The left ventricle in well newborns versus those with perinatal asphyxia, haemodynamically significant ductus arteriosus or fetal growth restriction

Introduction

The circulatory changes at the time of birth are perhaps the most sudden and dramatic adaptations in human life. During fetal life, the inferior vena caval blood streams via the eustachian valve, from the right to the left atrium through the foramen ovale, effectively ending into the left ventricle (LV) with the most highly oxygenated blood arising from the placenta. The circulatory changes must happen rapidly and in an orderly fashion, to enable successful transition from intrauterine life to “independent” extra-uterine existence (1). The in-utero high pulmonary vascular resistance (PVR) ensures that the majority of right ventricular (RV) blood bypasses the lungs and flows through the patent ductus arteriosus (PDA) into the aorta. There is transition from a high-resistance/low-compliance to a low-resistance/high-compliance pulmonary circulation. Fetal circulation functions in-parallel as both the right and left sides of the heart provide systemic blood flow. The in-parallel is converted to an in-series circulation with rapid reduction and subsequent closure initially functional and subsequently permanent, of the fetal shunts, namely the patent foramen ovale and PDA, generally over the first few minutes/hours or hours/days respectively. In-utero, the PVR is much greater than the systemic vascular resistance (SVR). The combined cardiac output at about 30 weeks gestational age (GA) increases as the fetus adapts toward extra-uterine existence (2). The RV is metabolically more active during fetal life contracting against a high PVR and supporting the systemic blood flow via the PDA as compared to the LV which contracts against a lower afterload represented by the placenta. The transition in the circulatory system, including cardiac authority from right to left heart dominance, is mediated by a reduction in vasoconstrictor thromboxanes, a greater production of nitric oxide which lowers the PVR, increased vasodilatory prostaglandins and a surge in catecholamines and cortisol secretion (3,4). Common neonatal interventions such as ventilation and surfactant replacement therapy (SRT) tend to influence this transition (5). Events before, at the time of birth or soon thereafter have the potential to hamper this orderly transition.

The objectives of this article aimed for clinicians involved in the care of newborns, include a discussion of the:

• Normal transition in term and preterm infants;
• The influence of acute neonatal disease on LV function for example perinatal asphyxia in term infants, PDA and its surgical ligation in preterms;
• The influence of chronic disease on LV function—in-utero maladaptation such as in fetal growth restriction (FGR);
• Echocardiographic (Echo) parameters to assess neonatal LV function and systemic arterial dynamics in the normal and affected newborns.

Neonatal transition in term and preterm infants

The transitional period involves rapidly evolving circulatory changes with impact on end-organ perfusion and function. Utilization of bedside clinician performed monitoring modality of point of care ultrasound (POCUS) is best suited to characterize the intricacies of the shift from RV to LV dominance. The transition from fetal circulation is facilitated by adequate alveolar aeration and recruitment, dilatation of pulmonary capillaries and constriction and eventual closure of shunts (foramen ovale and PDA), all aided by an adequate respiratory drive. The consequent changes in cardiac loading conditions and shunt-flow patterns may place the newborn, especially at extremes of prematurity, at risk of circulatory impairment. Pertinent to the LV, there is a significant increase in SVR and LV afterload once the umbilical cord is clamped, removing the placenta from the circulatory equation. LV contractility is influenced by variables of preload and afterload; with the inability of immature myocardium to increase contractility in response to increased preload more pronounced in the premature infant (Frank Starling Law); cardiac output increasing by a rise in heart rate. Myocardial performance is also impacted by ventricular interdependence (cross-talk between contractile fibres) and ventriculo-ventricular interactions (influence of changes in ventricular shape in response to pressure loading). A dilated-dysfunctional RV impinges on the LV relaxation capacity, restricting cardiac inflow and affecting contractility (6). Adequacy of LV preload is primarily influenced by pulmonary blood flow which in turn is affected by pulmonary distending pressures and affected by artificial ventilation strategies. We recently outlined the effects of spontaneous ventilation and various ventilator manoeuvres on LV pressures/function (5). SRT is a common neonatal intervention for preterm infants. The data on the influence of SRT on LV output have shown conflicting results. One study showed no change at two hours while the other noted a decrease in LV output following SRT administered in the delivery room (7,8). Both studies postulated that these changes were due to an increased left-to-right trans-atrial flow. Evidently, more prospective data is needed to better characterize the impact of SRT on preterm circulation, and consequently cardiac function.

