−0.80 to −0.09)* — — — — 
LV strain, %      
 PT versus T 2.53 (0.08 to 4.99)* 1.55 (0.89 to 2.21)*** −0.57 (−1.52 to 0.37) 2.01 (−0.14 to 4.17) 0.70 (−1.13 to 2.54) 
 <32 wk versus T 2.68 (0.10 to 5.25)*** 1.80 (1.08 to 2.51)*** −0.57 (−1.52 to 0.37) 0.79 (−3.81 to 5.40) 0.06 (−2.27 to 2.40) 
LVSVI, mL/m2      
 PT versus T — — −0.80 (−4.83 to 3.22) −3.59 (−4.99 to −2.19)*** — 
 <32 wk versus T — — −0.80 (−4.83 to 3.22) −4.11 (−5.64 to −2.59)*** — 
LVe’, cm/s      
 PT versus T −1.19 (−1.76 to −0.62)*** −0.87 (−1.50 to −0.23)** −1.28 (−1.82 to −0.74)*** −0.75 (−1.37 to −0.12)* −1.05 (−1.46 to −0.65)*** 
 <32 wk versus T −1.93 (−2.46 to −1.39)*** −1.48 (−2.63 to −0.32)*** −1.28 (−1.82 to −0.74)*** −0.86 (−1.54 to −0.17)* −1.12 (−1.54 to −0.70)*** 
 ≥32 wk versus T −0.70 (−0.98 to −0.41)*** — — — — 
LV E/e’      
 PT versus T 0.81 (−0.18 to 1.81) 2.10 (0.98 to 3.21)*** 0.57 (0.35 to 0.79)*** 0.13 (−0.19 to 0.45) 0.36 (0.10 to 0.61)* 
 <32 wk versus T 1.73 (0.96 to 2.50)*** 2.55 (1.82 to 3.27)*** 0.57 (0.35 to 0.79)*** 0.20 (−0.07 to 0.47) 0.40 (0.19 to 0.61)*** 
 ≥32 wk versus T 0.17 (−0.73 to 1.08) — — — — 
LV E/A      
 PT versus T −0.15 (−0.20 to −0.10)*** 0.01 (−0.07 to 0.05) 0.04 (−0.05 to 0.13) −0.14 (−0.25 to −0.02)* — 
 <32 wk versus T −0.20 (−0.31 to −0.09)*** 0.00 (−0.06 to 0.06) 0.04 (−0.05 to 0.13) −0.18 (−0.40 to 0.05) — 
 ≥32 wk versus T −0.12 (−0.17 to −0.06)*** 0.01 (−0.08 to 0.10) — — — 
LVEDVI, mL/m2      
 PT versus T — — — −6.91 (−8.84 to −4.97)*** — 
 <32 wk versus T — — — −7.93 (−10.82 to −5.04)*** — 
LVMI, g/m2      
 PT versus T −1.82 (−2.71 to −0.92)*** 3.31 (0.45 to 6.17)* −4.84 (−7.47 to −2.21)*** 4.80 (−1.80 to 11.40) — 
 <32 wk versus T −2.71 (−4.74 to −0.68)** 4.68 (−1.25 to 10.61) −4.84 (−7.47 to −2.21)*** 3.64 (−3.63 to 10.91) — 
 ≥32 wk versus T −1.66 (−2.71 to −0.62)** 3.07 (1.55 to 4.59)*** — — — 
RV strain, %      
 PT versus T 2.94 (0.54 to 5.35)* 2.73 (0.89 to 4.57)** — — 3.02 (2.23 to 3.82)*** 
 <32 wk versus T 3.87 (1.54 to 6.20)** 3.01 (0.81 to 5.22)** — — 3.02 (2.23 to 3.82)*** 
RVs’, cm/s      
 PT versus T −0.96 (−1.30 to −0.62)*** — — — — 
 <32 wk versus T −1.52 (−2.23 to −0.80)*** — — — — 
 ≥32 wk versus T −0.80 (−1.02 to −0.59)*** — — — — 
Neonates, WMD (95% CI)Infants, WMD (95% CI)Children, WMD (95% CI)Young Adults, WMD (95% CI)Pooled Children and Young Adults, WMD (95% CI)
LVEF, %      
 PT versus T −2.89 (−5.18 to −0.61)* −1.58 (−3.60 to 0.44) 1.67 (−0.48 to 3.82) 0.66 (−0.16 to 1.48) 0.79 (0.02 to 1.55)* 
 <32 wk versus T −2.48 (−5.78 to 0.82) −1.97 (−4.38 to 0.44) 1.67 (−0.48 to 3.82) 1.08 (0.18 to 1.98)* 1.15 (0.35 to 1.95)** 
 ≥32 wk versus T −4.54 (−6.69 to −2.40)*** — — — — 
LVs’, cm/s      
 PT versus T −0.81 (−1.13 to −0.49)*** 0.13 (−0.52 to 0.78) −0.73 (−1.05 to −0.41)*** 0.03 (−0.74 to 0.80) −0.34 (−0.83 to 0.14) 
 <32 wk versus T −0.93 (−1.15 to −0.71)*** −0.10 (−0.60 to 0.40) −0.73 (−1.05 to −0.41)*** −0.32 (−0.82 to 0.18) −0.61 (−0.88 to −0.34)*** 
 ≥32 wk versus T −0.45 (−0.80 to −0.09)* — — — — 
LV strain, %      
 PT versus T 2.53 (0.08 to 4.99)* 1.55 (0.89 to 2.21)*** −0.57 (−1.52 to 0.37) 2.01 (−0.14 to 4.17) 0.70 (−1.13 to 2.54) 
 <32 wk versus T 2.68 (0.10 to 5.25)*** 1.80 (1.08 to 2.51)*** −0.57 (−1.52 to 0.37) 0.79 (−3.81 to 5.40) 0.06 (−2.27 to 2.40) 
LVSVI, mL/m2      
 PT versus T — — −0.80 (−4.83 to 3.22) −3.59 (−4.99 to −2.19)*** — 
 <32 wk versus T — — −0.80 (−4.83 to 3.22) −4.11 (−5.64 to −2.59)*** — 
LVe’, cm/s      
 PT versus T −1.19 (−1.76 to −0.62)*** −0.87 (−1.50 to −0.23)** −1.28 (−1.82 to −0.74)*** −0.75 (−1.37 to −0.12)* −1.05 (−1.46 to −0.65)*** 
 <32 wk versus T −1.93 (−2.46 to −1.39)*** −1.48 (−2.63 to −0.32)*** −1.28 (−1.82 to −0.74)*** −0.86 (−1.54 to −0.17)* −1.12 (−1.54 to −0.70)*** 
 ≥32 wk versus T −0.70 (−0.98 to −0.41)*** — — — — 
LV E/e’      
 PT versus T 0.81 (−0.18 to 1.81) 2.10 (0.98 to 3.21)*** 0.57 (0.35 to 0.79)*** 0.13 (−0.19 to 0.45) 0.36 (0.10 to 0.61)* 
 <32 wk versus T 1.73 (0.96 to 2.50)*** 2.55 (1.82 to 3.27)*** 0.57 (0.35 to 0.79)*** 0.20 (−0.07 to 0.47) 0.40 (0.19 to 0.61)*** 
 ≥32 wk versus T 0.17 (−0.73 to 1.08) — — — — 
LV E/A      
 PT versus T −0.15 (−0.20 to −0.10)*** 0.01 (−0.07 to 0.05) 0.04 (−0.05 to 0.13) −0.14 (−0.25 to −0.02)* — 
 <32 wk versus T −0.20 (−0.31 to −0.09)*** 0.00 (−0.06 to 0.06) 0.04 (−0.05 to 0.13) −0.18 (−0.40 to 0.05) — 
 ≥32 wk versus T −0.12 (−0.17 to −0.06)*** 0.01 (−0.08 to 0.10) — — — 
LVEDVI, mL/m2      
 PT versus T — — — −6.91 (−8.84 to −4.97)*** — 
 <32 wk versus T — — — −7.93 (−10.82 to −5.04)*** — 
LVMI, g/m2      
 PT versus T −1.82 (−2.71 to −0.92)*** 3.31 (0.45 to 6.17)* −4.84 (−7.47 to −2.21)*** 4.80 (−1.80 to 11.40) — 
 <32 wk versus T −2.71 (−4.74 to −0.68)** 4.68 (−1.25 to 10.61) −4.84 (−7.47 to −2.21)*** 3.64 (−3.63 to 10.91) — 
 ≥32 wk versus T −1.66 (−2.71 to −0.62)** 3.07 (1.55 to 4.59)*** — — — 
RV strain, %      
 PT versus T 2.94 (0.54 to 5.35)* 2.73 (0.89 to 4.57)** — — 3.02 (2.23 to 3.82)*** 
 <32 wk versus T 3.87 (1.54 to 6.20)** 3.01 (0.81 to 5.22)** — — 3.02 (2.23 to 3.82)*** 
RVs’, cm/s      
 PT versus T −0.96 (−1.30 to −0.62)*** — — — — 
 <32 wk versus T −1.52 (−2.23 to −0.80)*** — — — — 
 ≥32 wk versus T −0.80 (−1.02 to −0.59)*** — — — — 

