Cimetidine is an H2-receptor antagonist that inhibits gastric acid secretion. In pregnancy, the antihistamine is primarily used for the treatment of peptic ulcer disease and for the prevention of gastric acid aspiration (Mendelson's syndrome) prior to delivery.
In studies with multiple animal species, no evidence of impaired fertility or teratogenesis was observed with doses up to 40 times higher than the usual human dose (1). Cimetidine does have weak antiandrogenic effects in animals, as evidenced by a reduction in the size of testes, prostatic glands, and seminal vesicles (2,3), and in humans, by reports of decreased libido and impotence (4). Conflicting reports on the antiandrogenic activity in animals exposed in utero to cimetidine have been published (5,6,7,8 and 9).
Three references, all from the same research group, described the effects on male rats of exposure to cimetidine from gestation up to the time of weaning (5,6 and 7). The rats had decreased weights of testicles, prostate gland, and seminal vesicles at 55 and 110 days of age as compared to nonexposed controls. Exposed animals also had reduced testosterone serum levels, lack of sexual motivation, and decreased sexual performance, but normal luteinizing hormone levels. The observed demasculinization effects were still present 35 days after discontinuation of the drug, indicating that exposure may have modified both central and end-organ androgen receptor activity or responsiveness (5,6 and 7). In contrast, researchers from the manufacturer treated rats similarly to rats in the above reports and found no effect on any of the parameters described previously (8). Another group found no effect of cimetidine exposure during gestation and lactation on masculine sexual development, except for an insensitivity of the pituitary gland to androgen regulation, and no effect at all on female pups (9). These authors concluded that cimetidine was not an animal teratogen.
Cimetidine crosses the placenta to the fetus by simple diffusion (10,11,12,13 and 14). In an in vitro study, the placental transfer of cimetidine across human and baboon placentas was similar (10). Cimetidine is not metabolized by the placenta (11). At term, cimetidine crosses the placenta, resulting in a peak mean fetal:maternal ratio of 0.84 at 1.5-2 hours (12). In an earlier study, 20 women were administered a single, 200-mg bolus injection of cimetidine prior to delivery (19 vaginal, 1 cesarean section) (13). The drug was detected in all but two cord blood samples with levels ranging from 0.05-1.22 pg/mL. The injection-to-delivery intervals in the two patients with no cimetidine in cord blood were prolonged, 435 and 780 minutes. A 1983 study measured a peak mean fetal:maternal ratio of about 0.5 at 2.5 hours (14).
The manufacturer has received a number of reports of women who took the drug during pregnancy, including throughout gestation (B. Dickson, personal communication, Smith Kline & French Laboratories, 1986). They are aware of three isolated incidences of congenital defects, apparently unrelated to cimetidine therapy, including congenital heart disease, mental retardation detected later in life, and clubfoot.
The drug has been used throughout pregnancy in a case ending in intrauterine fetal death, but the adverse outcome was believed to be due to severe maternal disease and captopril therapy (see Captopril) (15). Three pregnant women with gastric hemorrhage secondary to peptic ulcer disease were described in a 1982 report (16). The women, at 16, 12, and 31 weeks' gestation, were treated for various lengths of time with cimetidine and other standard therapy and all delivered healthy newborns without congenital defects or metabolic disturbances. Transient liver impairment has been described in a newborn exposed to cimetidine at term (17). However, other reports have not confirmed this toxicity (13,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34 and 35).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 460 newborns had been exposed to cimetidine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 20 (4.3%) major birth defects were observed (20 expected). Specific data were available for six defect categories, including (observed/expected) 8/5 cardiovascular defects, 0/1 oral clefts, 0/0 spina bifida, 1/1 polydactyly, 0/1 limb reduction defects, and 1/1 hypospadias. These data do not support an association between the drug and congenital defects.
Cimetidine has been used at term either with or without other antacids to prevent maternal gastric acid aspiration pneumonitis (Mendelson's syndrome) (13,^,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34 and 35). No neonatal adverse effects were noted in these studies.
Data from the Swedish Medical Birth Registry were presented in 1998 (36). A total of 553 infants (6 sets of twins) were delivered from 547 women who had used acid-suppressing drugs early in pregnancy. A number of other pharmaceutical agents, identified only by drug category, were also used by these women. Seventeen infants with birth defects were identified (3.1%; 95% confidence interval [CI] 1.8-4.9) compared with the crude malformation rate of 3.9% in the Registry. The odds ratio (OR) for a congenital malformation, stratified for birth year, maternal age, parity, and smoking was 0.72 (95% CI 0.41-1.24 (36). The OR for malformations after proton pump blocker exposure was 0.91 (95% CI 0.45-1.84) compared with 0.46 (95% CI 0.17-1.20) for H2-receptor antagonists (OR 0.86, 95% CI 0.33-2.23; p=0.13). Of the 17 infants with birth defects, 10 had been exposed to proton pump blockers, 6 to H2 antagonists, and 1 to both classes of drug. Cimetidine was the only acid-suppressing drug exposure in 35 infants. Three other offspring were exposed in utero to cimetidine combined either with famotidine (one infant) or with omeprazole (two infants). Two birth defects (5.7%) were observed in the group where cimetidine was the only acid-suppressing agent used. The defects were an encephalocele and an unstable hip (36).
Two databases, one from England and the other from Italy, were combined for a study published in 1999 that was designed to assess the incidence of congenital malformations in women who had received a prescription during the 1st trimester for an acid-suppressing drug (cimetidine, ranitidine, and omeprazole) (37). Nonexposed women were selected from the same databases to form a control group. Spontaneous abortions and elective abortions (except two cases for anomalies that were grouped with stillbirths) were excluded from the analysis. Stillbirths were defined as any pregnancy loss occurring at 28 weeks' gestation or later. Cimetidine was taken in 233 pregnancies, resulting in 234 live births (14 [6.0%] premature), 3 stillbirths, and 1 neonatal death. Eleven (4.7%) of the newborns had a congenital malformation (shown by system): craniofacial (cleft lip and palate), musculoskeletal (dysplastic hip/dislocation/clicking hip N=3; polydactyly), genital and urinary (hypospadias N=2; congenital hydrocele/inguinal hernia, ovarian cyst, renal defects/hydronephrosis), and gastrointestinal (pyloric stenosis). In addition, two newborns had a small head circumference for gestational age. In comparison, the outcomes of 1,547 nonexposed pregnancies included 1,560 live births (115 [7.4%] premature), 15 stillbirths (includes 2 elective abortions for anomalies), and 10 neonatal deaths. Sixty-four (4.1%) of the newborns had malformations involving the following: central nervous system (N=2), head/face (N=13), eye (N=2), heart (N=7), muscle/skeletal (N=13), genital/urinary (N=18), gastrointestinal (N=2), and those of polyformation (N=3) or known genetic defects (N=4). There were 21 newborns that were small for gestational age and 78 had a small head circumference for gestational age. The relative risk of malformation (adjusted for mother's age and prematurity) associated with cimetidine was 1.3 (95% CI 0.7-2.6), with omeprazole 0.9 (95% CI 0.4-2.4), and with ranitidine 1.5 (95% CI 0.9-2.6) (37).
In summary, no increased risk of congenital malformations attributable to cimetidine in humans have been reported. One group of reviewers has recommended that the drug not be used during pregnancy because of the possibility for feminization, as observed in some animals and in nonpregnant humans (38). Apparently, this potential toxicity has not been studied in humans exposed in utero to cimetidine, but research in this area is warranted.
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