Prostanoids and their analogues for the treatment of pulmonary hypertension in neonates

Abstract

Background

Persistent pulmonary hypertension of the newborn (PPHN) is a disease entity that describes a physiology in which there is persistence of increased pulmonary arterial pressure. PPHN is characterised by failure to adapt to a functional postnatal circulation with a fall in pulmonary vascular resistance. PPHN is responsible for impairment in oxygenation and significant neonatal mortality and morbidity. Prostanoids and their analogues may be useful therapeutic interventions due to their pulmonary vasodilatory and immunomodulatory effects.

Objectives

Primary objective

• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing mortality and the need for extracorporeal membrane oxygenation (ECMO) among neonates with PH

Secondary objective

• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) and improving neurodevelopmental outcomes among neonates with PH

Comparisons

• Prostanoids and their analogues at any dosage or duration used to treat PPHN versus ‘standard treatment without these agents’, placebo, or inhaled nitric oxide (iNO) therapy

• Prostanoids and their analogues at any dosage or duration used to treat refractory PPHN as an ‘add‐on’ therapy to iNO versus iNO alone

Search methods

We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE via PubMed (1966 to 16 September 2018), Embase (1980 to 16 September 2018), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 16 September 2018). We also searched clinical trials databases, conference proceedings of the Pediatric Academic Societies (1990 to 16 September 2018), and the reference lists of retrieved articles for randomized controlled trials and quasi‐randomized trials. We contacted authors who have published in this field as discerned from the reference lists of identified clinical trials and review authors' personal files.

Selection criteria

Randomized and quasi‐randomized controlled trials evaluating prostanoids or their analogues (at any dose, route of administration, or duration) used in neonates at any gestational age less than 28 days' postnatal age for confirmed or suspected PPHN.

Data collection and analysis

We used the standard methods of Cochrane Neonatal to conduct a systematic review and to assess the methodological quality of included studies (neonatal.cochrane.org/en/index.html). Three review authors independently assessed the titles and abstracts of studies identified by the search strategy and obtained full‐text versions for assessment if necessary. We designed forms for trial inclusion or exclusion and for data extraction. We planned to use the GRADE approach to assess the quality of evidence.

Main results

We did not identify any eligible neonatal trials evaluating prostanoids or their analogues as sole agents in the treatment of PPHN.

Authors' conclusions

Implications for practice

Currently, no evidence shows the use of prostanoids or their analogues as pulmonary vasodilators and sole therapeutic agents for the treatment of PPHN in neonates (age 28 days or less).

Implications for research

The safety and efficacy of different preparations and doses and routes of administration of prostacyclins and their analogues in neonates must be established. Well‐designed, adequately powered, randomized, multi‐center trials are needed to address the efficacy and safety of prostanoids and their analogues in the treatment of PPHN. These trials should evaluate long‐term neurodevelopmental and pulmonary outcomes, in addition to short‐term outcomes.

Plain language summary

Prostanoids in pulmonary hypertension of the newborn

Review question

Are prostanoids or their derivatives effective in the treatment of pulmonary hypertension in the newborn?

Background

Persistent pulmonary hypertension of the neonate (PPHN) is a life‐threatening condition. Before birth, a baby’s nourishment and oxygen are obtained through the placenta, hence blood circulates differently within the uterus. The baby with PPHN does not change over from fetal to normal newborn circulation. Blood flow is diverted from the lungs due to abnormally high blood pressure in the arteries that go to the lungs. This decreases the body’s supply of oxygen, causing significant injury to the brain and other organs.

The primary problem for newborns is that normal exchange of oxygen in the lung does not occur, so oxygen cannot be delivered to the body. Prostanoids are metabolites of fatty acid called 'arachidonic acid'. They have been shown to relax the lung bed blood vessels, improving blood flow to the lungs and helping with oxygenation in humans and animals. (Prostanoids are a class of drugs that dilate lung blood vessels and may help babies with PPHN. Prostacyclin (PGI₂) and prostaglandin E₁ (PGE₁) are two classes of prostanoids that have been used to treat PPHN in newborn babies.) The safety and effectiveness of these medicines have not been established.

Study characteristics

We searched the literature for studies that used prostanoids or their derivatives for the treatment of PPHN by injection or inhalation. We found no ongoing or completed randomized controlled studies. We found one small study that ended prematurely due to poor enrolment. Currently, no evidence for or against the use of prostanoids in newborn PPHN is available, and we recommend future studies to establish the safety and efficacy of these medicines.

Key results

We found no randomized controlled studies in our search. We found no ongoing studies that may answer our question when their results become available.

Quality of evidence

We could not assess this review question due to lack of eligible trials.

Background

Description of the condition

Pulmonary hypertension (PH) in neonates, or persistent pulmonary hypertension of newborns (PPHN), is a serious disorder of the pulmonary vasculature that results from failure of successful postnatal transition of faetal pulmonary circulation. A normal transition includes a decrease in pulmonary vascular resistance (PVR) to 50% of systemic vascular resistance (SVR), a 10‐fold increase in pulmonary blood flow due to expansion and oxygenation of the alveoli, a decrease in the ratio of pulmonary vasoconstrictors to vasodilators, and clamping of the umbilical cord (Teitel 1990; Cornfield 1992; Cabral 2013). In PPHN, the PVR is elevated compared to the SVR; this may be due to low oxygen tension in the lung and an increased ratio of pulmonary vasoconstrictors to vasodilators, or to abnormal function and/or anatomy of the musculature of lung blood vessels, independent of the mechanism(s) for high PVR, blood shunts away from the lungs through a right‐left shunt through the ductus arteriosus or foramen ovale, or both (Lakshminrusimha 1999). PPHN is confirmed by the presence of a right‐left shunt through the ductus arteriosus or foramen ovale, or both, without accompanying heart disease, irrespective of pulmonary artery pressure (Lakshminrusimha 2012; Porta 2012; Cabral 2013; Ivy 2013).

