AMSTERDAM- When the gynecologist Wessel Ganzevoort received a request for an urgent meeting from the independent committee last week, he thought it was one good news.
Ganzevoort is conducting a study to find out if sildenafil sold under the brand name Viagra could help poorly-growing fetuses when given to their pregnant mothers; The drug dilates the blood vessels and could theoretically bring more oxygen and nutrients to fetuses. However, a Data and Security Surveillance Committee had looked at the bared evidence in the middle of the study and wanted to speak. Ganzevoort, who works at the Amsterdam University Medical Center (AUMC), knew this was probably one of two things: either the drug worked so well that half of the mothers in the study would continue to be given a placebo because sildenafil had serious complications caused. Since previous studies had not shown any major side effects, Ganzevoort expected the former.
He was wrong. At the meeting on July 19, the committee informed him that a very specific complication, persistent pulmonary hypertension, in which the blood vessels in the baby's lungs did not open after birth, had appeared 17 times in the sildenafil-treated group , which led to 11 deaths. There were only three cases of the disease in the placebo group and no deaths. (Altogether, there were 19 deaths in the treatment group versus nine in the placebo group – the latter was no surprise as all fetuses were at high risk for their poor growth.) "It took very little time to make that decision to stop the study "says Ganzevoort. The same day, he and his colleagues called the women who had taken part in the study, including several who are still pregnant or whose babies are in the hospital.
Researchers at the University of British Columbia in Vancouver, Canada, have stopped a similar study until a thorough investigation of what happened in the Netherlands has taken place. But the sudden shutdown is likely to mark the end of the road for what many consider a promising therapeutic approach, says AUMC gynecologist Ben Willem Mol, who co-initiated the study.
"Fetal growth restriction" is caused by a lack of blood flow from the placenta to the unborn child, leading to malnutrition and stunted growth and development. It can lead to stillbirth or the death of newborns, and babies who survive still have a higher risk of infection and often suffer from long-term problems such as obesity and cardiovascular disease. Growth restriction is diagnosed by ultrasound, but now the only medical treatment is to closely monitor the pregnancy and induce childbirth if the risk of stillbirth is considered high. For physicians, this presents a difficult dilemma: premature delivery increases the risk of complications, but prolonged delays can lead to developmental abnormalities or stillbirths.
Increasing placental blood flow could drive fetal growth, and more and more doctors around the world are prescribing sildenafil to pregnant women whose fetuses suffer from growth disorders. Viagra has been known to expand some blood vessels, including those in the penis – making it a blockbuster of erectile dysfunction – and a number of animal studies and small human studies have suggested that the drug could benefit unborn children. However, for such use in pregnant women, it is not approved by any regulatory authority, so it is used by doctors in an off-label method.
Ganzevoort and a number of other experts in obstetrics wanted to consolidate the evidence on the subject. In 2012, they launched an initiative to conduct five separate but very similar studies that culminated in a meta-analysis.
The studies started in 2015, and even before the dramatic decision of last week, the results have been disappointing so far. A study by a team in the UK published online in The Lancet Child & Adolescent Health in December 2017 showed that sildenafil did not improve pregnancy duration, birth weight or fetal and neonatal survival. The team did not observe any adverse effects of the drug, except for a decrease in blood flow from the placenta to the fetus through a shunt between the placenta and the fetus, called the ductus venosus. "This was an unexpected result and it was the first evidence of a potential adverse effect of treatment," says Gordon Smith of the University of Cambridge in the UK, who was not involved in the study.
The New Zealand team, whose findings from a similar study were recently unveiled, also found no benefits, but saw no complications, says study director Katie Groom from the University of Auckland in New Zealand. A process in Ireland still needs to be started; Researchers in this study did not respond to emails today, but Mol expects them to fail.
The Dutch team has kept hope for a more positive outcome until last week's call. "There were no signs of serious damage, so we continued with our plan," says Ganzevoort.
The news was devastating for some study participants. "We were at peace with the death of our daughter, but now we are no longer," said a mother on Dutch public television. She also raised questions about the information parents got about the risks of the study. The consent form they had to sign does not mention any potential negative effects for the child. "We've found that sildenafil is not usually prescribed during pregnancy and that strange things were not observed in this indication, which is a fact," says Ganzevoort, "but we could have said more precisely that we do not know what we are I do not know how I did it with all the advice I did myself. "
How the drug could have caused the complications is unclear. The Dutch team plans to investigate all cases of newborn baby pulmonary hypertension and deaths to check if the diagnosis was correct and if there were other specific features in this group. One possible explanation is a "rebound effect," says Groom. Part of the drug has probably reached the fetus before birth, where it may have placed dilating forces on the pulmonary vessels, she says; this could have led to an increase of limiting signals from the fetus itself, to prevent them from prematurely opening. "After giving birth, the child ceased to receive the expanding drug, possibly resulting in a constriction of the pulmonary vessels," Groom speculates.
It is also unclear why the deaths happened only in the Dutch attempt. Study inclusion criteria differed slightly in the UK, Australia, New Zealand and the Netherlands, but not enough to explain the difference in results, says Groom. Researchers in the other two studies plan to review whether they may have missed cases of pulmonary hypertension in the newborn.
Given the low number of deaths, it is also possible that the result in the Netherlands is purely coincidental, although Ganzevoort says the odds are lower than 5%. "The combination of our results with those of the other studies and the zooming in of subgroups could provide more clarity," he says.
The decision to stop the process is a blow to the field, says Mol. "There were good reasons to believe that this drug would work and it was responsible to lead this process," he says. "I talk about it emotionally because we now have eleven grieving families and it does not help those people."
There is always a risk in clinical trials, says Indira van der Zande, who recently completed her Ph.D. Diploma thesis on pregnant women in clinical research at the University Hospital Utrecht in the Netherlands. "But we should always remember that there would have been a risk if we had not performed this study, and doctors may have prescribed this drug for years off-label, assuming that it was safe and effective."