A digital search was performed on MEDLINE and The Cochrane Library covering the period from January 1, 1993–December 31, 2023.We included observational studies, interventional studies and reviews that provided adequate information concerning the prevalence/incidence, mortality, predictors, etiologies, diagnosis and management of PPHN in the general neonatal population (aged 0–28 days). The search strategy used the following keywords: “neonate”, “persistent fetal circulation syndrome”, “prevalence”, “mortality”, “risk factor”, “etiologies”, “diagnosis and management”, and these were cross-referenced with the names of all countries to maximize the retrieval of relevant research articles. No restrictions related to language or geographical location were imposed on the search (Supplementary File S2). Two reviewers independently screened the titles and abstracts of the retrieved records. They subsequently examined the full texts of articles relevant to the prevalence/incidence, mortality, risk factors, etiologies, diagnosis, and management of PPHN. References from the included articles were assessed as potential sources for further studies. We excluded commentaries, expert opinions, editorial letters, case reports, and case series that involved fewer than 30 participants. To ensure more uniformity in the data concerning prevalence, etiology, and mortality of PPHN, we also discarded studies focusing on neonates selected based on the presence of PPHN-specific diseases or conditions, such as respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), meconium aspiration syndrome (MAS), COVID-19, and neonates born to high-risk pregnancies associated with PPHN (like gestational diabetes mellitus and mothers infected with COVID-19). A comprehensive description of the search strategy can be found in Supplementary File S2.

All relevant articles were imported into EndNote 21 reference management software to eliminate duplicates. Data extraction for the study was conducted using a standardized Microsoft Excel data extraction form. Title and abstract screening and full-text review of articles were performed independently by Yan Huang and Ting Yang. Any discrepancies were resolved through discussion and consensus, with consultation from a third author (L.Z.) if necessary. Authors of individual studies may be contacted to obtain additional data or to clarify results when required. A standardized and pre-tested data extraction form was utilized by the two reviewers to independently chart the following data from each included study: bibliometric information (including the name of the first author, the country in which the study was conducted, and the year of publication), study setting, diagnostic criteria used for PPHN, sample size, proportion of males, mean gestational age (GA), GA range, prevalence or incidence, in-hospital mortality rate, risk factors, etiologies, diagnostic criteria and management of PPHN. To ensure quality assurance, all extracted and charted data were reviewed for accuracy and completeness.

The evaluation of bias risk was carried out utilizing the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies, the criteria established by the Agency for Healthcare Research and Quality (AHRQ) for cross-sectional studies, and modified Jadad scores specifically designed for randomized controlled trials. This evaluation was conducted by a duo of researchers, Yan Huang and Ting Yang.

At the outset, we discovered 1,182 pertinent articles, removing 70 because of duplicates. We subsequently evaluated 1,112 articles according to established inclusion and exclusion criteria by examining the titles and abstracts, resulting in the exclusion of 787 articles. This left us with 325 articles, which were then assessed in full text. Following this full-text review, 197 articles were discarded for failing to satisfy the inclusion criteria (see Figure 1).

A total of 128 research articles were gathered from more than 600 centers spanning 27 different countries globally (see Figure 2). The largest proportion of these studies originated from the Americas (49.2%), with Asia following at 28.1%, Europe at 14.1%, Africa at 4.7%, and Oceania at 3.9% as detailed in Table 1. Specifically, the United States, China, and Thailand contributed 54, 13, and 8 citations, respectively (refer to Figure 2). Notably, most of the publications emerged within the previous decade, accounting for 44.5%. Additionally, there were 18 systematic reviews and 3 established guidelines (as shown in Table 1).

