What is the documentation about the use of ivermectin in pregnancy?/nThe questioner wants to update

Fråga: What is the documentation about the use of ivermectin in pregnancy?

The questioner wants to update a database, infpreg, concerning treatment of parasite diseases.

Sammanfattning: The WHO recommendation is that ivermectin should not be used in the first trimester even as a treatment for onchocerciasis, though there has been no increase in stillbirths, miscarriages or malformations in the three studies we found with about 350 women who were treated though they were pregnant. A search in the present literature indicates that more studies are needed. With the limited data available a restrictive use of ivermectin during pregnancy is recommended.

Svar: Ivermectin consists of two avermectins, avermectin B1a and avermectin B1b, and has been used against parasites in many animals for thirty years and in humans for two decades. Its mode of action is poorly understood but it alters the transfer of chloride ions across cell membrane ion channels and immobilizes microfiliariae by blocking postsynaptic neurotransmission. This makes it easier for the immune system to eliminate them. It appears to be a GABA-agonist (1).

Ivermectin is used in mass treatment programmes in countries where onchocerciasis, river blindness, is endemic. Those excluded are pregnant women, women who breast feed recently born babies, children weighing less than 15 kg and seriously ill (2). There have been reports of neurotoxicity in some breeds of dogs, though this has not been seen in cattle, horses or humans. Defects in the blood-brain barrier is thought to make some dogs vulnerable to ivermectin, which usually does not penetrate the blood-brain barrier (3). One report implied an increased death rate in elderly patients who were treated for scabies (4), but the statistical method used was afterwards questioned (5).

We have found two studies (6, 7) where women who were not aware of their being pregnant were unintentionally treated with ivermectin and one where most of the treated women did not know they were pregnant (8).

In the first study 203 children to women who received ivermectin during pregnancy were studied and no increase in malformations, stillbirths or miscarriages was seen (6). Most of the women were probably in the first trimester when they received ivermectin, but this is not well specified. In the second study 110 pregnant women received ivermectin and no increase in abortions, miscarriages or stillbirths was seen (7). Among those women 85% were under 4 months pregnant when they were treated. There was no increase in risk when a group of 97 mothers who were treated in the first trimester was compared with 142 untreated mothers either (7). In another study 50 pregnant women took ivermectin and albendazole in combination, without any observed increased risk of abortion or malformations (8). The majority of the women who took it did so because they did not know they were pregnant or because they did not know that they should not take it.

Ivermectin caused cleft palate in animal studies (9), but it is unclear if it passes the human placenta. Avermectin B1a is a P-glycoprotein substrate in the placenta and has caused cleft palate in mice fetuses lacking P-glycoprotein (10). However, the teratogenicity in the animal studies was only seen with doses near maternal toxicity and no teratogenicity has been observed in humans (9).

WHO has stated that the risk of blindness in onchocerciasis makes usage only after the first trimester probably acceptable (9). Richard-Lenoble D, Chandenier J, Gaxotte P. Ivermectin and filariasis. Fundam Clin Pharmacol 2003;17:199-203.

Martindale - The Complete Drug Reference. Thomson MICROMEDEX, Greenwood Village, Colorado (Edition expires (date))
Bredal WP. Deaths associated with ivermectin for scabies. Lancet 1997;350;216.
Barkwell R, Shields S. Deaths associated with ivermectin for scabies. Lancet 1997;349:1144-5.
Coyne PE, Addiss DG. Deaths associated with ivermectin for scabies. Lancet 1997;350;215-216.

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. Chippaux JP, Gardon-Wendel N, Gardon J, Ernould J-C. Absence of any adverse effects of in advertent ivermectin treatment during pregnancy. Trans R Soc Trop Med Hyg 1993;87:318. Gyapong JO, Chinbuah MA, Gyapong M. Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis. Inadvertent exposure of pregnant women to ivermectin and albendazole during mass drug administration for lymphatic filariasis. Trop Med Int Health 2003;8(12):1093-1101. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7th ed. Philadelphia: Lippincott Williams & Wilkins; 2005 Lankas GR, Wise LD, Cartwright ME, Pippert T, Umbenhauer DR. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod Toxicol 1998;8(4):457-63.