The incidence of PPHN ranges from 0.4 to 2 per 1000 live births, with associated mortality of around 11% (Walsh‐Sukys 2000; Cabral 2013). Several mechanisms for PPHN may be divided into the following categories.

• Acute pulmonary vasoconstriction as a result of abundance of endogenous pulmonary vasoconstrictors compared to vasodilators; this may be associated with maternal diabetes, antenatal exposure to non‐steroidal anti‐inflammatory medications, elective caesarean section delivery, perinatal asphyxia, meconium aspiration syndrome, pneumonia, sepsis, hyaline membrane disease, or metabolic acidosis.

• Pulmonary vascular remodeling, which is characterized by pulmonary artery smooth muscle hyperplasia, adventitial thickening, and muscularization of intra‐acinar arteries (e.g. congenital diaphragmatic hernia (CDH), chronic intrauterine hypoxia, antenatal ductal closure).

• Pulmonary vascular hypoplasia, a condition characterized by decreased pulmonary blood vessels and cross‐sectional area of the pulmonary vascular bed, thereby elevating PVR and causing flow restriction (e.g. CDH, intrathoracic space‐occupying lesions, chronic oligohydramnios).

• Pulmonary intravascular obstruction characterized by blood flow restriction from conditions such as polycythemia and obstructed anomalous pulmonary venous drainage (Lakshminrusimha 2012; Cabral 2013; Storme 2013).

The gold standard for the diagnosis of PH is cardiac catheterization. However, this invasive procedure is not performed in most patients suspected to have PH, and the diagnosis is based on one or more of the following echocardiographic (Echo) findings: right ventricular systolic pressure/systemic systolic blood pressure ratio > 0.5 ascertained via assessment, interventricular septal flattening, cardiac shunt with bidirectional or right‐to‐left blood flow, and right ventricular hypertrophy in the absence of congenital heart disease (Mourani 2008; Bhat 2012; Mourani 2015).

The only intervention proven to improve clinical outcomes in PPHN is inhaled nitric oxide (iNO), a selective pulmonary vasodilator. Sildenafil is a phosphodiesterase type 5 (PDE5) inhibitor that causes vasodilatation by preventing cyclic guanosine monophosphate (GMP) breakdown in smooth muscle cells. It is commonly used as add‐on therapy to iNO for infants with iNO‐refractory PH, for weaning off iNO therapy, or as primary therapy for PPHN in resource‐limited places where iNO is not available (Lakshminrusimha 2016). However, evidence is insufficient to support recommending this as first‐line or sole therapy for infants with PH (Kelly 2017). This review is focused mainly on prostanoids and their analogues for the treatment of pulmonary hypertension in neonates. Other therapeutic measures for PH in neonates include optimizing lung volumes, providing adequate alveolar recruitment, and optimizing cardiac function. These supportive measures provide the context for treatment with other pulmonary vasodilators such as inhaled nitric oxide (iNO), prostanoids, phosphodiesterase inhibitors such as sildenafil and milrinone, and endothelin antagonists such as bosentan, in addition to general supportive care such as maintenance of temperature and correction of electrolyte and metabolic derangements (Porta 2012; Steinhorn 2012; Cabral 2013; Storme 2013).

Description of the intervention

Prostanoids are metabolites of arachidonic acid that include prostaglandins, prostacyclin (also called prostaglandin I₂, or PGI₂), and thromboxanes. The enzyme cyclo‐oxygenase converts arachidonic acid to an unstable intermediate, prostaglandin G, and various synthase enzymes catalyze reactions leading to the production of various prostanoids including prostacyclin and prostaglandin E (PGE) (Ivy 2010). The prostanoids have numerous biological functions, and many are vasodilators, whereas thromboxanes are vasoconstrictors and are not useful in the treatment of PH. In addition to being a potent pulmonary vasodilator, PGI₂ exerts antithrombotic, antiproliferative, antimitogenic, and immunomodulatory activities (Read 1985; Jones 1997; Wharton 2000; Vane 2003). Prostanoids and their analogues that can be administered by various routes (e.g. intravenous, subcutaneous, by inhalation, by nebulization) are available for clinical use (Keller 2016).

