Disproportionate cardiac hypertrophy during early postnatal development in infants born preterm

Background Adults born very preterm have increased cardiac mass and reduced function. We investigated whether a hypertrophic phenomenon occurs in later preterm infants and when this occurs during early development. Methods Cardiac ultrasound was performed on 392 infants (33% preterm at mean gestation 34±2 weeks). Scans were performed during fetal development in 137, at birth and 3 months of postnatal age in 200, and during both fetal and postnatal development in 55. Cardiac morphology and function was quantified and computational models created to identify geometric changes. Results At birth, preterm offspring had reduced cardiac mass and volume relative to body size with a more globular heart. By 3 months, ventricular shape had normalized but both left and right ventricular mass relative to body size were significantly higher than expected for postmenstrual age (left 57.8±41.9 vs. 27.3±29.4%, P<0.001; right 39.3±38.1 vs. 16.6±40.8, P=0.002). Greater changes were associated with lower gestational age at birth (left P<0.001; right P=0.001). Conclusion Preterm offspring, including those born in late gestation, have a disproportionate increase in ventricular mass from birth up to 3 months of postnatal age. These differences were not present before birth. Early postnatal development may provide a window for interventions relevant to long-term cardiovascular health.


Clinical data collection
Characterisation of pregnancy complications and perinatal data related to the clinical care of the preterm infant were extracted from medical records retrospectively in a standardised way across studies. Preterm birth was defined as any birth before 37 weeks gestation.
Hypertensive pregnancy diagnosis (pregnancy induced hypertension, preeclampsia) was defined according to ISSHP guidelines 1 .
At birth and three months, three blood pressure measurements were recorded on the right calf, known to be comparable to arm measurements in neonates 2 , with an automated digital monitor (Dinamap technology® V100) using appropriate sized cuffs and were averaged for analysis.

Image analysis
Quantification of cardiac mass and volume -Fetal loops were retrospectively gated offline using TomTec Image Arena 4.6 and end diastole was defined as the point of mitral valve closure. Neonatal loops were acquired with ECG tracing for cardiac gating. Mass and volume measures were obtained by manual contouring of the endo and epicardium using TomTec Image Arena 4.6 from the apical four chamber view for fetal, neonatal and infant echocardiography. The end diastolic frame was manually selected using the point of mitral valve closure as the marker and contours manually set at the inner endocardial edge and outer epicardial edge within the pericardium. To maximise reproducibility, the entirety of the septum was contoured for both left (LV) and right ventricular (RV) measurements. In addition, LV septal and posterior wall thicknesses in diastole were measured in the neonatal cohort from the parasternal long axis view in 2D using Philips Xcelera 3.3. The measurement was made at the base of the LV perpendicular to the mitral annulus through the leaflet tips.
To assess intra and inter-observer variability for measures, 10 datasets were selected at random (i.e. not selected for image quality) from fetal and neonatal datasets and reanalysed using the same set of selected cardiac cycles. Intraclass Correlation Coefficients (ICC) for single measures with 95% confidence intervals for intra and inter-observer variability yielded

Quantification of Ventricular Systolic and Diastolic Function -LV systolic parameters
including ejection fraction, stroke volume and cardiac output were captured from automated tracking of the contours of the endocardium using TomTec Image Arena 4.6 as above.
Manual adjustments of the contours were made, as required, throughout the cardiac cycle to ensure appropriate tracking of all segments and excluded if this was not possible due to image quality. RV systolic function was quantified by taking an M-Mode slice through the tricuspid annulus using the cursor in real time to measure the tricuspid annular plane systolic excursion (TAPSE), analysed offline using Philips Xcelera 3.3. Furthermore, RV ejection fraction was calculated from automated tracking of the contours of the endocardium using TomTec Image Arena 4.6. In the neonatal cohort at birth and three month follow-up, routine diastolic function parameters were assessed. Pulse Wave Doppler was measured from the mitral valve tips to assess early and late diastolic inflow and the ratio of these flows weas characterised as E/A ratio using Philips Xcelera 3.3. Further Doppler interrogation of the lateral mitral valve annulus using Tissue Doppler Imaging was measured in early diastole (E') and was utilised in the ratio of early diastolic flow to early diastolic tissue velocity (E/E') to assess myocardial relaxation in relation to the filling velocities. 10 datasets were again selected at random and the ICC for single measures with 95% confidence intervals for intra and inter-observer variability were as follows: 0.99 (0.95-1.00) and 0.98 (0.94-1.00) for E/A ratio; 1.00 (1.00-1.00) and 0.93 (0.97-1.00) for lateral E'; 0.97 (0.87-0.99) and 0.90 (0.64-0.97) for TAPSE.

Morphology of the left ventricle -
The endocardial and epicardial contours were exported from TomTec Image Arena 4.6 as text files that encode these contours and were fitted to a parametric description of a line. As a result, each contour was described with 52 coefficients, with each ventricle in the four chamber view therefore being reported using 104 coefficients

Population characteristics
The mothers who delivered preterm had a similar body mass index (BMI) at pregnancy booking and prevalence of smoking. They were, however, on average a year older and were more likely to have had a hypertensive pregnancy disorder and a caesarean delivery (p<0.001). There was no bias by gender and birth order for term and preterm deliveries.
Gestational age in the preterm group was six weeks younger than the term group (34.0±2.2 vs 39.7± 1.3 weeks) and they were significantly lighter at birth, with a lower birthweight zscore. Of the n=121 preterm individuals studied postnatally, 102/121 (84.3%) were born between 32-36 weeks gestation (moderate to late preterm); n=16 (13.2%) were born between 28-31 weeks gestation (very preterm); and n=3 (2.5%) were born less than 28 weeks gestation. Those with postnatal measures had similar characteristics to the full study group at birth [Supplementary Table 1] and the preterm group still had significantly lower weight and smaller head circumference at three months. Their systolic and diastolic blood pressures were also lower at birth, but by three months postnatal age, only diastolic blood pressure was lower. 337 fetal echocardiographic datasets were acquired, with 19 unanalysable for LV mass and 14 for RV mass. 229 echocardiography scans were performed at birth (18 unanalysable for LV and 100 for RV) and 227 echocardiography scans were performed at three months of For trajectory changes, all analysable echocardiographic data were included and statistical approaches used as appropriate to allow for missing values in longitudinal datasets.