PT, preterm; T, term; wk, mean weeks’ gestation; —, not applicable.

*

P < .05.

**

P < .01.

***

P < .001.

As seen in Table 1 and Supplemental Table 4, all measures of LV and RV systolic function were lower in preterm versus term neonates, including LVEF (Fig 2) (WMD −2.89%; 95% CI −5.18 to −0.61; %WMD = −4.5%; P = .01). The preterm impairment in comparison with term neonates was greater (χ2 = 26.40; P < .001) for the RV measure TAPSE (WMD −2.29; 95% CI −2.81 to −1.77; %WMD = −26.3%; P < .001) than the corresponding LV measure MAPSE (WMD −0.87; 95% CI −1.03 to −0.71; %WMD = −15%; P < .001).

FIGURE 2

Forest plots demonstrating differences in LVEF in preterm-born compared with term-born individuals from neonatal life to young adulthood. WMDs calculated by using random-effects models are highlighted in bold and represented by diamonds. The size of data markers indicates study weight with respective 95% CIs.

FIGURE 2

Forest plots demonstrating differences in LVEF in preterm-born compared with term-born individuals from neonatal life to young adulthood. WMDs calculated by using random-effects models are highlighted in bold and represented by diamonds. The size of data markers indicates study weight with respective 95% CIs.

Close modal

Biventricular diastolic function, measured by LVe' and RVe', was also lower in preterm neonates compared with term neonates (Fig 3) (LVe’: WMD −1.19 cm/second, 95% CI −1.76 to −0.62, %WMD = −18.6%, P < .001; RVe’: WMD −2.08 cm/second, 95% CI −2.43 to −1.73, %WMD = −29.7%, P < .001). Preterm neonates showed lower LV E/A, although there were no significant differences in LV E/e'.

FIGURE 3

Forest plots demonstrating differences in LVe’ in preterm-born individuals compared with term-born controls from neonatal life to young adulthood. WMDs are highlighted in bold and represented by diamonds. The size of data markers indicates the study weight with respective 95% CIs.

FIGURE 3

Forest plots demonstrating differences in LVe’ in preterm-born individuals compared with term-born controls from neonatal life to young adulthood. WMDs are highlighted in bold and represented by diamonds. The size of data markers indicates the study weight with respective 95% CIs.

Close modal

Stratification of the preterm neonatal cohorts according to gestational age reduced the heterogeneity of analyses and revealed that preterm deficits were larger in those born at <32 weeks’ gestation than those born at ≥32 weeks’ gestation for all parameters except LVEF. In comparison with controls, LVs’ was twofold lower (χ2 = 5.05; P = .02) in preterm neonates born at <32 weeks’ gestation (WMD −0.93 cm/second; 95% CI −1.15 to −0.71; %WMD = −21.1%; P < .001) than those born at ≥32 weeks’ gestation (WMD −0.45 cm/second; 95% CI −0.80 to −0.09; %WMD = −10.5%; P = .01). Elevated E/e’ was only evident in preterm neonates born at <32 weeks’ gestation (WMD 1.73; 95% CI 0.96 to 2.50; %WMD = 20.1%; P < .001).