Epoprostenol (Flolan) is the most commonly administered synthetic PGI₂ analogue used to treat pulmonary arterial hypertension in adults (Dorris 2012). Epoprostenol has a very short half‐life (< 5 minutes) that requires stable vascular access for administration as a continuous infusion. Evidence in children and adults with PH suggests that epoprostenol improves pulmonary hemodynamics, exercise capacity, quality of life, and survival (Barst 1994; Barst 1996; Barst 1999; Rosenzweig 1999; Sitbon 2002; Yung 2004). Children usually require a higher dose of epoprostenol than adults to obtain beneficial vasodilatory effects (Ivy 2010; Steinhorn 2012). Intravenous epoprostenol is initiated at a dose of 1 ng/kg/min and is gradually titrated to a dose of up to 50 to 100 ng/kg/min (Ivy 2010; Porta 2012). The most common side effects of intravenous prostacyclin are secondary to systemic vasodilation that leads to systemic hypotension, flushing, diarrhea, headache, jaw pain, alterations in hepatic enzymes, and an erythematous blotchy skin rash (Ivy 2010; Steinhorn 2012). Any interruption of its infusion can result in severe rebound PH and even death (Rubin 1990; Barst 1994; Doran 2008).

Iloprost is a prostacyclin analogue with a half‐life of 20 to 30 minutes, which can be administered intravenously or by inhalation or nebulization (Ewert 2009). Administration by inhalation or nebulization results in selective pulmonary vasodilation and improved ventilation/perfusion mismatch, and limits systemic side effects. However, the need for repeated nebulizations and side effects such as development of reactive airway disease limit its use (Ivy 2008; Ivy 2010; Dorris 2012). The main side effects are increased need for inotropic support among infants, as reported in Janjindamal 2013, and headache and cough in adults (Saji 2016).

Treprostinil is a long‐acting tricyclic benzindene prostacyclin analogue with a half‐life of about three hours that can be administered subcutaneously, intravenously, orally, or by inhalation (McNulty 1993). It is most commonly administered subcutaneously via a microinfusion pump. The main side effect is pain at the site of subcutaneous administration. However, treprostinil has fewer side effects when compared to epoprostenol (Ivy 2007; Doran 2008; Ivy 2010). Common side effects of this medication used in adults are headache, diarrhea, flushing, and jaw pain (Tapson 2013).

Beraprost, an oral prostacyclin analogue that is readily absorbed from the small intestine, is rapidly and almost completely excreted in the urine and the faeces after oral dosing (Olschewski 2004). A retrospective study reports its use in neonates with PH (Nakwan 2011). Hypotension is a common side effect of this medication in infants (Nakwan 2011).

The optimal dose of iloprost and treprostinil for treatment of neonates and infants with PH remains to be determined.

PGE₁ is used widely in neonatology to maintain patency of the ductus arteriosus in cases of duct‐dependent congenital heart disease. Compared to PGI₂, PGE₁ has a shorter half‐life; in addition, PGE₁ exerts bronchodilatory action and anti‐inflammatory effects on the lung. Inhaled PGE₁ has been shown to be a selective pulmonary vasodilator in neonates with hypoxic respiratory failure (Sood 2004), as well as in adults with acute lung injury and pulmonary hypertension (Putensen 1998). In adults, the side effects of PGE₁ include hypotension, nausea, vomiting, and fatigue (Koch 2000).

How the intervention might work

Prostacyclins signal via G‐protein‐coupled cell surface receptors (Gomberg‐Maitland 2008), which when activated stimulate the enzyme adenylate cyclase. The resulting increase in intracellular cyclic AMP (cAMP), opening of Ca²⁺‐activated K⁺ channels, and membrane hyperpolarization lead to relaxation of vascular smooth muscle and vasodilatation (Vane 1995). Pulmonary hypertensive disorders of neonates, children, and adults are associated with a PGI₂‐deficient state, which forms the basis for PGI₂ therapy in PH (Christman 1992; Majed 2012). Among infants, prostacyclins are comparable to iNO in decreasing pulmonary artery pressure and improving oxygenation (Bos 1993; Nakayama 2007). PGE₁ is an effective pulmonary vasodilator in adults with acute respiratory distress syndrome (ARDS), with an action similar to that of iNO (Putensen 1998). Currently, prostacyclin and its analogues and PGE₁ are increasingly used as 'add‐on' therapy for iNO‐refractory PH (Kelly 2002; Ehlen 2003; Chotigeat 2007; De Luca 2007; Levy 2011).

Why it is important to do this review

Pulmonary hypertension is a serious debilitating illness that is associated with high neonatal mortality and may require extracorporeal membrane oxygenation (ECMO) for survival. Hence, optimal management of PH is critical for improving outcomes in high‐risk neonates. Inhaled NO is the only FDA‐approved pulmonary vasodilator for treating PH in infants, but 30% to 50% of neonates with severe PH have a suboptimal response to iNO (Lakshminrusimha 2016;Pedersen 2018). Therefore, systematically analyzing the efficacy and safety of treatment with other pulmonary vasodilators such as prostanoids, phosphodiesterase inhibitors such as sildenafil and milrinone, and endothelin antagonists such as bosentan is necessary to generate an evidence‐based consensus and to inform clinicians of appropriate therapeutic interventions for iNO‐resistant PH. Failure to do such analyses may lead to suboptimal management and increased mortality among these critically ill infants. We aimed to systematically review evidence for the use of prostanoids and their analogues in the treatment of PH in neonates and to identify gaps in knowledge that will inform future clinical trials.

Objectives

Primary objective

• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing mortality and the need for ECMO among neonates with PH

Secondary objective

• To determine the efficacy and safety of prostanoids and their analogues (iloprost, treprostinil, and beraprost) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) and improving neurodevelopmental outcomes among neonates with PH

Comparisons

• Prostanoids and their analogues at any dosage or duration used to treat PPHN versus ‘standard treatment without these agents’, placebo, or iNO therapy

• Prostanoids and their analogues at any dosage or duration used to treat refractory PPHN as an ‘add‐on’ therapy to iNO versus iNO alone

Methods

Criteria for considering studies for this review

Types of studies

We planned to include randomized, quasi‐randomized, cluster‐randomized, and cross‐over trials.

