Intrauterine exposure to efavirenz

In pre-clinical studies, efavirenz showed teratogenic effects in 3/13 exposed foetal monkeys, including severe neural tube defects in one. Efavirenz was given to the pregnant monkeys early in pregnancy in the period analogous to the human first trimester. As a result this drug is contraindicated in pregnancy.

A report from a French database survey of patients attending four hospitals in Seine-Saint-Denis, evaluated the effect on 10 pregnancies (out of 349 followed in this study since 1999), in which women inadvertently received efavirenz in the first trimester, including three that resulted in abnormalities.

Of the 10 pregnancies, six women delivered: there was one spontaneous abortion at eight weeks gestation, one voluntary abortion at six weeks and four days – and two therapeutic abortions at 24 weeks and 18 weeks and four days of pregnancy.

Abnormalities were observed in three infants: one had facial dysmorphy, another facial dysmorphy and severe hypotrophy and a third lung segmentation abnormalities, bicuspid pulmonary valves and severe accelerated skeletal maturation. The exposure periods to efavirenz were the first three weeks, the first six weeks and four days and the first 18 weeks and four days of gestation respectively.

The investigators reported that in this small study: “It is not certain that there is a relationship between efavirenz exposure and the described abnormalities.” Nevertheless inadvertent exposure to efavirenz in pregnancy is not uncommon and the investigators stress the importance of pharmacovigilance notification in all possible foetal or childhood abnormalities possibly related to intrauterine exposure to efavirenz.

Ref: Khoung-Josses MA, Jeantils V, Delassus JL et al. Abnormalities and intrauterine exposure to efavirenz. 9th EACS, Warsaw. 25-29 October 2003. Abstract 4.5/1.

Comment

It would be unwise to read too much into this abstract. Facial dysmorphism in infants is not easily defined, and no details were given in the poster.

Rubinstein et al originally described a syndrome of facial dysmorphism that they ascribed to ‘congenital HIV infection’ which has been convincingly refuted in subsequent studies.

It has frequently been pointed out that no other antiretroviral drug has been tested in the foetal monkey, thus efavirenz may have acquired an unfair reputation for teratogenicity. Data from the international Antiretroviral Pregnancy Registry have not suggested any adverse fetal effects from exposure to efavirenz.

Prospective pharmacovigilance notification of all pregnancies in which antiretrovirals are used is essential in order to evaluate potential toxicities in human fetuses and young infants.

All physicians prescribing antiretrovirals to pregnant women are encouraged to report prospectively to the Registry which can be accessed at www.apregistry.com