Untangling the impact of sildenafil on unborn babies

By Hudson Institute communications

A discovery by Hudson Institute researchers sheds light on the potential reasons why exposing unborn babies affected by fetal growth restriction (FGR) to sildenafil may have led to unexpected neonatal deaths.
L-R: Dr Ishmael Inocencio and Dr Beth Allison

A discovery by Hudson Institute researchers sheds light on the potential reasons why exposing unborn babies affected by fetal growth restriction (FGR) to sildenafil may have led to unexpected neonatal deaths.

FGR facts

  • Affects 1 in 7 – more than 20,000 – Australian babies per year
  • Up to 20 per cent of babies born globally affected each year
  • Can cause cardiovascular disease, lung and brain injury, cognitive, learning and behavioural problems, cerebral palsy and autism
  • FGR increases the risk of stillbirth 20-fold and is a principal cause of perinatal death

Sildenafil, a drug that dilates blood vessels and increases blood flow has been trialled as a potential therapy to restore blood flow in growth restricted pregnancies where placental blood flow is reduced. Poor placental blood flow can lead to fetal growth restriction, which has numerous health implications for the baby.

Hudson Institute researchers investigated how sildenafil impacts the developing fetus, a study carried out in pre-clinical models. It was found to have a negative and potentially harmful effect.

“This finding was important because we show that the use of a drug that is safe in one context, i.e. postnatally, is not in another,” said first author Dr Ishmael Inocencio, postdoctoral scientist, Neonatal Brain Protection, at Hudson Institute.

Clinical trial halted

At the same time the Hudson Institute study was taking place, a large multi-centre clinical trial in humans called the STRIDER study was halted early when a number of babies died.

The STRIDER trial was investigating whether using sildenafil during pregnancy for those babies affected by fetal growth restriction could improve placental function and babies’ growth by increasing blood flow.

It was not understood at the time whether the medication caused the increased death rates in babies, however the Hudson Institute-led study published in The Journal of Physiology provides a crucial insight.

Mechanisms of fetal growth restriction

“Fetal growth restriction occurs when the womb does not supply the developing baby with enough nutrients and oxygen to ensure that it grows to its full potential,” Dr Inocencio said.

“If there is low blood flow in the mother’s placenta, there is a lower level of oxygen available to the growing baby. The fetus has a mechanism to respond to this by redirecting the blood flow to essential organs such as the brain and heart, and away from non-essential organs – called ‘brain sparing’,” he said.

Sildenafil exacerbates fetal growth restriction

“We found that far from having a positive effect, giving sildenafil impaired this mechanism, decreased the already low oxygen levels, and exacerbated fetal growth restriction,” he said.

Medicinal interventions caution during pregnancy

Study leader Dr Beth Allison, Senior Research Scientist, at Hudson Institute said fetal growth restriction occurs in about one in seven pregnancies in Australia.

“Our research shows that consideration of the consequences on the developing fetus should be paramount when giving medicinal interventions to the mother during pregnancy,” Dr Allison said.

“Our findings suggest the use of sildenafil in the clinical treatment for placental insufficiency should be approached with caution.”

This research was supported by | NHMRC

Journal | The Journal of Physiology

Title | Maternal sildenafil impairs the cardiovascular adaptations to chronic hypoxaemia in fetal sheep

View publication | https://doi.org/10.1113/JP279248

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