European Journal of Cardiovascular Medicine

Persistent pulmonary hypertension of the newborn (PPHN) is a life-threatening condition characterized by the failure of normal postnatal fall in pulmonary vascular resistance, resulting in sustained elevation of pulmonary artery pressure, right-to-left extrapulmonary shunting through the ductus arteriosus and foramen ovale, and severe hypoxemia [1]. Normally, at birth, expansion of the lungs and increase in oxygen tension trigger a rapid fall in pulmonary vascular resistance; however, in PPHN, this physiological adaptation is impaired due to a variety of factors such as abnormal pulmonary vascular remodeling, parenchymal lung disease, or maladaptation following perinatal stress [2]. The incidence of PPHN is reported to be around 1.8–2 per 1000 live births worldwide, though variations are noted based on population demographics, underlying etiologies, and healthcare resources [3]. Despite improvements in neonatal intensive care, this condition remains associated with high morbidity and mortality, with death rates ranging from 4% to 30% in different series and survivors frequently suffering from long-term complications such as neurodevelopmental delay, hearing impairment, and chronic pulmonary dysfunction [4,5].

Echocardiography plays a pivotal role in the diagnosis, monitoring, and prognostication of PPHN. It is indispensable for differentiating PPHN from cyanotic congenital heart disease and for providing real-time hemodynamic assessment [6]. Doppler echocardiography allows estimation of pulmonary arterial pressures by measuring tricuspid regurgitation velocity, while the presence and direction of ductal and atrial shunting provide indirect evidence of pulmonary vascular resistance [7]. In addition, advanced echocardiographic indices such as tricuspid annular plane systolic excursion (TAPSE), myocardial performance index (MPI), eccentricity index, and global longitudinal strain have been increasingly recognized as markers of right ventricular function and predictors of disease severity [8]. Several studies have shown that abnormal values in these parameters, particularly reduced TAPSE, abnormal interventricular septal motion, and persistent right-to-left ductal shunting, are associated with higher risk of treatment failure, morbidity, and mortality [8]. Thus, echocardiography serves not only as a diagnostic tool but also as a guide for clinical management and risk stratification.

The management of PPHN requires a multifaceted approach. Initial supportive strategies include ensuring adequate oxygenation, optimizing lung recruitment with mechanical ventilation, correcting metabolic acidosis, maintaining systemic blood pressure, and minimizing stimuli that exacerbate pulmonary vasoconstriction [2,6]. Surfactant therapy is beneficial in cases associated with parenchymal lung disease such as meconium aspiration syndrome or pneumonia [3]. Inhaled nitric oxide (iNO) has revolutionized PPHN treatment as a selective pulmonary vasodilator, improving oxygenation and reducing the need for extracorporeal membrane oxygenation (ECMO) in high-income settings [9]. However, the response to iNO is variable, with a significant subset of neonates failing to improve, necessitating alternative therapies such as sildenafil or milrinone [4]. High-frequency ventilation is often employed in severe cases with refractory hypoxemia. For the most critically ill neonates, ECMO remains the definitive rescue therapy, though its availability is limited in resource-constrained settings [9,10].

Although survival has improved with these therapeutic advances, morbidity remains high, particularly in low- and middle-income countries where access to iNO and ECMO is limited and delays in referral to tertiary care are common [5]. This highlights the importance of identifying reliable predictors of outcome early in the disease course. Clinical parameters such as perinatal asphyxia, low Apgar scores, sepsis, and underlying lung disease, along with echocardiographic findings like persistent right-to-left shunting and impaired right ventricular function, can help stratify risk [7,8]. Evaluating the response to treatment modalities also provides insight into prognosis, as infants requiring prolonged ventilation or multiple adjunctive therapies tend to have poorer outcomes [4,9].

Given these considerations, there is a pressing need for studies from tertiary care neonatal intensive care units in resource-limited regions to evaluate predictors of outcome in PPHN. Understanding the interplay between associated morbidities, echocardiographic parameters, and treatment responses will help optimize management strategies, guide timely escalation of therapy, and ultimately improve both survival and long-term outcomes. The present study is designed to address these gaps by systematically assessing the predictors of morbidity and mortality in neonates with PPHN admitted to a tertiary care NICU, with a special focus on echocardiographic findings and treatment modalities.

