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DIPHENHYDRAMINE

Fetal Risk Summary

Diphenhydramine is a first generation antihistamine agent. Reproductive studies with diphenhydramine in rats and rabbits at doses up to 5 times the human dose revealed no evidence of impaired fertility or fetal harm (1). Rapid placental transfer of diphenhydramine has been demonstrated in pregnant sheep with a fetal:maternal ratio of 0.85 (2). Peak fetal concentrations occurred within 5 minutes of a 100-mg IV dose.

The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 595 of which had 1st trimester exposure to diphenhydramine (3, pp. 323–37). For use anytime during pregnancy, 2,948 exposures were recorded (3, p. 437). In neither case was evidence found to suggest a relationship to large categories of major or minor malformations. Several possible associations with individual malformations were found, but the statistical significance of these is unknown and independent confirmation is required to determine the actual risk (3, pp. 323–37,437,475).

Genitourinary (other than hypospadias) (5 cases) Hypospadias (3 cases) Eye and ear defects (3 cases) Syndromes (other than Down's syndrome) (3 cases) Inguinal hernia (13 cases) Clubfoot (5 cases) Any ventricular septal defect (open or closing) (5 cases) Malformations of diaphragm (3 cases) Cleft palate and diphenhydramine usage in the 1st trimester were statistically associated in a 1974 case-control study (4). A group of 599 children with oral clefts were compared to 590 controls without clefts. In utero exposures to diphenhydramine in the groups were 20 and 6, respectively, a significant difference. However, in a 1971 report significantly fewer infants with malformations were exposed to antihistamines in the 1st trimester as compared to controls (5). Diphenhydramine was the second most commonly used antihistamine. In addition, a 1985 study reported 1st trimester use of diphenhydramine in 270 women from a total group of 6,509 (6). No association between the use of the drug and congenital abnormalities was found.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 1,461 newborns had been exposed to diphenhydramine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 80 (5.5%) major birth defects were observed (62 expected). Specific data were available for six defect categories, including (observed/expected) 14/14 cardiovascular defects, 3/2 oral clefts, 0/1 spina bifida, 9/4 polydactyly, 1/2 limb reduction defects, and 3/4 hypospadias. Possible associations with congenital defects are suggested for the total number of anomalies and for polydactyly, but other factors, including the mother's disease, concurrent drug use, and chance may be involved.

Diphenhydramine withdrawal was reported in a newborn infant whose mother had taken 150 mg/day during pregnancy (7). Generalized tremulousness and diarrhea began on the 5th day of life. Treatment with phenobarbital resulted in the gradual disappearance of the symptoms.

A stillborn, full-term, 1000-g female infant was exposed during gestation to high doses of diphenhydramine, theophylline, ephedrine, and phenobarbital, all used for maternal asthma (8). Except for a ventricular septal defect, no other macroscopic internal or external anomalies were observed. However, complete triploidy was found in lymphocyte cultures, which is unusual because very few such infants survive until term (8). No relationship between the chromosome abnormality or the congenital defect and the drug therapy can be inferred from this case.

A 1996 report described the use of diphenhydramine, droperidol, metoclopramide, and hydroxyzine in 80 women with hyperemesis gravidarum (9). The mean gestational age at the start of treatment was 10.9 ± 3.9 weeks. The patients received 200 mg/day IV of diphenhydramine for 2–3 days and 12 (15%) required a second course of therapy when their symptoms recurred. Three of the mothers (all treated in the 2nd trimester) delivered offspring with congenital defects: Poland's syndrome, fetal alcohol syndrome, and hydrocephalus and hypoplasia of the right cerebral hemisphere. Only the latter anomaly is a potential drug effect, but the most likely cause was thought to be the result of an in utero fetal vascular accident or infection (9).

A 2001 study, using a treatment method similar to the above study, described the use of droperidol and diphenhydramine in 28 women hospitalized for hyperemesis gravidarum (10). Pregnancy outcomes in the study group were compared to a historical control of 54 women who had received conventional anti-emetic therapy. Oral metoclopramide and hydroxyzine were used after discharge from the hospital. Therapy was started in the study and control groups at mean gestational ages of 9.9 and 11.1 weeks', respectively. The study group appeared to have more severe disease then controls as suggested by a greater mean loss from the pre-pregnancy weight, 2.07 kg vs. 0.81 kg (n.s.), and a slightly lower serum potassium level, 3.4 vs. 3.5 mmol/L (n.s.). Compared to controls, the droperidol group had a shorter duration of hospitalization (3.53 vs. 2.82 days, p=0.023), fewer readmissions (38.9% vs. 14.3%, p=0.025), and lower average daily nausea and vomiting scores (both p<0.001). There were no statistical differences (p>0.05) in outcomes (study vs. controls) in terms of spontaneous abortions (N=0 vs. N=2 [4.3%]), elective abortions (N=3 [12.0%] vs. N=3 [6.5%]), Apgar scores at 1, 5, and 10 minutes, age at birth (37.3 vs. 37.9 weeks'), and birth weight (3114 vs. 3347 g) (10). In controls, there was one (2.4%) major malformation of unknown cause, an acardiac fetus in a set of triplets, and one newborn with a genetic defect (Turner syndrome). There was also one unexplained major birth defect (4.4%) in the droperidol group (bilateral hydronephrosis), and two genetic defects (translocation of chromosomes 3 and 7; tyrosinemia) (10).

