H
HALOPERIDOL
Antipsychotic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although the animal data suggest moderate risk, the limited human pregnancy experience with haloperidol prevents a more complete assessment of embryo–fetal risk. Neonatal tardive dyskinesia may be an uncommon complication of exposure throughout gestation. There does not appear to be an increased risk of major congenital defects, but there were three cases of limb defects after 1st trimester haloperidol exposure and a fourth case after exposure to a drug in the same class (penfluridol). This potential association requires further study. Until such data are available, avoiding 1st trimester exposure, if possible, should be considered.
FETAL RISK SUMMARY
Haloperidol, a butyrophenone, is indicated for the management of manifestations of psychotic disorders (e.g., schizophrenia) and Tourette’s disorder. It is available in both oral and IM formulations (1).
Animal reproductive studies with haloperidol in mice, rats, rabbits, and dogs have not revealed a teratogenic effect attributable to this tranquilizer. In rodents, doses 2–20 times the usual maximum human dose (oral or parenteral) were associated with an increased incidence of resorption, reduced fertility, delayed delivery, and pup mortality (1,2). With single injections up to maternal toxic levels in hamsters, haloperidol was associated with fetal mortality and dose-related anomalies (3). Exposure of male rats in utero to haloperidol throughout most of gestation had no effect on typical parameters of adult sexual activity other than subtle changes involving ultrasonic vocalization (4).
Consistent with the molecular weight (about 376), haloperidol crosses the human placenta. In a 2007 study, 13 women taking a staple dose (mean 2.2 mg/day) of haloperidol for a mean 22 weeks before delivery had maternal and cord concentrations of the drug determined at birth (5). The cord blood concentration was 65.5% of the maternal concentration. The mean Apgar scores were 7.4 and 8.9 at 1 and 5 minutes, respectively. There were four neonatal complications (two cardiovascular, 1 respiratory, and 1 hypotonia; complications were not further described). No infants were admitted to the neonatal intensive care unit (5).
A 31-year-old woman with atypical psychosis was treated with oral haloperidol 3 mg/day and biperiden 3 mg/day at 36 weeks’ (6). As her condition worsened, her doses were increased to IM 5 mg twice daily for each drug. At about 38 weeks’, 3.5 hours after a dose of both drugs, she gave birth to a healthy 3260-g male infant with Apgar scores of 9 and 9. At delivery, maternal plasma concentrations of haloperidol and biperiden were 10.2 and 4.4 ng/mL, whereas in the newborn they were 4.6 ng/mL and not detectable, respectively (6).
Three reports have described limb defects in three infants after 1st trimester exposure to haloperidol (7–9). In one of these cases, high doses (15 mg/day) were used (8). Defects were observed in two infants: ectromelia (phocomelia) in one infant (7), and multiple upper- and lower-limb defects and an aortic valve defect in the other (8). The infant in the latter case died.
The third case was identified in a 2005 international prospective cohort study that compared 215 pregnancies exposed to either haloperidol (N = 188) or penfluridol (N = 27) (a butyrophenone antipsychotic not available in the United States) with 631 controls (9). The pregnancy outcomes were determined by telephone interviews and/or mailed questionnaires. In 161 pregnancies, exposure occurred in the 1st trimester, 136 to haloperidol and 25 to penfluridol. The median doses for haloperidol were oral 5 mg/day (2.25–10 mg) or parenteral 100 mg/4 weeks. There were no statistical differences between the butyrophenone and control groups in terms of spontaneous abortions (8.8% vs. 5.5%), ectopic pregnancies (0.5% vs. 0.2%), stillbirths (0 vs. 0.2%), or major malformations (3.4% vs. 3.8%). Significant differences were observed in the rates of elective terminations (8.8% vs. 3.8%), preterm births (13.9% vs. 6.9%), birthweight (3155 vs. 3370 g), birthweight of full-term infants (3250 vs. 3415 g), and cesarean section delivery (25.5% vs. 16.3%). There were three major defects in pregnancies exposed to haloperidol in the 1st trimester: absent left fourth finger, common wrist (carpal) of left first and second fingers; carbamazepine syndrome, developmental delay, congenital heart defect (also exposed to carbamazepine); and ventricular septal defect (also exposed to perphenazine). The haloperidol doses in the three cases were 12.5 mg IM every 4 weeks, 150 mg IM every month, and 10 mg/day orally. There was one major defect with 1st trimester exposure to penfluridol (oral 20 mg/ week): upper limb reduction defect and foot deformity. The small size of the study prevented excluding a possible association between butyrophenones and limb defects (9). Of interest, though, other studies have not observed limb defects in haloperidol-exposed pregnancies (10–14).
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