Study Design: prospective observational study.

Place of Study: This present study was conducted in neonatal intensive care unit, Department of Pediatrics, SSG Hospital Baroda.

Study Duration: 12 months of time bound study

Study Population: Neonates admitted in intramural and extramural NICU in Department of Pediatrics, Government Medical College and Hospital, Vadodara with clinical suspicion of PPHN, confirmed by bedside 2D echocardiography.

Sample Size: Total 80, bedside echocardiography based diagnosed cases of PPHN patients were enrolled during study period.

Study Variables: Sex, Maturity, Birth weight, GA+BW combined and Outcome

Inclusion Criteria: All newborns admitted in intramural and extramural NICU of tertiary care center diagnosed as having PPHN on clinical basis confirmed by bedside 2D echocardiography.

Exclusion Criteria

• Patients presented with congenital heart disease.
• Patient having major congenital malformations including congenital diaphragmatic hernia.
• Unwillingness of parents/guardians for enrollment of admitted neonate in the study.

Statistical Analysis: In our study data was collected from SNCU sheet used in neonatal intensive care unit SSG hospital Baroda and added as predesigned Performa, epi info software and master chart in Microsoft excel sheet. Data was analyzed in Microsoft excel with help of Med Calc statistical software (licensed version). Statistical analysis of the data was performed using frequency, proportion, difference between two means, chi square test, fisher exact test and mann whitney U test with significance was defined as P value <0.05.

Table 1: Distribution of Sex

Table 2: Distribution of Maturity

Table 3: Distribution of Birth weight

Table 4: Distribution of GA+BW combined

Table 5: Distribution of Outcome

Figure 1: Distribution of Maturity

Figure 2: Distribution of Outcome

In our study, out of a total of 80 patients, 41 were males (51.25%) and 39 were females (48.75%). The difference in sex distribution between the two groups was not statistically significant (p = 0.749).

In our study, out of 80 patients, 67 (83.75%) were full-term (>37 weeks) and 13 (16.25%) were preterm (<37 weeks). The difference in maturity distribution was highly statistically significant (p < 0.00001).

In our study, out of 80 patients, 48 (60%) had a birth weight >2.5 kg, 26 (32%) had a birth weight between 1.5–2.5 kg, and 6 (8%) had a birth weight between 1–1.5 kg. The difference in birth weight distribution was highly statistically significant (p < 0.00001).

In our study, out of 80 patients, 36 (45%) were appropriate for gestational age (AGA), 44 (55%) were small for gestational age (SGA), and none were large for gestational age (LGA). The difference in the combined gestational age and birth weight distribution was highly statistically significant (p < 0.00001).

In our study, out of 80 patients, 36 (45%) survived and 44 (55%) did not survive. The difference in outcomes between survivors and non-survivors was not statistically significant (p = 0.208).

In our study of 80 neonates, 41 (51.25%) were males and 39 (48.75%) were females, demonstrating no statistically significant difference in sex distribution (p = 0.749), a finding that is consistent with the observations of Thompson et al. [10], who reported similar outcomes between male and female neonates, suggesting that sex may not be a primary determinant of early neonatal risk in the population studied. Regarding gestational maturity, 67 neonates (83.75%) were full-term, defined as gestational age exceeding 37 weeks, while 13 neonates (16.25%) were preterm, defined as gestational age less than 37 weeks, with this difference being highly statistically significant (p < 0.00001). This result aligns closely with the findings of Li et al. [11], who reported that preterm infants are at significantly higher risk for adverse neonatal outcomes due to immature organ systems and vulnerability to metabolic and infectious complications, highlighting the critical role of gestational age as a determinant of neonatal prognosis. In evaluating birth weight, our cohort showed that 48 neonates (60%) weighed more than 2.5 kg at birth, 26 neonates (32%) had weights ranging from 1.5 to 2.5 kg, and 6 neonates (8%) weighed between 1 and 1.5 kg, with this distribution also demonstrating a highly significant difference (p < 0.00001). These findings are consistent with the study by Voskamp et al. [12], who emphasized the association between higher birth weights and improved neonatal survival and reduced complications, underlining the importance of adequate intrauterine growth and maternal nutritional and health status in influencing birth weight. When combining gestational age and birth weight classifications, 36 neonates (45%) were categorized as appropriate for gestational age (AGA), while 44 neonates (55%) were small for gestational age (SGA), with no neonates classified as large for gestational age (LGA), again showing a highly significant difference (p < 0.00001). This observation supports the work of Li et al. [11], who reported that SGA infants are at higher risk of perinatal morbidity and mortality due to factors such as intrauterine growth restriction, placental insufficiency, and increased susceptibility to hypothermia, hypoglycemia, and infection. Finally, analysis of survival outcomes in our cohort revealed that 36 neonates (45%) survived, while 44 neonates (55%) did not, with no statistically significant difference observed (p = 0.208). This contrasts with data reported by CMCH [13], which indicated an 82% survival rate among extremely low birth weight infants, reflecting potential differences in the availability and quality of neonatal care resources, such as access to neonatal intensive care units, trained personnel, and timely interventions. Overall, our study underscores that while sex did not significantly influence neonatal outcomes, gestational maturity, birth weight, and SGA status were strongly associated with neonatal risk and survival, emphasizing the critical need for targeted prenatal monitoring, early identification of at-risk pregnancies, and the provision of optimized neonatal care to improve survival and long-term health outcomes in vulnerable neonates. These findings highlight the multifactorial nature of neonatal morbidity and mortality and provide evidence to support resource allocation and intervention strategies aimed at improving neonatal health in both hospital and community settings.

