Is Sildenafil Safe for Very Premature Babies with Serious Lung Disease?

What families can take from the SILDI-SAFE trial by Jackson and colleagues (J Pediatr 2026), which tested a widely used lung blood-vessel medicine in premature babies

Many very premature babies with long-term lung disease are given sildenafil, a medicine that relaxes the blood vessels in the lungs, even though it had not been tested in a large, carefully controlled trial in these babies. A careful study in 30 American hospitals has now found that, given by mouth or feeding tube, it did not increase dangerous drops in blood pressure or serious eye disease. Whether it actually prevents lung blood-pressure problems still needs a larger study.

Why some premature babies need help with their lungs for so long

Babies born very early, months before their due date, often need help breathing for weeks. Some go on to develop bronchopulmonary dysplasia, usually shortened to BPD. BPD is a chronic lung disease of prematurity: the tiny, still-developing lungs are injured and heal slowly, so the baby keeps needing extra oxygen or a breathing machine long after birth. The researchers behind the new study point out that BPD affects nearly half of babies born extremely early [1][2]. Doctors grade BPD by how much breathing support a baby needs at around the time they would have been 36 weeks along in pregnancy, and babies still on a breathing machine at that point face the toughest road [3].

In some babies with BPD, the blood vessels in the lungs also become narrow and stiff. This is called pulmonary hypertension, which simply means high blood pressure inside the lungs (it is different from the blood pressure measured on the arm). It makes the right side of the heart work harder. Studies over many years have shown that this complication is fairly common in babies with BPD and makes their illness more serious [4][5][6]. The study team estimates that about 1 in 5 babies with severe BPD develop it, and that up to 4 in 10 of those babies die, usually because the heart becomes overworked [1].

How a medicine came into use before it was fully tested

Sildenafil works by helping the blood vessels in the lungs relax and widen [1]. Experiments in young laboratory animals with oxygen-damaged lungs suggested it might also help the lungs grow more normally [7]. Doctors began giving sildenafil "off-label" to premature babies with BPD, mainly to treat high blood pressure in the lungs [1]. Off-label means that the medicine is used outside its official approval: in the United States, sildenafil is not approved for babies younger than 1 year or for this lung condition [1]. Its use in newborn intensive care units grew steadily: across more than 300 units, none of 35 977 babies received it in 2001, but 151 of 90 544 did in 2016, and 95 in every 100 of the very premature babies who received it had BPD [8]. Expert guidelines on high lung blood pressure in children exist [9], but no large, carefully controlled trial had shown whether sildenafil was safe for these particular babies.

Doctors had a few specific worries. When sildenafil was given into a vein to newborns born closer to term with a different lung blood-pressure problem, low blood pressure in the body was a common side effect [10]. An earlier small study by the same research team found one serious drop in blood pressure in a premature baby when a vein dose was given too quickly [11]. Given by mouth, the medicine seemed gentler on blood pressure [12][13]. There were also concerns about the eyes: premature babies can develop retinopathy of prematurity, or ROP, an eye condition in which blood vessels at the back of the eye grow abnormally. A report of one baby who developed severe ROP after sildenafil raised alarm [14], although later studies of larger groups mostly did not find a link [15][16]. Finally, in adults, hearing problems had occasionally been reported in people taking this type of medicine [17].

How the study was done

The SILDI-SAFE trial (its full title is Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia) took place in 30 newborn intensive care units across the United States between 2021 and 2024, and was paid for by the US National Heart, Lung, and Blood Institute [1]. It included babies born before 29 weeks of pregnancy who, weeks or months later, still needed a breathing machine or strong breathing support through the nose. Babies who already had high lung blood pressure were not included, since the study focused on babies at risk of developing it.

Babies were placed by chance into groups. For every baby who received a dummy medicine (a placebo), three received sildenafil. Neither the families nor the doctors and nurses knew which one a baby was getting, which helps keep the results fair. The study started with a low dose; only after an independent safety committee had reviewed the results did the next group of babies receive a higher dose, and then a higher one again. Each baby got the medicine three times a day for 28 days, building up slowly to the target dose. The main thing the researchers watched for was low blood pressure serious enough that doctors needed to treat it, for example with extra fluid or blood-pressure medicines [1].

