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).
In 98 of 100 patients treated with haloperidol for hyperemesis gravidarum in the 1st trimester, no effects were produced on birth weight, duration of pregnancy, sex ratio, or fetal or neonatal mortality, and no malformations were found in abortuses, stillborn, or liveborn infants (10). Two of the patients were lost to follow-up. In 31 infants with severe reduction deformities born over a 4-year period, none of the mothers remembered taking haloperidol (11). Haloperidol has been used for the control of chorea gravidarum and manic-depressive illness during the 2nd and 3rd trimesters (15,16). During labor, the drug has been administered to the mother without causing neonatal depression or other effects in the newborn (12).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 56 newborns had been exposed to haloperidol during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Three (5.4%) (two expected) major birth defects were observed, two of which were cardiovascular defects (0.6 expected). No anomalies were observed in five other defect categories (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.
A 1989 report described a case of withdrawal emergent syndrome, a subtype of tardive dyskinesia, in a newborn infant who had been exposed to oral haloperidol (2–6 mg/day) throughout gestation (17). The mother had been treated with haloperidol for schizophrenia, but she stopped the drug 2 weeks before delivery at 38 weeks’ gestation. The male infant (weight not given except as “appropriate for gestational age”) had Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. One hour after delivery, he became irritable and developed continuous tongue thrust. In addition, poor suck resulting in difficult feeding, vomiting, abdominal posturing of the hands, and tremors of the trunk and extremities were noted. By 8 days of age, all of the signs had resolved except for the tongue thrusting. This symptom continued to persist at 6 months of age, but otherwise, his development and examination were normal (17). A second, similar case of tardive dyskinesia was described in a 2003 case report (18). The mother had been treated for schizophrenia with haloperidol 200 mg IM every 2 weeks throughout gestation. She received her last dose 3 weeks before delivery of an infant (sex and weight not given) with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively. The newborn was noted to be jittery and developed diarrhea and metabolic acidosis. Irritability increased over the next 8 days when tonic-clonic movements in all extremities were noted (seizures were excluded by an electroencephalogram) as well as tongue thrusting and torticollis. Treatment with clonazepam resolved the condition and the infant was discharged home at 21 days of age (18).
Premature labor, loss of fetal cardiac variability and acceleration, an unusual fetal heart rate pattern (double phase baseline), and depression at birth (Apgar scores of 4 and 7 at 1 and 5 minutes, respectively) were observed in a comatose mother and her infant after an acute overdose of an unknown amount of haloperidol and lithium at 31 weeks’ gestation (19). Because of progressive premature labor, the 1526-g female infant was delivered about 3 days after the overdose. The lithium concentrations of the maternal plasma, amniotic fluid, and cord vein plasma were all >4 mmol/L (severe toxic effect >2.5 mmol/L), whereas the maternal level of haloperidol at delivery was about 1.6 ng/mL. The effects observed in the fetus and newborn were attributed to cardiac and cerebral manifestations of lithium intoxication. No follow-up on the infant was reported (19).
BREASTFEEDING SUMMARY
Haloperidol is excreted into breast milk. In a patient receiving an average of 29.2 mg/day, a milk level of 5 ng/mL was detected (20). When the dose was decreased to 12 mg, a level of 2 ng/mL was measured. In a second patient taking 10 mg daily, milk levels up to 23.5 ng/mL were found (21). A milk:plasma ratio of 0.6–0.7 was calculated. No adverse effects were noted in the nursing infant.
In a 1985 report, the haloperidol milk concentration was 1.7 ng/mL 3 hours after an unspecified dose (total daily dose 6 mg but the number of doses per day not specified) and 12 days after birth (6). However, the mother had not been breastfeeding and attempts had been made to halt milk production.
A 1992 reference measured haloperidol in the breast milk of three women receiving chronic therapy (22). The maternal doses were 3, 4, and 6 mg/day, and the corresponding haloperidol concentrations in their milk were 32, 17, and 4.7 ng/mL, respectively. The patient receiving 6 mg/day, but with the lowest milk concentration, was thought to be noncompliant with her therapy. No mention of nursing infants was made (22).
A study published in 1998 described 12 mothers who breastfed their infants while taking haloperidol, chlorpromazine, or trifluoperazine for bipolar depression (3 cases), manic disorder (1 case), schizo-affective disorder (5 cases), or schizophrenia (3 cases) (23). Haloperidol doses were 1–40 mg/day. The ages of the nursing infants at the start of therapy were 1–18 weeks. Using an enzyme immunoassay technique, the range of concentrations in fore-milk and hind-milk were <10–988 and 23–140 ng/mL, respectively, whereas the range of ratios of fore-milk and hind-milk to maternal plasma were 0.8–5.2 and 1.7–8.0, respectively. Plasma concentrations of haloperidol in the four nursing infants who were tested were 0.8, 1.2 and 2.1, 6.8, and 8.0 ng/mL, respectively. Two of the samples (6.8 and 8.0 ng/ mL) were in the adult range. In addition, the urine of all seven infants tested contained haloperidol (1.6–7.9 ng/mL). The maximum infant dose ingested was 3% of the weight-adjusted maternal dose. As assessed using the Bayley Scales of Infant Development, all three of the infants whose mothers were taking both haloperidol (20–40 mg/day) and chlorpromazine (200–600 mg/day) showed a decline in mental and psychomotor development from the first (at 1–4 months of age) to the second assessment (at 12–18 months of age). Because of this decline, the investigators concluded that breastfeeding might not be best if a breastfeeding mother is taking neuroleptics, either alone or in combination, at the upper end of their recommended dose ranges (23).
The American Academy of Pediatrics classifies haloperidol as an agent whose effect on the nursing infant is unknown but may be of concern (24).
References
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