Diphenhydramine / pseudoephedrine Pregnancy and Breastfeeding Warnings

Brand names: Actifed Allergy Day/Night, Benadryl Allergy Sinus, Benadryl Children's Allergy And Sinus, Benaphen Plus, Benylin Multi-Symptom, Respa SA, Tavist NightTime Allergy, Tekral

Diphenhydramine / pseudoephedrine Pregnancy Warnings

Diphenhydramine-pseudoephephrine has been not been formally assigned to a pregnancy category by the FDA.

Pseudoephedrine has not been formally assigned to a pregnancy category by the FDA. Pseudoephedrine has been assigned to pregnancy Risk Factor C by Briggs et al. Animal studies have revealed evidence of teratogenicity. There are no controlled data in human pregnancy. Pseudoephedrine is only recommended for use during pregnancy when benefit outweighs risk.

Diphenhydramine has been assigned to pregnancy category B by the FDA. Animal studies have failed to reveal teratogenicity. The Collaborative Perinatal Project reported 595 first-trimester exposures and 2,948 exposures anytime during pregnancy. No relationship was found to large categories of malformations. Possible associations with individual malformation were found. One study reported a statistical relationship between diphenhydramine use in the first trimester and cleft palate. One case of withdrawal in an infant whose mother ingested 150 mg per day of diphenhydramine has been reported. This infant developed tremor on the fifth day of life which was treated with phenobarbital. Diphenhydramine is only recommended for use during pregnancy only when benefit outweighs risk. Diphenhydramine has been assigned to pregnancy category B by the FDA. Animal studies have failed to reveal teratogenicity. The Collaborative Perinatal Project reported 595 first-trimester exposures and 2,948 exposures anytime during pregnancy. No relationship was found to large categories of malformations. Possible associations with individual malformation were found. One study reported a statistical relationship between diphenhydramine use in the first trimester and cleft palate. One case of withdrawal in an infant whose mother ingested 150 mg per day of diphenhydramine has been reported. This infant developed tremor on the fifth day of life which was treated with phenobarbital. Diphenhydramine is only recommended for use during pregnancy when benefit outweighs risk.

The Collaborative Perinatal Project reported 595 first-trimester exposures and 2948 exposures any time during pregnancy to diphenhydramine. No relationship was found to large categories of malformations. Possible associations with individual malformations were found. One study reported a statistically significant relationship between diphenhydramine use in the first trimester and cleft palate. One case of withdrawal has been reported in an infant whose mother ingested 150-mg of diphenhydramine per day during pregnancy. On the fifth day of life, this infant developed tremor which was treated with phenobarbital.

A review of prenatal drug use in 3026 women with premature infants demonstrated an increased risk of retrolental fibroplasia with antihistamine use during the last two weeks of pregnancy. The dosage used or the particular antihistamine was not specified. The incidence of retrolental fibroplasia in premature infants exposed in utero to antihistamine during this time was 21% compared to 11% in premature infants not exposed.

A case-controlled surveillance study reported an elevated relative risk (3.2) of gastroschisis with first-trimester pseudoephedrine use in 76 cases. The relative risk for other drugs was 1.6 for salicylates, 1.7 for acetaminophen, 1.3 for ibuprofen, and 1.5 for phenylpropanolamine (not significant). The authors hypothesized vascular disruption was the etiology of gastroschisis. A second group of 416 infants with heterogenous defects suspected to have a vascular etiology was reviewed. There was no increased risk associated with salicylates, ibuprofen, pseudoephedrine, phenylpropanolamine, or other decongestants. These data require independent confirmation.

In a review of 229,101 deliveries to Michigan Medicaid patients, 940 first-trimester exposures to pseudoephedrine and 1919 exposures anytime during pregnancy were recorded. A total of 37 birth defects were reported with first trimester exposure (40 expected) and included (observed/expected) 3/9 cardiovascular defects, 2 oral clefts, and 3.2 polydactyly. These researchers reviewed nine cases of abdominal wall defects in the 1980-1983 Medicaid data compared to 3752 pseudoephedrine-exposed pregnancies. Seven of the nine cases had been exposed to pseudoephedrine providing a relative risk of 1.8. Only one case was a surgically treated abdominal wall defect. (written communication, Franz Rosa, MD, Food and Drug Administration, 1994)

The Collaborative Perinatal Project monitored 50,282 mother-child pairs. Only 39 first-trimester exposures to pseudoephedrine were recorded, with one birth defect observed. For use anytime during pregnancy, 194 exposures were recorded with three birth defects observed (3.22 expected).

The effect of pseudoephedrine on uterine and fetal blood flow was studied in 12 healthy pregnant women between 26 and 40 weeks gestation. Following a single 60-mg dose of pseudoephedrine, no significant effect was seen on fetal heart rate, uterine blood flow, or fetal aortic blood flow.

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Diphenhydramine / pseudoephedrine Breastfeeding Warnings

Diphenhydramine is excreted into human milk and may also inhibit lactation. Because newborns and infants have a higher sensitivity to antihistamines, diphenhydramine use is not recommended in nursing mothers by the manufacturer.

Pseudoephedrine is also excreted into human milk. Three mothers given pseudoephedrine demonstrated milk concentrations consistently higher than plasma concentrations. Maximum milk concentrations were reached 1 to 1.5 hours after dosing. In one woman, the milk:plasma concentration ratio at 1,3, and 12 hours was 3.3, 3.9, and 2.6, respectively. The authors calculated that 1000 mL of breast milk consumed over 24 hours would provide an infant with 0.25 to 0.33 mg of pseudoephedrine or 0.5% to 0.7% of the dose ingested by the mother. There are no reports of adverse effects in infants who were exposed to pseudoephedrine by breast milk. The American Academy of Pediatric considers pseudoephedrine to be compatible with breast-feeding.

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Further information

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