LAS VEGAS – Increased rates of persistent neonatal pulmonary hypertension in neonates put the brakes on STRIDER, an international placebo-controlled study looking at sildenafil as a treatment for early-onset intrauterine growth restriction (IUGR).
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The study’s independent data safety monitoring board halted STRIDER (Sildenafil Therapy in Dismal Prognosis Early-Onset Fetal Growth Restriction) last July, after an interim safety analysis identified possible fetal harm and no signal of benefit over placebo, Dr. Anouk Pels reported at the annual meeting of the Society for Maternal-Fetal Medicine. The late-breaking presentation at the meeting revealed the first outcome data details.
The board had “serious concerns that sildenafil may cause harm to newborn children. … Given the results , it is extremely unlikely that any benefit could be shown on the primary endpoint if the trial is continued to its completion,” said Dr. Pels of the University of Amsterdam. “Our recommendation is not to use sildenafil for this indication in pregnant women.”
Although the link remains as-yet unproven, pulmonary hypertension among sildenafil-exposed neonates is biologically plausible, she said. It could have been a symptomatic rebound response to the discontinuation of constant intrauterine sildenafil exposure – or it could have been a hint of something more profound. Like the genital vasculature, pulmonary vasculature is a target of the drug. Intrauterine exposure to sildenafil could theoretically alter its development.
“It’s possible that sildenafil may be causing structural changes in the pulmonary vasculature of fetuses. This needs to be explored further, and we will do so by performing additional analyses on autopsy data and placental histology.”
STRIDER involved 261 pregnant women diagnosed with severe early-onset fetal growth restriction. They were randomized to sildenafil 25 mg or placebo three times daily until delivery or 32 weeks’ gestation. A safety analysis was conducted after every 50 patients were enrolled. The preplanned interim analysis was conducted after half of the cohort had been enrolled and received at least one dose of the study medication.
The primary outcome was a composite measure of neonatal mortality or major neonatal morbidity at hospital discharge.
Gestational age at baseline was about 24.6 weeks, and the estimated fetal weight by ultrasound, 465 g. About 45% of pregnancies had evidence of a notching in the uterine artery. In about 42%, the pulsatility index of the umbilical artery was above the 95th percentile; the pulsatility index of the middle cerebral artery was below the 5% percentile in about 70% of cases.
About a quarter of the women had a diagnosis of pregnancy-induced hypertension, and another quarter, preeclampsia. Women used the study medication for a mean of 22 days.
There were no significant between-group differences in maternal outcomes. Median gestational age at delivery was 28 weeks in both groups. About 10% in each group experienced new-onset pregnancy-induced hypertension; About a quarter of each group developed new-onset preeclampsia or HELLP (hemolysis, elevated liver enzymes, low platelet count). There were no between-group differences in the number of maternal antihypertensives prescribed.
The primary combined outcome of neonatal mortality or major neonatal morbidity occurred in 66 of the sildenafil-exposed neonates and 58 of the placebo-exposed infants (61% vs. 54%) – not a significant difference. Fetal death occurred in 23 and 29 pregnancies, respectively (21% and 27%); neonatal death occurred in 21 and 11, respectively (19% and 10%). Overall, fetal/neonatal mortality was similar between the sildenafil and placebo groups (41% and 37%, respectively).
Of the 64 sildenafil-exposed neonates who survived to hospital discharge, 22 exhibited clinically relevant morbidity. Of the 67 in the placebo-treated group who survived to hospital discharge, 18 had clinically relevant morbidity. Overall, 42 in the sildenafil group and 49 of the placebo group survived to hospital discharge without relevant morbidity.
There were a number of secondary outcomes, none exhibiting any significant between-group differences. These included the median weights of those who experienced intrauterine death (425 g and 350 g), median live birth weight (725 g and 783 g), intraventricular hemorrhage of grade II or IV (3% and 2%), periventricular hemorrhage grade II or higher (0%, both groups), necrotizing enterocolitis grade II or higher (7% and 8%), and at least one culture-proven or clinical infection (41% and 33%).
The significantly higher rates of pulmonary hypertension in the sildenafil-exposed neonates was the showstopper. Almost half of the 21 who died had proven pulmonary hypertension (10), as did 6 of the 64 who survived – an excess of 16 cases. Of proven cases, 11 were persistent pulmonary hypertension. There were also two cases of sepsis-associated pulmonary hypertension and four cases of bronchopulmonary dysplasia associated with the disorder. In the placebo-exposed group, pulmonary hypertension occurred in 3 of the 11 deaths and 1 of the 67 who survived. Of proven cases, two were persistent pulmonary hypertension. There was no sepsis-associated pulmonary hypertension, but there were three cases of bronchopulmonary dysplasia associated with the disorder. Some children had both persistent pulmonary hypertension and bronchopulmonary dysplasia.
“While there was no difference in the primary outcomes or in overall mortality, there were more cases of pulmonary hypertension in the sildenafil group,” Dr. Pels said. “We can speculate on the cause, whether it was related to sildenafil and why, or whether it was simply chance. This is the reason we need to conduct more in-depth analyses of these data.”
Funding came from federal health agencies and universities in the countries where STRIDER was conducted, including New Zealand, Australia, the United Kingdom, Ireland, and the Netherlands. Dr. Pels had no relevant financial disclosures.
SOURCE: Pels A et al. The Pregnancy Meeting, Late-Breaker 2.