In infancy, LVEF and LVs’ were similar between preterm and term individuals, although longitudinal systolic strain (WMD 1.55%; 95% CI 0.89 to 2.21; %WMD = −7.1%; P < .001) and LVFS (WMD −1.11%; 95% CI −2.18 to −0.04; %WMD = −3.3%; P = .04) were inferior in preterm infants. LVEF and LVFS were similar in childhood, but they revealed nonsignificant trends of higher preterm function in young adulthood, which reached statistical significance for LVEF in pooled analysis of children and young adults (WMD 0.79%; 95% CI 0.02 to 1.55; %WMD = 1.3%; P = .04). LVEF data from 2 studies11,51  in children were excluded because of estimations based on parasternal long-axis ventricular dimensions, although inclusion of these data yields similar results (WMD 1.13%; 95% CI 0.00 to 2.26; %WMD = 1.8%; P = .03) (Supplemental Fig 20). Although LVs’ was lower in preterm-born children (WMD −0.73 cm/second; 95% CI −1.05 to −0.41; %WMD = −8.2%; P < .001), it did not differ significantly compared with that in term-born controls in young adulthood or in pooled analysis of children and adults. Preterm LVSVI was lower in young adulthood (Fig 4A) (WMD −3.59 mL/m2; 95% CI −4.99 to −2.19; %WMD = −8.2%; P < .001).

FIGURE 4

Forest plots demonstrating differences in cardiac structure and function in preterm-born individuals compared with term-born controls in young adulthood. A, LVSVI. B, LV E/A. C, LVEDVI. WMDs calculated by using random-effects models are highlighted in bold and represented by diamonds. The size of data markers in forest plots indicates the study weight with respective 95% CIs.

FIGURE 4

Forest plots demonstrating differences in cardiac structure and function in preterm-born individuals compared with term-born controls in young adulthood. A, LVSVI. B, LV E/A. C, LVEDVI. WMDs calculated by using random-effects models are highlighted in bold and represented by diamonds. The size of data markers in forest plots indicates the study weight with respective 95% CIs.

Close modal

In stratification of preterm-born cases <32 weeks’ gestation, LVs’ was significantly lower compared with term-born controls in pooled data for children and young adults (WMD −0.61 cm/second; 95% CI −0.88 to −0.34; %WMD = −6.5%; P < .001), and LVEF in young adulthood was significantly higher (WMD 1.08%; 95% CI 0.18 to 1.98; %WMD = 1.7%; P = .02), whereas LVSVI in young adulthood was even lower in those born at <32 weeks’ gestation (WMD −4.09 mL/m2; 95% CI −5.61 to −2.57; %WMD = −8.9%; P < .001).

RV longitudinal systolic strain was lower by a similar magnitude in preterm neonates (WMD: 2.94%; 95% CI: 0.54 to 5.35; %WMD: −12.9%; P = .02), infants (WMD: 2.73%; 95% CI: 0.89 to 4.57; %WMD: −10.6%; P = .004), and pooled data for children and young adults (WMD: 3.02%; 95% CI: 2.23 to 3.82; %WMD: −14.3%; P < .001). Because of insufficient numbers, data from Aye et al23  were excluded for RV strain stratification of preterm neonates and infants <32 weeks’ gestation. Stratification for those born at <32 weeks’ gestation resulted in greater differences compared with term controls (neonates: WMD 3.87%, 95% CI 1.54 to 6.20, %WMD = −16.2%, P = .001; infants: WMD 3.01%, 95% CI 0.81 to 5.22, %WMD = −11.7%, P = .007).

LVe' was lower in preterm-born versus term-born individuals at a similar magnitude across all stages of development, with a pooled WMD in children and young adults of −1.05 cm/second (95% CI −1.46 to −0.65; %WMD = −5.9%; P < .001). Preterm E/e’ was higher in infants (WMD 2.10; 95% CI 0.98 to 3.21; %WMD = 23.9%; P < .001) and in childhood (WMD 0.57; 95% CI 0.35 to 0.79; %WMD = 11.2%; P < .001). Although E/e’ was higher in pooled data from preterm children and young adults, no significant difference was detected when just data from young adults born preterm were analyzed. There was no difference in E/A between groups in infancy and childhood, but it was significantly lower in preterm-born young adults compared with term-born controls (Fig 4B) (WMD −0.14; 95% CI −0.25 to −0.02; %WMD = −7.0%; P = .02).

In stratification of preterm-born cases <32 weeks’ gestation, LVe’ deficits in comparison with term controls were numerically higher, with a WMD in pooled children and young adults of −1.12 cm/second (95% CI −1.54 to −0.70; %WMD = −6.3%; P < .001). Preterm E/e’ differences in young adulthood remained nonsignificant with stratification; however, differences between groups for pooled data of children and young adults were greater (WMD 0.40; 95% CI 0.19 to 0.61; %WMD = 7.7%; P < .001), and heterogeneity was lower (I2 = 23%).

LVMI was lower in preterm compared with term neonates (WMD −1.82 g/m2; 95% CI −2.71 to −0.92; %WMD = −8.9%; P < .001), although it was significantly higher in preterm infants compared with term infants (WMD 3.31 g/m2; 95% CI 0.45 to 6.17; %WMD = 11.7%; P = .02). LVPWd, although similar in neonates, was significantly higher in preterm compared with term infants (WMD 0.30 mm; 95% CI 0.16 to 0.43; %WMD = 9.4%; P < .001). Both LVMI (WMD −4.84 g/m2; 95% CI −7.47 to −2.21; %WMD = −9.0%; P < .001) and LVPWd (WMD −0.23 mm; 95% CI −0.44 to −0.01; %WMD = −4.0%; P = .04) were lower in preterm- versus term-born children. In young adulthood, there was a high I2 in analyses (LVMI: I2 = 93%; LVPWd: I2 = 96%), with numerically higher LVMI in the preterm group that failed to reach statistical significance (WMD 4.80 g/m2; 95% CI −1.80 to 11.40; %WMD = 6.1%; P = .15).

