Clinical Trial For Fetal Growth Restriction Cancelled
After 11 Fetal Deaths
Jovian Wat, PhD
A clinical trial began in 2015 in the Netherlands to test if the drug sildenafil could improve the growth of fetuses who were severely growth restricted. This trial was recently halted due to fetal safety concerns.
In this trial, known as the Dutch STRIDER trial, 90 women with growth restricted babies were treated with the drug sildenafil. Out of these 90 babies, 19 babies died (21%) - 11 of these deaths were due to lung complications shortly after birth. In contrast, only 9 babies died in the 93 women who did not receive the drug sildenafil (10%). None of these 9 deaths were due to lung complications.
What is fetal growth restriction?
Babies are considered to be small for gestational age if they are below the 10th centile, or are within the lowest 10% of baby weights. A small for gestational age baby is naturally small due to factors not related to a medical condition. For example, babies born to shorter parents can be smaller than average, but healthy with no medical conditions.
Fetal growth restriction, or intrauterine growth restriction, is a distinct condition from small for gestational age, occurring when the fetus is smaller than normal due to a medical condition. Fetal growth restriction is typically caused by placental insufficiency, meaning that the placenta is not functioning properly due to improper placental growth or damage. The healthy placenta transfers nutrients and oxygen from the mother's blood to support the growth of the developing baby through the umbilical cord. When the placental transfer of nutrients to the fetus is impaired, the developing baby is not fully supported and growth can be stunted. Approximately 3-5% of newborns are growth-restricted.
There are currently no approved therapies to treat fetal growth restriction. Researchers have assessed different strategies to treat fetal growth restriction, including supplementing mom's diet, putting mom on best rest and different types of drug therapies. Unfortunately, none of these strategies have been shown to be effective to increase the baby's weight.
The Dutch STRIDER trial was examining if sildenafil could increase fetal weight in growth restricted babies, and be used as a potential treatment for fetal growth restriction.
Wait, isn't sildenfil also known as Viagra®?
In the Dutch STRIDER study, researchers gave sildenafil to pregnant women with fetal growth restriction. Sildenafil is the generic form of the brand name drug Viagra®. Pfizer, the maker of sildenafil, was not involved in this study.
Let's look at some of the science that explains why researchers were interested in sildenafil for treatment of fetal growth restriction.
Sildenafil was originally tested as a drug to lower blood pressure. Scientists believed that sildenafil could relax blood vessels across the body, lower resistance of the blood vessels and lower blood pressure. However, researchers found that sildenafil is only effective at relaxing specific blood vessels in the body that contain high levels of the enzyme phosphodiesterase-5 (PDE5), such as the penis. This discovery led to the use of sildenafil for men with erectile dysfunction.
In recent years, scientists discovered that PDE5 is also present in the placenta. Based on this information, the STRIDER group hypothesized that sildenafil could possibly help to relax the blood vessels that lead to the placenta to increase blood flow, in the same way that sildenafil relaxes blood vessels in the penis and increases blood flow.
Therefore, sildenafil therapy in women with fetal growth restriction could possibly increase blood flow to the developing fetus to support growth.
What’s the evidence that sildenafil could treat fetal growth restriction?
As required by federal regulators such as the Canadian Institutes of Health Research and the United States Food and Drug Administration, a large amount of research must clearly show the potential benefits of a new drug with minimal safety concerns before a clinical trial is started.
Scientists found that women with fetal growth restriction pregnancies had less relaxed uterine blood vessels, when compared to uterine blood vessels from healthy pregnant women. In the laboratory setting, treatment of these constricted uterine blood vessels with sildenafil caused them to behave more like normal uterine blood vessels.
In a mouse model of fetal growth restriction, ultrasound assessments showed that sildenafil increased blood flow to the placenta and increased the size of the mouse babies, compared to mice not treated with sildenafil. Pregnant sheep with fetal growth restriction who were treated with sildenafil also showed an increase in fetal weight.
There have also been a small number of small randomized controlled trials in pregnant women with fetal growth restriction. A single dose of sildenafil in pregnant women with signs of fetal growth restriction improved blood flow to the placenta.
Together, this preliminary evidence suggested that sildenafil could be a promising therapy to treat fetal growth restriction.
The next step was to see if sildenafil could treat fetal growth restriction in pregnant women. A small trial conducted at the University of British Columbia showed that sildenafil increased birthweight when administered to 10 pregnant women with fetal growth restriction, compared to pregnant women who did not receive sildenafil treatment. However, there has been conflicting evidence from other research groups - a more in-depth summary of studies investigating sildenafil as treatment for fetal growth restriction can be found here.
It sounded promising! So what happened?
The STRIDER trial is actually a group of independent clinical trials being conducted in New Zealand, Australia, United Kingdom, the Netherlands, and Canada. This group collectively designed the trial protocol, and each country gained its own regulatory agency's approval to carry out the trial.
Earlier this year, the UK team of the STRIDER group completed their study and published their findings in The Lancet. The UK team's results found that sildenafil does not increase fetal growth in women with fetal growth restriction. In addition, sildenafil did not trigger any safety concerns for pregnant women or their babies - there were 2/70 (3%) fetal deaths in the women receiving sildenafil treatment, compared to 6/65 (9%) fetal deaths in women not receiving sildenafil treatment.
However, the results of the Dutch team of the STRIDER group came as a surprise and highlight significant safety concerns with sildenafil treatment. The Dutch team found that pregnant women with fetal growth restriction being treated with sildenafil had more fetal deaths (21%), compared to pregnant women not receiving sildenafil treatment (10%).
Why did the Dutch team see an unexpected increase in fetal deaths?
Most of the fetal deaths in the group of pregnant women receiving sildenafil were due to lung complications. The PDE5 enzyme that sildenafil inhibits is also found in the lungs, meaning that sildenafil could potentially be interfering with development of the fetal lungs. This action of sildenafil could potentially explain why fetal lung complications were seen in pregnant women receiving sildenafil therapy in the trial.
It is not currently understood why sildenafil was associated with increased rates of fetal death in the Dutch arm of the trial, but not in the UK arm.
Even though the results of the preliminary research looked promising and did not raise concern regarding safety concern, it is difficult for researchers to guarantee that the findings in animal models will be the same in humans. In a similar way, the small clinical studies studying the effects of sildenafil in pregnant women with fetal growth restriction did not indicate that sildenafil could interfere with the development of the fetal lungs, leading to increased rates of death.
Despite promising molecular and animal model findings that sildenafil could increase fetal weight in women with fetal growth restriction, the Dutch arm of the STRIDER trial found that sildenafil is associated with increased fetal death. The majority of these fetal deaths were due to lung complications, leading researchers to hypothesize that sildenafil may have interfered with fetal lung development. It remains unknown whether sildenafil could be a safe treatment option for pregnant women to treat fetal growth restriction.
Every woman and every pregnancy is unique. Pregnant women should speak to their healthcare provider to ensure maternal and fetal safety. This article is meant to provide readers with current information and opinions. All medical and treatment decisions should be discussed with your healthcare provider.