What the researchers found

In total, 122 babies received at least one dose: 92 got sildenafil and 30 got the placebo. Typically they had been born at about 25 weeks of pregnancy, and they started the study medicine when they were roughly 11 to 13 weeks old. Almost all the babies on sildenafil, 87 of 92, received it only by mouth or feeding tube [1].

Low blood pressure needing treatment happened in just 1 of the 92 babies on sildenafil and none of the 30 on placebo. That one baby received a heart-supporting medicine around the time of an operation, and the doctors judged that sildenafil was not the cause; the baby carried on with the study medicine. Serious side effects of any kind happened in about 8 in 100 babies on sildenafil and about 13 in 100 on placebo. Eye disease (ROP) serious enough to need treatment occurred in 16 of 92 babies on sildenafil and 9 of 30 on placebo, so sildenafil did not appear to make ROP worse [1].

A few things were slightly more common with sildenafil, though the numbers were small. Abnormal hearing test results occurred in 7 of 92 babies on sildenafil and 2 of 30 on placebo, and in 4 of the 32 babies on the highest dose. A type of jaundice (yellowing caused by a liver-related form of bilirubin) occurred in 4 of 92 versus 1 of 30, and raised liver blood tests in 3 of 92 versus none. The liver changes were temporary, and by the end of the study the levels were below the limit that would have kept a baby out of the trial [1].

The researchers also looked, as a first glimpse, at whether sildenafil might prevent high lung blood pressure. Among babies who did not have it at the start, it developed in 3 of 75 babies on sildenafil and 4 of 25 on placebo. That is encouraging, but the study was too small to tell whether this was a real effect or chance, and the researchers say clearly that no conclusion about benefit can be drawn [1].

What this means for your baby

If your baby has severe BPD and the medical team suggests sildenafil by mouth or tube, this study offers real reassurance that the medicine, given carefully, did not increase dangerous drops in blood pressure or serious eye disease. Because hearing and liver test changes were slightly more common, it is reasonable to ask whether your baby's hearing test and liver blood tests will be checked. It is also fair to ask why the team is recommending sildenafil, since this study did not prove that it prevents lung blood-pressure problems. Almost all the babies received the medicine by mouth or tube, so the findings say less about sildenafil given into a vein.

Every trial has limits. This one included 122 babies, which is enough to spot common problems but not rare ones, and it did not follow the babies' development after they went home. The babies studied did not yet have high lung blood pressure, so the results do not directly apply to babies already being treated for it [1].

What researchers are working on next

The study team says a larger trial is now needed to find out whether sildenafil can actually prevent high lung blood pressure in babies with BPD, while continuing to watch hearing and liver health closely [1]. Finding medicines that protect premature babies' lungs remains an active area of research, and the evidence for most options is still uncertain [18]. If you would like to learn more about lung blood-pressure problems in BPD, you can read our article on pulmonary hypertension in BPD.

The bottom line

For very premature babies with severe lung disease, sildenafil given by mouth or feeding tube appeared safe in this carefully run study: low blood pressure was rare and serious eye disease was not increased. Small changes in hearing and liver tests are worth keeping an eye on. Whether sildenafil truly helps prevent high lung blood pressure is the question the next, larger study will need to answer.

