SUMMARY

• Macitentan demonstrated teratogenicity in rats and rabbits at all tested doses, with cardiovascular and craniofacial abnormalities.¹
  • The pattern of malformations is similar to those observed in homozygous endothelin (ET) receptor knockout mice and with other endothelin receptor antagonists (ERAs), indicating the macitentan findings are most likely a potential class effect related to ET receptor antagonism.
• A review of Johnson & Johnson’s safety database identified 231 reported pregnancies in patients treated with macitentan, including 29 from clinical trials.²
  • Among the reported congenital cases, 1 involved chondrodysplasia punctata, another involved a secundum atrial septal defect, and the third involved oculocerebrorenal syndrome of Lowe (OCRL).
  • Medical evaluations indicated no causal link to macitentan exposure.
• Memon et al (2018)³ reported a 20-year-old female patient who received OPSUMIT combined with tadalafil and subcutaneous (SC) treprostinil as background therapy for pulmonary arterial hypertension (PAH) until around 13 weeks gestation. At 26 weeks of gestation, an emergent cesarean section was performed due to fetal distress, resulting in the delivery a healthy male infant.
• Ji et al (2025)⁴ reported a 31-year-old female patient (gravida 5, para 3 [G5P3]) with group I PAH (mean pulmonary arterial pressure [mPAP], 53 mmHg), right heart failure, and Eisenmenger syndrome secondary to a congenital atrial septal defect. She presented at 37 weeks gestational age with worsening hypotension and dyspnea after being off of PAH therapy for a year and was started on OPSUMIT, sildenafil, treprostinil, and inhaled nitric oxide. She underwent a successful cesarean delivery and was discharged on tadalafil and treprostinil.
• Overall, data on the use of macitentan in pregnant women is limited.

clinical data

Pre-Clinical and Clinical Studies

Macitentan was found to be teratogenic in both rats and rabbits at all doses (up to 1500 mg/kg/day) tested, with no established No Observed Adverse Effect Level (NOAEL) for teratogenicity in either species. These teratogenic effects observed included cardiovascular and craniofacial abnormalities.¹

The observed pattern of malformations, being similar to that observed in ET receptor knockout mice and with other ERAs, indicates the macitentan findings are likely a class effect related to ET receptor antagonism.¹

Due to its teratogenic potential, clinical study protocols for macitentan have mandated the exclusion of pregnant patients and required reliable forms of contraception for those of childbearing potential.¹

Pregnancy Outcomes and Safety Assessment of Macitentan: Clinical and Post-Marketing Data

A search of the macitentan safety database was conducted (cutoff date of October 17, 2025) for cases of pregnancies reported to Johnson & Johnson in patients treated with macitentan during clinical studies and the post-marketing period. Johnson & Johnson received reports of 231 pregnancies, including 29 from clinical trials and an additional 8 reports describing pregnancies in female partners of male patients treated with macitentan.²

No cases of congenital abnormalities were reported during the macitentan clinical development program, and no fetal malformations were reported in cases where the pregnancy outcome was either induced or spontaneous abortion. Among the 231 pregnancies reported, a total of 50 live births were noted. Of these, 1 clinical trial case involved a premature baby born at 24 weeks of gestation who suffered complications related to extreme prematurity (neonatal respiratory distress syndrome, sepsis, intracranial hemorrhage, and skin atrophy) and died 3 days after birth due to persistent hypotension. In another clinical trial case, a baby with intrauterine growth retardation was born prematurely at 32 weeks of gestation due to pre-eclampsia of the mother, who had a history of tobacco consumption during pregnancy.²

Among the live births, 47 (23 babies born prematurely, 5 born full term, and 19 of unknown gestational age) were reported without congenital anomalies. Of the 3 reported cases of congenital anomalies, 1 baby was diagnosed with chondrodysplasia punctata (characterized by bilaterally shortened second digits of the hands and feet), which was confounded by the mother’s underlying systemic lupus erythematosus disease and concomitant medications. There was another baby born prematurely with secundum-type atrial septal defect. One baby was born with OCRL and one additional case referred to possible chromosomal aberrations in a terminated pregnancy. Medical assessments of the 4 cases concluded that there was no evidence of a contributory role of macitentan, as none of the anomalies corresponded to the expected patterns of malformations related to ERAs based on nonclinical findings (eg, defects in neural crest derivatives).^1,2

Additionally, induced abortions were reported in 73 pregnancies, and spontaneous abortions occurred in 24 pregnancies; among these, no fetal defects were reported, with the exception of the 1 aforementioned case of possible chromosomal aberrations in a terminated pregnancy. Other pregnancy outcomes included the following: 2 pregnancies resulting in fetal death/stillbirth, 1 ectopic pregnancy, and 2 maternal deaths during pregnancy. The outcome was unknown for 77 pregnancies.^1,2

Information From a Literature Search

Memon et al (2018)³ reported a 20-year-old female patient who received OPSUMIT combined with tadalafil and SC treprostinil as background therapy for PAH. All 3 medications were stopped around 13 weeks of gestation and SC treprostinil was changed to intravenous epoprostenol. At 26 weeks of gestation, due to fetal distress, emergent cesarean section was undertaken to deliver a healthy male infant.

Ji et al (2025)⁴ reported the case of a 31-year-old female (G5P3) with group I PAH (mPAP, 53 mmHg), right heart failure, and Eisenmenger syndrome secondary to a congenital atrial septal defect. She presented at 37 weeks of gestation with worsening dyspnea and hypotension after being off of PAH therapy for a year. By the time of admission, the patient was in cardiogenic shock with acute right heart failure and received epinephrine and vasopressin. She was started on PAH therapy with OPSUMIT, sildenafil, treprostinil, and inhaled nitric oxide. The patient underwent a successful cesarean delivery and was discharged on tadalafil and treprostinil.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 06 January 2026.