Risk Factor: C
Class: Gastrointestinal agents/ Antiemetics

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary

Fetal Risk Summary

Promethazine is a phenothiazine antihistamine that is sometimes used as an antiemetic in pregnancy and as an adjunct to narcotic analgesics during labor.

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 114 of which had promethazine exposure in the 1st trimester (1, pp. 323324). For use anytime during pregnancy, 746 exposures were recorded (1, p. 437). In neither group was evidence found to suggest a relationship to large categories of major or minor malformations or to individual defects. A 1964 report also failed to show an association between 165 cases of promethazine exposure in the 1st trimester and malformations (2). In a 1971 Reference, infants of mothers who had ingested antiemetics during the 1st trimester actually had significantly fewer abnormalities when compared with controls (3). Promethazine was the most commonly used antiemetic in this latter study.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1,197 newborns had been exposed to promethazine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 61 (5.1%) major birth defects were observed (51 expected). Specific data were available for six defect categories, including (observed/expected) 1/2 oral clefts, 0/1 spina bifida, 4/3 polydactyly, 1/2 limb reduction defects, 1/3 hypospadias, and 17/12 cardiovascular defects. Only with the latter defect is there a suggestion of a possible association, but other factors, including the mother’s disease, concurrent drug use, and chance, may be involved.

At term, the drug rapidly crosses the placenta, appearing in cord blood within 1.5 minutes of an IV dose (4). Fetal and maternal blood concentrations are at equilibrium in 15 minutes, with infant levels persisting for at least 4 hours.

Several investigators have studied the effect of promethazine on labor and the newborn (5,6,7,8,9,10,11,12 and 13). Significant neonatal respiratory depression was seen in a small group of patients (5). However, in three large series, no clinical evidence of promethazine-induced respiratory depression was found (6,7 and 8). In a series of 33 mothers at term, 28 received either promethazine alone (one patient) or a combination of meperidine with promethazine or phenobarbital (27 patients). Transient behavioral and electroencephalographic changes, persisting for less than 3 days, were seen in all newborns (10). These and other effects prompted one author to recommend that promethazine should not be used during labor (14).

Maternal tachycardia as a result of promethazine (mean increase 30 beats/minute) or promethazine-meperidine (mean increase 42 beats/minute) was observed in one series (9). The maximum effect occurred about 10 minutes after injection. The fetal heart rate did not change significantly.

The antiemetic effects of promethazine 25 mg and metoclopramide 10 mg following the use of meperidine in labor were described in a study involving 477 women (13). Both drugs were superior to placebo as antiemetics, but significantly more of the promethazine-treated mothers had persistent sedation that extended into the immediate postpartum period. Moreover, an antianalgesic effect, as evidenced by pain score, duration of analgesia, and an increased need for meperidine, was observed when promethazine was used.

Fatal shock was reported in a pregnant woman with an undiagnosed pheochromocytoma given promethazine (15). A precipitous drop in blood pressure resulted from administration of the drug, probably secondary to unmasking of hypovolemia (15).

Effects on the uterus have been mixed, with both increases and decreases in uterine activity reported (8,9,11).

Promethazine used during labor has been shown to markedly impair platelet aggregation in the newborn but less so in the mother (12,16). Although the clinical significance of this is unknown, the degree of impairment in the newborn is comparable to those disorders associated with a definite bleeding state.

Promethazine has been used to treat hydrops fetalis in cases of anti-erythrocytic isoimmunization (17). Six patients were treated with 150 mg/day orally between the 26th and 34th weeks of gestation while undergoing intraperitoneal transfusions. No details on the infants’ conditions were given except that all were born alive. Other authors have reported similarly successful results in Rh-sensitized pregnancies (18,19). As described by some authors, doses up to 6.5 mg/kg/day may be required (18). However, a 1991 review concluded that the benefits of promethazine in the treatment of Rh immunization were marginal and may be hazardous to the fetus (20).

Two female anencephalic infants were born to mothers after ovulatory stimulation with clomiphene (21). One of the mothers had taken promethazine for morning sickness. No association between promethazine and this defect has been suggested.

Breast Feeding Summary

Available laboratory methods for the accurate detection of promethazine in breast milk are not clinically useful because of the rapid metabolism of phenothiazines (M. Lipshutz, personal communication, Wyeth Laboratories, 1981). Because of the low molecular weight (about 284), however, passage of the drug into breast milk, should be expected. The potential effects of this exposure on a nursing infant are unknown.



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