Study Population

All data were prospectively obtained as part of an observational research study that included patients who were enrolled between August 2011 and January 2016 at hospitals affiliated with two academic institutions (Washington University School of Medicine, St. Louis Children’s Hospital, and the Royal College of Surgeons in Ireland, Rotunda Hospital). Two hundred thirty-nine preterm infants (born at 23-0/7 to 28-6/7 weeks gestation) were recruited at birth and longitudinally followed until 1 year CA. The preterm infants enrolled from the Washington University site were among infants participating in the Prematurity and Respiratory Outcomes Program ( ClinicalTrials.gov identifier NCT01435187 ). Infants with any suspected congenital anomalies of the airways, congenital heart disease (except atrial septal defects), chromosomal anomalies, intrauterine growth restriction, or small for gestational age (birth weight < 10th centile for gestation) were excluded from the healthy uncomplicated cohort arm of the study.

At both centers, reference values and maturational patterns of RV fractional area of change from these cohorts have been recently published, but deformation imaging by 2D STE has not been reported. At the Washington University School of Medicine site, a small proportion of the deformation data were previously used to test feasibility and reproducibility. At the Royal College of Surgeons in Ireland site, deformation imaging by tissue Doppler has been assessed in the transitional period and up to 36 weeks postmenstrual age (PMA). The institutional review board of Washington University and the ethics committee on human research at the Royal College of Surgeons approved the protocol. Written informed consent was obtained from the parents or guardians of all participants.

Inclusion Criteria in Uncomplicated Cohort

Only infants with “cardiorespiratory healthiness” were classified as healthy uncomplicated infants in this study. In the early neonatal period, a large proportion of premature infants present with acute respiratory failure and often require some sort of respiratory support up to 36 weeks PMA, making it difficult to determine a true definition of “respiratory healthiness.” Respiratory disease syndrome and the need for invasive and noninvasive ventilation are common in extremely preterm birth in the early postnatal period. BPD, defined as the need for persistent supplemental oxygen support at 36 weeks PMA, is recognized as the most significant respiratory consequence of premature birth in the late postnatal period. If preterm infants still required any respiratory support at or beyond 36 weeks PMA, they were excluded from the uncomplicated cohort. We assessed for the contributions of BPD, as defined by a modified definition of the 2001 National Institutes of Health BPD workshop, in a subanalysis.

Infants with any of the following echocardiographic signs of late-onset PH, identified at any time point from 32 weeks PMA through 1 year CA, were excluded: estimated RV systolic pressure (RVSP) > 40 mm Hg, a ratio of RVSP to systemic systolic blood pressure > 0.5, any cardiac shunt with bidirectional or right-to-left flow, unusual degree of RV hypertrophy or dilatation, or ventricular septal wall flattening. They were assessed in a separate analysis. Because the incidence of PH ranges from 12% to 25% of infants with BPD, we performed stepwise regression to analyze the influence of PH and BPD on ventricular strain patterns.

The significance of a PDA and its impact on long-term cardiorespiratory health remain areas of ongoing debate in neonatology. Even the persistent patency of a PDA remains an ongoing clinical conundrum, as most premature neonates in whom the PDA fails to close in the first week of age or even by the time of discharge will undergo spontaneous closure a few weeks later. Prolonged patency is associated with numerous adverse outcomes, but the extent to which these adverse outcomes are attributable to the hemodynamic consequences of ductal patency, if at all, has not been established. However, infants with moderate to large PDA, on the basis of its size relationship to the left pulmonary artery (LPA), have a 15 times greater likelihood of requiring treatment for clinically and hemodynamically significant PDA than those with small PDA. We therefore excluded any infant with a moderate to large hemodynamically significant PDA (hsPDA) in the first week of age, and any size PDA from 32 weeks and beyond, but a separate subanalysis was performed for this cohort. For this study, an hsPDA was defined as a PDA diameter of >1.5 mm with the presence of flow reversal in the descending aorta and a left atrial–to–aortic root ratio of >1.5. In addition, we used the relationship of the PDA to LPA to define size and clinical significance (large, PDA/LPA ratio > 1; moderate, PDA/LPA ratio < 1 but >0.5; and small, PDA/LPA ratio < 0.5). Combined, these approaches allowed us to properly assess PDA characteristics, signs of pulmonary overcirculation, and left heart loading condition. Finally, infants that underwent pharmacologic or surgical intervention at any time point in their neonatal course to close a PDA were also excluded from this cohort.