LVEDD was smaller in preterm infants (WMD −2.25 mm; 95% CI −3.95 to −0.55; %WMD = −11.0%; P < .001), children (WMD −1.80 mm; 95% CI −2.97 to −0.64; %WMD = −4.7%; P = .002), and young adults (WMD −2.49 mm; 95% CI −4.26 to −0.72; %WMD = −4.9%; P = .006). In adulthood, both preterm LVEDVI (Fig 4C) (WMD −6.91 mL/m2; 95% CI −8.84 to −4.97; %WMD = −9.9%; P < .001) and LV length (WMD −0.56 cm; 95% CI −0.74 to −0.38; %WMD = −6.0%; P < .001) were significantly smaller than in term-born controls.

The magnitude of LVPWd differences in preterm versus term infants was greater in those born at <32 weeks’ gestation than those born at ≥32 weeks’ gestation (WMD 0.42 mm, 95% CI 0.14 to 0.70, %WMD = 14.0%, P = .004; versus WMD 0.20 mm, 95% CI 0.04 to 0.36, %WMD = 5.9%, P = .02). In analyses of young adults born preterm at <32 weeks’ gestation, LVPWd and LVMI remained heterogeneous and nonsignificant compared with those in term-born controls, whereas the magnitudes of difference in LVEDD, LVEDVI, and LV length were larger.

Meta-regression results are displayed in Supplemental Tables 5 and 6 and Supplemental Fig 1. In pooled analyses of neonates and infants, gestational age revealed a strong inverse relationship to LV systolic (LVs’: P = .03) and diastolic deficits (LVe’: P < .001; E/e’: P < .001). Within the limitations of there being a small number of studies in children and adults for these parameters, the results indicated that gestational age continued to be a strong determinant of lower LV systolic function (LVs’: P < .001); however, there was no significant relationship with LV diastolic function (LVe’: P = .20; E/e’: P = .09). The lower magnitude of RV strain was proportional to gestational age in pooled analyses of all developmental stages (P = .002). Meta-regression analyses for birth weight revealed similar significant relationships to LVs’, LVe’, E/e’, and RV strain. However, lower birth weight was the only variable associated with higher LVEF in preterm children and young adults (P = .05). Although the percentage of male participants did not significantly relate to LVMI, LVEF, LVe’, or E/e’ in meta-regression analyses, it was significantly related to LVs’ and LVEDD across developmental stages (P < .05).

Because the reporting of IUGR, SGA, and BPD incidence was incomplete, meta-regressions were not possible for all parameters, although BPD was significantly related to LVe’ in neonates and infants (P = .001). Lastly, 60% of the heterogeneity in LVMI changes in children and young adults born preterm was explained by postnatal age, indicating an increase in comparison with controls of 0.71 g/m2 per year from childhood (95% CI 0.20 to 1.22; P = .007; R2 = 0.60).

We present the first meta-analysis comparing cardiac structure and function between preterm-born cases and age-matched term-born controls from birth to young adulthood. Preterm-born individuals have persistently smaller ventricular dimensions, lower LV diastolic function that worsens with age, RV systolic impairment across all developmental stages, and an accelerated rate of LV hypertrophy from childhood to young adulthood. These cardiac alterations may make the myocardium more vulnerable to secondary insults, which may explain their increased risk of early heart failure and long-term risk of ischemic heart disease.

Preterm birth occurs during a key cardiac developmental period that normally occurs in utero and is associated with an increased risk of early heart failure in childhood to young adulthood, particularly in those born at earlier gestations.4  The results from this meta-analysis reveal that LVs’ is lower across gestational ages in neonates and remains lower in childhood and young adulthood in those who were born at <32 weeks’ gestation. These subtle functional differences may make the preterm heart less resilient to common causes of early heart failure, such as myocarditis,57,58  potentially explaining part of the increased risk with lower gestational ages.4  Biological variation associated with preterm birth, such as elevated blood pressure, abnormal vascular and respiratory development, and altered metabolic profile and immunity, will likely act as additional negative stimuli on their already compromised cardiac physiology.5961  We believe that when exposed to adult cardiovascular risk, such as hypertension or myocardial injury, preterm-born adults will be more likely to develop heart failure. In further support of a reduced myocardial functional reserve, it has been shown by using echocardiography imaging at prescribed exercise intensities that preterm-born young adults have an impaired ability to increase LVEF and cardiac index under physiologic stress, which is suggestive of a reduced myocardial functional reserve.6,62  The greatest predictors of this reduced LV function during exercise were the degree of prematurity and smaller LVEDVI, primarily driven by shorter LV lengths.6  The results from our meta-analysis reveal consistently smaller LVEDD in the preterm group compared with term controls across developmental stages, with smaller LVEDVI and shorter LV length in young adulthood. Our finding that LVEF at rest is marginally higher in children and young adults born preterm should be interpreted cautiously. LVEF is not a direct measure of myocardial contractility, is strongly influenced by structural changes, and may be preserved or elevated despite systolic impairment in the setting of reduced LVEDVI.63 

We report lower LV myocardial relaxation velocities throughout development, which may reflect greater myocardial fibrosis, as seen in animal models of preterm birth.64,65  Although studies are needed to confirm this in humans, more fibrosis in the ventricular walls would alter myocardial viscoelastic properties, thereby decreasing compliance. Clinically, LV diastolic dysfunction is associated with a higher risk for invasive ventilation and pulmonary hemorrhage within the first day of life in premature infants,66  and it has a direct correlation to abnormal coupling of the RV to its afterload during the transitional period.67  As individuals progress to adulthood, reductions in diastolic function have diagnostic, therapeutic, and prognostic value.68  These measures are predictive of cardiovascular disease outcomes and disease progression, such as severity of heart failure. Continuous monitoring throughout life of diastolic function in preterm-born individuals therefore has immediate and long-term clinical value. Diastolic function may also be further worsened by myocardial hypertrophy.69  Compared with term controls, our meta-analysis reveals higher LVMI and wall thickness in preterm infants. LVMI is lower in preterm children, but there is an accelerated hypertrophy rate from childhood to young adulthood. Whether this worsens with natural aging and progression of the known greater blood pressure and cardiovascular risk factors in preterm-born individuals remains to be determined.70 

