Which Medicine Works Best to Close an Open Heart Vessel in Very Premature Babies?

A Canadian study by Mitra and colleagues (JAMA Network Open, 2026) compared four common treatment options, and babies who received none, in 19 neonatal units

Many babies born very early have an open blood vessel near the heart, called a patent ductus arteriosus, and doctors sometimes give medicine to close it. A Canadian study of 1356 babies born before 29 weeks found that four common treatment options (three medicines, one of them given at two doses) worked about equally well, and that about 4 in every 10 treated babies needed more treatment after the first course. Whether giving these medicines helps babies survive is still uncertain.

Why this small blood vessel causes so much discussion

The ductus arteriosus is a short blood vessel near the heart that normally closes soon after birth. In babies born very early, it can stay open. Doctors call this a patent ductus arteriosus, or PDA ("patent" simply means open). A large open PDA can send extra blood to the lungs. The big question, and the reason this research matters to families, is whether closing it with medicine actually helps the baby or simply exposes them to a drug without real benefit. A large Canadian study, led by Dr. Mitra and colleagues, set out to answer part of that question using information from everyday hospital care [1].

How doctors have handled an open duct over the years

The PDA is the most common heart and circulation problem in extremely premature babies, and for many years the usual answer was a medicine called indomethacin [1][2]. Even so, a 2016 report from the American Academy of Pediatrics described ongoing "uncertainty and controversy" about how important the PDA really is and how to manage it, which meant that different hospitals did very different things [2]. Researchers noticed that closing the duct had not clearly reduced the problems doctors worried about most, such as bleeding in the brain, long-term lung disease and a serious bowel illness [3], and many units began to take a more watchful, "wait and see" approach [4]. Over time a related medicine, ibuprofen, became the favourite because trials found it closed the duct as often as indomethacin with fewer bowel and kidney side effects, as a large review later confirmed [5]. Some studies suggested that higher doses of ibuprofen closed the duct more often [5][6], and a third medicine, acetaminophen (also called paracetamol, the same medicine used for fever), was added to the options [1]. Then, in recent years, careful trials began asking whether treatment was needed at all. The BeNeDuctus trial, run by doctors in the Netherlands, Belgium and Denmark, found that waiting was not worse than giving ibuprofen early, and babies who waited had less long-term lung disease [7]. The Outcome after Selective early treatment for Closure of patent ductus ARteriosus in preterm babies (Baby-OSCAR) trial, in 32 neonatal units in the United Kingdom, found no benefit from early ibuprofen [8]. A 2025 review of all such trials concluded that early treatment probably makes little difference to survival overall, and raised a concern that very early ibuprofen might moderately increase the risk of death in the most premature babies [9]. You can read more in our article on the Baby-OSCAR trial. What nobody knew was how the different medicines compared when used in ordinary hospital care, across a whole country.

How the Canadian study worked

The study took place in 19 large neonatal intensive care units (NICUs) across Canada that belong to the Canadian Neonatal Network, between January 2020 and July 2023 [1]. It included 1356 babies born before 29 weeks of pregnancy, on average at about 25 and a half weeks and weighing about 828 grams (just under 2 pounds). Every baby had a heart ultrasound, called an echocardiogram, showing a moderate or large PDA.

This was an observational study. That means doctors cared for babies as they normally would, and researchers recorded what happened; nobody was assigned a medicine by chance, as in a randomized trial. Before the study began, each hospital chose its usual first medicine: ibuprofen at the standard dose, ibuprofen at a higher dose, indomethacin or acetaminophen. In the end, 1097 babies (about 8 in 10) received medicine and 259 (about 2 in 10) did not.

Real life did not quite follow the plan. In about 28 of every 100 treated babies, the medicine given was not the hospital's chosen one, usually because the team used acetaminophen instead. The researchers therefore compared babies by the medicine they actually received. They also compared treated babies with untreated babies, using statistical methods to account for differences between them.

What the researchers found

The first course of medicine did not do the job in 464 of the 1097 treated babies, which is about 42 out of every 100 [1]. These babies needed a second course of medicine or a procedure to close the vessel. Importantly, this rate was about the same for all four treatment options once differences between babies and hospitals were taken into account. No medicine stood out as better than standard-dose ibuprofen. Only about 4 in 100 treated babies needed a procedure to close the vessel.

When the researchers compared treated with untreated babies, treated babies more often developed long-term lung disease, called bronchopulmonary dysplasia: about 55 in every 100 treated babies compared with about 32 in every 100 untreated babies. Treated babies also more often developed a serious bowel illness called necrotizing enterocolitis (about 12 vs 6 in every 100). Survival to going home was similar in both groups before any adjustment: about 15 in every 100 babies died in each group. One of the statistical methods suggested treated babies had a lower chance of dying, but the main method and a further check did not confirm this, so it remains uncertain.

The study also found that babies given acetaminophen had a somewhat higher chance of dying in the main analysis and one other check, but not in several other analyses. The authors caution that acetaminophen may sometimes have been chosen because the other medicines seemed unsafe for a particular baby, so sicker babies may have been the ones who received it, and they did not record all the reasons behind that choice [1]. A large American study had seen a similar pattern [10]. Indomethacin seemed to do surprisingly well on some measures, but it was used at only one hospital, and the authors themselves describe those results as "implausible", meaning unlikely to be real.