Echocardiographic Examination

Echocardiography was performed at six time points from birth to 1 year CA ( Figure 1 ): at the Washington University School of Medicine site, echocardiography was performed serially at day 1 ( n = 30), day 2 ( n = 30), 32 weeks PMA ( n = 117), 36 weeks PMA ( n = 117), and 1 year CA ( n = 80). At the Royal College of Surgeons in Ireland site, echocardiography was performed at day 1 ( n = 102), day 2 ( n = 102), days 5 to 7 ( n = 98), and 36 weeks PMA ( n = 47) ( Figure 1 ). We chose three time points in the first week of age to capture the physiologic changes that occur during the transitional period in preterm infants. The timings of the echocardiographic studies at 32 weeks PMA, 36 weeks PMA and 1 year CA were carefully selected to avoid the early postnatal period of clinical and cardiopulmonary instability and early mortality associated with extremely preterm birth. Choosing to study all infants at a common PMA and CA optimizes the determination of the impact of gestational and chronologic age on cardiac function at a specific developmental stage and allows the analysis of measures by postgestational weeks from birth. The infants’ antenatal, delivery, and demographic characteristic were obtained.

Enrollment and follow-up of study participants. ^∗ Of 222 infants, 119 were excluded from the healthy uncomplicated cohort because they were diagnosed with BPD, defined as the requirement any respiratory support at 36 weeks PMA and based on a modified National Institutes of Health workshop definition ; had evidence of PH on echocardiography at 32 and/or 36 weeks PMA, defined as any infant with any conventional echocardiographic signs identified by an estimated RVSP > 40 mm Hg, a ratio of RVSP to systemic blood pressure > 0.5, any cardiac shunt with right-to-left flow, unusual degree of RV hypertrophy or dilatation, or any degree of ventricular septal wall flattening ; or had evidence of a hemodynamically significant PDA by days 5 to 7 (defined by PDA characteristics, signs of pulmonary overcirculation, and left heart loading condition) or any PDA at 32 and 36 weeks PMA. There was significant overlap among these categories. ^{∗ ∗} There were 239 infants recruited for this study (137 infants from the Washington University School of Medicine site in St. Louis and 102 infants from the Royal College of Surgeons site in Dublin, Ireland). Echocardiography was performed at day 1 ( n = 30), day 2 ( n = 30), 32 weeks PMA ( n = 117), 36 weeks PMA ( n = 117), and 1 year CA ( n = 81) in St. Louis. Echocardiography was performed at day 1 ( n = 102), day 2 ( n = 102), day 5 ( n = 98), and 36 weeks PMA ( n = 47) in Dublin. GA , Gestational age.

Echocardiography was performed using the same commercially available ultrasound imaging system (Vivid 7 and 9; GE Medical Systems, Milwaukee, WI) at each center. One designated trained pediatric cardiac sonographer at each center obtained all echocardiographic images using a phased-array transducer (7.5–12 MHz). The echocardiographic images were acquired using a standardized image acquisition protocol in decubitus position during a restful period without changing the position of the infant or disturbing the hemodynamic condition to minimize heart rate and respiratory variation during image acquisition. The image data were digitally stored in raw Digital Imaging and Communications in Medicine cine-loop format for offline analysis. Heart rate and blood pressure readings were recorded at the time of each echocardiogram.

Strain Analysis

Reproducibility of Strain Imaging in Preterm Infants

We along with other groups have previously demonstrated that 2D STE–derived LS imaging of the RV, LV, and IVS is highly feasible and reproducible in premature infants using specific cardiac image acquisition and postprocessing data analysis protocols. These protocols have improved the image acquisition and reduced variance that has resulted in improved reliability of strain as a measure of ventricular function in preterm infants. Reproducibility of SLS has not been comprehensively analyzed in preterm infants. We assessed SLS reproducibility using intra- and interobserver variability analysis (Bland-Altman plot analysis, intraclass correlation coefficient, and coefficient of variation) in 25% of the images at each time point. Two observers performed offline analysis using the same measurement protocol and were blinded to the patients’ clinical status and each other.