In our study, there was no significant difference in outcomes based on sex. Full-term neonates were more common than preterm infants, indicating a significant association between gestational maturity and overall neonatal profile. Birth weight and combined gestational age with weight classification also showed significant variation, with a higher proportion of small-for-gestational-age infants. However, survival outcomes did not show a statistically significant difference, suggesting that factors beyond sex, gestational age, and birth weight may influence neonatal survival. Overall, the findings highlight the importance of monitoring gestational maturity and growth parameters to identify at-risk neonates and optimize care strategies.

1. Mathew B, Lakshminrusimha S. Persistent pulmonary hypertension of the newborn. Children. 2017;4(8):63.
2. Steinhorn RH. Neonatal pulmonary hypertension. Pediatr Crit Care Med. 2010;11(2 Suppl):S79-84.
3. Sharma V, Berkelhamer SK, Lakshminrusimha S. Persistent pulmonary hypertension of the newborn. Matern Health Neonatol Perinatol. 2015;1:14.
4. Walsh-Szabo E, Wilson A. Persistent pulmonary hypertension of the newborn: current insights. Pediatr Health Med Ther. 2020;11:231-43.
5. Konduri GG, Vohr B, Robertson C, Sokol GM, Solimano A, Singer J, et al. Early inhaled nitric oxide therapy and neurodevelopmental outcome in PPHN. Pediatrics. 2007;120(1):e90-8.
6. de Boode WP, Singh Y, Gupta S, Austin T, Kluckow M, Paradis S, et al. Application of neonatologist-performed functional echocardiography in the newborn. Pediatr Res. 2018;84(1):19-34.
7. Singh Y. Echocardiographic evaluation of persistent pulmonary hypertension of the newborn. Early Hum Dev. 2012;88(12):947-52.
8. Malowitz JR, Forsha DE, Smith PB, Cotten CM, Barker PC, Tatum GH, et al. Right ventricular echocardiographic indices predict poor outcomes in infants with PPHN. Eur Heart J Cardiovasc Imaging. 2015;16(11):1224-31.
9. Roberts JD Jr, Fineman JR, Morin FC, Shaul PW, Rimar S, Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. N Engl J Med. 1997;336(9):605-10.
10. Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL, Perez JA, et al. Low-dose nitric oxide therapy for PPHN. N Engl J Med. 2000;342(7):469-74.
11. Thompson E, et al. Birth outcomes and survival by sex among newborns. PMC. 2024.
12. Li L, et al. Association of neonatal outcome with birth weight for gestational age in Chinese very preterm infants: a retrospective cohort study. PMC. 2024.
13. Voskamp BJ, et al. Association between fetal sex, birthweight percentile and adverse pregnancy outcome. Obstet Gynecol Sci. 2020;63(5):499–507.
14. CMCH's Special Neonatal Care: Where extremely low birth weight babies survive the most. Times of India. 2025.