On side effects, the researchers reported no differences between the medicines in blood tests of kidney function or bilirubin (the substance that causes jaundice) [1]. Liver blood tests were checked only in babies receiving acetaminophen, so the study could not compare the medicines on that measure. Two other problems the researchers had planned to look at, serious bleeding in the brain and kidney injury, were not reported in the published paper.

What these results mean for your baby

The most important point for parents is that there does not seem to be a "best" medicine to close a PDA. If your baby's team prefers ibuprofen, indomethacin or acetaminophen, that choice is unlikely, on its own, to change how well the treatment works. It is also normal for a first course not to be enough; that happened to about 4 in 10 babies in this study.

It is natural to read "treated babies had more lung disease" and worry. But the babies who were not treated were, on average, born a little later, were bigger, had smaller open vessels and needed less help with breathing. Doctors tend to treat the babies who seem sickest, and those babies are already more likely to develop lung disease. This study cannot tell whether the medicine caused any of the difference. A large international study of 139 neonatal units in 6 countries has also found that babies in hospitals that treated either very few or very many PDAs had worse outcomes than babies in hospitals taking a middle path [11].

Hospitals also differ in their written rules for when and how to treat a PDA, as our article on differences between hospital PDA guidelines describes, so it is reasonable to ask how your unit decides. Good questions to ask your baby's team include: how large is the open vessel, how is it affecting breathing, why are they recommending treatment or waiting, which medicine they use and why, and how they will check whether it worked.

What researchers are working on next

The authors suggest the next step is not finding a better medicine but finding the right babies to treat [1]. They hope to use blood tests, more detailed heart ultrasound patterns, how each baby processes a medicine, and genetic information to predict which babies are most likely to be harmed by an open PDA and which are most likely to respond. New trials are also testing when, and whether, to treat; our article on two 2026 trials that reframe PDA care explains them in plain terms. An earlier trial, run at 17 hospitals in the United States, Turkey, Sweden and the United Kingdom, had already shown that routinely treating babies at about one week of age did not reduce the need for later procedures or the chance of the vessel still being open at discharge [12], and the Canadian results point in the same direction.

The bottom line

In 19 Canadian neonatal units, the four common treatment options for an open PDA worked about equally well, and the first course was not enough for about 4 in every 10 treated babies. Treated babies had more lung disease, but because the sickest babies are the ones most often treated, this does not prove the medicine caused it. Whether treatment helps babies survive remains an open question, and researchers are now focusing on choosing the right baby, at the right time, rather than the right drug.

References

  1. Mitra S, Jain A, Ting JY, et al. Pharmacologic Therapies for Patent Ductus Arteriosus in Extremely Preterm Infants. JAMA Netw Open. 2026;9(6):e2617477. doi:10.1001/jamanetworkopen.2026.17477 ↩
  2. Benitz WE. Patent Ductus Arteriosus in Preterm Infants. Pediatrics. 2016;137(1):e20153730. doi:10.1542/peds.2015-3730 ↩
  3. Jain A, Shah PS. Diagnosis, Evaluation, and Management of Patent Ductus Arteriosus in Preterm Neonates. JAMA Pediatr. 2015;169(9):863-872. doi:10.1001/jamapediatrics.2015.0987 ↩
  4. Mitra S, Rønnestad A, Holmstrøm H. Management of patent ductus arteriosus in preterm infants--where do we stand? Congenit Heart Dis. 2013;8(6):500-512. doi:10.1111/chd.12143 ↩
  5. Ohlsson A, Walia R, Shah SS. Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants. Cochrane Database Syst Rev. 2020;2(2):CD003481. doi:10.1002/14651858.CD003481.pub8 ↩
  6. Mitra S, Florez ID, Tamayo ME, et al. Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis. JAMA. 2018;319(12):1221-1238. doi:10.1001/jama.2018.1896 ↩
  7. Hundscheid T, Onland W, Kooi EMW, et al. Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus. N Engl J Med. 2023;388(11):980-990. doi:10.1056/NEJMoa2207418 ↩
  8. Gupta S, Subhedar NV, Bell JL, et al. Trial of Selective Early Treatment of Patent Ductus Arteriosus with Ibuprofen. N Engl J Med. 2024;390(4):314-325. doi:10.1056/NEJMoa2305582 ↩
  9. Mitra S, Scrivens A, Fiander M, Disher T, Weisz DE. Early treatment versus expectant management of hemodynamically significant patent ductus arteriosus for preterm infants. Cochrane Database Syst Rev. 2025;6(6):CD013278. doi:10.1002/14651858.CD013278.pub3 ↩
  10. Jensen EA, DeMauro SB, Rysavy MA, et al. Acetaminophen for Patent Ductus Arteriosus and Risk of Mortality and Pulmonary Morbidity. Pediatrics. 2024;154(2):e2023065056. doi:10.1542/peds.2023-065056 ↩
  11. Isayama T, Kusuda S, Reichman B, et al. Neonatal Intensive Care Unit-Level Patent Ductus Arteriosus Treatment Rates and Outcomes in Infants Born Extremely Preterm. J Pediatr. 2020;220:34-39.e5. doi:10.1016/j.jpeds.2020.01.069 ↩
  12. Clyman RI, Liebowitz M, Kaempf J, et al. PDA-TOLERATE Trial: An Exploratory Randomized Controlled Trial of Treatment of Moderate-to-Large Patent Ductus Arteriosus at 1 Week of Age. J Pediatr. 2019;205:41-48.e6. doi:10.1016/j.jpeds.2018.09.012 ↩