Our meta-analyses reveal a greater right-sided systolic deficit with neonatal impairments in TAPSE approximately twofold greater than the corresponding LV measure MAPSE, revealing a persistent level of RV strain impairment throughout development that is proportional to gestational age. It is unlikely that early postnatal respiratory complications alone account for the observed deficits in RV performance because the overall incidence of BPD was low, due to exclusion of studies stratified by BPD and exclusion of BPD cases when possible. Nevertheless, higher pulmonary vascular resistance in immature preterm lungs is expected to impose greater RV afterload in early life, whereas invasive measures of pulmonary elastance have confirmed increased RV afterload in preterm-born young adults.71  We, therefore, acknowledge that preterm RV systolic deficits may, in part, reflect the sensitivity of the thin-walled RV to loading conditions caused by preterm pulmonary abnormalities.

The importance of these results should be interpreted within the framework of the inherent limitations of this meta-analysis. The causes of preterm birth and impact of preterm-related complications on cardiac structure and function could not be fully explored. It is possible that comorbidities, such as IUGR,53  may influence preterm cardiac phenotype. However, we demonstrated an inverse relationship between gestational age and impairments of LV and RV systolic function throughout development in analyses that excluded studies containing specific stratification for preterm-related complications. Although the majority of analyses were possible for our primary outcome measures, insufficient data statistically prevented the exploration of all intended measures at each developmental stage as well as stratification by gestational age >32 weeks and <32 weeks, highlighting the need for further research in the field. In addition, high I2 values for some of the measures suggest that heterogeneity may have impacted some aspects of the meta-analysis. Furthermore, because analyses at each developmental stage are cross-sectional, we cannot make conclusions on whether alterations track throughout life in the same individuals, but rather we can only conclude that differences exist between groups at different developmental stages. Further longitudinal studies with serial cardiac imaging, including echocardiography and cardiovascular magnetic resonance, are needed to determine how cardiac remodeling in those born preterm progresses over time.

Individuals born preterm have a unique cardiac phenotype with persistent morphologic and functional differences across developmental stages from birth to young adulthood. These changes in cardiac structure and function may make the myocardium more vulnerable to secondary insults, contributing to an increased risk of early heart failure and ischemic heart disease. Given the high rates of preterm delivery and increasing survival rates,1,72  it is of particular public health interest to design primary prevention strategies for this growing cohort of susceptible individuals with newly recognized cardiovascular disease predisposition. Regular and long-term clinical cardiovascular follow-up of people born preterm is warranted and should be encouraged.

Drs Lewandowski and Telles conceptualized and designed the study, gathered the data, interpreted the data, and drafted the manuscript; Dr Levy contributed to the study design, data analysis and interpretation, and critically reviewed the manuscript for important intellectual content; Dr McNamara independently completed study selection, data extraction, and quality assessment and provided critical review of the article for intellectual content; Drs Nanayakkara, Leeson, and Marwick contributed to the interpretation of the data and critically reviewed the manuscript for important intellectual content; Drs Doyle and Williams assisted with initial data analyses and provided critical review of the article for intellectual content; Ms Yaeger designed and ran the search strategies for data collection, assisted with writing the methodology section, and provided critical review of the article for intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

This trial has been registered with PROSPERO (https://www.crd.york.ac.uk/prospero/) (identifier CRD42016038650).

FUNDING: Dr Lewandowski is funded by a British Heart Foundation Intermediate Research Fellowship (FS/18/3/33292). Funders were not involved in the design or conduct of the meta-analysis; the collection, management, or interpretation of the data; or the preparation, review, or approval of the article.

     
  • BPD

    bronchopulmonary dysplasia

  •  
  • CI

    confidence interval

  •  
  • E/A

    Doppler early/late diastolic mitral inflow velocity ratio

  •  
  • E/e’

    early Doppler inflow velocity/peak early diastolic tissue velocity ratio

  •  
  • IUGR

    intrauterine growth restriction

  •  
  • LV

    left ventricular

  •  
  • LVe’

    left ventricular peak early diastolic tissue velocity

  •  
  • LVEDD

    left ventricular end-diastolic dimension

  •  
  • LVEDVI

    left ventricular end-diastolic volume indexed to body surface area

  •  
  • LVFS

    left ventricular fractional shortening

  •  
  • LVMI

    left ventricular mass indexed to body surface area

  •  
  • LVPWd

    left ventricular posterior wall thickness at end diastole

  •  
  • LVs’

    left ventricular peak systolic tissue velocity

  •  
  • LVSVI

    left ventricular stroke volume indexed to body surface area

  •  
  • MAPSE

    mitral annular plane systolic excursion

  •  
  • RV

    right ventricular

  •  
  • RVe’

    right ventricular peak early diastolic tissue velocity

  •  
  • RVs’

