Sildenafil is a phosphodiesterase type-5 inhibitor with vasodilatory effects that is most commonly used to treat male erectile dysfunction (commonly sold under the brand name Viagra®). It is also licensed in the UK (brand name Revatio®) to treat pulmonary arterial hypertension. Several clinical trials have explored the use of sildenafil as a maternally-administered in utero treatment to improve fetal outcomes following detection of severe fetal growth restriction.
In 2018 an ongoing multicentre randomised controlled trial (RCT) was halted following the detection of a potential safety signal. One of three study sites reported that persistent pulmonary hypertension of the newborn (PPHN) appeared to be more prevalent in infants exposed in utero to sildenafil (n=93) compared to placebo-exposed infants. Two further study sites for this trial (numbers of participants as yet unreported) detected no increased risk of PPHN and overall this trial has not identified a clear beneficial effect of sildenafil on fetal outcome. A further four small RCTs/cohort studies that include a total of 159 sildenafil-exposed pregnancies raise no cause for concern regarding neonatal death rates compared to those in control groups, although for one of these studies exposure times were short. Case reports/series describe fetal outcomes for a further 18 sildenafil-exposed pregnancies, with no neonatal deaths reported. Further assessment of these data, in particular cases for which adverse outcomes have been reported and the potential role of confounding factors, is required.
Data relating to other pregnancy outcomes following in utero sildenafil exposure are too limited to facilitate an evidence-based assessment of risk or benefit. Case reports document seven confirmed first trimester exposures, with no infant malformations recorded. A small number of studies have found no statistically significant increased risks of stillbirth, preterm delivery or infants being born small for gestational age. There are no data relating to other neonatal or childhood outcomes following gestational sildenafil exposure.
In view of the potential safety signal described above, it has been recommended that ‘sildenafil should not be prescribed for fetal growth restriction outside the setting of high-quality randomized clinical trials’. UKTIS also recommends that general use of sildenafil in pregnancy should be avoided where possible. Where gestational use of sildenafil to treat maternal pulmonary arterial hypertension is being considered, the benefits of treatment should be weighed against the potential risks to fetus/neonate, and to both mother and fetus of discontinuing treatment. Discussion with the patient of the available data relating to use in pregnancy should occur.
Exposure to sildenafil at any stage of pregnancy would not usually be regarded as medical grounds for termination of pregnancy. Additional fetal monitoring may be indicated due to the largely unknown effects of the exposure. The ability of the unit at which a patient is booked for delivery to identify and manage neonates with PPHN should be considered in advance. Other risk factors may also be present in individual cases which may independently increase the risk of adverse pregnancy outcome. Clinicians are reminded of the importance of consideration of such factors when performing case-specific risk assessments.
This is a summary of the full UKTIS monograph for health care professionals and should not be used in isolation. The full UKTIS monograph and access to any hyperlinked related documents is available to NHS health care professionals who are logged in.
If you have a patient with exposure to a drug or chemical and require assistance in making a patient-specific risk assessment, please telephone UKTIS on 0344 892 0909 to discuss the case with a teratology specialist.
If you would like to report a pregnancy to UKTIS please click here to download our pregnancy reporting form. Please encourage all women to complete an online reporting form.