In summary, inherent neonatal issues such as prematurity and common neonatal disorders affect LV function which POCUS may allow for a better understanding and informed therapeutic choices.

Influence of acute neonatal disease on LV function

Perinatal asphyxia

Approximately 1–2 neonates/1,000 live births may be affected by severe perinatal asphyxia (9). It is characterized by significant disturbances in cardiovascular homeostasis and organ blood flow. Therapeutic hypothermia has been the standard of care for such infants (10). Recent data in neonates have highlighted the physiological interactions between ‘disease’ and therapeutic interventions. A recent study evaluated the relationship between LV function, LV perfusion [left anterior descending (LAD) coronary artery flow] and serum cardiac troponin (biochemical marker of myocardial injury) in infants with severe perinatal asphyxia (11). Echo data for fourteen infants with severe asphyxia were compared with 20 healthy term infants. Therapeutic hypothermia was initiated at a median of 1 hour, range or 1–5 hours. Echos in the asphyxiated subjects were done at a median of 7.7 hours, range of 3–10 hours. LV output and superior vena cava flow {median [range]} were significantly lower in the asphyxiated infants {108 [61–150] vs. 222 [156–321] mL/kg/min, P<0.001 and 34 [13–80] vs. 78 [60–99] mL/kg/min, P<0.001, respectively}. Serum cardiac troponin was high. Markedly low coronary flows were noted {median, 0.77 µg/L; range, 0.17–2.6). Coronary flow had a significantly positive correlation with LV output. Gebauer and colleagues also noted that in infants with severe asphyxia, the LV output was reduced to 67% of the post-hypothermic levels (9). Importantly, a dichotomy between blood pressure (BP) and flow parameters was noted, indicating the limitations of clinical assessments, and the importance of POCUS. The neonate’s BP may only partially reflect the extent and profile of LV dysfunction due to the variation in SVR, necessitating the need for further haemodynamic evaluations (11). In essence, the LV bears the brunt in perinatal asphyxia; therapeutic choices for inotropes may be guided by the information provided by POCUS.

Patent ductus arteriosus

A hemodynamically significant PDA remains one of the most common cardiovascular problems in preterm infants, occurring in approximately 60% of infants <28 weeks GA (12). The assignment of hemodynamic significance (clinically or by echo) to a PDA remains a challenge for the neonatal clinician. The inability to accurately distinguish the PDA which needs treatment from the ‘innocent’ ductus arteriosus arises from the lack of scientific evidence of benefit or causality (13-15). The traditional definition of a PDA, which forms the basis of clinical trials conducted to date, is limited to the use of single parameters. Traditional echo markers such as ductal size and left atrial:aorta (LA:Ao) ratio do not predict neonatal outcomes (16,17). Ductal hemodynamics are influenced not only by ductal size but also by PVR and SVR and by the compensatory ability of the immature LV. We have proposed a ductal disease staging system to assess the cumulative effect of a hemodynamically significant PDA on LV performance as adjudicated by graded clinical and echo characteristics (15,18). A comprehensive appraisal of these echo markers to allow for a more meaningful and more systematic and structured approach for PDA evaluation. Table 1 summarizes the range of cardiac parameters which may be used in such hemodynamic assessments though not all can or need be performed by the busy clinician (19). Table 2 highlights those parameters that may be most helpful (19).

