Risk Factor: C
Class: Central nervous system drugs/ Tranquilizers
Fetal Risk Summary
Trifluoperazine is a piperazine phenothiazine. The drug readily crosses the placenta (1). Trifluoperazine has been used for the treatment of nausea and vomiting of pregnancy, but it is primarily used as a psychotropic agent.
Reproduction studies with trifluoperazine have been conducted in rats, rabbits, and monkeys (2). In rats, doses over 600 times the human dose revealed an increased incidence of malformations and reduced litter size and weight associated with maternal toxicity. These effects were not observed when the dose was reduced in half (2). No fetal adverse effects were observed in rabbits or monkeys at doses of 700 and 25 times the human dose, respectively.
In 1962, the Canadian Food and Drug Directorate released a warning that eight cases of congenital defects had been associated with trifluoperazine therapy (3). This correlation was refuted in a series of articles from the medical staff of the manufacturer of the drug (4,5 and 6) . In 480 trifluoperazine-treated pregnant women, the incidence of live-born infants with congenital malformations was 1.1%, as compared with 8,472 nontreated controls with an incidence of 1.5% (5). Two reports of phocomelia appeared in 19621963 and a case of a congenital heart defect in 1969 (7,8 and 9) : Twins, both with phocomelia of all four limbs (7) Phocomelia of upper limbs (8) Complete transposition of great vessels in heart (9) In none of these cases is there a clear relationship between use of the drug and the defect. Extrapyramidal symptoms have been described in a newborn exposed to trifluoperazine in utero, but the reaction was probably caused by chlorpromazine (see Chlorpromazine) (10).
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 42 of whom had 1st-trimester exposure to trifluoperazine (11). No evidence was found to suggest a relationship to malformations or an effect on perinatal mortality rate, birth weight, or intelligence quotient scores at 4 years of age.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 29 newborns had been exposed to trifluoperazine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (3.4%) major birth defect (one expected), a cardiovascular malformation (0.5 expected), was observed.
Attempted maternal suicide at 31 weeks’ gestation with trifluoperazine and misoprostol resulting in fetal death has been described (12). The adverse fetal outcome was attributed to tetanic uterine contractions caused by misoprostol (see Misoprostol).
In summary, although some reports have attempted to link trifluoperazine with congenital defects, the bulk of the evidence indicates that the drug is safe for mother and fetus. Other reviewers have also concluded that the phenothiazines are not teratogenic (13,14).
Breast Feeding Summary
No reports describing the use of trifluoperazine during lactation have been located. The molecular weight (about 480 for the dihydrochloride salt) is low enough, however, that passage into milk should be anticipated. The effects of this exposure on a nursing infant are unknown, but other closely related drugs (e.g., see Chlorpromazine) are classified by the American Academy of Pediatrics as agents that may be of concern during breast feeding because of toxicity in the infant, and because of galactorrhea induced in adults (15).
- Moya F, Thorndike V. Passage of drugs across the placenta. Am J Obstet Gynecol 1962;84:177898.
- Product information. Stelazine. SmithKline Beecham Pharmaceuticals, 2000.
- Canadian Department of National Health and Welfare, Food and Drug Directorate. Letter of notification to Canadian physicians. Ottawa, December 7, 1962.
- Moriarity AJ. Trifluoperazine and congenital malformations. Can Med Assoc J 1963;88:97.
- Moriarty AJ, Nance MR. Trifluoperazine and pregnancy. Can Med Assoc J 1963;88:3756.
- Schrire I. Trifluoperazine and foetal abnormalities. Lancet 1963;1:174.
- Corner BD. Congenital malformations. Clinical considerations. Med J Southwest 1962;77:4652.
- Hall G. A case of phocomelia of the upper limbs. Med J Aust 1963;1:44950.
- Vince DJ. Congenital malformations following phenothiazine administration during pregnancy. Can Med Assoc J 1969;100:223.
- Hill RM, Desmond MM, Kay JL. Extrapyramidal dysfunction in an infant of a schizophrenic mother. J Pediatr 1966;69:58995.
- Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S. Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score. Am J Obstet Gynecol 1977;128:4868.
- Bond GR, Zee AV. Overdosage of misoprostol in pregnancy. Am J Obstet Gynecol 1994;171:5612.
- Ayd FJ Jr. Children born of mothers treated with chlorpromazine during pregnancy. Clin Med 1964;71:175863.
- Ananth J. Congenital malformations with psychopharmacologic agents. Compr Psychiatry 1975;16:43745.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.