Sildenafil in Term and Premature Infants: A Systematic Review

Purpose: Numerous medications are used off-label in term and premature infants, with limited safety or efficacy data. Although sildenafil is approved by the US Food and Drug Administration for the treatment of pulmonary hypertension in adults, it is not approved for use in children. However, sildenafil use in term and premature infants with pulmonary hypertension is increasing. The goal of this study was to review controlled trials evaluating the efficacy of sildenafil use in: (1) term infants with pulmonary hypertension; (2) premature infants at risk for developing bronchopulmonary dysplasia (BPD); and (3) premature infants with BPD-associated pulmonary hypertension.

Methods: MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and International Pharmaceutical Abstracts databases were searched for citations related to sildenafil use in term or near-term infants with pulmonary hypertension or premature infants at risk for BPD or with BPD-associated pulmonary hypertension. Randomized and nonrandomized controlled trials were searched for that evaluated sildenafil use in term and premature infants compared with placebo or inhaled nitric oxide alone. Included studies were limited to English or Spanish language. Risk of bias was determined by using the Cochrane risk of bias tool.

Findings: Five trials (4 full-text articles and 1 abstract) of the 802 screened citations met the criteria for inclusion. All 5 trials were randomized controlled trials; the largest had 51 participants. Four of the trials (with a total of 137 subjects) evaluated the use of sildenafil versus placebo for term or near-term infants with persistent pulmonary hypertension of the newborn in low-resource settings in which inhaled nitric oxide was unavailable; there were no trials of sildenafil in areas in which inhaled nitric oxide is routinely available. The trials showed improvements in oxygenation index and a reduction in mortality in the sildenafil groups (5.9% vs 44%). One trial evaluated early sildenafil use (after day 7 of life) in premature infants for the prevention of BPD (n = 20). More premature infants in the sildenafil group died, were exposed to postnatal steroids, and had higher right-sided ventricular pressures later during hospitalization; these differences were not statistically significant. No trials evaluated sildenafil versus placebo in premature infants with BPD-associated pulmonary hypertension.

Implications: There is currently little evidence to support the use of sildenafil in term or near-term infants with persistent pulmonary hypertension of the newborn in areas in which inhaled nitric oxide is available. More data are needed to determine the effectiveness and dosing of sildenafil in improving outcomes for term and premature infants. Sildenafil dosing and safety studies are needed, especially among premature infants, before efficacy trials are performed.