Atropine / diphenoxylate Pregnancy and Breastfeeding Warnings
Atropine / diphenoxylate Pregnancy Warnings
Atropine-diphenoxylate has been assigned to pregnancy category C by the FDA. Animal studies have revealed evidence of decreased maternal weight gain of 30% at 20 mg/kg/day (50 times the maximum recommended human dose, on a per kg basis) and 10% at 4 mg/kg/day (10 times MRHD). There is also evidence of decreased average litter size at 4 mg/kg/day. Adequate teratologic data are not available. There are no controlled data in human pregnancy. Atropine-diphenoxylate should only be given during pregnancy when there are no alternatives and benefit outweighs risk.
The use of atropine-diphenoxylate has been associated with congenital anomalies (rare case reports). In one case the mother had taken atropine-diphenoxylate for diarrhea (probably of a viral etiology) during gestational week 10. A term infant was born at 36 weeks' gestation with multiple defects, including Ebstein's anomaly, hypertelorism, epicanthal folds, low-set ears, a cleft uvula, deafness, and blindness. Since exposure to atropine or diphenoxylate was at a later time during her gestation than when these stages of development are known to occur, the authors of this case report did not consider the drugs causative of the anomalies. The Michigan Medicaid surveillance study (MMSS) showed no association between the use of diphenoxylate and congenital defects (written communication, Franz Rosa, MD, Food and Drug Administration, 1994). This report is a retrospective study of 179 of 229,101 pregnant women who received diphenoxylate during the first trimester between 1985 to 1992. Nine total defects and three cardiovascular defects were observed (seven and two were expected, respectively). The incidences of total and cardiovascular defects were not statistically greater than expected. Cleft palate was not observed. Of the 229,101 deliveries, 562 were exposed to atropine at some time during pregnancy. There were no statistically significant differences between the observed and expected incidences of brain or eye abnormalities among these 562. These data do not support an association between the use of diphenoxylate and some congenital defects. The MMSS did, however, show an association between the use of atropine and congenital defects. Of 381 of 229,101 pregnant women who received atropine during the first trimester between 1985 to 1992, 18 total defects and 4 cardiovascular defects were observed (16 and 4 were expected, respectively). The incidences of total and cardiovascular defects were not statistically greater than expected, but a statistically significant incidence of limb reduction defects was observed (2 observed; 0.4 expected). Cleft palate was not observed. Of the 229,101 deliveries, 3,996 were exposed to atropine during pregnancy. There were no statistically significant differences between the observed and expected incidences of brain or eye abnormalities among these 3,996. These data support an association between the use of atropine and some congenital defects, although other factors, such as underlying disease(s) of the mother and concomitant medications were not controlled. Atropine rapidly crosses the human placenta. In one study of 44 healthy pregnant women, a maximum umbilical to maternal vein ratio of 1.27 was observed 6 minutes after administration of 0.01 mg/kg intravenously. The corresponding maternal and umbilical vein atropine levels were 17 and 12 nmol/L, respectively. The concentrations after intramuscular injection were lower. In another study of 25 pregnant women, labeled atropine was given intravenously prior to delivery to quantify placental transfer and fetal distribution of the drug. The concentrations in the umbilical vein 1 and 5 minutes after injection were 12% and 93%, respectively, of the corresponding maternal value. Concentrations in the umbilical artery were approximately 50% of those in the umbilical vein during the same period. Studies have shown that administration of atropine to a pregnant woman during the last trimester can mask the effects of vagal stimulation on the fetal heart, producing tachycardia within 5 to 30 minutes after injection. Limited data have shown that atropine can suppress fetal breathing, although fetal hypoxia has not been observed. There has also been concern that atropine could reduce lower esophageal sphincter pressure enough to predispose the newborn to aspiration. Uterine contractility does not appear to be significantly affected by atropine. This is thought to be due to a decrease in the sensitivity of muscarinic receptors on myometrial tissue during pregnancy. The Collaborative Perinatal Project monitored 50,282 mother-child pairs, of which 401 pairs were exposed to atropine during lunar months 1 through 4. Of the 401 pairs, 25 malformed children were observed. The calculated crude relative risk for malformation associated with atropine was 0.96. These data do not support an association between the use of atropine and congenital defects. Of the 50,282 mother-child pairs, 2,323 pairs had been exposed to parasympatholytic drugs, in general. Of these 2,323 pairs, 168 malformed children were observed, yielding a crude relative risk of 1.13. These data support an association between the use of parasympatholytic agents and congenital defects.
Atropine / diphenoxylate Breastfeeding Warnings
There are no data on the excretion of diphenoxylate into human milk. Atropine is probably excreted into human milk. The manufacturer recommends caution since the physicochemical characteristics of a major metabolite, diphenoxylic acid, are such that it may be excreted in breast milk. Some experts recommend cautious use of atropine during breast-feeding because of neonates' sensitivity to anticholinergic agents (probably because of immaturity of motor end-plates). The gastrointestinal bioavailability of neither drug in neonates has been reported. The American Academy of Pediatrics considers atropine (no mention of diphenoxylate) to be compatible with breast-feeding.
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