Risk Factor: CM
Class: Central nervous system drugs/ Tranquilizers
Fetal Risk Summary
Animal reproductive studies with haloperidol in mice, rats, rabbits, and dogs have not revealed a teratogenic effect attributable to this tranquilizer (1,2). In rodents, doses 2 to 8 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).
Two reports describing limb reduction malformations after 1st trimester use of haloperidol have been located (5,6). In one of these cases, high doses (15 mg/day) were used (6). Other investigations have not found these defects (7,8,9,10 and 11). Defects observed in the two infants were: ectromelia (phocomelia) (5), multiple upper and lower limb defects, aortic valve defect, and death (6).
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 (7). Two of the patients were lost to followup. In 31 infants with severe reduction deformities born over a 4-year period, none of the mothers remembered taking haloperidol (8). Haloperidol has been used for the control of chorea gravidarum and manic-depressive illness during the 2nd and 3rd trimesters (12,13). During labor, the drug has been administered to the mother without causing neonatal depression or other effects in the newborn (9).
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.
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 (14). 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 greater than 4 mmol/L (severe toxic effect >2.5 mmol/L) whereas the maternal level of haloperidol at delivery was about 1.6 ng/mL (14). 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.
Breast Feeding Summary
Haloperidol is excreted into breast milk. In one patient receiving an average of 29.2 mg/day, a milk level of 5 ng/mL was detected (15). 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 (16). A milk:plasma ratio of 0.60.7 was calculated. No adverse effects were noted in the nursing infant.
A 1992 Reference measured haloperidol in the breast milk of three women receiving chronic therapy (17). 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 (17).
A study published in 1998 described 12 mothers who breast-fed 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) (18). Haloperidol was given in a dose ranging from 1 to 40 mg/day. The age of the nursing infants at the start of therapy ranged from 1 to 18 weeks. Using an enzyme immunoassay technique, the range of concentrations in fore-milk and hind-milk were
The American Academy of Pediatrics classifies haloperidol as an agent whose effect on the nursing infant is unknown but may be of concern (19).
- Tuchmann-Duplessis H, Mercier-Parot L. Influence of neuroleptics on prenatal development in mammals. In: Malformations, Tumors and Mental Defects, Pathogenetic Correlations. H Tuchmann- Duplessis, G Fanconi and GR Burgio, eds. Milan:Carlo Erba Foundation, 1971. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:3089.
- Product information. Haldol. Ortho-McNeil Pharmaceutical, 2000.
- Gill TS, Guram MS, Geber WF. Haloperidol teratogenicity in the fetal hamster. Dev Pharmacol Ther 1982;4:15. As cited in Elia J, Katz IR, Simpson GM. Teratogenicity of psychotherapeutic medications. Psychopharmacol Bull 1987;23:53186.
- Bignami G, Laviola G, Alleva E, Cagiano R, Lacomba C, Cuomo V. Developmental aspects of neurobehavioural toxicity. Toxicol Ltrs 1992;64/65:2317.
- Dieulangard P, Coignet J, Vidal JC. Sur un cas d’ectrophocomelie peutetre d’origine medicamenteuse. Bull Fed Gynecol Obstet 1966;18:857.
- Kopelman AE, McCullar FW, Heggeness L. Limb malformations following maternal use of haloperidol. JAMA 1975;231:624.
- Van Waes A, Van de Velde E. Safety evaluation of haloperidol in the treatment of hyperemesis gravidarum. J Clin Pharmacol 1969;9:2247.
- Hanson JW, Oakley GP. Haloperidol and limb deformity. JAMA 1975;231:26.
- Ayd FJ Jr. Haloperidol: fifteen years of clinical experience. Dis Nerv Syst 1972;33:45969.
- Magnier P. On hyperemesis gravidarum; a therapeutical study of R 1625. Gynecol Prat 1964;15:1723.
- Loke KH, Salleh R. Electroconvulsive therapy for the acutely psychotic pregnant patient: a review of 3 cases. Med J Malaysia 1983;38:1313.
- Donaldson JO. Control of chorea gravidarum with haloperidol. Obstet Gynecol 1982;59:3812.
- Nurnberg HG. Treatment of mania in the last six months of pregnancy. Hosp Community Psychiatry 1980;31:1226.
- Nishiwaki T, Tanaka K, Sekiya S. Acute lithium intoxication in pregnancy. Int J Gynecol Obstet 1996;52:1912.
- Stewart RB, Karas B, Springer PK. Haloperidol excretion in human milk. Am J Psychiatry 1980;137:84950.
- Whalley LJ, Blain PG, Prime JK. Haloperidol secreted in breast milk. Br Med J 1981;282:17467.
- Ohkubo T, Shimoyama R, Sugawara K. Measurement of haloperidol in human breast milk by high-performance liquid chromatography. J Pharm Sci 1992;81:9479.
- Yoshida K, Smith B, Craggs M, Kumar R. Neuroleptic drugs in breast milk: a study of pharmacokinetics and of possible adverse effects in breast-fed infants. Psychol Med 1998;28:8191.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.