Left heart function characterization in PDA

The quantifications of left heart size and function (systolic and diastolic) are important indirect measures of the pressure and volume loading effects of increased pulmonary blood flow. The LA:Ao ratio is a well-recognized surrogate of ductal significance. It has been suggested that the rate of ductal misclassification is the lowest with LA:Ao ratio >1.4 (20). A ratio <1.4 may also represent a smaller shunt. Similarly, the ratio of left ventricular: atria diameter ratio, with the LV measured as an end diastolic dimension form a parasternal long axis view, has also been previously proposed as a surrogate marker; a value of >2.1 providing the lowest misclassification rate (20). However, patient related factors such as hydration, LV performance, or trans-atrial shunting may lead to over or underestimation of these unidimensional measures. The trans-mitral Doppler seems a useful marker of LA pressure/volume loading. A low E/A ratio amongst preterms reflects developmental immaturity of the myocardium, which is different from newly born term infants where the E/A ratio is higher (>0.8). In infants with a hemodynamically significant PDA, an increase in passive trans-mitral flow due to a greater LA pressure leads to pseudo-normalization of the E/A ratio >1.0, resembling the normal term neonatal pattern (21). The isovolumic relaxation time reflects the time between closure of the mitral valve and opening of the aortic valve and decreases significantly in preterm infants with a hemodynamically significant PDA due to early pressure-related valve closure/opening (22). In keeping with increased pulmonary blood flow, the increased cardiac inflow leads to a higher LV output (accompanied by a higher LV output: superior vena cava flow ratio). Importantly, impairment of LV performance (lower LV output) in the presence of a hemodynamically significant PDA suggests a failing myocardium, which will lead to higher end-diastolic LA pressure and an increased the risk of pulmonary haemorrhage.

An international study performed serial evaluations at multiple time-points in the first week of life in preterm infants to identify the parameters with the best discriminatory ability (23). Among the various parameters, PDA diameter and flow velocity, LV output, and LV A’ wave on the second day of life were independently associated with chronic lung disease (CLD)/death. In a similar study on preterm infants <32 weeks GA, an echo score (which included LV function parameters) was assigned on the day of therapy for hemodynamically significant PDA (24). Infants were then prospectively followed to ascertain the occurrence of CLD. Higher composite scores were associated with an increased subsequent risk of developing CLD. Together, these studies indicated merit in the use of early comprehensive echo examination which included LV parameters, to define the most suitable candidates where treatment is likely to improve neonatal outcomes. Our group has previously tabulated comprehensive echo assessments useful in the evaluation and assignment of hemodynamic significance to a PDA (13,15,18).

Surgical ligation of a hemodynamically significant PDA and the effects on LV performance

Failure of medical intervention or contraindication to medical therapy necessitates surgical intervention. This scenario is often times complicated by systemic hypotension and oxygenation failure (21,25). The ability of the immature LV myocardium to compensate for the dramatic elevation in afterload has been the focus of recent research. McNamara et al. prospectively studied 46 preterm infants undergoing surgical duct ligation (25). Echos were done pre-operatively, and then 1, 8 and 24 hours after the procedure. Duct ligation was followed by an increased SVR, temporally coinciding with reduced LV contractility and output. Infants with pre-operatively impaired LV systolic performance were more likely to require inotropic support for a low systolic BP and abnormal base-deficit in the post-operative period, which are accompanied by cardiorespiratory deterioration, greater respiratory support requirements, pulmonary edema on chest radiographs, possibly related to an increased SVR and end-diastolic LA pressure. This scenario is termed ‘Post-Ligation Cardiac Syndrome’. Multiple authors have documented that it may happen approximately 6–12 hours after surgery (26,27). Clinical/demographic parameters like age at surgery <28 days of age, weight at surgery <1,000 g, previous use of inotropes and low Apgar scores at birth, identified this high-risk sub-cohort, allowing for focussed physiologically-appropriate peri-operative care. Echocardiographically ductal size and pre-operative lower coronary perfusion identify this sub-cohort (21).