    right ventricular peak systolic tissue velocity

  •  
  • SGA

    small for gestational age

  •  
  • TAPSE

    tricuspid annular plane systolic excursion

  •  
  • WMD

    weighted mean difference

  •  
  • %WMD

    percentage weighted mean difference

1
Blencowe
H
,
Cousens
S
,
Oestergaard
MZ
, et al
.
National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications
.
Lancet
.
2012
;
379
(
9832
):
2162
2172
2
Goldenberg
RL
,
Culhane
JF
,
Iams
JD
,
Romero
R
.
Epidemiology and causes of preterm birth
.
Lancet
.
2008
;
371
(
9606
):
75
84
3
Crump
C
,
Sundquist
K
,
Sundquist
J
,
Winkleby
MA
.
Gestational age at birth and mortality in young adulthood
.
JAMA
.
2011
;
306
(
11
):
1233
1240
4
Carr
H
,
Cnattingius
S
,
Granath
F
,
Ludvigsson
JF
,
Edstedt Bonamy
AK
.
Preterm birth and risk of heart failure up to early adulthood
.
J Am Coll Cardiol
.
2017
;
69
(
21
):
2634
2642
5
Crump
C
,
Howell
EA
,
Stroustrup
A
,
McLaughlin
MA
,
Sundquist
J
,
Sundquist
K
.
Association of preterm birth with risk of ischemic heart disease in adulthood
.
JAMA Pediatr
.
2019
;
173
(
8
):
736
743
6
Huckstep
OJ
,
Williamson
W
,
Telles
F
, et al
.
Physiological stress elicits impaired left ventricular function in preterm-born adults
.
J Am Coll Cardiol
.
2018
;
71
(
12
):
1347
1356
7
Lewandowski
AJ
,
Bradlow
WM
,
Augustine
D
, et al
.
Right ventricular systolic dysfunction in young adults born preterm
.
Circulation
.
2013
;
128
(
7
):
713
720
8
Mohamed
A
,
Lamata
P
,
Williamson
W
, et al
.
Multimodality imaging demonstrates reduced right-ventricular function independent of pulmonary physiology in moderately preterm-born adults [published online ahead of print May 8, 2020]
.
JACC Cardiovasc Imaging
.
2020
. doi:
9
Lewandowski
AJ
,
Augustine
D
,
Lamata
P
, et al
.
Preterm heart in adult life: cardiovascular magnetic resonance reveals distinct differences in left ventricular mass, geometry, and function
.
Circulation
.
2013
;
127
(
2
):
197
206
10
Stroup
DF
,
Berlin
JA
,
Morton
SC
, et al
.
Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group
.
JAMA
.
2000
;
283
(
15
):
2008
2012
11
Mohlkert
LA
,
Hallberg
J
,
Broberg
O
, et al
.
The preterm heart in childhood: left ventricular structure, geometry, and function assessed by echocardiography in 6-year-old survivors of periviable births
.
J Am Heart Assoc
.
2018
;
7
(
2
):
e007742
12
Kowalski
RR
,
Beare
R
,
Doyle
LW
,
Smolich
JJ
,
Cheung
MM
;
Victorian Infant Collaborative Study Group
.
Elevated blood pressure with reduced left ventricular and aortic dimensions in adolescents born extremely preterm
.
J Pediatr
.
2016
;
172
:
75
80.e2
13
Cox
DJ
,
Bai
W
,
Price
AN
,
Edwards
AD
,
Rueckert
D
,
Groves
AM
.
Ventricular remodeling in preterm infants: computational cardiac magnetic resonance atlasing shows significant early remodeling of the left ventricle
.
Pediatr Res
.
2019
;
85
(
6
):
807
815
14
Breatnach
CR
,
Forman
E
,
Foran
A
, et al
.
Left ventricular rotational mechanics in infants with hypoxic ischemic encephalopathy and preterm infants at 36 weeks postmenstrual age: a comparison with healthy term controls
.
Echocardiography
.
2017
;
34
(
2
):
232
239
15
Breatnach
CR
,
El-Khuffash
A
,
James
A
,
McCallion
N
,
Franklin
O
.
Serial measures of cardiac performance using tissue Doppler imaging velocity in preterm infants <29weeks gestations
.
Early Hum Dev
.
2017
;
108
:
33
39
16
Cohen
E
,
Whatley
C
,
Wong
FY
, et al
.
Effects of foetal growth restriction and preterm birth on cardiac morphology and function during infancy
.
Acta Paediatr
.
2018
;
107
(
3
):
450
455
17
Koestenberger
M
,
Nagel
B
,
Ravekes
W
, et al
.
Longitudinal systolic left ventricular function in preterm and term neonates: reference values of the mitral annular plane systolic excursion (MAPSE) and calculation of z-scores
.
Pediatr Cardiol
.
2015
;
36
(
1
):
20
26
18
Koestenberger
M
,
Nagel
B
,
Ravekes
W
, et al
.
Right ventricular performance in preterm and term neonates: reference values of the tricuspid annular peak systolic velocity measured by tissue Doppler imaging
.
Neonatology
.
2013
;
103
(
4
):
281
286
19
Koestenberger
M
,
Nagel
B
,
Ravekes
W
, et al
.
Systolic right ventricular function in preterm and term neonates: reference values of the tricuspid annular plane systolic excursion (TAPSE) in 258 patients and calculation of z-score values
.
Neonatology
.
2011
;
100
(
1
):
85
92
20
Suursalmi
P
,
Eerola
A
,
Poutanen
T
,
Korhonen
P
,
Kopeli
T
,
Tammela
O
.
Very low birthweight bronchopulmonary dysplasia survivors had similar cardiac outcomes to controls at six years to 14 years of age
.
Acta Paediatr
.
2017
;
106
(
2
):
261
267
21
Eriksen
BH
,
Nestaas
E
,
Hole
T
,
Liestøl
K
,
Støylen
A
,
Fugelseth
D
.
Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation
.
Early Hum Dev
.
2014
;
90
(
7
):
359
364
22
Bassareo
PP
,
Fanos
V
,
Puddu
M
,
Marras
S
,
Mercuro
G
.
Epicardial fat thickness, an emerging cardiometabolic risk factor, is increased in young adults born preterm
.
J Dev Orig Health Dis
.
2016
;
7
(
4
):
369
373
23
Aye
CYL
,
Lewandowski
AJ
,
Lamata
P
, et al