Types of participants

We sought to include term or preterm neonates less than 28 days of age with PH who are cared for in the neonatal intensive care unit.

Neonates were diagnosed with PH if they had one or more of the following Echo findings: right ventricular systolic pressure/systemic systolic blood pressure ratio > 0.5, interventricular septal flattening, cardiac or ductal shunt with bidirectional or right‐to‐left blood flow, and right ventricular hypertrophy in the absence of congenital heart disease (Mourani 2008; Bhat 2012; Mourani 2015).

Types of interventions

We included prostanoids and their analogues given at any dosage or duration by any route (intravenous, subcutaneous, inhaled, or enteral).

Comparisons

• Prostanoids and their analogues at any dosage or duration or route of administration used to treat neonatal PH versus standard treatment without these agents (which may include optimizing lung volumes, providing adequate alveolar recruitment, and optimizing cardiac function), placebo, or iNO therapy

• Prostanoids and their analogues at any dosage or duration or route of administration used to treat refractory neonatal PH as ‘add‐on’ therapy to iNO versus iNO alone

• Head‐to‐head comparisons of the different prostanoid analogues for treatment of PH

Types of outcome measures

Primary outcomes

• 'All‐cause mortality' at 28 days of life, during hospital stay

• Need for ECMO in infants > 2000 g and at > 34 weeks during hospital stay. We define the need for ECMO according to extracorporeal life support organization (ELSO) guidelines (ELSO 2013)

  • Oxygenation index > 40 for > 4 hours

  • Oxygenation index > 20 with lack of improvement despite prolonged (> 24 hours) maximal medical therapy or persistent episodes of decompensation

  • Severe hypoxic respiratory failure with acute decompensation (partial pressure of oxygen (PaO₂))

  • Progressive respiratory failure with or without PPHN with right ventricular dysfunction or continued inotrope

Secondary outcomes

• Adverse effects: systemic hypotension (decrease in mean blood pressure lower than the 10th percentile for gestational and postnatal age (Nuntnarumit 1999), worsening oxygenation (oxygen saturations < 10% from before therapy started), rebound PH (increase in pulmonary arterial pressures > 10% as defined by Echo)) during treatment

• Neurodevelopmental outcome assessed by a validated test at ≥ 18 months of age (Neurodevelopmental impairment defined as one or more of the following outcomes: Bayley Scales of Infant Development II Mental Development Index < 70, Bayley Scales of Infant Development II Psychomotor Development Index < 70, bilateral blindness, bilateral hearing aid use, and cerebral palsy. If Bayley III scales are used, we will use scores equivalent to Bayley II (Payne 2013))

• Decrease in pulmonary arterial pressure (20% from baseline before start of therapy) as demonstrated by Echo or by cardiac catheterization during treatment

• Decrease in oxygenation index of any duration (20% from baseline before start of therapy) during therapy

• NEC (definite NEC and perforated NEC, Bell's stage II or III) during hospital stay (Bell 1978)

• CLD (defined as oxygen requirement at 36 weeks' postmenstrual age (Jobe 2001))

• PVL (defined as necrosis of white matter in a characteristic distribution, i.e. in the white matter dorsal and lateral to the external angles of lateral ventricles involving particularly the centrum semi ovale and optic and acoustic radiations, and diagnosed by magnetic resonance imaging (MRI) during hospital stay (Volpe 2008))

• IVH: severe grade III or IV during hospital stay (Papile 1978)

• ROP: stages III and IV during hospital stay (CCRP 1984)

• Use of inotropic agents, dopamine, epinephrine, or vasopressin during therapy with prostanoids or their analogues

• Length of hospital stay in days

• Duration of mechanical ventilation in days

Search methods for identification of studies

We used the criteria and standard methods of Cochrane and Cochrane Neonatal (see the Cochrane Neonatal search strategy for specialized register).

Electronic searches

We conducted a comprehensive search including Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), in the Cochrane Library; MEDLINE and PREMEDLINE via PubMed (1966 to 16 September 2018); Embase (1980 to 16 Septmeber 2018); and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 16 September 2018), using the following search terms: (pulmonary hypertension, refractory pulmonary hypertension, prostacyclin, PGI₂, prostaglandin I₂, epoprostenol, Flolan, iloprost, treprostinil, beraprost, neonate, and newborn), plus database‐specific limiters for randomized controlled trials (RCTs) and neonates (see Appendix 1 for the full search strategy for each database). We did not apply language restrictions.

We also searched abstracts of conference proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Paediatric Research) from 1990 in the Pediatric Research journal and Abstracts 2 View (2000 to 16 September 2018). We searched biological abstracts in the database BIOSIS and conference abstracts from Proceedings First (from 1992 to 16 September 2018).

We searched clinical trial registries for ongoing and recently completed trials (clinicaltrials.gov; the World Health Organization’s International Trials Registry and Platform; and the International Standard Randomized Controlled Trials Number (ISRCTN) Registry).

Searching other resources

We contacted trial authors who published in this field for possible unpublished studies. We performed additional searches from the reference lists of identified clinical trials and from the review authors' personal files.