One of the features of a hemodynamically significant PDA is a wide pulse pressure (low diastolic BP). Since coronary artery perfusion depends on aortic diastolic BP, a low diastolic BP may compromise coronary perfusion in premature infants with a PDA, causing chronic myocardial ischemia (28). Previous data demonstrating ST-segment depression on the electrocardiogram and elevated plasma troponin that normalized after ductal closure in premature infants with hemodynamically significant PDA (29,30) support this hypothesis. A prospective study performed serial echos in 20 preterm infants requiring duct ligation to document systolic and diastolic LV function. Simultaneous coronary flow was evaluated by LAD diastolic Doppler flow, before and after (1, 8, and 24 hours) of surgical ligation (21). A low baseline LAD velocity time integral was associated with a lower systolic BP, low LV output and the post-operative need for inotropes. Lastly, the role of POCUS has been investigated in ‘predicting’ cardiorespiratory instability after PDA ligation. In a study of 62 preterm infants, a predictive model was developed based on the echo criteria (in Table 1). LV output <200 mL/kg/min at 1 hour after PDA ligation was noted to be a sensitive predictor of systemic hypotension and the need for inotropes (31). In essence, duct ligation is associated with major adaptive changes in systemic hemodynamics. The greater risk of clinical deterioration in infants with impaired pre-operative LV systolic performance further emphasizes the need to better characterize this critical peri-operative period to neonatal outcomes.

Influence of chronic disease on LV function: FGR

Cardiac maladaptation may occur in infants with FGR, secondary to utero-placental insufficiency. FGR is defined as a birthweight <10^th centile for GA and sex with abnormal fetal Doppler recordings. It affects 21–30% of pregnancies delivered prematurely at <32 weeks GA (32-34). Amongst infants <32 weeks born in Australia and New Zealand in 2020, 668 (21%) were born <10^th centile for GA and sex; approximately half (45%) amongst them were <3^rd centile (severe FGR) (32). A decade of circulatory research done by our group has shed light on LV adaptation amongst infants with FGR. In a prospective echo study, we compared preterm infants 28–32 weeks GA with FGR with infants who were appropriate for GA. Preterm FGR infants had significantly greater inter-ventricular septal thickness and LV free wall thickening and a lower sphericity index (1.53±0.15 vs. 1.88±0.2, P<0.001), signifying globular and hypertrophied hearts. The diastolic and systolic dysfunction were characterized by a significantly raised trans-mitral E/A ratio and isovolumic relaxation time in the FGR cohort (0.84±0.05 vs. 0.78±0.03, P<0.001 and 61.4±4.1 vs. 53.2±3.2 ms, P<0.001, respectively). The rate corrected mean velocity of circumferential fibre shortening was reduced (1.93±0.4 vs. 2.77±0.5 circ/s, P<0.001) in the FGR cohort (35). Essentially, on assessments done in the initial postnatal weeks of life, preterm infants with FGR had altered cardiac function. FGR infants also had significantly higher systolic BP, aorta intima-media thickness, wall stiffness and peripheral resistance (36). Similar findings were noted in term FGR infants, in comparison with those whose weights were appropriate for GA infants. These included lower LV output, impaired LV relaxation, and thicker and stiffer systemic arteries (37,38).

Table 2 summarizes salient alterations in LV function in the aforementioned neonatal disorders. They may further complement the echo parameters used in the retrospective study of Vijayashankar et al. (39).

Echo parameters to assess LV function and systemic arterial dynamics

Although perinatal care has seen major advances, the diagnostic and therapeutic approach to cardiovascular dysfunction remains suboptimal owing to an overreliance on poorly predictive clinical parameters such as urine output, heart rate or capillary refill time. In the hands of appropriately trained frontline neonatal care providers, POCUS enables real-time evaluation of LV performance to characterize accurate acute physiology and aetiology of cardiovascular compromise, to guide physiologically-appropriate therapeutic decisions (18). The ability to monitor response to therapy is an added benefit. It is also a useful tool to determine the ‘need to treat’, differentiating normal transitional physiological changes from pathological ones. Its utility in improving clinical outcomes in newborns has been demonstrated (40,41). Echo assessments may provide greater insight into a rapidly evolving circulatory milieu in premature and term infants. Table 1 summarizes the range of cardiac and vascular echo parameters which may be used in hemodynamic assessments in acute and chronic neonatal conditions (19,35-38). Few however have had the training, skill or time to carry out such a wide range of investigations suggesting the need to select those that may be most helpful as summarised in Table 2 (19).