References

  1. Jackson WM, Foote HP, Stephenson N, et al. Safety of Sildenafil in Premature Infants with Severe Bronchopulmonary Dysplasia (SILDI-SAFE): A Randomized Controlled Trial. J Pediatr. 2026;295:115147. doi:10.1016/j.jpeds.2026.115147 ↩
  2. Bell EF, Hintz SR, Hansen NI, et al. Mortality, In-Hospital Morbidity, Care Practices, and 2-Year Outcomes for Extremely Preterm Infants in the US, 2013-2018. JAMA. 2022;327(3):248-263. doi:10.1001/jama.2021.23580 ↩
  3. Jensen EA, Dysart K, Gantz MG, et al. The Diagnosis of Bronchopulmonary Dysplasia in Very Preterm Infants. An Evidence-based Approach. Am J Respir Crit Care Med. 2019;200(6):751-759. doi:10.1164/rccm.201812-2348OC ↩
  4. Mourani PM, Sontag MK, Younoszai A, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;191(1):87-95. doi:10.1164/rccm.201409-1594OC ↩
  5. Khemani E, McElhinney DB, Rhein L, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics. 2007;120(6):1260-1269. doi:10.1542/peds.2007-0971 ↩
  6. Kim DH, Kim HS, Choi CW, Kim EK, Kim BI, Choi JH. Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. Neonatology. 2012;101(1):40-46. doi:10.1159/000327891 ↩
  7. Ladha F, Bonnet S, Eaton F, Hashimoto K, Korbutt G, Thébaud B. Sildenafil improves alveolar growth and pulmonary hypertension in hyperoxia-induced lung injury. Am J Respir Crit Care Med. 2005;172(6):750-756. doi:10.1164/rccm.200503-510OC ↩
  8. Thompson EJ, Perez K, Hornik CP, Smith PB, Clark RH, Laughon M. Sildenafil Exposure in the Neonatal Intensive Care Unit. Am J Perinatol. 2019;36(3):262-267. doi:10.1055/s-0038-1667378 ↩
  9. Abman SH, Hansmann G, Archer SL, et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015;132(21):2037-2099. doi:10.1161/CIR.0000000000000329 ↩
  10. Pierce CM, Zhang MH, Jonsson B, et al. Efficacy and Safety of IV Sildenafil in the Treatment of Newborn Infants with, or at Risk of, Persistent Pulmonary Hypertension of the Newborn (PPHN): A Multicenter, Randomized, Placebo-Controlled Trial. J Pediatr. 2021;237:154-161.e3. doi:10.1016/j.jpeds.2021.05.051 ↩
  11. Jackson W, Gonzalez D, Smith PB, et al. Safety of sildenafil in extremely premature infants: a phase I trial. J Perinatol. 2022;42(1):31-36. doi:10.1038/s41372-021-01261-w ↩
  12. Hornik CP, Onufrak NJ, Smith PB, et al. Association between oral sildenafil dosing, predicted exposure, and systemic hypotension in hospitalised infants. Cardiol Young. 2018;28(1):85-92. doi:10.1017/S1047951117001639 ↩
  13. Chetan C, Suryawanshi P, Patnaik S, et al. Oral versus intravenous sildenafil for pulmonary hypertension in neonates: a randomized trial. BMC Pediatr. 2022;22(1):311. doi:10.1186/s12887-022-03366-3 ↩
  14. Marsh CS, Marden B, Newsom R. Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. Br J Ophthalmol. 2004;88(2):306-307. doi:10.1136/bjo.2003.021956 ↩
  15. Fang AY, Guy KJ, König K. The effect of sildenafil on retinopathy of prematurity in very preterm infants. J Perinatol. 2013;33(3):218-221. doi:10.1038/jp.2012.84 ↩
  16. Samiee-Zafarghandy S, van den Anker JN, Laughon MM, Clark RH, Smith PB, Hornik CP. Sildenafil and retinopathy of prematurity risk in very low birth weight infants. J Perinatol. 2016;36(2):137-140. doi:10.1038/jp.2015.126 ↩
  17. Khan AS, Sheikh Z, Khan S, Dwivedi R, Benjamin E. Viagra deafness--sensorineural hearing loss and phosphodiesterase-5 inhibitors. Laryngoscope. 2011;121(5):1049-1054. doi:10.1002/lary.21450 ↩
  18. Zhao R, Guo W. Efficacy of pharmacologic therapies for reducing bronchopulmonary dysplasia and mortality in preterm infants: a network meta-analysis. BMC Pediatr. 2026;26(1):782. doi:10.1186/s12887-026-07408-y ↩