Anthelmintic
PREGNANCY RECOMMENDATION: Human Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Ivermectin was teratogenic in three animal species, but only at doses at or near those producing maternal toxicity. No teratogenicity or toxicity attributable to ivermectin has been observed in limited human pregnancy experience. A 1997 review, citing a World Health Organization reference, stated that because of the high risk of blindness from onchocerciasis, and the lack of reported adverse outcomes, the use of ivermectin after the 1st trimester was probably acceptable (1).
FETAL RISK SUMMARY
Ivermectin is a semisynthetic anthelmintic. It is a mixture of two components derived from the avermectins, a class of antiparasitic agents isolated from the fermentation of Steptomyces avermitilis. Ivermectin is indicated for the treatment of intestinal strongyloidiasis infections due to the nematode Strongyloides stercoralis and onchocerciasis due to the nematode Onchocerca volvulus (2).
In reproduction studies with mice, rats, and rabbits, ivermectin was teratogenic when given in repeated doses of 0.2, 8.1, and 4.5 times, respectively, the maximum recommended human dose based on BSA. The malformations observed, cleft palate (in all three species) and clubbed forepaws in rabbits, however, were only observed at or near doses producing maternal toxicity. The results were thought to indicate that ivermectin was not selectively toxic to the developing fetus (2).
It is not known if ivermectin crosses the human placenta. The molecular weights of the two components in the product, approximately 875 and 861, are low enough that some exposure of the embryo or fetus probably occurs.
A well-conducted study published in 1990 described the pregnancy outcomes of women who were inadvertently exposed to ivermectin during community-based ivermectin distribution programs (1987–1989) for onchocerciasis on a Liberian rubber plantation (14,000 people) (3). The average oral ivermectin dose was 150 mcg/kg as a single dose. Because the women did not recall the date of their last menstrual period before delivery, pregnancy exposure was defined as a delivery occurring within 40 weeks of treatment. During the distribution programs, 2884 women received treatment, including 200 (7%) that were inadvertently treated during pregnancy. Of those treated during pregnancy, 85% were treated in the first 12 weeks of pregnancy and 36% occurred within the first 4 weeks. The outcomes of all pregnancies were followed up by a field census team, systematic examination of all babies born at the hospital, and a year-round plantation-wide surveillance system of all births and deaths. All children under 12 months of age were examined by a physician and children aged 12–24 months were examined by a pediatrician. Among the 203 pregnancy outcomes from exposed pregnancies, there were 10 (4.9%) abnormal events—5 stillbirths and 5 congenital malformations (single-dose exposure in weeks before delivery shown in parentheses): anal atresia (34 weeks); cleft palate and lip (33 weeks); Pierre–Robin syndrome, micrognathia, glossoptosis, low-slung ears, and shortening of limbs in a stillborn infant (32 weeks); Turner’s syndrome (24 weeks); and deafness plus probable ventricular septal defect (VSD) (33 weeks). Among the 1767 pregnancy outcomes not exposed to ivermectin, there were 76 (4.3%) abnormal events: 55 stillbirths or miscarriages and 21 congenital anomalies. The congenital anomalies were: polydactyly (N = 6), convergent strabismus (N = 3), talipes equinovarus (N = 2), unspecified (N = 2), and 1 each deafness, facial malformations, hypopigmented skin, hypospadias, microcephaly, Down’s syndrome, syndactyly, and VSD. There were no significant differences between the treated and untreated groups in the rates of congenital malformations, stillbirths, or all abnormalities (congenital malformations, stillbirths, and miscarriages). Also, no statistical differences were found in terms of health status and malformations between infants (aged 2–7 months) and children (aged 12–24 months) whose mothers had been treated in comparison with untreated controls, matched for age, sex, and distance from the hospital (3).
A brief 1993 communication from Cameroon described the outcomes of pregnancies in 110 women who had inadvertently received ivermectin treatment during a mass treatment campaign for onchocerciasis (4). During the 2-year campaign, 401 of 2710 women were excluded from treatment because of pregnancy. Of the remaining 2309 women who were treated, 110 were discovered to be pregnant during regularly scheduled follow-up. Treatment was considered to have been given during pregnancy if delivery occurred within 40 weeks of ivermectin distribution. A comparison of the 110 women treated during gestation with the 401 pregnant women who did not receive treatment revealed no statistical differences in early abortion (<4 months) (3.6% vs. 2.2%), late abnormal events (abortion, miscarriage, stillbirth) (15.5% vs. 11%), children lost to follow-up (7.3% vs. 11.2%), infants with malformations (0 vs 0.5%), or normal infants (74.5% vs. 75.8%). The prevalence of all abnormal obstetric events of treated women was similar to that of those not treated (p >0.37). Only two newborns with congenital malformations were observed, both in the untreated group. In a second analysis, pregnancy outcomes of 97 women treated in the 1st trimester were compared with the outcomes of 142 untreated women. As before, no statistical differences were observed. The authors concluded that ivermectin did not present a major risk to the fetus (4).
BREASTFEEDING SUMMARY
Ivermectin is excreted into breast milk, but its use during breastfeeding has not been reported. Four healthy women, who had lost their babies at birth, were given a single 150 mcg/kg oral ivermectin dose after an overnight fast (5). Ivermectin was detected in the plasma and breast milk within 1 hour. The mean peak concentration in plasma was 37.9 ng/mL and in milk was14.1 ng/mL. The mean milk:plasma ratio was 0.51 (range 0.39–0.57). The steady-state ivermectin concentration in milk over a 24-hour period was approximately 10 ng/mL. The investigators estimated that the dose a 1-month-old African infant would receive from breast milk was 2.75 mcg/kg. This dose is much lower than an estimated dose of 21.8 mcg/kg they calculated for a 1-month-old infant (5). (Note: In the United States, because the safety and effectiveness have not been established, ivermectin is not recommended for children weighing<15 kg [1]). In Nigeria, where the study was conducted, lactating women within the first week of breastfeeding were excluded from community-wide ivermectin distribution because of the concerns for infant safety (5). The investigators concluded, however, that the benefits of treatment for the lactating woman, combined with the impracticality of withholding nursing for a week, the low drug levels in milk, and the lack of reported adverse effects in nursing infants in their population, suggested that the drug should be given to the mother regardless of her lactation status (5). The American Academy of Pediatrics classifies ivermectin as compatible with breastfeeding (6).
References
1.de Silva N, Guyatt H, Bundy D. Anthelmintics. A comparative review of their clinical pharmacology. Drugs 1997;53:769–88.
2.Product information. Stromectol. Merck, 2002.
3.Pacque M, Munoz B, Poetschke G, Foose J, Greene BM, Taylor HR. Pregnancy outcome after inadvertent ivermectin treatment during community-based distribution. Lancet 1990;336:1486–9.
4.Chippaux JP, Gardon-Wendel N, Gardon J, Ernould JC. Absence of any adverse effect of inadvertent ivermectin treatment during pregnancy. Tran R Soc Trop Med Hyg 1993;87:318.
5.Ogbuokiri JE, Ozumba BC, Okonkwo PO. Ivermectin levels in human breastmilk. Eur J Clin Pharmacol 1993;45:389–90.
6.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.