Loading ...

The use of sildenafil does not appear to reduce the risk for fetal hypoxia in women, according to results from a phase 3 randomized clinical trial published in JAMA.

Researchers have studied using sildenafil citrate, the active ingredient in Viagra, in people who are pregnant as a way to reduce adverse outcomes related to low oxygen during gestation, including fetal growth restriction. Animal studies have shown the medication, which dilates blood vessels in the placenta, can protect fetal heart development.

“I had this idea that if you administered a drug that preferentially dilated the blood vessels around the uterus, that it would then get more oxygen to the fetus,” said Sailesh Kumar, a professor of obstetrics and gynecology at The University of Queensland in Brisbane, Australia, and an author of the study. “We know many babies that suffer hypoxic issues or get distressed during labor because of loss of oxygen.”

In a smaller pilot study published in May 2020, the researchers found that women who took sildenafil during labor had substantially lower rates of assisted vaginal delivery with instruments like forceps. Based on the promising results of that single-site study, the researchers designed a trial that would test the use of sildenafil citrate for another use — preventing intrapartum hypoxia, a common issue during labor that can result in stillbirth.

The trial also tested whether giving sildenafil during labor could prevent other adverse outcomes for the infant, including seizures within a month of birth, needing respiratory support for more than 4 hours, brain damage, and death. Other outcomes analyzed were a neonatal unit stay of more than 48 hours, meconium aspiration syndrome, and persistent hypertension.

They recruited 3257 pregnant women at 13 hospitals throughout Australia who gave birth between 2021 and 2024.

Once participants went into labor, half the women were given 50 mg of oral sildenafil citrate every 8 hours, up to 150 mg. The other half took a placebo. The two groups had a similar rate of induction — 83.5% for the sildenafil group and 82.9% for the placebo group.

Babies born to the two groups of women had nearly identical outcomes overall — 5.2% of babies born to women in the placebo group had at least one of the primary adverse outcomes compared to 5.1% of those born to women in the treatment group. Rates in the two groups for other outcomes were also not different.

Taking sildenafil did not have any significant effect on emergency cesarean delivery or assisted vaginal birth necessary because of fetal distress (relative risk, 1.12; 95% CI, 0.98-1.29).

Sildenafil is used off-label to treat maternal pulmonary hypertension and preeclampsia, as well as pulmonary hypertension in newborns. The FDA has not officially approved the drug for use in pregnant women. Although some studies have shown the drug to be safe during pregnancy, the agency cited a lack of clinical trial data as its reasoning for not recommending it for pregnant women.

The FDA does not recommend sildenafil for use in newborns, and the drug is only approved to treat pulmonary hypertension in adults. However, a 2016 warning letter from the agency clarified that it could be beneficial in children in certain circumstances.

“Healthcare professionals must consider whether the benefits of treatment with the drug are likely to outweigh its potential risks for each patient,” the letter said.

Despite promising early research in animal models, the current study adds to a growing body of research showing the drug does not appear to prevent fetal hypoxia. Some studies indicated the drug showed promise in treating fetal growth restriction, which is caused by lack of oxygen during development of the fetus. However, a clinical trial in the Netherlands that tested the drug for this use was halted in 2018 after 11 infants in the study died.

The reason sildenafil does not appear to be helpful in mitigating issues related to hypoxia could be because while it does help deliver more oxygen to the placenta, the drug may weaken a fetus’ natural defenses, said Dino Giussani, MD, PhD, a professor of developmental cardiovascular physiology and medicine at the University of Cambridge in the Cambridge, England, who was not involved in the trial.

Contractions during labor constrict blood vessels that deliver oxygen to the placenta, which naturally cut off some of the oxygen flow to a fetus. In late gestation, fetuses develop strong defense mechanisms against hypoxia. Blood vessels in the extremities contract, forcing oxygenated blood to the fetus’ brain. But some babies still suffer a lack of oxygen to their brain, which can cause permanent damage.

“There was biological plausibility that sildenafil would increase blood flow to the placenta during pregnancy,” said Yalda Afshar, MD, PhD, an associate professor of obstetrics and gynecology at UCLA Health in Los Angeles, who was not involved in the new trial.

Giussani said he is researching antioxidants that may be able to combat oxidative stress during pregnancy without compromising a fetus’ defense mechanisms against hypoxia.

If such a drug is found, “that’s the holy grail,” he said.

Kumar said one of the biggest wins and takeaways for the research community is that they were able to recruit more than 3000 pregnant women for a pharmacological trial. Afshar said these large, randomized control trials protect people who are pregnant.

“They don’t need to get care based on what small studies have found or hunches about what might work,” she said.

This study was funded by the Australian National Health and Medical Research Council Future Fund. Kumar reported receiving grants from the NHMRC. Other authors reported receiving consultancy fees, travel support, and grants from Merck KGaA, Ferring, Roche, Bristol Myers Squibb, among others.

Kaitlin Sullivna is a freelance journalist.