Clinical trial on sildenafil may have caused harm to growth restricted babies

One of the hardest things to hear when something is wrong during a pregnancy is that nothing can be done to help your baby. While researchers are actively evaluating potential treatments to improve fetal growth in pregnancies complicated by intrauterine growth restriction (IUGR), there are still no effective treatments.

One potential treatment under investigation is sildenafil. Sildenafil is the generic formulation of Viagra and works by dilating blood vessels. In pregnancies complicated by IUGR, sildenafil may dilate the blood vessels of the uterus and placenta and deliver more nutrients and oxygen to the fetus. Results of using sildenafil in animal studies has been mixed, with some studies showing improved fetal growth and other studies showing no difference.

Early case studies and small clinical trials of using sildenafil in human pregnancies complicated by IUGR showed some promise. One small clinical trial published in the British Journal of Obstetrics and Gynecology in 2011 showed that in severe IUGR sildenafil increased babies’ growth. Another small clinical trial published in Ultrasound in Obstetrics & Gynecology in 2016 showed that sildenafil increased blood flow to the placenta and the fetus. More recently, a clinical trial published in the Taiwanese Journal of Obstetrics and Gynecology in 2018 showed that when sildenafil was given to women pregnant with growth restricted babies, the babies had improved growth. None of these studies showed that sildenafil caused harm to either the mother or the baby. Due to the promising results of these and other small studies, larger clinical trials using sildenafil to improve IUGR were started.

A recent international group of investigators started the STRIDOR collaboration, which is designed to evaluate the potential benefits of giving sildenafil to pregnant women whose babies were affected by severe IUGR early in pregnancy. The severe IUGR pregnancies were selected for this collaboration because these babies are at highest risk of dying, and therefore the potential benefit of an intervention with sildenafil is greater. The first two studies completed from the STRIDOR collaboration were in the United Kingdom, New Zealand, and Australia. The UK trial results have been published. The UK trial included 135 pregnant mothers and showed no benefit of using sildenafil to prolong pregnancy, improve survival of the baby, or improve blood flow to the placenta. The UK trial also showed no harmful effects of giving sildenafil to pregnant women. While the trial from New Zealand and Australia has not been published yet, 122 pregnant women were included in the study and no harmful effects of using sildenafil were identified. Long-term follow-up of the children involved in these studies is planned, but the results are not available at this time.

Another trial in the STRIDOR collaboration took place in Amsterdam. The Dutch STRIDOR trial was recently stopped before finishing enrollment of the goal number of patients. Before being stopped, 93 women were given sildenafil and 90 were given a placebo, which is a control pill that did not contain sildenafil. The trial was stopped early because there was a concern that more babies were dying in the group of mothers who were taking sildenafil. 11 babies died after their mothers took sildenafil, and 3 babies died after their mothers took a placebo. It is not clear whether the increased deaths were caused by sildenafil. The results of the Dutch trial have not been published yet, but the data is undergoing intense scrutiny by researchers directly involved in the STRIDOR collaboration, independent researchers, and a data safety monitoring board. In the meantime, the Canada STRIDOR trial has been put on hold pending the results of the evaluation of the Dutch STRIDOR trial results.

The loss of any baby is tragic, even more so when the loss may have been prevented. We do not know why the Dutch STRIDOR showed increased deaths of babies when the earlier small trials of sildenafil and the first two STRIDOR trials did not show harm to either the mother or baby. It is important to remember that the researchers in the STRIDOR trials did not think that sildenafil would harm either the mother or the baby.

Clinical trials are the way that we discover and test new therapies. Every clinical trial must be approved by an institutional review board (IRB) before patients can be enrolled. The IRB scrutinizes the clinical trial very closely and makes sure that all possible known risks and benefits are disclosed to the potential study patients. When patients are enrolled, a data safety monitoring board closely follows the clinical trial, and as in the case of the Dutch STRIDOR trial, stops the trial if there is concern that the study therapy may be causing harm. On the other hand, the data safety monitoring board also stops the trial early if the study therapy may be vastly better than the placebo, so that all patients can benefit from the study therapy. Transparency and open discussion about the risks and benefits of participating in clinical trials is critical for people to feel comfortable participating in a clinical trial. Each person will need to weigh the risks and possible benefits about participation in a specific clinical trial and decide what is right for him or her.

Ongoing research is underway to develop other interventions to improve blood flow to the placenta and increase growth of growth restricted fetuses. Hopefully we will soon have effective therapies to help our small but mighty babies before they are born.