Antipsychotic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Several case reports have described the use of aripiprazole in human pregnancy. No developmental toxicity was observed in these cases. The animal data suggest a risk of developmental toxicity and possibly teratogenicity, but the very limited human pregnancy experience prevents a complete assessment of the embryo–fetal risk. Until such data are available, the safest course is to avoid the drug in pregnancy. However, if the mother’s condition requires treatment with aripiprazole, the lowest effective dose, avoiding the 1st trimester if possible, should be used. In addition, long-term evaluation of the infant is warranted.
FETAL RISK SUMMARY
Aripiprazole is an antipsychotic used in the treatment of schizophrenia. Activity is due to both the parent drug and its active metabolite. Both are extensively (>99%) bound to serum proteins, primarily albumin. The mean elimination half-lives of aripiprazole and the active metabolite are about 75 and 94 hours, respectively (1,2). The drug is in the quinolinone subclass of antipsychotics that has no other members.
Reproduction studies have been conducted in rats and rabbits. Female rats were treated for 2 weeks before mating through day 7 of gestation with doses up to six times the maximum recommended human dose based on BSA (MRHD). Fertility was not impaired but increased pre-implantation loss was seen at a dose twice the MRHD or greater and decreased fetal weight was noted at six times the MRHD. In pregnant rats, a dose 10 times the MRHD given during organogenesis caused a slightly prolonged gestation, and a slight delay in fetal development, as evidenced by decreased fetal weight, undescended testes, and delayed skeletal ossification. The latter effect was also seen at three times the MRHD. Some maternal toxicity was observed at 10 times the MRHD, but there was no evidence that the observed adverse effects were secondary to maternal toxicity (1,2). There were no effects on embryo, fetal, or pup survival, but offspring had decreased bodyweights (at 3 and 10 times the MRHD), and increased incidences of hepatodiaphragmatic nodules and diaphragmatic hernia (at 10 times the MRHD). Adverse effects in female offspring exposed in utero at 10 times the MRHD included delayed vaginal opening and impaired reproductive performance (decreased fertility rate, corpora lutea, implants, and live fetuses, and increased post-implantation loss). In perinatal and postnatal rat studies, a dose 10 times the MRHD given from day 17 of gestation through postpartum day 21 resulted in slight maternal toxicity and prolongation of gestation, increases in stillbirths, and decreases in pup weight (persisting into adulthood) and survival. Disturbances in spermatogenesis and prostate atrophy, but not impaired fertility, were observed in male rats given doses 13–19 times the MRHD from 9 weeks before mating through mating (1,2).
In rabbits, a dose 11 times the human exposure at the maximum recommended human dose based on AUC (HE) (up to 65 times the MRHD) during organogenesis resulted in decreased maternal food consumption and increased abortions. Other adverse effects noted were increased fetal mortality (at 11 times the HE), decreased fetal weight (at 3 and 11 times the HE), and increased incidences of skeletal abnormalities (fused sternebrae at 3 and 11 times the HE) and minor skeletal variations (at 11 times the HE) (1,2).
It is not known if aripiprazole or its active metabolite crosses the human placenta early in gestation. However, consistent with the molecular weight of the parent compound (about 448), combined with the prolonged elimination half-lives of aripiprazole and the active metabolite, both cross the placenta to the fetus at term (see case report below).
A 2006 case report described the use of aripiprazole in a 22-year-old woman with a 3-year history of paranoid schizophrenia (3). She had been treated with a variety of antipsychotics, including aripiprazole, but had stopped all therapy 1 year before conception. When her disease relapsed at 29 weeks’ gestation, the woman was restarted on aripiprazole 10 mg/day and subsequently increased to 15 mg/day. After 85 days of therapy, the drug was stopped 6 days before spontaneous delivery at the end of week 37 of gestation. The normal, 2.6-kg male infant had Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. He remained healthy at 6 months of age (3).
A second 2006 case report described a 27-year-old woman with schizophrenia who conceived while taking aripiprazole 15 mg/day (4). The woman stopped the drug during the 8th week of gestation. After a relapse during the 20th week of gestation, she restarted aripiprazole 10 mg/day and continued this dose throughout the remainder of her pregnancy. Fetal distress, including tachycardia, was noted at term and a healthy, 3.25-kg infant (sex not specified) was delivered by cesarean section. The infant was doing well at 6 months of age (4).