The prevalence of PPHN was obtained from 43 studies involving 6,128,630 neonates across 27 different countries (Table 2). In general, the worldwide prevalence of PPHN fluctuated between 0.1% and 8.1%. The prevalence varied by region as follows: Asia 0.12%–8.1% (13–28), the Americas 0.13%–5.7% (7, 11, 28–41), Europe 0.1%–8.0% (42–48), and Africa 5.0% (49, 50). More nationally representative prevalence data show that the highest prevalence of PPHN was 8.1% in Japan (19), and the lowest rate was 0.1% in a study published in Italy in 2010 (45), see Table 2.

In our analysis of the causes of PPHN within the subgroup, we assessed information from 34 studies including 4,170,496 neonates from 17 countries (Table 3). Globally, the leading etiologies of PPHN were neonatal infection (n = 3,709), MAS (n = 2,918), idiopathic pulmonary hypertension (n = 1,909) and RDS (n = 1,205) (Table 3). The leading etiologies of PPHN varied regionally. Neonatal infections were the leading etiology of PPHN in Asia, the Americas and Africa,whereas MAS was the leading etiology in Europe, as indicated at the conclusion of Table 3.

Predictors associated with mortality in PPHN included a minimum PaO2/FIO2 ratio of less than 0.3 (OR = 8.26, 95% CI 1.78–38.41), a urine output of below 1.0 ml/kg/h within the initial 12 h (OR = 7.30, 95% CI 1.16–45.95), and a lowest mean blood pressure under 30 mm Hg (OR = 5.58, 95% CI 1.15–26.99). Infants presenting with SNAP-II score of 43 or higher faced the highest rist of mortality, reflected by an odds ratio (OR) of 10.00 (95% CI 1.03–97.50). Each one-point increase in the SNAP score was linked to a 1.04 increase in the odds of mortality (95% CI 1.01–1.07, P < 0.01) (14). The major risk factors for PPHN across various age groups encompassed male sex, cesarean deliveries, MAS, and RDS. Notably, RDS (RR = 5), birth asphyxia (RR = 2.5), and male gender (RR = 2) correlated with a heightened mortality risk in preterm infants in comparison to their term and post-term counterparts (51). A multicenter study in Malaysia identified that lower APGAR scores at five minutes and impaired cardiac function were linked to poorer outcomes. Key independent mortality risk factors comprised reverse flow detected in the descending aorta (OR = 15.91, 95% CI 5.64–44.92), APGAR scores of five or less at 5 min (OR = 6.72, 95% CI 2.04–22.15), and idiopathic pulmonary hypertension (OR = 6.46, 95% CI 1.52–27.43) (24). On a different note, pneumothorax (adjusted HR = 2.07, 95% CI 1.09–3.93, p = 0.03) and acute kidney injury (AKI) (adjusted HR = 2.99, 95% CI 1.59–5.61, p < 0.01) were significantly related to a higher likelihood of death. Conversely, conditions such as ventilator-associated pneumonia (VAP) (adjusted HR = 0.32, 95% CI 0.15–0.67) and the administration of total parenteral nutrition (TPN) (adjusted HR = 0.22, 95% CI 0.10–0.50) were linked to reduced mortality rates (17). Variations in plasma concentrations of atrial natriuretic peptide (ANP), endothelin-1 (ET-1) and von Willebrand factor (vWF) could indicate pulmonary artery systolic pressure (PASP) in newborns suffering from PPHN throughout their treatment. Ongoing assessment of these biomarkers may facilitate an evaluation of PPHN severity and direct appropriate treatment approaches (52).

Worldwide, the in-hospital mortality rates linked to PPHN fluctuated between 3.0 and 57.9%,showing regional variations as follows: Asia 7.3–57.9% (13–24, 28), the Americas 3.0–53.5% (7, 11, 28–40), Europe 3.1%–32% (42–48, 53) and Africa 25% (49). At the national level,this mortality rate was highest in Malaysia 57.9% (15) and Canada 53.5% (54) and lowest in the USA 3% (36)and the UK 3.1% (43), see Table 2. A California report focused on late preterm and term infants indicated that the one-year mortality associated with PPHN was significantly influenced by the underlying causes, with the highest rates seen in infants with other congenital respiratory anomalies (32%), followed by congenital diaphragmatic hernia (CDH) at 25.0%, respiratory distress syndrome (RDS) at 6.9%, and other causes at 8% (40).