A potential drug interaction between diphenhydramine and temazepam resulting in the stillbirth of a term female infant has been reported (11). The mother had taken diphenhydramine 50 mg for mild itching of the skin and approximately 1.5 hours later, took 30 mg of temazepam for sleep. Three hours later she awoke with violent intrauterine fetal movements, which lasted several minutes and then abruptly stopped. The stillborn infant was delivered approximately 4 hours later. Autopsy revealed no gross or microscopic anomalies. In an experiment with pregnant rabbits, neither of the drugs alone caused fetal mortality but when combined, 51 (81%) of 63 fetuses were stillborn or died shortly after birth (11). No definite mechanism could be established for the suggested interaction.

A 1980 report described the oxytocic properties of diphenydramine when used in labor (12). Fifty women were given 50 mg IV over 3.5 minutes in a study designed to compare its effect with dimenhydrinate (see also Dimenhydrinate). The effects on the uterus were similar to those of dimenhydrinate but not as pronounced. Although no uterine hyperstimulation or fetal distress was observed, the drug should not be used for this purpose due to these potential complications.

Regular (every 1–2 minutes with intervening uterine relaxation), painful uterine contractions were observed in a 19-year-old woman at 26 week's gestation, following ingestion of about 35 capsules of diphenhydramine and an unknown amount of acetaminophen in a suicide attempt (13). The uterine contractions responded promptly to IV magnesium sulfate tocolysis and 5 hours later, after treatment with oral activated charcoal for the overdose, no further contractions were observed. The eventual outcome of the pregnancy was not mentioned.

An association between exposure during the last 2 weeks of pregnancy to antihistamines in general and retrolental fibroplasia in premature infants has been reported. See Brompheniramine for details.

In summary, both the animal data and the published human experience suggest that diphenydramine is safe for use in human pregnancy. The exception is the case-control study showing an association with cleft palate. At least one review has concluded that diphenhydramine is the drug of choice if parenteral antihistamines are indicated in pregnancy (14).

Breast Feeding Summary

Diphenhydramine is excreted into human breast milk, but levels have not been reported (15). Although the levels are not thought to be sufficiently high to affect the infant after therapeutic doses, the manufacturer considers the drug contraindicated in nursing mothers (1). The reason given for this is the increased sensitivity of newborn or premature infants to antihistamines.

References

1. Product information. Benadryl. Parke-Davis, 1997.
2. Yoo GD, Axelson JE, Taylor SM, Rurak DW. Placental transfer of diphenhydramine in chronically instrumented pregnant sheep. J Pharm Sci 1986;75:685–7.
3. Heinonen OP, Sloan D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
4. Saxen I. Cleft palate and maternal diphenhydramine intake. Lancet 1974;1:407–8.
5. Nelson MM, Forfar JO. Associations between drugs administered during pregnancy and congenital abnormalities of the fetus. Br Med J 1971;1:523–7.
6. Aselton P, Jick H, Milunsky A, Hunter JR, Stergachis A. First-trimester drug use and congenital disorders. Obstet Gynecol 1985;65:451–5.
7. Parkin DE. Probable Benadryl withdrawal manifestations in a newborn infant. J Pediatr 1974;85:580.
8. Halbrecht I, Komlos L, Shabtay F, Solomon M, Bock JA. Triploidy 69,XXX in a stillborn girl. Clin Genet 1973;4:210–2.
9. Nageotte MP, Briggs GG, Towers CV, Asrat T. Droperidol and diphenhydramine in the management of hyperemesis gravidarum. Am J Obstet Gynecol 1996;174:1801–6.
10. Turcotte V, Ferreira E, Duperron L. Utilité du dropéridol et de la diphenhydramine dans l'hyperemesis gravidarum. J Soc Obstet Gynaecol Can 2001;23:133–9.
11. Kargas GA, Kargas SA, Bruyere HJ Jr, Gilbert EF, Opitz JM. Perinatal mortality due to interaction of diphenhydramine and temazepam. N Engl J Med 1985;313:1417.
12. Hara GS, Carter RP, Krantz KE. Dramamine in labor: potential boon or a possible bomb? J Kans Med Soc 1980;81:134–6,155.
13. Brost BC, Scardo JA, Newman RB. Diphenhydramine overdose during pregnancy: lessons from the past. Am J Obstet Gynecol 1996;175:1376–7.
14. Schatz M, Petitti D. Antihistamines and pregnancy. Ann Allergy Asthma Immunol 1997;78:157–9.
15. O'Brien TE. Excretion of drugs in human milk. Am J Hosp Pharm 1974;31:844–54.
    
    

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