Risk Factor: C
Class: Central nervous system drugs/ Tranquilizers
Fetal Risk Summary
Chlorpromazine is a propylamino phenothiazine. The drug readily crosses the placenta (1,2,3 and 4). Reproductive studies in rodents have shown a potential for embryotoxicity, increased neonatal mortality, and decreased offspring performance (5). In animals, selective accumulation and retention occur in the fetal pigment epithelium (6). Although delayed ocular damage from high prolonged doses in pregnancy has not been reported in humans, concern has been expressed for this potential toxicity (6,7).
Chlorpromazine has been used for the treatment of nausea and vomiting of pregnancy during all stages of gestation, including labor, since the mid-1950s (8,9 and 10). The drug seems to be safe and effective for this indication. Its use in labor to promote analgesia and amnesia is usually safe, but some patients, up to 18% in one series, have a marked unpredictable fall in blood pressure that could be dangerous to the mother and the fetus (11,12,13,14 and 15). Use of chlorpromazine during labor should be discouraged because of this adverse effect.
One psychiatric patient, who consumed 8000 mg of chlorpromazine in the last 10 days of pregnancy, delivered a hypotonic, lethargic infant with depressed reflexes and jaundice (4). The adverse effects resolved within 3 weeks.
An extrapyramidal syndrome, which may persist for months, has been observed in some infants whose mothers received chlorpromazine near term (16,17,18,19 and 20). This reaction is characterized by tremors, increased muscle tone with spasticity, and hyperactive deep tendon reflexes. Hypotonicity has been observed in one newborn and paralytic ileus in two after exposure at term to chlorpromazine (4,21). However, most reports describing the use of chlorpromazine in pregnancy have concluded that it does not adversely affect the fetus or newborn (22,23,24,25,26 and 27).
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 142 of whom had 1st trimester exposure to chlorpromazine (28). For use anytime during pregnancy, 284 exposures were recorded. No evidence was found in either group to suggest a relationship to malformations or an effect on perinatal mortality rate, birth weight, or intelligence quotient scores at 4 years of age. Opposite results were found in a prospective French study that compared 315 mothers exposed to phenothiazines during the 1st trimester with 11,099 nonexposed controls (29). Malformations were observed in 11 exposed infants (3.5%) and in 178 controls (1.6%) (p
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 36 newborns had been exposed to chlorpromazine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (two expected).
In an in vitro study, chlorpromazine was shown to be a potent inhibitor of sperm motility (31). A concentration of 53 mmol/L produced a 50% reduction in motility.
Using data from the CPP, researchers discovered that offspring of psychotic/neurotic mothers who had consumed chlorpromazine or other neuroleptics for more than 2 months during gestation, whether or not they were breast fed, were significantly taller than nonexposed controls at 4 months, 1 year, and 7 years of age (32). At 7 years of age, the difference between the exposed and nonexposed groups was approximately 3 cm. The mechanisms behind these effects were not clear, but may have been related to the dopamine receptor-blocking action of the drugs.
In summary, although one survey found an increased incidence of defects and a report of ectromelia exists, most studies have found chlorpromazine to be safe for both mother and fetus if used occasionally in low doses. Other reviewers have also concluded that the phenothiazines are not teratogenic (26, 33). Another review concluded that because of its extensive clinical experience, chlorpromazine should be included among the treatments of choice if antipsychotic therapy was required during pregnancy (34). However, use near term should be avoided due to the danger of maternal hypotension and adverse effects in the newborn.
Breast Feeding Summary
Chlorpromazine is excreted into breast milk in very small concentrations. Following a 1200 mg oral dose (20 mg/kg), peak milk levels of 0.29 mg/mL were measured at 2 hours (35). This represented a milk:plasma ratio of less than 0.5. The drug could not be detected following a 600 mg oral dose. In a study of four lactating mothers consuming unspecified amounts of the neuroleptic, milk concentrations of chlorpromazine ranged from 798 ng/mL with maternal serum levels ranging from 1652 ng/mL (36). In two mothers, more of the drug was found in the milk than in the plasma. Only two of the mothers breast-fed their infants. One infant, consuming milk with a level of 7 ng/mL, showed no ill effects, but the second took milk containing 92 ng/mL and became drowsy and lethargic.
With the one exception described above, there has been a lack of reported adverse effects in breast-fed babies whose mothers were ingesting chlorpromazine (26). Based on this report, however, nursing infants exposed to the agent in milk should be observed for sedation. The American Academy of Pediatrics classifies chlorpromazine as an agent whose effect on the nursing infant is unknown but may be of concern because of the drowsiness and lethargy observed in the infant described above, and because of the galactorrhea induced in adults (37).
- Franchi G, Gianni AM. Chlorpromazine distribution in maternal and fetal tissues and biological fluids. Acta Anaesthesiol (Padava)1957;8:197207.
- Moya F, Thorndike V. Passage of drugs across the placenta. Am J Obstet Gynecol 1962;84:177898.
- O’Donoghue SEF. Distribution of pethidine and chlorpromazine in maternal, foetal and neonatal biological fluids. Nature 1971;229:1245.