Statistical Analysis

All data are expressed as mean ± SD or as percentages. Continuous variables of strain imaging were tested for normality using the Kolmogorov-Smirnov test and a histogram of the data. Analysis of variance and Student’s t tests were used to compare the changes in deformation values from birth to 1 year CA in the preterm infants and to compare the patterns between uncomplicated preterm infants and those with BPD, PH, and/or a persistent PDA, respectively. All outcome variables with non-normal distributions were analyzed in simple comparisons using Wilcoxon rank-sum tests or Kruskal-Wallis one-way analysis of variance for tests with more than two independent groups. Chi-square tests (or Fisher exact tests as appropriate) were used to assess associations between categorical variables. Two-way analysis of variance with repeated measures was used to compare change over time between infants with and those without BPD, PDA, and PH. Percentile charts (mean ± SD) were created using linear regression to assess the independent effect of postnatal age (in weeks) and weight (at the time of echocardiography) on each strain measurement, while adjusting for gestational age at birth and gender. Finally, generalized logistic regression models were developed to identify risk factors for BPD and/or PH at 36 weeks PMA using stepwise variable selection. The statistical analysis was performed using SPSS version 14.0 (SPSS, Chicago, IL).

Study Population Characteristics

Two hundred thirty-nine infants with a median gestational age of 27.0 weeks (interquartile range, 26.0–28.0 weeks) and a median birth weight of 960 g (interquartile range, 800–1,138 g) were recruited in this study (137 patients from the Washington University site and 102 patients from the Royal College of Surgeons site). Of the 239 patients, 17 infants (7% with equal distribution among centers) died before hospital discharge and were excluded from the analysis, leaving 222 infants with data to be analyzed. Ninety-five (43%) were female, and 182 (82%) were delivered by caesarean section. Two hundred thirteen (96%) received at least one course of antenatal steroids, and all infants received postnatal surfactant replacement therapy. There were relatively lower rates of chorioamnionitis ( n = 20 [9%]), pre-eclampsia ( n = 56 [25%]), and antepartum hemorrhage ( n = 38 [17%]). Complete studies were available for >95% of infants on days 1, 2, and 5 to 7 and at 32 weeks PMA. Fifty-eight infants were transferred to peripheral hospitals before 36 weeks PMA, leaving 164 infants (74%) available for assessment at that time point ( Figure 1 ). Although echocardiographic data were unavailable at 36 weeks for the transferred infants, their respiratory outcome data at 36 weeks PMA were obtained. At 1 year CA, 81 infants (69% of the eligible infants from the Washington University cohort) returned for echocardiography. The clinical and demographic characteristics of the preterm patients are summarized and compared by time point in Table 1 .

BPD was diagnosed in 52% of all infants ( n = 116 of 222). There were echocardiographic signs of PH in 15% at 32 weeks PMA and 9% at 36 weeks PMA. On days 5 to 7, 57 infants (58%) had PDA, of which 33 (34% of the total cohort) were classified as hsPDA. None of the infants underwent PDA treatment during the first week of age. However, 66 infants (30%) eventually received pharmacologic therapy, and 26 (12%) underwent surgical intervention to close the PDA. Of the remaining infants who did not receive any intervention to augment its closure, a PDA was evident in 19 infants (16%) at 32 weeks PMA and 18 infants (16%) at 36 weeks PMA. None of the infants received inotropes or administration of inhaled nitric oxide. Therefore, after meeting all inclusion criteria, 103 infants (47%) were classified as “healthy uncomplicated preterm infants” ( Figure 1 ). Table 2 compares the maternal and infant characteristics between those infants classified as healthy uncomplicated and infants classified with cardiorespiratory disease.