.
Disproportionate cardiac hypertrophy during early postnatal development in infants born preterm
.
Pediatr Res
.
2017
;
82
(
1
):
36
46
24
Levy
PT
,
Patel
MD
,
Choudhry
S
,
Hamvas
A
,
Singh
GK
.
Evidence of echocardiographic markers of pulmonary vascular disease in asymptomatic infants born preterm at one year of age
.
J Pediatr
.
2018
;
197
:
48
56.e2
25
Hundley
WG
,
Bluemke
D
,
Bogaert
JG
, et al
.
Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance examinations
.
J Cardiovasc Magn Reson
.
2009
;
11
:
5
26
Lang
RM
,
Bierig
M
,
Devereux
RB
, et al;
Chamber Quantification Writing Group
;
American Society of Echocardiography’s Guidelines and Standards Committee
;
European Association of Echocardiography
.
Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology
.
J Am Soc Echocardiogr
.
2005
;
18
(
12
):
1440
1463
27
Nagueh
SF
,
Smiseth
OA
,
Appleton
CP
, et al
.
Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging
.
J Am Soc Echocardiogr
.
2016
;
29
(
4
):
277
314
28
Rudski
LG
,
Lai
WW
,
Afilalo
J
, et al
.
Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography
.
J Am Soc Echocardiogr
.
2010
;
23
(
7
):
685
713–788
29
Higgins
JPT
,
Thomas
J
,
Chandler
J
, et al, eds.
Cochrane Handbook for Systematic Reviews of Interventions.
Version 6.0 (updated July 2019).
2019
. Available at: www.training.cochrane.org/handbook. Accessed March 23, 2020
30
Egger
M
,
Davey Smith
G
,
Schneider
M
,
Minder
C
.
Bias in meta-analysis detected by a simple, graphical test
.
BMJ
.
1997
;
315
(
7109
):
629
634
31
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
(
6
):
728
737
32
Appleton
RS
,
Graham
TP
 Jr.
,
Cotton
RB
,
Moreau
GA
,
Boucek
RJ
 Jr.
.
Altered early left ventricular diastolic cardiac function in the premature infant
.
Am J Cardiol
.
1987
;
59
(
15
):
1391
1394
33
Ciccone
MM
,
Scicchitano
P
,
Zito
A
, et al
.
Different functional cardiac characteristics observed in term/preterm neonates by echocardiography and tissue doppler imaging
.
Early Hum Dev
.
2011
;
87
(
8
):
555
558
34
Elkiran
O
,
Karakurt
C
,
Kocak
G
,
Karadag
A
.
Tissue Doppler, strain, and strain rate measurements assessed by two-dimensional speckle-tracking echocardiography in healthy newborns and infants
.
Cardiol Young
.
2014
;
24
(
2
):
201
211
35
Ghandi
Y
,
Habibi
D
,
Farahani
E
.
Reference values of longitudinal systolic right and left ventricular function measured by M-mode echocardiography in healthy preterm and term neonates
.
J Cardiovasc Echogr
.
2018
;
28
(
3
):
177
181
36
Harada
K
,
Takahashi
Y
,
Tamura
M
,
Orino
T
,
Takada
G
.
Serial echocardiographic and Doppler evaluation of left ventricular systolic performance and diastolic filling in premature infants
.
Early Hum Dev
.
1999
;
54
(
2
):
169
180
37
Johnson
GL
,
Moffett
CB
,
Noonan
JA
.
Doppler echocardiographic studies of diastolic ventricular filling patterns in premature infants
.
Am Heart J
.
1988
;
116
(
6, pt 1
):
1568
1574
38
Kozák-Bárány
A
,
Jokinen
E
,
Saraste
M
,
Tuominen
J
,
Välimäki
I
.
Development of left ventricular systolic and diastolic function in preterm infants during the first month of life: a prospective follow-up study
.
J Pediatr
.
2001
;
139
(
4
):
539
545
39
Mannarino
S
,
Garofoli
F
,
Mongini
E
, et al
.
BNP concentrations and cardiovascular adaptation in preterm and fullterm newborn infants
.
Early Hum Dev
.
2010
;
86
(
5
):
295
298
40
Negrine
RJS
,
Chikermane
A
,
Wright
JGC
,
Ewer
AK
.
Assessment of myocardial function in neonates using tissue Doppler imaging
.
Arch Dis Child Fetal Neonatal Ed
.
2012
;
97
(
4
):
F304
F306
41
Poon
CY
,
Wilson
DG
,
Joshi
S
,
Fraser
AG
,
Kotecha
S
.
Longitudinal evaluation of myocardial function in preterm infants with respiratory distress syndrome
.
Echocardiography
.
2019
;
36
(
9
):
1713
1726
42
Schubert
U
,
Müller
M
,
Abdul-Khaliq
H
,
Norman
M
.
Preterm birth is associated with altered myocardial function in infancy
.
J Am Soc Echocardiogr
.
2016
;
29
(
7
):
670
678
43
Toyono
M
,
Harada
K
,
Takahashi
Y
,
Takada
G
.
Maturational changes in left ventricular contractile state
.
Int J Cardiol
.
1998
;
64
(
3
):
247
252
44
Walther
FJ
,
Siassi
B
,
King
J
,
Wu
PYK
.
Echocardiographic measurements in normal preterm and term neonates
.
Acta Paediatr Scand
.
1986
;
75
(
4
):
563
568
45
Walther
FJ
,
Siassi
B
,
Wu
PY
.
Echocardiographic measurement of left ventricular stroke volume in newborn infants: a correlative study with pulsed Doppler and M-mode echocardiography
.
J Clin Ultrasound
.
1986
;
14
(
1
):
37
41
46
Kang
SJ
,
Kim
M
,
Hwang
SJ
,
Kim
HJ
.
Progression of right ventricular systolic dysfunction detected by myocardial deformation imaging in asymptomatic preterm children
.
J Cardiovasc Ultrasound
.
2017
;
25
(
3
):
98
104
47
Hirose
A
,
Khoo
NS
,
Aziz
K
, et al
.
Evolution of left ventricular function in the preterm infant
.
J Am Soc Echocardiogr
.
2015
;
28
(
3
):
302
308
48
Joshi
S
,
Wilson
DG
,
Kotecha
S
,
Pickerd
N
,
Fraser
AG
,
Kotecha
S
.
Cardiovascular function in children who had chronic lung disease of prematurity
.
Arch Dis Child Fetal Neonatal Ed
.
2014
;
99
(
5
):