Data collection and analysis

We used the standard methods of Cochrane Neonatal for conducting a systematic review (http://neonatal.cochrane.org/).

Selection of studies

Review authors (BS, SG, and MP) independently assessed the titles and abstracts of studies identified by the search strategy for eligibility for inclusion in this review. We resolved any differences by mutual discussion. We obtained a full‐text version of all available studies for quality assessment.

Data extraction and management

We used pre‐designed forms for determining trial inclusion and exclusion, for performing data extraction, and for requesting additional published information from authors of the original reports. Review authors independently performed data extraction by using specifically designed paper forms for identified eligible trials.

Assessment of risk of bias in included studies

Three review authors (BS, SG, and MP) would have independently assessed risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool for the following domains (Appendix 2) (Higgins 2011).

• Sequence generation (selection bias).

• Allocation concealment (selection bias).

• Blinding of participants and personnel (performance bias).

• Blinding of outcome assessment (detection bias).

• Incomplete outcome data (attrition bias).

• Selective reporting (reporting bias).

• Any other bias.

We planned to resolve any disagreements by discussion or by consultation with a third assessor. See Appendix 2 for a more detailed description of risk of bias for each domain. 

Measures of treatment effect

We did not identify any eligible studies for inclusion. If we had included trials, we planned to report risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. We would have calculated the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH) with 95% CIs if there was a statistically significant reduction or increase in RR.

If cross‐over trials were identified, and if neither carry‐over nor period effects were thought to be a problem, we planned to perform a paired t‐test for continuous data from a two‐period, two‐intervention cross‐over trial (Higgins 2011).

Unit of analysis issues

The unit of analysis is the participating infant in individually randomized trials, and the cluster (e.g. neonatal unit or subunit) in cluster‐randomized trials (Higgins 2011).

Dealing with missing data

We planned to contact the authors of published studies if clarifications were required, or to obtain additional information. In the case of missing data, we planned to describe the number of participants with missing data in the Results section and in the Characteristics of included studies table. We planned to present only results for available participants. We planned to discuss the implications of missing data in the discussion of the review.

Assessment of heterogeneity

If eligible trials are identified in our updated version, we plan to estimate the treatment effects of individual trials and to examine heterogeneity between trials by inspecting forest plots and by using the Chi² test, which assesses whether observed differences in results are compatible with chance alone (Higgins 2011). A low P value (< 0.1) (or a large Chi² statistic relative to its degree of freedom) provides evidence of heterogeneity of intervention effects (variation in effect estimates beyond chance). However the Chi² statistic has low power when meta‐analyzed studies have small sample sizes or are few in number. We will also quantify the impact of heterogeneity using the I² statistic (which incorporates the Chi² statistic). We will grade the degree of heterogeneity as none if less than 25%, low if between 25% and 49%, moderate if between 50% and 74%, and high if greater than 75%. If we detect statistical heterogeneity, we will explore possible causes (e.g. differences in study quality, participants, intervention regimens, or outcome assessments) using post‐hoc subgroup analyses. We planned to use a fixed‐effect model for meta‐analysis if we identify eligible trials for data synthesis.

Assessment of reporting biases

We planned to obtain study protocols of all included studies and to compare outcomes reported in the protocols versus those reported in the included studies and to investigate reporting and publication bias by examining the degree of asymmetry of a funnel plot if at least 10 studies were included in the meta‐analysis in our update. If we suspected reporting bias, we would have attempted to contact study authors to ask them to provide missing outcome data. If this was not possible, and missing data were thought to introduce serious bias, we would have explored the impact of including such studies in the overall assessment of results by performing sensitivity analyses.

Data synthesis

If we identified eligible trials, we planned to use Review Manager 5 software for statistical analysis and a fixed‐effect model for meta‐analysis (RevMan 2014). We would have performed statistical analyses according to Cochrane Neonatal recommendations. For cluster‐randomized trials, if analyzed appropriately at the level of the cluster, and if summary estimates were available, we planned to synthesise data using the generic inverse variance method. If summary estimates were unavailable, or if trials were not analyzed at the cluster level, we would have adjusted the sample size by using the intracluster coefficient (ICC) and design effect (approximate analyses) (Higgins 2011). We would have reported RR and RD (NNTH and NNTB if the RR value is significant) for dichotomous outcomes, and MD values for continuous outcomes ‐ all with 95% CIs.

Quality of the evidence

We planned to use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE Handbook for Grading Quality of Evidence and Strength of Recommendations, to assess the quality of evidence for the following (clinically relevant) outcomes (Schünemann 2013).

• "All‐cause mortality" at 28 days of life.

• Need for ECMO.

• Decrease in pulmonary arterial pressure (20% from baseline before start of therapy) as demonstrated by Echo or by cardiac catheterization.

• Adverse effects.

Three review authors (BS, SG, and MP) planned to independently assess the quality of evidence for each of the outcomes above. We planned to consider evidence from RCTs as high‐quality evidence but will downgrade the quality of evidence by one level for serious (or by two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of evidence, precision of estimates, and presence of publication bias.

The GRADE approach results in an assessment of the quality of a body of evidence to one of four grades.

• High quality: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate quality: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low quality: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect.

• Very low quality: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.

If we had identified eligible studies, we planned to use the GRADEpro Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of evidence (GRADEpro GDT 2015).

