Vasodilator/Impotence Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Pregnancy is not advised in women with pulmonary arterial hypertension because of the high risk of morbidity and death. However, pregnancies have continued because of the mother’s wishes and have been treated successfully with sildenafil. Although the data are very limited, no embryo–fetal harm has been observed. The drug has not caused developmental toxicity in animals. Because pulmonary arterial hypertension is a high-risk condition, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Sildenafil is an inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type-5 in the smooth muscle of the pulmonary vasculature and in the corpus cavernosum of the penis. It is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) to improve exercise ability and delay clinical worsening (1). It is also indicated for the treatment of erectile dysfunction (2). The drug is available in formulations for oral and IV use. Sildenafil has an active metabolite and both are about 96% bound to plasma proteins. The terminal half-life of sildenafil and its active metabolite are about 4 hours (1,2).
Reproduction studies have been conducted in rats and rabbits. In these species, doses up to 20–32 and 40–68 times, respectively, the recommended human dose based on BSA (RHD) revealed no evidence of teratogenicity, embryotoxicity, or fetotoxicity (1,2). In the rat prenatal and postnatal development study, the no-observed-adverse-effect-level (NOAEL) was 5 times the RHD (1) or about 20 times human exposure based on AUC (2).
Studies for carcinogenicity, mutagenicity, and clastogenicity were negative. In addition, the drug did not impair the fertility of male and female rats (1,2).
It is not known if sildenafil crosses the human placenta. The molecular weight (about 667) and terminal half-life suggest that the drug and its active metabolite will cross to the embryo–fetus, but the high plasma protein binding should limit the exposure.
A 22-year-old woman with Eisenmenger’s syndrome that was managed with sildenafil 50 mg/day was diagnosed with an atrial septal defect that was closed surgically (3). Eight days after surgery, the patient reported 7 weeks of amenorrhea and a pregnancy test was positive. Sildenafil 150 mg/day and diltiazem 60 mg/day were started. Two weeks later, sildenafil was discontinued because of its high cost and the dose of diltiazem was increased to 180 mg/day. Because of worsening pulmonary hypertension at 31 weeks, sildenafil 150 mg/day was restarted and diltiazem was discontinued. The fetal weight was estimated to be in the 15th percentile. At 32 weeks, L-arginine (a nitric oxide donor) 3 g/day was started. During the next 2 weeks, the estimated fetal weight increased to the 35th percentile. Because of superimposed preeclampsia, a cesarean section was performed at 36 weeks’ to deliver a 2.290-kg male infant with Apgar scores of 9 and 9. No additional information on the infant was provided (3).
A 2005 case report described the use of bosentan throughout pregnancy in a woman with Eisenmenger’s syndrome due to pulmonary hypertension (4). Sildenafil was added at 27 weeks’ gestation. At 30 weeks, a planned cesarean section delivered a healthy 1.41-kg female infant. Postoperatively, the mother was treated with bosentan, sildenafil, and warfarin. Her infant was nursed in the hospital for 11 weeks without problems, but died at 26 weeks of age from a respiratory infection (4).
Sildenafil (150 mg/day), bosentan (250/day), hydroxychloroquine (200 mg/day), azathioprine (100 mg/day), and phenprocoumon were used up to 5 weeks’ gestation in a 29-year-old woman with systemic lupus erythematosus-associated pulmonary arterial hypertension (5). At that time, bosentan and phenprocoumon were discontinued and the other three agents were continued along with low-molecular-weight heparin. At 35 weeks, inhaled iloprost was added. At 37 weeks’, a planned cesarean section delivered a healthy 2.760-kg female infant with Apgar scores of 8, 9, and 10. Breastfeeding was declined. At the time of the report, the child was doing well (5).
BREASTFEEDING SUMMARY
No reports describing the use of sildenafil during human lactation have been located. The molecular weight (about 667) and terminal half-life (about 4 hours) suggest that the drug and its active metabolite will be excreted into breast milk, but the high plasma protein binding should limit the amount excreted. The effect of this exposure on a nursing infant is unknown. In clinical trials in adults, the three most common adverse effects were headache, flushing, and dyspepsia (1,2).
References
1.Product information. Revatio. Pfizer Labs, 2009.
2.Product information. Viagra. Pfizer Labs, 2010.
3.Lacassie HJ, Germain AM, Valdes G, Fernandez MS, Allamand F, Lopez H. Management of Eisenmenger syndrome in pregnancy with sildenafil and L-arginine. Obstet Gynecol 2004;103:1118–20.
4.Molelekwa V, Akhter P, McKenna P, Bowen M, Walsh K. Eisenmenger’s syndrome in a 27 week pregnancy—management with bosentan and sildenafil. Ir Med J 2005;98:87–8.
5.Streit M, Speich R, Fischler M, Ulrich S. Successful pregnancy in pulmonary arterial hypertension associated with systemic lupus erythematosus: a case report. J Med Case Reports 2009;3:7255.