Afterload forces play a major role in determining cardiac performance, supporting the view that systemic arterial dynamics is a salient variable. Meta-analyses found arterial stiffness as an independent risk marker for future cardiovascular disease risk (42,43). Longitudinal appraisal between arterial stiffness and hypertension indicates a precursor role for arterial properties (44). Recent data in neonates have noted a similar value in evaluating arterial stiffness and distensibility which may provide indices of early vascular changes that predispose to the development of further vascular disease (36,37). These include arterial intima-media thickness, stiffness index and compliance, which have emerged as important predictors of coronary artery disease and cerebrovascular accident in adults (45-48). FGR is the archetypal disease process which involves primary vascular remodelling which may explain the increased predisposition to cardiovascular disease in adult life (49).

Conclusions

The transition from a dominant RV to LV can be hampered by a range of medical conditions in preterm and term infants. The skillset of POCUS has a seminal role in delineating physiologic detail to facilitate rational therapy. Timely and physiologically appropriate inotropic support, as guided by clinical decision making and aided by POCUS has the potential to improve outcomes. The assessment of the LV as the major contractile force in the postnatal period is facilitated by coalescing clinical and echo information. Assuming that there are adequate training facilities to develop the skills to carry out the range of echo investigations, further study is needed to clarify which parameters may be the most helpful in each clinical scenario as time remains a limited luxury in a busy nursery.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-23-59/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-23-59/coif). The authors have no conflicts of interest to declare.

