Phosphodiesterase‐5 inhibitors in pregnancy: Systematic review and meta‐analysis of maternal and perinatal safety and clinical outcomes

Abstract

Background:The efficacy and safety profile of phosphodiesterase-5 inhibitors (PDE-5i) in pregnancy are unclear from the few relatively small diverse studies that have used them.Objective: To assess the safety profile and clinical outcomes of PDE-5i use in pregnancy. Search strategy:We searched Embase, PubMed, CENTRAL, Prospero and Google Scholar to identify randomised controlled trials (RCTs) reporting the use of any PDE-5i in pregnancy up to September 2021.Selection criteria: RCTs reporting obstetric or perinatal outcomes or maternal adverse outcomes in women taking PDE5i in pregnancy. Data collection and analysis:Risk ratios (RR), 95% confidence intervals (95% CI) and 95% prediction intervals were calculated and pooled for analysis. Results:We identified 1324 citations, of which 10 studies including 1090 participants met the inclusion criteria. Only tadalafil and sildenafil were reported as used in pregnancy. Two studies using tadalafil and eight sildenafil. Nine of ten studies were assessed at having of low risk of bias. PDE-5i use was associated with an increased risk of headaches (RR 1.41, 95% CI 0.97-2.05), flushing (RR 2.59, 95% CI 0.69-9.90) and nasal bleeding (RR 10.53,); an increase in vaginal birth when used for nonfetal growth restriction (FGR) indications (RR 1.24, 95% CI 1.00-1.55) and a reduction in risk of operative birth for intrapartum fetal compromise (RR 0.58, 95% CI 0.38-0.88). There was no evidence of any increase in risk of perinatal death (RR 0.89, 95% CI 0.56-1.43). However, use for the treatment of FGR increased the risk of persistent pulmonary hypertension of the newborn (PPHN) (RR 2.52, 95% CI 1.00-6.32). Conclusions:This meta-analysis suggests PDE-5i use in pregnancy is associated with mild maternal side effects and lower risk of operative birth for intrapartum fetal distress. Prolonged use for the treatment of FGR may increase the risk of PPHN.

Sildenafil during the 2nd and 3rd Trimester of Pregnancy: Trials and Tribulations

“…Whether sildenafil during pregnancy is safe was addressed in two systematic clinical reviews. Both studies agreed on the occurrence of mild maternal side effects, i.e., headaches, flushing, visual disturbances, dizziness, palpitations, arthralgia, dyspepsia, and epigastric pain, though not an increased risk compared to placebo [ 12 , 117 ]. Nasal bleeding was the only side-effect significantly more associated with sildenafil therapy (RR 10.53, 95% CI 1.36–81.3) [ 12 ].…”

“…Both studies agreed on the occurrence of mild maternal side effects, i.e., headaches, flushing, visual disturbances, dizziness, palpitations, arthralgia, dyspepsia, and epigastric pain, though not an increased risk compared to placebo [ 12 , 117 ]. Nasal bleeding was the only side-effect significantly more associated with sildenafil therapy (RR 10.53, 95% CI 1.36–81.3) [ 12 ]. Hypotension, a maternal side-effect of sildenafil that was anticipated, was not reported [ 117 ].…”

“…Moreover, the hepatic CYP3A4 and CYP2C19 isoenzymes involved in sildenafil’s metabolization were present and active prenatally [ 10 , 11 ]. Tadalafil, vardenafil, mirodenafil, avanafil, and udenafil are other PDE5 inhibitors, however only tadalafil has also been trialed during pregnancy for fetal growth restriction [ 12 , 13 ]. Compared to sildenafil, clinical experience with tadalafil is very limited, and immaturity of the glucuronidation pathway used for its metabolization forms a contraindication for its use during pregnancy [ 14 ].…”

“…Obstetric outcomes depended on the underlying pathologic condition. Sildenafil reduced the risk of operative birth when used for intrapartum fetal distress and was not associated with new-onset pre-eclampsia, FGR, or antepartum hemorrhage [ 12 ].…”

“…Fetal and neonatal outcomes of prenatal sildenafil also depended on the underlying condition, as detailed above. Prenatal sildenafil was associated with an increased risk of persistent pulmonary hypertension only for FGR because of the findings in the Dutch STRIDER arm [ 12 , 75 ]. Meta-analysis could not find evidence for increased perinatal or neonatal mortality and morbidity (respiratory distress syndrome, necrotizing enterocolitis, intracranial hemorrhage, and retinopathy of the premature) associated with the use of PDE5-inhibitors during pregnancy [ 12 ].…”