Subgroup analysis and investigation of heterogeneity

• Gestational age: term (≥ 37 completed weeks' gestation); extremely preterm (< 28 weeks); very preterm (28 to < 32 weeks); moderate to late preterm (32 to < 37 weeks)

• Birth weight: ≥ 2500 g; 1000 to 2499 g; < 1000 g

• Route of administration: Intravenous, subcutaneous, inhalation, enteral

• Patient subgroups based on etiology of PH: sepsis, meconium aspiration syndrome, perinatal asphyxia, lung hypoplasia, alveolar capillary dysplasia, drug‐induced PH (e.g. non‐steroidal anti inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs))

• Responsiveness to iNO (defined as improvement in saturation by 10 points from baseline before start of therapy): iNO‐responsive PH; iNO‐resistant PH

Sensitivity analysis

If eligible studies are identified in future updates, we will explore methodological heterogeneity through the use of sensitivity analyses by excluding studies with high risk of bias.

Results

Description of studies

We did not find any eligible RCTs for inclusion.

Results of the search

We identified one pilot study that used aerosolized iloprost for the treatment of PPHN in extremely preterm infants (Eifinger 2008), along with two pilot randomized multi‐centre phase 2 clinical trials (testing feasibility) that used inhaled PGE₁ and a re‐designed second pilot that coadministered inhaled PGE₁ and iNO (Sood 2014). None of these studies met our inclusion criteria. We excluded these studies because the first one was an observational study in preterm infants between 23 and 25 weeks’ gestation with weight < 1000 g, and the second study was an aggregate of two pilot studies. The first pilot failed to enrol a single patient in four months. The re‐designed second pilot study that coadministered inhaled PGE₁ and iNO was halted for recruitment futility after six months.

Included studies

We found no RCTs.

Excluded studies

We excluded the following studies because they were not completed RCTs. They were incomplete RCTs, case series, or cohort studies.

Sood 2014

The National Institute of Child Health and Human Development (NICHD) Neonatal Research Network conducted two pilot multi‐centre phase 2 RCTs. In the first pilot, late preterm and term infants with neonatal hypoxemic respiratory failure (NHRF) who were not exposed to iNO and had an oxygenation index (OI) between 15 and 25 were randomly assigned to receive two doses of inhaled PGE₁ or placebo. In the second pilot RCT, coadministration of inhaled PGE₁ and iNO was allowed. Infants refractory to iNO received either aerosolized saline or two different doses of PGE₁ for a maximum of 72 hours. We excluded the first pilot study because no infants were enrolled, and the second because it was discontinued for recruitment futility.

Ahmad 2018

Ahmad et al retrospectively reviewed the efficacy of intravenous PGI₂ in 36 PPHN neonates who were refractory to iNO therapy. In this case series without controls, results suggest that PGI₁ decreased oxygenation index (OI) within four hours and prevented death or ECMO. Most non‐responders had pulmonary hypoplasia.

Park 2017

Park and Chung in a case report without controls reported that intravenous treprostinil improved oxygenation within 12 hours for two preterm infants with sepsis who had PPHN refractory to iNO therapy.

Carpentier 2017

Carpentier and colleagues reported the safety and efficacy of subcutaneous treprostinil therapy in 14 term neonates with CDH and severe PH who were refractory to iNO and oral sildenafil therapies. In this case series without controls, treprostinil improved pulmonary blood flow in 12 infants.

Olson 2015

In a case report of short‐term treprostinil use in two term neonates with CDH, improved PPHN and decreased PVR were reported.

Yilmaz 2014

Yilmaz et al did a retrospective chart review assessing the safety and efficacy of inhaled iloprost for treatment of pulmonary hypertension in 15 preterm infants with respiratory distress syndrome and pulmonary hypertension refractory to surfactant and conventional mechanical ventilation. Gestational age and birth weight ranged between 25 and 37 weeks and 780 and 2360 g, respectively. Researchers excluded infants with OI < 25 and those who had congenital heart disease and major anomalies. This retrospective study without controls suggests that iloprost therapy may decrease OI, alveolar‐arterial oxygen difference, and pulmonary arterial pressure, and that it increased partial pressure of oxygen (PaO₂) and peripheral capillary oxygen saturation (SpO₂). No reported side effects are attributable to iloprost.

Nakwan 2011

Nakwan et al retrospectively reviewed the efficacy of enteral beraprost sodium (BPS) as therapy for PPHN in seven neonates who responded poorly to high‐frequency oscillatory ventilation and alkali therapy. This retrospective study suggests that beraprost therapy may have improved OI among included infants without significant adverse effects.

Eifinger 2008

Eifinger and coinvestigators evaluated the efficacy of aerosolised iloprost in four extremely low‐gestational‐age newborns (ELGAN) with PPHN who were spontaneously breathing with assistance from a nasal continuous positive airway. These 23 to 25 weeks’ gestation infants received 44 to 65 inhalations of iloprost at a dose of 2 mcg/kg, starting within the first hour of life for up to seven postnatal days. This small case series without controls suggests that inhaled iloprost may increase the PaO₂/fraction of inspired oxygen (FiO₂) ratio and may decrease oxygen requirements and pulmonary vascular resistance.