Ethical Statement: Both authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Singh Y, Tissot C. Echocardiographic Evaluation of Transitional Circulation for the Neonatologists. Front Pediatr 2018;6:140. [Crossref] [PubMed]
2. Berhrsin J, Gibson A. Cardiovascular system adaptation at birth. Paediatr Child Health 2011;21:1-6. [Crossref]
3. Reynolds P. Fetal to neonatal transition – how does it take place? Surgery (Oxf) 2013;31:106-9. [Crossref]
4. Cavaliere TA. From fetus to neonate: a sensational journey. Newborn Infant Nurs Rev 2016;16:43-7. [Crossref]
5. Sehgal A, Ruoss JL, Stanford AH, et al. Hemodynamic consequences of respiratory interventions in preterm infants. J Perinatol 2022;42:1153-60. [Crossref] [PubMed]
6. Das A, Haque M, Chikhani M, et al. Hemodynamic effects of lung recruitment manoeuvres in acute respiratory distress syndrome. BMC Pulm Med 2017;17:34. [Crossref] [PubMed]
7. Skinner JR, Boys RJ, Hunter S, et al. Pulmonary and systemic arterial pressure in hyaline membrane disease. Arch Dis Child 1992;67:366-73. [Crossref] [PubMed]
8. Sehgal A, Mak W, Dunn M, et al. Haemodynamic changes after delivery room surfactant administration to very low birth weight infants. Arch Dis Child Fetal Neonatal Ed 2010;95:F345-51. [Crossref] [PubMed]
9. Gebauer CM, Knuepfer M, Robel-Tillig E, et al. Hemodynamics among neonates with hypoxic-ischemic encephalopathy during whole-body hypothermia and passive rewarming. Pediatrics 2006;117:843-50. [Crossref] [PubMed]
10. Jacobs SE, Tarnow-Mordi WO. Therapeutic hypothermia for newborn infants with hypoxic-ischaemic encephalopathy. J Paediatr Child Health 2010;46:568-76. [Crossref] [PubMed]
11. Sehgal A, Wong F, Mehta S. Reduced cardiac output and its correlation with coronary blood flow and troponin in asphyxiated infants treated with therapeutic hypothermia. Eur J Pediatr 2012;171:1511-7. [Crossref] [PubMed]
12. Van Overmeire B, Chemtob S. The pharmacologic closure of the patent ductus arteriosus. Semin Fetal Neonatal Med 2005;10:177-84. [Crossref] [PubMed]
13. Sehgal A, McNamara PJ. The ductus arteriosus: a refined approach! Semin Perinatol 2012;36:105-13. [Crossref] [PubMed]
14. Sehgal A, McNamara PJ. International perspective on management of a patent ductus arteriosus: Lessons learned. Semin Fetal Neonatal Med 2018;23:278-84. [Crossref] [PubMed]
15. McNamara PJ, Sehgal A. Towards rational management of the patent ductus arteriosus: the need for disease staging. Arch Dis Child Fetal Neonatal Ed 2007;92:F424-7. Erratum in: Arch Dis Child Fetal Neonatal Ed 2008;93:F78. [Crossref] [PubMed]
16. Schmidt B, Roberts RS, Fanaroff A, et al. Indomethacin prophylaxis, patent ductus arteriosus, and the risk of bronchopulmonary dysplasia: further analyses from the Trial of Indomethacin Prophylaxis in Preterms (TIPP). J Pediatr 2006;148:730-4. [Crossref] [PubMed]
17. Ohlsson A, Shah SS. Ibuprofen for the prevention of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2011;CD004213. [Crossref] [PubMed]
18. Sehgal A, McNamara PJ. Does echocardiography facilitate determination of hemodynamic significance attributable to the ductus arteriosus? Eur J Pediatr 2009;168:907-14. [Crossref] [PubMed]
19. Menahem S, Sehgal A. Left ventricular dysfunction in the newborn. Transl Pediatr 2023;12:794-9. [Crossref] [PubMed]
20. Johnson GL, Breart GL, Gewitz MH, et al. Echocardiographic characteristics of premature infants with patient ductus arteriosus. Pediatrics 1983;72:864-71. [Crossref] [PubMed]
21. Sehgal A, McNamara PJ. Coronary artery perfusion and myocardial performance after patent ductus arteriosus ligation. J Thorac Cardiovasc Surg 2012;143:1271-8. [Crossref] [PubMed]
22. Schmitz L, Stiller B, Koch H, et al. Diastolic left ventricular function in preterm infants with a patent ductus arteriosus: a serial Doppler echocardiography study. Early Hum Dev 2004;76:91-100. [Crossref] [PubMed]
23. El-Khuffash A, James AT, Corcoran JD, et al. A Patent Ductus Arteriosus Severity Score Predicts Chronic Lung Disease or Death before Discharge. J Pediatr 2015;167:1354-1361.e2. [Crossref] [PubMed]
24. Sehgal A, Paul E, Menahem S. Functional echocardiography in staging for ductal disease severity: role in predicting outcomes. Eur J Pediatr 2013;172:179-84. [Crossref] [PubMed]
25. McNamara PJ, Stewart L, Shivananda SP, et al. Patent ductus arteriosus ligation is associated with impaired left ventricular systolic performance in premature infants weighing less than 1000 g. J Thorac Cardiovasc Surg 2010;140:150-7. [Crossref] [PubMed]