Additionally, in a separate analysis of PPHN-related mortality, we evaluated data from 20 studies encompassing 5,942, 464 neonates across 13 countries (Table 4). Globally, the predominant causes of PPHN-related fatalities included neonatal infections (n = 334), CDH/lung hypoplasia (n = 269), MAS (n = 162) and RDS (n = 118). These trends showed minimal regional variation, with CDH/lung hypoplasia being the primary cause of PPHN-related in-hospital mortality in the Americas. In Asia, neonatal infections led as the primary cause of death. Conversely, fewer PPHN-related deaths were studied in Europe and Africa (Table 4).

The global prevalence of PPHN The findings regarding the prevalence of PPHN indicate a significant variability across the 43 studies analyzed, influenced by multiple factors. Early investigations conducted in central Thailand identified an incidence of PPHN that fluctuated between 0.38 and 0.99 per 1,000 live births (85). In contrast, research from southern Thailand revealed a higher incidence of 2.8 per 1,000 live births (17). Prior to the extensive application of iNO therapy, data from a multicenter study in the United States reported a PPHN prevalence of 1.9 per 1,000 live births (from a cohort of 71,558 infants), with marked variation noted among different centers, ranging from 0.43–6.82 per 1,000 live births) (33). A separate investigation focusing on late preterm and term infants in California found an incidence of PPHN at 1.8 per 1,000 live births (0.18%).Notably, late preterm infants (gestational age between 34 and 36 weeks) had the highest incidence at 5.4 per 1,000 live births, whereas term infants presented a lower incidence of 1.6 per 1,000 live births (40). A retrospective review of medical records from several centers across six Asian nations (Japan, Kuwait, India, Pakistan, Singapore, and Thailand) conducted between January 1, 2014, and December 31, 2016, demonstrated that the incidence of PPHN varied from 1.2–4.6 per 1,000 live births (22). Additionally, a decade-long multicenter study involving extremely preterm infants (n = 12,954 cases) in Japan reported a prevalence of PPHN at 8.1% (95% CI 7.7%–8.6%), which showed an upward trend annually, and a notably higher prevalence with decreasing gestational age: 18.5% (range, 15.2%–22.4%) for those born at 22 weeks, vs. 4.4% (range, 3.8%–5.2%) for infants born at 27 weeks (19). The prevalence of PPHN is influenced by geographical locations, population characteristics, and gestational age. As illustrated by the aforementioned data, countries with the highest and lowest prevalence rates of PPHN suggest that low- and middle-income countries (LMICs), particularly in Africa and Asia, are disproportionately affected compared to high-income countries (HICs) in the Americas and Europe. Additionally, several advancements in neonatal care, including the creation of NICUs, the induction of fetal lung development through antenatal steroid administration, refinement of neonatal resuscitation protocols, the use of exogenous surfactant immature lungs, and the development of advanced respiratory support techniques like continuous positive airway pressure (CPAP), HFV, are often inadequate or lacking in LMICs. Moreover, the significant variability in prevalence rates can be attributed to differences in research methodologies, which report varying figures for the clinical diagnosis of PPHN. The diagnostic criteria for PPHN have shown inconsistencies, potentially leading to both underestimation and overestimation of its prevalence. Furthermore, study context might contribute to this variability; it was anticipated that single-center studies would report lower PPHN prevalence rates compared to multicenter studies. However, data revealed that PPHN prevalence in single-center investigations ranged from 0.1%–5.7%, while multicenter studies reported lower rates of 0.12%–8.1%. This discrepancy could be due to single-center studies being conducted in specialized neonatal care facilities, whereas multicenter studies were carried out across a broader range of institutions (see Table 2). Additionally, the prevalence variations across the 43 included studies may reflect the differing gestational ages of the newborns involved: from 8.3%–100% in premature infants (7, 19, 21–26, 32, 35, 38–40, 42, 47, 48, 51, 54, 58, 66, 86) compared to exclusively extremely preterm infants (19). Collectively, these results suggest that the incidence of PPHN diminishes with advancing gestational age, which is attributed to the functional and structural immaturity of the lungs in premature neonates.