Shiyanagi 2008

Shivanagi et al retrospectively compared the efficacy of iNO alone versus iNO + PGE₁ for the management of pulmonary hypertension in 49 CDH patients. Although survival rates were similar in these two groups, surgical repair was performed earlier and the hospital stay was shorter in the iNO alone group than in the iNO + PGE₁ group.

Kelly 2002

A case series of four infants with PPHN suggests improvement in oxygenation with the use of inhaled PGI₂ among those who were refractory to iNO therapy.

Eronen 1997

In a case series without controls, Eronen et al reported the efficacy and safety of intravenous PGI₂ in eight late preterm and term neonates with PPHN. Researchers excluded infants with birth weight < 2500 g and those with congenital heart disease, sepsis, and diaphragmatic hernia. This case series suggests that PGI₂ therapy may decrease pulmonary arterial pressure and may improve oxygenation without the need for ECMO.

Risk of bias in included studies

No trials were included in this review.

Allocation

No trials were included in this review.

Blinding

No trials were included in this review.

Incomplete outcome data

No trials were included in this review.

Selective reporting

No trials were included in this review.

Other potential sources of bias

No trials were included in this review.

Effects of interventions

No trials were included in this review.

Discussion

Summary of main results

We did not find any eligible randomized or quasi‐randomized trials in neonates using prostanoids or their analogues for the treatment of pulmonary hypertension in neonates (PPHN). We also did not identify any ongoing neonatal trials that are potentially eligible for inclusion on completion. We identified one pilot study that was completed (Eifinger 2008), and we found two pilot multi‐centre phase 2 randomized controlled trials (Sood 2014). Effinger et al evaluated the effects of aerosolized iloprost for the treatment of PPHN in extremely preterm infants. The trial included only four extremely low birth weight (ELBW) infants and no term infants. Sood et al attempted to conduct two pilot multi‐centre phase 2 randomized controlled trials, and both were discontinued due to recruitment futility (Sood 2014).

Despite the critical nature of PPHN in neonates, a paucity of evidence‐based therapeutic interventions for this disorder remains. Prostanoids are metabolites of arachidonic acid and have other actions in addition to vasodilatation, including anti‐inflammatory and immunomodulatory effects. The multi‐modal functions of these compounds make them promising therapeutic agents for PPHN; however, they have not been evaluated in randomized clinical trials in neonates. This paucity of evidence needs to be addressed in well‐designed trials.

The major hurdle for the development of neonatal trials is the establishment of safety of these different formulations in neonates, especially in preterm and very low birth weight (VLBW) infants who are already at high risk of other morbidities such as bronchopulmonary dysplasia (BPD), cerebral palsy (CP), and developmental delay. Pilot studies establishing the safety and tolerability of these medications in neonates are paramount before large multi‐centre randomized trials are undertaken.

Overall completeness and applicability of evidence

No trials were included in this review.

Quality of the evidence

We could not assess evidence quality due to lack of eligible trials.

Potential biases in the review process

We used the standard methods of Cochrane Neonatal for conducting this systematic review. We strove to decrease biases in the review process. Two review authors performed literature searches using an inclusive search strategy and combined their results. Our search strategy did not identify any eligible trials for inclusion. We contacted investigators in this field and searched conference proceedings for eligible studies with no success.

Agreements and disagreements with other studies or reviews

We know of no other eligible studies or reviews.

Authors' conclusions

Implications for practice.

Currently, no evidence is available from randomized controlled trials for the use of prostanoids or their analogues as pulmonary vasodilators for the treatment of PPHN (age 28 days or less) as sole therapeutic agents. This review did not study evidence for infants beyond the neonatal period.

Implications for research.

This systematic review identified a gap in clinical knowledge that needs to be addressed, including the safety and efficacy of prostanoids and their analogues; their preparations and doses and routes of administration need to be established in neonates. Well‐designed, adequately powered, randomized multi‐centre trials are needed to address the efficacy and safety of prostanoids, their analogues in PPHN, and their effects on short‐term outcomes (e.g. mortality) and long‐term neurodevelopmental and pulmonary outcomes.

Appendices

Appendix 1. Search strategy

MEDLINE and PREMEDLINE:

1. explode 'pulmonary hypertension' [all subheadings in MIME, MJME]

2. 'refractory pulmonary hypertension'

3. #1 OR #2

4. 'prostacyclin' or PGI₂ or 'Prostaglandin I₂ [all subheadings in MIME, MJME]

5. 'epoprostenol or Flolan'

6. 'Ilioprost'

7. 'Treprostinil'

8. 'Beraprost'

9. #4 OR #5 OR #6 OR #7 OR #8

10. explode 'infant ‐ newborn' [all subheadings in MIME, MJME]

11. Neonat*

12. Newborn*

13. #10 or #11 or #12

14. #3 AND #9 AND #13

No language restrictions were applied.

