Small risk of neurological birth defects due to efavirenz confirmed in French cohort

Jeanne Sibiude of Louis Mourier Hospital, France, presenting at CROI 2013.
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A large French study has found an elevated risk of some birth defects in children born to women exposed to some antiretroviral drugs during the first trimester of pregnancy, French researchers reported on 5 March at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) in Atlanta.

The study found an elevated risk of neurological defects in infants exposed to efavirenz (Sustiva or Stocrin) during the first trimester, and an elevated risk of heart defects in infants exposed to AZT (zidovudine, Retrovir) during the first trimester. The study also found an elevated risk of head and neck defects in infants exposed to either ddI (didanosine, Videx) or 3TC (lamivudine, Epivir) during the first trimester.

However, the number of children born with any specific birth defect apart from a heart defect was very small, and the increase in risk for any specific birth defect amounted was in the region of a two- to three-fold elevation.


adjusted odds ratio (AOR)

Comparing one group with another, expresses differences in the odds of something happening. An odds ratio above 1 means something is more likely to happen in the group of interest; an odds ratio below 1 means it is less likely to happen. Similar to ‘relative risk’. 


The result of a statistical test which tells us whether the results of a study are likely to be due to chance and would not be confirmed if the study was repeated. All p-values are between 0 and 1; the most reliable studies have p-values very close to 0. A p-value of 0.001 means that there is a 1 in 1000 probability that the results are due to chance and do not reflect a real difference. A p-value of 0.05 means there is a 1 in 20 probability that the results are due to chance. When a p-value is 0.05 or below, the result is considered to be ‘statistically significant’. Confidence intervals give similar information to p-values but are easier to interpret. 


Relating to the period around the time of birth. Perinatal transmission is when HIV is passed on during pregnancy, childbirth or breastfeeding. People with perinatally-acquired HIV have been living with HIV since birth or infancy.


Relating to the brain or central nervous system.


Relating to the period starting a few weeks before birth and including the birth and a few weeks after birth.

Almost all of the associations between specific drugs and types of birth defects were already known, and indeed, the study failed to detect any association between nelfinavir (Viracept) exposure and any elevated risk of birth defect, despite previous reports of an association. Nevertheless, the review of the French Paediatric Cohort is the largest study to date of the potential risks of birth defects attached to specific antiretroviral drugs.


Many birth defects are either genetically determined, or have multifactorial causes. In a small minority of cases they may be caused by exposure to chemicals, including medicines, during the first trimester of pregnancy. Due to the regulation of medicines, and the requirement for studies that examine the teratogenic effects of drugs before they are licensed, the risks associated with most drugs are well understood, and women can be warned against taking these drugs during pregnancy.

However, in the case of HIV infection, some drugs known to cause a small risk of birth defects are routinely prescribed because the benefits of their use – for both mother and child – outweighs the small risk. Efavirenz, for example, has been associated with neural tube defects in animal studies, and until 2010 its use during the first trimester of pregnancy was contraindicated for this reason. This recommendation was revised in 2011, following meta-analysis of large cohorts of women who had been exposed nevertheless to efavirenz during the first trimester. That study found no excess risk of neural tube defects compared to the general population. The World Health Organization concluded that the benefit of efavirenz-based antiretroviral treatment for pregnant women and women who might conceive while taking it far outweighed any risk of birth defects.


The study presented today looked at the incidence of birth defects diagnosed up to the age of two years in 13,214 children born to HIV-positive women enrolled in the French Perinatal Cohort between 1994 and 2010, who were exposed to antiretroviral drugs during gestation and born alive.

Birth defects were classified using two scales, developed by EUROCAT and MACDP. The overall prevalence was 4.4% on the EUROCAT scale and 7% on the MACDP scale (this includes minor defects), but no information was presented on the comparative levels of birth defects seen in the French infant population over the same period.

Three hundred and seventy two infants were exposed to efavirenz in the first trimester. The risk of neurological defects was approximately three times greater than for unexposed infants (adjusted odds ratio 3.15 [1.39-9.09]). This amounted to four defects: one pachygyria, one hydrocephaly, one cerebral cyst and one agenesis of the corpus callosum.

Among the 3267 infants exposed to zidovudine (AZT) during the first trimester, the risk of heart defect was approximately doubled (adjusted odds ratio 2.34 [1.39-3.94] when compared to unexposed infants. Most of these cases were ventricular septal defects (holes in the heart).

Neither drug was associated with an elevated risk of other types of birth defects.

Other defects were seen in association with exposure to the following drugs:

  • Didanosine: head and neck defects (AOR 1.93, p<0.05)
  • Lamivudine (3TC): musculoskeletal defects (AOR 1.40, p=0.04) and head and neck defects (AOR 1.96, p=0.03)
  • Indinavir (Crixivan): overall birth defects (AOR 1.52, p=0.04)

No other drugs were implicated.

This study did not report on the incidence of pre-term delivery and low birth weight, another risk associated with exposure to some antiretroviral drugs during pregnancy that has been reported in some – but not all – cohort studies.

Jeanne Sibiude, for the French Perinatal Cohort, concluded that recommendations to avoid efavirenz during the first trimester should be maintained in countries where other drug options exist, but other experts at the meeting emphasised that the risks needed to be balanced against the benefits to mother and child of antiretroviral therapy that contains efavirenz.


Sibiude J et al. Birth defects and ART in the French Perinatal Cohort, a prospective exhaustive study among 13,124 live births from 1994 to 2010. 20th Conference on Retroviruses and Opportunistic Infections, Atlanta, abstract 81, 2012.

View abstract 81 on the conference website.

A webcast of the session in which this research was presented, MTCT and HIV treatment in children, is available on the conference website.