In a 2008 case report, a 24-year-old woman with schizoaffective disorder took aripiprazole 20 mg/day up to the time of conception and then discontinued the drug because she did not want to expose her fetus (5). She also had stopped her intermittent use of marijuana about 2 weeks before conception. At about 8 weeks’, she experienced a severe relapse and aripiprazole was restarted and continued throughout pregnancy. At 40 weeks’, she gave birth to a healthy, 3.24-kg male infant with Apgar scores of 9 and 9. The infant was doing well at 12 months of age (5).
Five other reports, similar to those above, have described the use of aripiprazole in six pregnancies (6–10). No adverse effects of the drug therapy were observed in the newborns. In one case, a woman taking aripiprazole 10 mg/day had an elective cesarean section at 39 weeks’ gestation (9). At birth, samples were obtained from cord blood 8.6 hours after the last dose. The cord serum concentrations of aripiprazole and the active metabolite were 17 and 8 mcg/L, respectively, while the concentrations in the mother, taken 9.6 hours after dose, were 70 and 45 mcg/L, respectively. The cord:maternal ratios were 0.64 and 0.47, respectively (9).
BREASTFEEDING SUMMARY
In a case mentioned above, a woman taking aripiprazole 15 mg/day breastfed her newborn infant (6). Breast milk samples were collected on postpartum day 3 but the analysis for the drug was unsuccessful. On day 27, milk samples were collected 24 hours after the last dose (30 minutes before the next dose) and 4 and 10 hours after a dose. On day 28, the mother’s serum concentrations of the parent drug and metabolite were 207 and 42 ng/mL, respectively. Neither aripiprazole nor its metabolite was detected in any of the three milk specimens. Based on a detection limit of 10 ng/mL, the milk:plasma ratios were <0.04. The estimated relative infant dose based on the mother’s weight-adjusted dose was <0.7%. At 3 months of age, the infant was growing normally (6).
Although the above case was unable to find detectable milk concentrations of aripiprazole and its metabolite, confirmation of these results is warranted. Until such data are available, if a woman taking the drug chooses to breastfeed, the infant should be closely monitored for adverse effects. Recommendations for counseling breastfeeding mothers who are taking an antipsychotic drug were listed in a 2013 reference (11). Moreover, long-term evaluation of exposed infants is warranted.
References
1.Product information. Abilify. Bristol-Myers Squibb, 2004.
2.Product information. Abilify. Otsuka America Pharmaceutical, 2004.
3.Mendhekar DN, Sharma JB, Srilakshmi P. Use of aripiprazole during late pregnancy in a woman with psychotic illness. Ann Pharmacother 2006;40:575.
4.Mendhekar DN, Sunder K, Andrade C. Aripiprazole use in a pregnant schizoaffective woman. Bipolar Disord 2006;8:299–300.
5.Mervak B, Collins J, Valenstein M. Case report of aripiprazole usage during pregnancy. Arch Women’s Ment Health 2008;11:249–50.
6.Lutz UC, Hiemke C, Wiatr G, Farger G, Arand J, Wildgruber D. Aripiprazole in pregnancy and lactation. A case report. J Clin Psychopharmacol 2010;30:204–5.
7.Watanabe N, Kasahara M, Sugibayashi R, Nakajima K, Watanabe O, Murashima A. Perinatal use of aripiprazole. A case report. J Clin Psychopharmacol 2011;31:377–9.
8.Gentile S, Tofani S, Bellantuono C. Aripiprazole and pregnancy. A case report and literature review. J Clin Psychopharmacol 2011;31:531–2.
9.Nguyen T, Teoh S, Hackett P, Ilett K. Placental transfer of aripiprazole. Aust N Z J Psychiatry 2011;45:500–1.
10.Widschwendter CG, Hofer A. Aripiprazole use in early pregnancy: a case report. Pharmacopsychiatry 2012;45:299–300.
11.Klinger G, Stahl B, Fusar-Poli P, Merlob P. Antipsychotic drugs and breastfeeding. Pediatr Endocrinol 2013;10:308–17.