Between 1993 and 2023, there has been no noteworthy reduction in mortality rates associated with PPHN. The fact that neonatal infections remain the primary cause of PPHN and contribute significantly to in-hospital fatalities suggests that, despite advancements in the management of PPHN over the last thirty years, additional therapeutic developments are still necessary. These initiatives should be especially focused on the Americas and Asia, where neonates experience varying impacts from neonatal infections. As expected, preventable neonatal infections remain a major global health problem, particularly in Asia and Africa. A preponderance of congenital diaphragmatic hernia and/or pulmonary dysplasia in the Americas may reflect a high local prevalence of congenital anomalies. More research is required to explore the role of environmental, genetic, and other factors alongside early prevention strategies.

Factors that may predict the occurrence of PPHN include cesarean section, which is widely acknowledged as a contributing risk factor for this condition. A study conducted by Winovitch indicated that the rate of PPHN among those undergoing elective cesarean delivery was 6.9 per 1,000 births (61). Various research efforts have shown a greater prevalence of PPHN in infants born via cesarean section (CS) compared to those delivered vaginally (VD) (35, 55, 61, 87, 88). Specifically, the occurrence of PPHN was found to be around 0.37% in neonates delivered by CS, nearly five times higher than in those delivered vaginally (88). Elective cesarean sections, in particular, disrupt the physiological processes, such as the release of catecholamines and glucocorticoids that promote pulmonary fluid absorption, surfactant production, and pulmonary vasodilation, which are critical for the newborn's normal cardiorespiratory adjustment during labor (87, 89). Furthermore, fetal distress frequently leads to cesarean deliveries, which is another prevalent risk factor for PPHN. Consequently, the elevated rate of PPHN associated with CS may primarily stem from the activation of latent fetal factors rather than from a direct causal link with CS or the absence of VD. Notably, the incidence of PPHN in infants delivered through elective cesarean procedures before labor begins is significantly higher than in those born vaginally (OR = 4.9, 95% CI 1.7–14.0), indicating that cesarean delivery itself constitutes a risk factor for PPHN (60). CS has been linked to respiratory distress syndrome (RDS), which poses a higher mortality risk from PPHN in preterm infants compared to those born at term or post-term (51). Therefore, it is critical for obstetricians to conduct a comprehensive evaluation during CS procedures, particularly in cases of preterm labor. Meconium aspiration syndrome (MAS) is recognized as the leading contributor to PPHN. The presence of meconium interferes with pulmonary surfactants, triggering lung inflammation and causing alveolar hypoxia, which results in pulmonary vasoconstriction. Furthermore, meconium lodged in the airways can cause obstruction, gas trapping, and increased pulmonary vascular resistance. Nevertheless, the relationship between PPHN and meconium aspiration remains ambiguous; it is uncertain whether PPHN emerges directly from the aspiration or serves as an indirect indicator of in utero stress factors, such as hypoxia or infection. Additionally, a multicenter retrospective study of preterm infants indicated that clinical chorioamnionitis and premature rupture of membranes were correlated with PPHN (19). Inflammatory mediators leading to functional or structural pulmonary deficits, alongside severe infections that may compromise circulation or induce shock, could contribute to the emergence of PPHN, potentially accounting for the rising prevalence of this condition, particularly among preterm births.