Maturational Patterns of Myocardial Strain in Uncomplicated Preterm Infants

In uncomplicated preterm infants ( n = 103), a time-specific maturational pattern revealed that RV FWLS and FWLSRs had a stable pattern from days 1 and 2, and their magnitudes increased by days 5 to 7 ( P < .05) ( Table 3 ). RV FWLS and FWLSRs continued to increase in magnitude from days 5 to 7 to 1 year CA (−20.5 ± 3.2% to −27.2 ± 2.3% [ P < .01] and −2.7 ± 1.2% to −3.3 ± 0.3% [ P < .01]; Figure 2 A). IVS GLS and GLSRs followed the same pattern as RV strain mechanics ( Figure 2 B, Table 3 ). The magnitudes of LV GLS and LV GLSRs increased from day 1 to days 5 to 7 (−18.4 ± 3.5% to −21.8 ± 3.2% and −1.8 ± 0.3 to −2.4 ± 0.4 1/sec, P < .05 for both) and then remained stable through 1 year CA (−21.8 ± 3.3% to 21.1 ± 0.4% [ P = .56] and −1.9 ± 0.2 to −1.9 ± 0.7 1/sec; Figure 2 C).

Maturational patterns of ventricular deformation over the first year of age. (A) RV FWLS: in all infants, RV FWLS increased from days 5 to 7 to 1 year CA ( P < .01). RV FWLS was higher and tracked superior in the uncomplicated preterm infants ( blue circles with blue solid line ) compared with the preterm infants who developed BPD ( red squares, dotted red lines ) on echocardiography at the time of evaluation. (B) IVS GLS: in all infants, IVS GLS increased from 32 weeks PMA to 1 year CA ( P < .01). IVS GLS was higher and tracked superior in the uncomplicated preterm infants compared with the preterm infants who developed BPD on echocardiography at the time of evaluation. (C) LV GLS: LV GLS was preserved and relatively unchanged from 32 weeks PMA to 1 year CA ( P = .6), irrespective on neonatal cardiopulmonary disease.

Maturational changes in LV, RV, and IVS strain were further analyzed to produce percentile charts (mean ± 2 SDs) related to gestational age at birth and postnatal age- and weight-related changes. RV FWLS and IVS GLS were linearly associated with gestational age ( r = 0.76 and r = 0.77, P = .001), while LV GLS and FWLS were not ( r = 0.34 and r = 0.44, P > .10). Stepwise regression analysis of the effects of gender, birth weight, change in postnatal weight, total oxygen days, length of stay, and common neonatal morbidities (necrotizing enterocolitis, intraventricular hemorrhage, and retinopathy of prematurity; Table 2 ) on maturation of LS revealed that at all time points, increasing RV FWLS and IVS GLS were associated with both increasing weight ( r = 0.76 and r = 0.78, P < .01) and postnatal age ( r = 0.78 and r = 0.81, P < .01) ( Table 4 ). LV, RV, and IVS SRs imaging followed similar patterns as strain values, when adjusted for weight and postnatal age ( Tables 4 and 5 ).

Table 5

Ventricular deformation in uncomplicated preterm infants by age beyond the first week

Age (wk)	Infants ∗ ( n )	RV FWLS (%)	RV FWLSRs (1/sec)	LV GLS (%)	LV GLSRs (1/sec)	IVS GLS (%)	IVS GLSRs (1/sec)
4–6	40	−21.0 ± 2.5	−2.3 ± 0.4	−19.7 ± 2.3	−1.9 ± 0.3	−17.9 ± 2.3	−1.8 ± 0.4
6–8	57	−23.2 ± 2.8	−2.6 ± 0.5	−20.4 ± 2.4	−1.9 ± 0.2	−18.9 ± 2.0	−2.1 ± 0.3
9–11	18	−22.7 ± 2.2	−2.7 ± 0.5	−20.0 ± 2.3	−1.8 ± 0.2	−19.1 ± 1.5	−2.4 ± 0.3
60–79	26	−27.5 ± 2.4	−2.9 ± 0.5	−21.4 ± 2.0	−1.9 ± 0.2	−21.4 ± 3.0	−2.5 ± 0.4
80–99	4	−28.7 ± 2.5	−3.5 ± 0.4	−21.1 ± 1.6	−1.7 ± 0.3	−22.1 ± 2.3	−2.6 ± 0.6

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