Vasodilator
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Not Relevant
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Pregnancy is not advised in women with pulmonary arterial hypertension (PAH) because of the high risk of morbidity and death. However, pregnancy exposures to iloprost have occurred apparently without embryo–fetal harm. The animal reproduction data are not relevant because the oral and IV doses were not compared with the human dose. Nevertheless, PAH is a high-risk condition and, if indicated, the drug should not be withheld because of pregnancy.
FETAL RISK SUMMARY
Iloprost is a synthetic analog of prostacyclin PGI2 given by inhalation or IV (outside of the U.S.). Iloprost is indicated for the treatment of PAH. The agent dilates systemic and pulmonary arterial vascular beds. There are no other agents in its subclass of prostacyclin analogs. The absolute bioavailability of inhaled iloprost has not been determined, but it was generally not detectable in plasma 30–60 minutes after a dose. When given IV, the half-life is 20–30 minutes and the plasma protein binding was about 60%, mainly to albumin. The main metabolite was inactive in animals (1).
Reproduction studies have been conducted in rats, rabbits, and monkeys. In Han-Wistar rats, a continuous IV dose (serum levels not specified) caused shortened digits of the thoracic extremity in fetuses–pups. In comparable studies giving oral or IV iloprost to Sprague-Dawley rats, rabbits, and monkeys, these anomalies were not observed. However, a maternal toxic oral dose in Sprague-Dawley rats significantly increased the number of nonviable fetuses and an IV dose that was 10 times the teratogenic dose in Han-Wistar rats was embryolethal (1). None of the studies compared the exposures with the human exposure from inhalation or IV use.
Iloprost was not carcinogenic, mutagenic, or clastogenic in multiple studies and assays, and did not cause chromosomal aberrations. The fertility of male and female rats was not impaired with embryolethal IV doses (1).
It is not known if iloprost crosses the human placenta. The molecular weight (about 360) is low enough, but the very short plasma half-life suggests that exposure of the embryo–fetus will be limited.
A 2005 report described three women with PAH who were treated with inhaled iloprost (2). Treatment was initiated at 8, 19, and 17 weeks’ with doses titrated to the patient’s condition and administered 7 times daily. The first woman had been treated with bosentan and warfarin until the therapy was changed at 8 weeks’. This woman suffered a cardiorespiratory arrest at about 25 weeks but was successfully resuscitated after about 1 minute and was converted to IV iloprost for 5 days. At that time, a cesarean section delivered a 0.65-kg male infant with Apgar scores of 8 and 9. The child was progressing well at 16 months of age. Because of premature labor, the second woman underwent a cesarean section at 36 weeks’ to deliver a 2.8-kg male infant with Apgar scores of 9 and 9. At 18 months, the mother and her son were doing well. Placenta previa was diagnosed in the third woman and a cesarean section at 35 weeks delivered a 2.16-kg female infant with Apgar scores of 9, 9, and 10. At 12 weeks, the mother and her daughter were doing well. No congenital anomalies were noted in the three infants (2).
A 21-year-old with idiopathic PAH was treated with inhaled iloprost from 24 to 34 weeks’ gestation, at which time she underwent a cesarean section because of oligohydramnios (3). The mother and infant were clinically well and were discharged home 8 days after delivery. No other details about the infant were provided.
Bosentan (250/day), sildenafil (150 mg/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 PAH (4). At that time, bosentan and phenprocoumon were discontinued and the other three agents were continued 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 (4).
A 2013 case report described a 30-year-old pregnant woman who was diagnosed with PAH at 24 weeks’ (5). She was treated with inhaled iloprost, oral sildenafil, oxygen, and low-molecular-weight heparin. Five days before delivery, inhaled iloprost was replaced with IV iloprost. At about 32 weeks’, a cesarean section gave birth to 1.7-kg male infant with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. Weight, length, and head circumference were within normal limits for gestational age. No congenital anomalies were noted, but the infant had sinusal tachycardia and mild respiratory distress syndrome. He was apparently doing well at 18 days of age (5).
BREASTFEEDING SUMMARY
No reports describing the use of iloprost during human lactation have been located. The molecular weight (about 360) is low enough, but the very short plasma half-life suggests that excretion of the drug into breast milk will be limited. The effect of exposure on a nursing infant is unknown.
References
1.Product information. Ventavis. Actelion Pharmaceuticals US, 2010.
2.Elliot CA, Stewart P, Webster VJ, Mills GH, Hutchinson SP, Howarth ES, Bu’lock FA, Lawson RA, Armstrong IJ, Kiely DG. The use of iloprost in early pregnancy in patients with pulmonary hypertension. Eur Respir J 2005;26:168–73.
3.Cotrim C, Simoes O, Loureiro MJ, Cordeiro P, Miranda R, Silva C, Avillez T, Carrageta M. Acute resynchronization with inhaled iloprost in a pregnant woman with idiopathic pulmonary artery hypertension. Rev Port Cardiol 2006;25:529–33.
4.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 Rep 2009;3:7255.
5.Terek D, Kayikcioglu M, Kultursay H, Ergenoglu M, Yalaz M, Musayev O, Mogulkoc N, Gunusen I, Akisu M, Kultursay N. Pulmonary arterial hypertension and pregnancy. J Res Med Sci 2013;18:73–6.