26. Finan E, Sehgal A, Khuffash AE, et al. Targeted neonatal echocardiography services: need for standardized training and quality assurance. J Ultrasound Med 2014;33:1833-41. [Crossref] [PubMed]
27. Sehgal A, Linduska N, Huynh C. Cardiac adaptation in asphyxiated infants treated with therapeutic hypothermia. J Neonatal Perinatal Med 2019;12:117-25. [Crossref] [PubMed]
28. Arnold G, Kosche F, Miessner E, et al. The importance of the perfusion pressure in the coronary arteries for the contractility and the oxygen consumption of the heart. Pflugers Arch Gesamte Physiol Menschen Tiere 1968;299:339-56. [Crossref] [PubMed]
29. Way GL, Pierce JR, Wolfe RR, et al. ST depression suggesting subendocardial ischemia in neonates with respiratory distress syndrome and patent ductus arteriosus. J Pediatr 1979;95:609-11. [Crossref] [PubMed]
30. El-Khuffash AF, Molloy EJ. Influence of a patent ductus arteriosus on cardiac troponin T levels in preterm infants. J Pediatr 2008;153:350-3. [Crossref] [PubMed]
31. Jain A, Sahni M, El-Khuffash A, et al. Use of targeted neonatal echocardiography to prevent postoperative cardiorespiratory instability after patent ductus arteriosus ligation. J Pediatr 2012;160:584-589.e1. [Crossref] [PubMed]
32. Chow SSW, Creighton P, Chambers GM, et al. Report of the Australian and New Zealand Neonatal Network Sydney 2020. Sydney: ANZNN; 2022.
33. Sehgal K, Sehgal K, Tan K. Increased incidence of chronic lung disease and respiratory sequelae in growth restricted versus appropriately grown preterms. Indian J Child Health 2021;8:280-3. [Crossref]
34. Ferdynus C, Quantin C, Abrahamowicz M, et al. Can birth weight standards based on healthy populations improve the identification of small-for-gestational-age newborns at risk of adverse neonatal outcomes? Pediatrics 2009;123:723-30. [Crossref] [PubMed]
35. Sehgal A, Allison BJ, Gwini SM, et al. Cardiac Morphology and Function in Preterm Growth Restricted Infants: Relevance for Clinical Sequelae. J Pediatr 2017;188:128-134.e2. [Crossref] [PubMed]
36. Sehgal A, Allison B, Gwini S, et al. Vascular ageing and cardiac maladaptation in growth restricted preterm infants. J Perinatol 2018;38:92-7. [Crossref] [PubMed]
37. Sehgal A, Doctor T, Menahem S. Cardiac function and arterial biophysical properties in small for gestational age infants: postnatal manifestations of fetal programming. J Pediatr 2013;163:1296-300. [Crossref] [PubMed]
38. Sehgal A, Skilton MR, Crispi F. Human fetal growth restriction: a cardiovascular journey through to adolescence. J Dev Orig Health Dis 2016;7:626-35. [Crossref] [PubMed]
39. Vijayashankar SS, Sanatani G, Franciosi S, et al. Left ventricular dysfunction in the immediate post-natal period. Transl Pediatr 2023;12:13-9. [Crossref] [PubMed]
40. El-Khuffash A, Herbozo C, Jain A, et al. Targeted neonatal echocardiography (TnECHO) service in a Canadian neonatal intensive care unit: a 4-year experience. J Perinatol 2013;33:687-90. [Crossref] [PubMed]
41. Carmo KB, Evans N, Paradisis M. Duration of indomethacin treatment of the preterm patent ductus arteriosus as directed by echocardiography. J Pediatr 2009;155:819-822.e1. [Crossref] [PubMed]
42. Ben-Shlomo Y, Spears M, Boustred C, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects. J Am Coll Cardiol 2014;63:636-46. [Crossref] [PubMed]
43. van Sloten TT, Sedaghat S, Laurent S, et al. Carotid stiffness is associated with incident stroke: a systematic review and individual participant data meta-analysis. J Am Coll Cardiol 2015;66:2116-25. [Crossref] [PubMed]
44. Najjar SS, Scuteri A, Shetty V, et al. Pulse wave velocity is an independent predictor of the longitudinal increase in systolic blood pressure and of incident hypertension in the Baltimore Longitudinal Study of Aging. J Am Coll Cardiol 2008;51:1377-83. [Crossref] [PubMed]
45. 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;18:815-31. [Crossref] [PubMed]
46. Chen X, Wang Y. Tracking of blood pressure from childhood to adulthood: a systematic review and meta-regression analysis. Circulation 2008;117:3171-80. [Crossref] [PubMed]
47. de Swiet M, Fayers P, Shinebourne EA. Blood pressure in first 10 years of life: the Brompton study. BMJ 1992;304:23-6. [Crossref] [PubMed]
48. Keijzer-Veen MG, Finken MJ, Nauta J, et al. Is blood pressure increased 19 years after intrauterine growth restriction and preterm birth? A prospective follow-up study in The Netherlands. Pediatrics 2005;116:725-31. [Crossref] [PubMed]
49. Sehgal A, Alexander BT, Morrison JL, et al. Fetal Growth Restriction and Hypertension in the Offspring: Mechanistic Links and Therapeutic Directions. J Pediatr 2020;224:115-123.e2. [Crossref] [PubMed]