Embase:

#1)'Pulmonary hypertension'/exp OR 'Pulmonary hypertension' #2) (PGI2 OR prostaglandin) AND I2 OR epoprostenol OR flolan OR Iloprost OR Beraprost OR Trepostinil , #3)Newborn OR Neonate# 4)#1 AND #2 AND #3

CINAHL:

S1) Pulmonary hypertension. S2) (MM "Pulmonary Arterial Hypertension") OR (MM "Hypertension, Pulmonary") OR (MM "Persistent Fetal Circulation Syndrome") OR "pulmonary hypertension", S3) (MH "Prostaglandins F, Synthetic+") OR (MH "Prostaglandins, Synthetic+") OR (MH "Prostaglandins+") OR (MH "Prostaglandins I+") OR (MM "Prostaglandins E+") OR (MM "Iloprost") OR (MM "Epoprostenol") OR "prostaglandin, PGI2, epoprostenol, flolan, iloprost, treprostinil, beraprost", S4) (MH "Infant, Newborn, Diseases+") OR (MH "Infant, Newborn+") OR "newborn, neonate", S4) ((MH "Infant, Newborn, Diseases+") OR (MH "Infant, Newborn+") OR "newborn, neonate") AND (S1 AND S2 AND S3 AND S4)

CENTRAL:

#1) Pulmonary hypertension, #2) Prostaglandin OR PGI2 OR epoprostenol OR iloprost OR treprostinil OR beraprost, #3) Newborn OR infant OR neonate,
 #4) #1 AND #2 AND #3

PubMed:

[(pulmonary hypertension OR refractory pulmonary hypertension OR PPHN OR persistent fetal circulation) AND (prostaglandin OR prostaglandin I2 OR PGI2 OR epoprostenol OR flolan OR treprostinil OR beraprost) AND (neonat* OR newborn OR infant‐newborn)]

Appendix 2. Risk of bias

We planned to use the standard methods of Cochrane and Cochrane Neonatal to assess the methodological quality of trials. For each trial, we planned to seek information regarding the method of randomisation, blinding, and reporting of all outcomes of all infants enrolled in the trial. We planned to asses each criterion as being at low, high, or unclear risk of bias. Two review authors separately planned to assess each study and to resolve any disagreements through discussion. We planned to add this information to the ‘Characteristics of included studies' table. We planned to evaluate the following issues and enter the findings into the ‘Risk of bias' table.

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we planned to categorize the method used to generate the allocation sequence as:

· low risk (any truly random process, e.g. random number table; computer random number generator);

· high risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

· unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we planned to categorize the method used to conceal the allocation sequence as:

· low risk (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);

· high risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

· unclear risk.

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we planned to categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We categorize the methods as:

· low risk, high risk, or unclear risk for participants; and

· low risk, high risk, or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we planned to categorize the methods used to blind outcome assessment. Blinding was to be assessed separately for different outcomes or classes of outcomes. We planned to categorize the methods as:

· low risk for outcome assessors;

· high risk for outcome assessors; or

· unclear risk for outcome assessors.

5. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?

For each included study and for each outcome, we planned to describe the completeness of data including attrition and exclusions from the analysis. We planned to note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we planned to re‐include missing data in the analyses. We planned to categorize the methods as:

· low risk (< 20% missing data);

· high risk (≥ 20% missing data); or

· unclear risk.

6. Selective reporting bias. Are reports of the study free of the suggestion of selective outcome reporting?

For each included study, we planned to describe how we investigated the possibility of selective outcome reporting bias and what we found. For studies for which study protocols were published in advance, we planned to compare pre‐specified outcomes versus outcomes eventually reported in the published results. If the study protocol was not published in advance, we planned to contact study authors to gain access to the study protocol. We planned to assess the methods as:

· low risk (when it is clear that all of the study's pre‐specified outcomes and all expected outcomes of interest to the review have been reported);

· high risk (when not all of the study's pre‐specified outcomes have been reported; when one or more reported primary outcomes were not pre‐specified outcomes of interest and are reported incompletely and so cannot be used; or when the study fails to include results of a key outcome that would have been expected to have been reported); or

· unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias?

For each included study, we planned to describe any important concerns we had about other possible sources of bias (e.g. whether a potential source of bias was related to the specific study design, whether the trial was stopped early due to some data‐dependent process). We planned to assess whether each study was free of other problems that could put it at risk of bias as:

· low risk;

· high risk; or

· unclear risk.

If needed, we planned to explore the impact of the level of bias by undertaking sensitivity analyses.

Characteristics of studies

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Ahmad 2018	Not a randomized controlled trial
Carpentier 2017	Not a randomized controlled trial
Eifinger 2008	Not a randomized controlled trial
Eronen 1997	Not a randomized controlled trial
Kelly 2002	Not a randomized controlled trial
Nakwan 2011	Not a randomized controlled trial
Olson 2015	Not a randomized controlled trial
Park 2017	Not a randomized controlled trial
Shiyanagi 2008	Not a randomized controlled trial
Sood 2014	No patients enrolled in the first pilot study, and the second pilot study was stopped due to recruitment futility
Yilmaz 2014	Not a randomized controlled trial

Differences between protocol and review

SG was included as an additional author based on her expertise in neonatal cardiovascular disease, including pulmonary hypertension.

Contributions of authors

BS, SG, and MP wrote the protocol.
 SW and KB commented on the protocol and incorporated comments.
 SG, BS, and MP performed the literature search and wrote the review.

Sources of support

Internal sources

• No sources of support supplied

External sources

• Vermont Oxford Network, USA.

  Cochrane Neonatal Reviews are produced with support from Vermont Oxford Network, a worldwide collaboration of health professionals dedicated to providing evidence‐based care of the highest quality for newborn infants and their families.

Declarations of interest

BS has no known conflicts of interest.
 SG has no known conflicts of interest.
 SW has no known conflicts of interest.
 KB has no known conflicts of interest.
 MP has no known conflicts of interest.

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