- Hammond JE, Toseland PA. Placental transfer of chlorpromazine. Arch Dis Child 1970;45:13940.
- Product information. Thorazine. SmithKline Beecham Pharmaceuticals, 2000.
- Ullberg S, Lindquist NG, Sjostrand SE. Accumulation of chorio-retinotoxic drugs in the foetal eye. Nature 1970;227:12578.
- Anonymous. Drugs and the fetal eye. Lancet 1971;1:122.
- Karp M, Lamb VE, Benaron HBW. The use of chlorpromazine in the obstetric patient: a preliminary report. Am J Obstet Gynecol 1955;69:7805.
- Benaron HBW, Dorr EM, Roddick WJ, et al. Use of chlorpromazine in the obstetric patient: a preliminary report I. In the treatment of nausea and vomiting of pregnancy. Am J Obstet Gynecol 1955;69:7769.
- Sullivan CL. Treatment of nausea and vomiting of pregnancy with chlorpromazine. A report of 100 cases. Postgrad Med 1957;22:42932.
- Harer WB. Chlorpromazine in normal labor. Obstet Gynecol 1956;8:19.
- Lindley JE, Rogers SF, Moyer JH.Analgesic-potentiation effect of chlorpromazine during labor; a study of 2093 patients. Obstet Gynecol 1957;10:5826.
- Bryans CI Jr, Mulherin CM. The use of chlorpromazine in obstetrical analgesia. Am J Obstet Gynecol 1959;77:40611.
- Christhilf SM Jr, Monias MB, Riley RA Jr, Sheehan JC. Chlorpromazine in obstetric analgesia. Obstet Gynecol 1960;15:6259.
- Rodgers CD, Wickard CP, McCaskill MR. Labor and delivery without terminal anesthesia. A report of the use of chlorpromazine. Obstet Gynecol 1961;17:925.
- Hill RM, Desmond MM, Kay JL. Extrapyramidal dysfunction in an infant of a schizophrenic mother. J Pediatr 1966;69:58995.
- Ayd FJ Jr, ed. Phenothiazine therapy during pregnancy-effects on the newborn infant. Int Drug Ther Newslett 1968;3:3940.
- Tamer A, McKay R, Arias D, Worley L, Fogel BJ. Phenothiazine-induced extrapyramidal dysfunction in the neonate. J Pediatr 1969;75:47980.
- Levy W, Wisniewski K. Chlorpromazine causing extrapyramidal dysfunction in newborn infant of psychotic mother. NY State J Med 1974;74:6845.
- O’Connor M, Johnson GH, James DI. Intrauterine effect of phenothiazines. Med J Aust 1981;1:4167.
- Falterman CG, Richardson J. Small left colon syndrome associated with maternal ingestion of psychotropic drugs. J Pediatr 1980;97:30810.
- Kris EB, Carmichael DM. Chlorpromazine maintenance therapy during pregnancy and confinement. Psychiatr Q 1957;31:6905.
- Kris EB. Children born to mothers maintained on pharmacotherapy during pregnancy and postpartum. Recent Adv Biol Psychiatry 1962;4:1807.
- Kris EB. Children of mothers maintained on pharmacotherapy during pregnancy and postpartum. Curr Ther Res 1965;7:7859.
- Sobel DE. Fetal damage due to ECT, insulin coma, chlorpromazine, or reserpine. Arch Gen Psychiatry 1960;2:60611.
- Ayd FJ Jr. Children born of mothers treated with chlorpromazine during pregnancy. Clin Med 1964;71:175863.
- Loke KH, Salleh R. Electroconvulsive therapy for the acutely psychotic pregnant patient: a review of 3 cases. Med J Malaysia 1983;38:1313.
- Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S. Antenatal exposure to the pheothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score. Am J Obstet Gynecol 1977;128:4868.
- Rumeau-Rouquette C, Goujard J, Huel G. Possible teratogenic effect of phenothiazines in human beings. Teratology 1976;15:5764.
- O’Leary JL, O’Leary JA. Nonthalidomide ectromelia; report of a case. Obstet Gynecol 1964;23:1720.
- Levin RM, Amsterdam JD, Winokur A, Wein AJ. Effects of psychotropic drugs on human sperm motility. Fertil Steril 1981;36:5036.
- Platt JE, Friedhoff AJ, Broman SH, Bond RN, Laska E, Lin SP. Effects of prenatal exposure to neuroleptic drugs on children’s growth. Neuropsychopharmacology 1988;1:20512.
- Ananth J. Congenital malformations with psychopharmacologic agents. Compr Psychiatry 1975;16:43745.
- Elia J, Katz IR, Simpson GM. Teratogenicity of psychotherapeutic medications. Psychopharmacol Bull 1987;23:53186.
- Blacker KH, Weinstein BJ, Ellman GL. Mothers milk and chlorpromazine. Am J Psychol 1962;114:1789.
- Wiles DH, Orr MW, Kolakowska T. Chlorpromazine levels in plasma and milk of nursing mothers. Br J Clin Pharmacol 1978;5:2723.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.