Jury's out on whether sildenafil (Viagra) helps growth-restricted babies

As results from a major New Zealand-Australian clinical trial are revealed, the jury's out on whether sildenafil , also known as Viagra - taken by mothers during pregnancy could help babies suffering from stunted growth in the womb by increasing blood supply to the placenta.

Auckland boy Archie McDonnell, now 3.5 years, participated in the trial and its follow-up

Results from STRIDER NZAus will be presented by chief investigator Associate Professor Katie Groom, Hugo Charitable Trust Clinical Research Fellow at the University of Auckland-based Liggins Institute, at a conference on mother and baby health research on Tuesday, and a public lecture on Wednesday evening.

Fetal growth restriction, also called intrauterine growth restriction, is when a baby cannot grow properly due to problems with the placenta. It affects 5-10 percent of babies, or 25 million per annum globally (3,000-6,000 in New Zealand), and can lead to stillbirth or to babies being born very small and at high risk of disabilities, developmental problems, short-term and later illness. Currently there is no treatment except early delivery, which can exacerbate those potential long-term problems.

Combining all four trial results should tell us with certainty whether our finding was real or chance, and whether or not to pursue sildenafil as a therapy for the future.

Dr Katie Groom

The STRIDER NZAus trial involved 122 women recruited in Christchurch, Wellington, Auckland and six Australian cities. Half took sildenafil, half took a placebo. The women and babies were closely monitored until surviving babies left neonatal units.

The researchers found no effect on growth in the womb, but did detect a trend towards higher survival of the babies in the sildenafil group before and after birth: 81 percent, or 51 out of 63 babies compared to 73 percent, or 43 out of 59 babies, in the control group. They also found that 11 percent more babies in the sildenafil group survived free of major illness before leaving hospital, and fewer new cases of a serious pregnancy complication called preeclampsia in mothers after starting treatment (14 percent versus 23 percent).

Dr Groom: “Because of the small size of the study these differences are not statistically significant - this may mean this is simply a chance finding. However, if we saw the same differences in a larger group of mother and babies, this would be a very important difference, really having the potential to change lives in the future.”

The opportunity to explore the effect of this drug in a larger group is already underway. STRIDER NZAus is part of an international network of four trials across five countries. The STRIDER UK trial, led by the University of Liverpool, published its findings late 2017. It found that when sildenafil was given to pregnant women with severely growth-restricted babies, it did not prolong pregnancy, improve survival, or reduce short-term illness in the babies after birth.

“Babies in the UK trial were sicker and needed earlier delivery than the babies in our trial, so it is possible with more time available for the drug to make a difference that we may find a different result to this British study,” says Dr Groom, also an obstetrician and Maternal Fetal Medicine Subspecialist at Auckland City Hospital.

Results from the other two trials – across Canada and The Netherlands – are expected by the end of 2020.

The four trials are designed so that researchers will then be able to systematically pool the data, enabling more powerful and revealing analysis.

“Combining all four trial results should tell us with certainty whether our finding was real or chance, and whether or not to pursue sildenafil as a therapy for the future,” says Dr Groom.

Researchers are now assessing the development of the surviving babies from the Australasian and UK trials at the ages two to three years.

Dr Groom and Dr Chris McKinlay, a fellow researcher at the Institute and neonatologist at Middlemore Hospital, are leading the local follow-up study called the STRIDER NZAus Childhood Outcome Study.

“The results will tell us whether there are any longer term benefits of sildenafil that extend into childhood,” he says. “It will also give us valuable information about the health and development of babies born very small, which is really valuable information for parents.”

Viagra, used for male erectile dysfunction, captured the imagination of maternal and fetal researchers in the 1990s. Promising early scientific evidence prompted the trials.

"The theory behind our trials,” says Dr Groom, “is that Viagra dilates blood vessels in the male pelvis, increasing blood supply, so we wondered: could this drug also increase blood supply to the female pelvis and placenta?”

Dr Groom will present the findings at the Perinatal Society of Australia and New Zealand (PSANZ) Annual Scientific Congress 2018 on Tuesday 27 March, and at the Liggins Institute Public Lecture, “A Healthy Start to a Healthy Life”, on Wednesday 28 March, at the University of Auckland Fale Pasifika, 20 Wynyard Street.

Details of the Liggins Institute Public Lecture are here. Information on the PSANZ congress can be found here.

The STRIDER NZAus trial and the Childhood Outcome Study are funded by the Health Research Council of New Zealand, Cure Kids, Auckland Medical Research Foundation, the Neurological Foundation of New Zealand, the University of Auckland, the Mercia Barnes Trust, the Nurture Foundation and the Hugo Charitable Trust.

KEY POINTS:

  • The STRIDER NZAus Trial – part of an international collaboration involving four trials across five countries – looked at whether sildenafil – also known as Viagra - taken by mothers during pregnancy could help growth-restricted babies who face risks of stillbirth, disabilities and illness into adulthood
  • Researchers found no effect from sildenafil on growth in the womb, but did detect a trend towards improved survival and reduced short-term illness in the babies whose mothers took sildenafil, and fewer new cases of a serious pregnancy complication called preeclampsia in mothers
  • Chief investigator Dr Katie Groom, Associate Professor at the Liggins Institute and obstetrician at Auckland City Hospital, says the effect was not statistically significant, but that may have reflected the relatively small study size (122 pregnant women). “The combined results from all four trials will tell us with certainty whether our finding was real or chance, and whether or not to pursue sildenafil as a therapy”
  • Follow-up studies underway that assess the babies at ages two to three will also give valuable new insights into what parents can expect when their baby is born so early and so small

Archie’s story: “We dodged every medical bullet”

Watching Archie McDonnell play with his friends at age three and a half, you’d never guess he weighed a tiny 795g at birth, born with a condition that carries major short and long-term health risks.

Archie had fetal growth restriction – problems with his placenta stunted his growth in the womb. The condition, affecting up to one in 10 babies born, can lead to stillbirth, serious short-term and long-term illness, disability and developmental problems, and, in the mother, a serious pregnancy complication called pre-eclampsia.

“He’s a bit smaller than his peers, but there are no developmental effects,” says his mother, Anne McDonnell. “We know how incredibly lucky we are – we talk about the fact we dodged every medical bullet we possibly could have.”

Archie was Anne and husband Deane’s first baby (they have since had a second son, Xavier - a healthy pregnancy and birth).

Referred to specialist care at 24 weeks, the Ellerslie couple met Auckland obstetrician Dr Katie Groom, who was leading a trial of a potential new treatment for growth restriction – sildenafil, also known as Viagra. Dr Groom asked if they’d join the trial, called STRIDER NZAus.

“Deane and I talked it over, and we decided that we would. This could potentially really help the child if I was on the drug, and if I was on the placebo instead, I’d still be getting amazing monitoring and the best care, so it was a win-win situation.”

The baby’s condition deteriorated and Anne was admitted to hospital at 27 weeks, where she developed pre-eclampsia. Archie was born by c-section at 30 weeks.

“He was tiny, so small. He was fragile, his skin was translucent, he just looked so vulnerable. We couldn’t hold him, we couldn’t feed him, we couldn’t dress him.”

Archie started life in an incubator, on constant oxygen support, and was fed intravenously for the first seven weeks.

“I remember at two and a half months when he was taken off all the monitors, I walked to the window with him in my arms and I burst into tears because it was the first time I was able to walk anywhere with him.”

After three months – 91 days - Archie was discharged from Auckland Hospital. Archie continues to contribute to science through participating in the follow-up study that assesses the children’s development at two to three years.

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