Regarding the fetal risk factors related to delayed pulmonary biomechanics and vascular development, elevated levels of serum androgens in males compared to females contribute significantly (90, 91). Testosterone delays fetal lung maturation by regulating growth factors, and fetal androgens also inhibit fetal lung surfactant secretion. Meanwhile, estrogen promotes the synthesis of surfactant components, the growth of type II lung cells, and an overall increase in fetal lung surfactant secretion (92, 93). RDS is frequently a contributing factor to PPHN. Consequently, preterm infants face a greater risk of developing PPHN than their term counterparts. The insufficient synthesis and release of lung surfactant along with a limited number of respiratory units in preterm infants make them more susceptible to atelectasis and, ultimately, hypoxia associated with RDS. Factors such as poor lung compliance, reduced tidal volumes, increased physiological dead space, and inadequate alveolar ventilation lead to hypercapnia. The interplay of hypercapnia, hypoxia, and acidosis results in pulmonary vasoconstriction and enhanced right-to-left shunting through the patent foramen ovale and arterial ducts, as well as within the lungs, all of which exacerbate the risk of PPHN. GDM and PGDM result in intrauterine exposure to maternal hyperglycemia, which increases the transplacental transfer of glucose to the fetus, resulting in fetal hyperglycemia. This fetal hyperglycemia, in turn, inhibits the synthesis of fetal lung surfactant. Adverse outcomes are more prevalent in patients with inadequate blood glucose control, such as RDS (χ² = 13.373, P < 0.01). In addition, elevated fasting plasma glucose (FPG) has been deemed an independent risk factor for preterm birth, with an odds ratio (OR) of 1.460 (P < 0.001) (94). Simultaneously, there is a significant correlation between maternal obesity and advanced maternal age with an increased likelihood of experiencing obstetric complications, including maternal diabetes/GDM, pregnancy-related hypertensive disorders, and antepartum hemorrhage, all of which can predispose PPHN. All of these increase the probability of a cesarean section. Fetal distress and APGAR scores at birth often have interlocking or cascading mechanisms in predicting PPHN. Moreover, both hypoxia and acidosis are unequivocally powerful pulmonary vasoconstrictors, blocking changes in the cardiopulmonary circulation in normal newborns after birth, therefore, any factors leading to intrauterine hypoxia may play a role in the onset of PPHN.

The topic of using antidepressants during pregnancy remains contentious. Selective serotonin reuptake inhibitors (SSRIs) have been linked to a higher incidence of severe cardiac malformations as well as persistent pulmonary hypertension of the newborn (PPHN). Nevertheless, the majority of neurodevelopmental studies tracking follow-up have not uncovered significant cognitive impairments, observing only minor transient gross motor delays, slight language issues, and potential behavioral modifications. The dangers associated with halting treatment seem to surpass those tied to continuing it, as serious maternal depression could adversely affect a child's development. If deemed necessary, it is advisable to maintain treatment throughout pregnancy at the minimum effective dosage (95, 96).

It remains uncertain whether some of these risk factors are definitively a direct cause of persistent pulmonary hypertension in newborns or if they are merely co-contributors. Genetic variations have been identified in individuals with PPHN. Research within a single-center Chinese cohort has identified CPS1, NOTCH3, and SMAD9 as genetic risk factors for late preterm and term PPHN (21). These discoveries contribute further genetic support to the understanding of PPHN's pathogenesis and provide new perspectives on potential therapeutic strategies for the condition. Given the elevated risk of mortality and poor outcomes for survivors of PPHN, healthcare providers must be particularly attentive to the heightened need for monitoring and intervention in pregnant women or newborns presenting these risk factors. In addition, the influence of maternal factors, (e.g., maternal diabetes, maternal obesity, hypertensive disorders of pregnancy), on offspring warrant further exploration. In the future, in addition to databases of children with PPHN, more high-quality cohorts and databases of targeted therapeutic agents used could be established, especially in low- and middle-income settings, with closer and longer follow-up to assess the long-term impact.