F373
F379
49
Korhonen
P
,
Hyödynmaa
E
,
Lautamatti
V
,
Iivainen
T
,
Tammela
O
.
Cardiovascular findings in very low birthweight schoolchildren with and without bronchopulmonary dysplasia
.
Early Hum Dev
.
2005
;
81
(
6
):
497
505
50
Morsing
E
,
Liuba
P
,
Fellman
V
,
Maršál
K
,
Brodszki
J
.
Cardiovascular function in children born very preterm after intrauterine growth restriction with severely abnormal umbilical artery blood flow
.
Eur J Prev Cardiol
.
2014
;
21
(
10
):
1257
1266
51
Kwinta
P
,
Jagła
M
,
Grudzień
A
,
Klimek
M
,
Zasada
M
,
Pietrzyk
JJ
.
From a regional cohort of extremely low birth weight infants: cardiac function at the age of 7 years
.
Neonatology
.
2013
;
103
(
4
):
287
292
52
Bassareo
PP
,
Fanos
V
,
Puddu
M
,
Cadeddu
C
,
Balzarini
M
,
Mercuro
G
.
Significant QT interval prolongation and long QT in young adult ex-preterm newborns with extremely low birth weight
.
J Matern Fetal Neonatal Med
.
2011
;
24
(
9
):
1115
1118
53
Crispi
F
,
Bijnens
B
,
Figueras
F
, et al
.
Fetal growth restriction results in remodeled and less efficient hearts in children
.
Circulation
.
2010
;
121
(
22
):
2427
2436
54
Kazanci
E
,
Karagöz
T
,
Tekinalp
G
, et al
.
Myocardial performance index by tissue Doppler in bronchopulmonary dysplasia survivors
.
Turk J Pediatr
.
2011
;
53
(
4
):
388
396
55
Ciccone
MM
,
Cortese
F
,
Gesualdo
M
, et al
.
The role of very low birth weight and prematurity on cardiovascular disease risk and on kidney development in children: a pilot study [published online ahead of print June 29, 2016]
.
Minerva Pediatr
.
2016
56
Xie
L
,
Chee
YY
,
Wong
KY
,
Cheung
YF
.
Cardiac mechanics in children with bronchopulmonary dysplasia
.
Neonatology
.
2016
;
109
(
1
):
44
51
57
Andrews
RE
,
Fenton
MJ
,
Ridout
DA
,
Burch
M
;
British Congenital Cardiac Association
.
New-onset heart failure due to heart muscle disease in childhood: a prospective study in the United Kingdom and Ireland
.
Circulation
.
2008
;
117
(
1
):
79
84
58
Leeson
P
,
Lewandowski
AJ
.
A new risk factor for early heart failure: preterm birth
.
J Am Coll Cardiol
.
2017
;
69
(
21
):
2643
2645
59
Ligi
I
,
Simoncini
S
,
Tellier
E
, et al
.
A switch toward angiostatic gene expression impairs the angiogenic properties of endothelial progenitor cells in low birth weight preterm infants
.
Blood
.
2011
;
118
(
6
):
1699
1709
60
Lewandowski
AJ
,
Davis
EF
,
Yu
G
, et al
.
Elevated blood pressure in preterm-born offspring associates with a distinct antiangiogenic state and microvascular abnormalities in adult life
.
Hypertension
.
2015
;
65
(
3
):
607
614
61
Yu
GZ
,
Aye
CY
,
Lewandowski
AJ
, et al
.
Association of maternal antiangiogenic profile at birth with early postnatal loss of microvascular density in offspring of hypertensive pregnancies
.
Hypertension
.
2016
;
68
(
3
):
749
759
62
Huckstep
OJ
,
Burchert
H
,
Williamson
W
, et al
.
Impaired myocardial reserve underlies reduced exercise capacity and heart rate recovery in preterm-born young adults [published online ahead of print April 17, 2020]
.
Eur Heart J Cardiovasc Imaging
.
doi:10.1093/ehjci/jeaa060
63
Konstam
MA
,
Abboud
FM
.
Ejection fraction: misunderstood and overrated (changing the paradigm in categorizing heart failure)
.
Circulation
.
2017
;
135
(
8
):
717
719
64
Bensley
JG
,
Stacy
VK
,
De Matteo
R
,
Harding
R
,
Black
MJ
.
Cardiac remodelling as a result of pre-term birth: implications for future cardiovascular disease
.
Eur Heart J
.
2010
;
31
(
16
):
2058
2066
65
Bertagnolli
M
,
Huyard
F
,
Cloutier
A
, et al
.
Transient neonatal high oxygen exposure leads to early adult cardiac dysfunction, remodeling, and activation of the renin–angiotensin system
.
Hypertension
.
2014
;
63
(
1
):
143
150
66
Bussmann
N
,
Breatnach
C
,
Levy
PT
,
McCallion
N
,
Franklin
O
,
El-Khuffash
A
.
Early diastolic dysfunction and respiratory morbidity in premature infants: an observational study
.
J Perinatol
.
2018
;
38
(
9
):
1205
1211
67
Bussmann
N
,
El-Khuffash
A
,
Breatnach
CR
, et al
.
Left ventricular diastolic function influences right ventricular - pulmonary vascular coupling in premature infants
.
Early Hum Dev
.
2019
;
128
:
35
40
68
Nagueh
SF
.
Left ventricular diastolic function: understanding pathophysiology, diagnosis, and prognosis with echocardiography
.
JACC Cardiovasc Imaging
.
2020
;
13
(
1, pt 2
):
228
244
69
Lorell
BH
,
Carabello
BA
.
Left ventricular hypertrophy: pathogenesis, detection, and prognosis
.
Circulation
.
2000
;
102
(
4
):
470
479
70
Markopoulou
P
,
Papanikolaou
E
,
Analytis
A
,
Zoumakis
E
,
Siahanidou
T
.
Preterm birth as a risk factor for metabolic syndrome and cardiovascular disease in adult life: a systematic review and meta-analysis
.
J Pediatr
.
2019
;
210
:
69
80.e5
71
Goss
KN
,
Beshish
AG
,
Barton
GP
, et al
.
Early pulmonary vascular disease in young adults born preterm
.
Am J Respir Crit Care Med
.
2018
;
198
(
12
):
1549
1558
72
Saigal
S
,
Doyle
LW
.
An overview of mortality and sequelae of preterm birth from infancy to adulthood
.
Lancet
.
2008
;
371
(
9608
):
261
269

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data