The application of inhaled nitric oxide (iNO) for treating pulmonary hypertension (PH) in newborns delivered at less than 34 weeks of gestation has been extensively reviewed. Meta-analyses from randomized controlled trials focusing on the use of iNO for preventing bronchopulmonary dysplasia (BPD) have led groups from the National Institutes of Health (NIH) and the American Academy of Pediatrics (AAP) to determine that there is insufficient evidence to support the routine implementation of iNO in preterm infants. Nonetheless, existing research indicates that administering iNO can enhance oxygen levels in these infants, and the inclination to employ iNO is on the rise. The NIH consensus recommends that healthcare providers must evaluate the appropriateness of iNO treatment for preterm infants suffering from PH. Additionally, the American Heart Association, American Thoracic Society, and the Pediatric Pulmonary Hypertension Collaborative Network endorse the application of iNO in cases of persistent pulmonary hypertension of the newborn (PPHN) when standard respiratory and circulatory interventions fail to yield adequate results. It's important to note that both iNO and ECMO are not universally accessible and pose significant challenges in low- and middle-income countries (LMICs). Moreover, around 40% of neonates diagnosed with PPHN do not respond to iNO therapy (8). ECMO represents a resource-heavy treatment modality that necessitates a collaborative approach from a team of skilled healthcare professionals with specialized training in the setup, ongoing care, and cessation of ECMO for critically ill PPHN patients facing diverse causes and associated health complications. The principal risks linked to ECMO include bleeding, clot formation, and infections related to catheters. Comprehensive preparation, strategic resource distribution, and rigorous training of personnel to implement complex treatment strategies while following stringent infection control protocols are vital aspects of any ECMO operational strategy. There is a pressing need for additional prospective multi-institutional research to broaden the existing registry data.

Consequently, further interventions are under investigation. Recent years have seen significant progress in our comprehension of the physiopathology associated with PPHN, encompassing elements such as phosphodiesterase, endothelin receptors, and the supplementation of exogenous prostaglandins. These medications can be utilized individually or in conjunction with one another or with iNO. Sildenafil has undergone the most comprehensive research. A systematic review and network meta-analysis exploring various PPHN treatment comparisons indicated that a median concentration of 10–20 parts per million (ppm) of iNO (MNO), in combination with sildenafil given orally at a dose of 1–3 mg/kg every 6–8 h (OSID), showed the highest efficacy (OR = 27.53, 95% CI 2.36–321.75). In situations where iNO is unavailable, OSID paired with intravenous milrinone also demonstrated commendable efficacy (OR = 25.13, 95% CI 1.67–377.78) (97). PPHN is a complex and variable disease, and it is challenging for clinicians to make the right choice of individual drugs based on good evidence in routine practice. Meanwhile, most vasodilator drugs are still used outside the prescription instructions in neonates. Their clinical efficacy and potential and long-term adverse reactions are still being monitored and followed-up. At the same time, the treatment of PPHN is complex, expensive and limited in resource-limited regions. Alternative or cheaper treatments are being sought. Moreover, because the signaling pathways that control pulmonary vascular tone are intricate and highly interconnected, addressing only one particular pathway may not fully rectify vascular anomalies and could potentially upset the equilibrium between vasodilator and vasoconstrictor production. Each of the therapies mentioned may have significance, and a combined approach utilizing multiple treatments could be beneficial in certain severe cases.

Employing a combination of therapies could enhance outcomes in certain severe instances. A significant drawback of the present research is the variability among all studies included, which complicates the meta-analysis. Specifically, conducting a meta-analysis utilizing combined prevalence, mortality rates for PPHN, and risk assessments is unsuitable due to the diverse methodological approaches present in the studies examined. Nonetheless, this scoping review acts as a modern reference document that has been globally referenced for PPHN throughout the last three decades. It lays the foundation for systematic reviews and meta-analyses pertaining to epidemiological research on PPHN.