Small increase in birth defects in the French Perinatal Cohort
Polly Clayden, HIV i-Base
Data presented at CROI 2013 showed a small increased risk of some birth defects with first trimester exposure to some antiretrovirals in the French Perinatal Cohort (EPF). 
In an oral presentation, Jeanne Sibiude from INSERM showed findings from the ANRS funded French Perinatal Cohort (EPF) – a national multicentre cohort started in 1986. EPF prospectively enrols HIV positive pregnant women delivering in 90 participating centres. Children are followed for two years.
The aim of the study was to estimate the prevalence of birth defects in children born to women receiving antiretroviral drugs during pregnancy, compared to unexposed children. The study also investigated associations with specific drugs. There was no comparison to background population.
Live births, exposed to antiretrovirals in utero, between 1994 and 2010, were included (n=13,124). Birth defects were evaluated using both the EUROCAT (Europe) and the MACDP (US) classifications. Univariate and multivariate logistic regression were used to investigate associations with antiretrovirals.
EUROCAT classification identified 575 birth defects, giving a prevalence of 4.4% (95% CI 4.0-4.7); with MACDP classification, which included minor defects, 914 were identified, giving a prevalence of 7.0% (95% CI 6.5-7.4).
There was no association between efavirenz exposure (n=372) and overall birth defects. According to MACDP classification there was an association between efavirenz exposure in the first trimester and neurological defects, AOR 3.2 (95% CI 1.1 – 9.1), p=0.03. The four defects were: pachygyria, agenisis of corpus colossum, hydrocephaly and cerebral cyst.
First trimester exposure to AZT (n=3,267) was associated with overall birth defects, AOR 1.4 (95% CI 1.1-1.8), p=0.002. There was an organ system specific association with heart defects, AOR 2.5 (95% CI 1.6-4.2), p=0.001, according to both classification systems.
ddI exposure (n=927) was associated with head and neck birth defects, AOR 1.93 (95% CI 1.11-3.34), p<0.05.
3TC exposure (n=3,772) was associated with muscoskeletal, AOR 1.4 (95% CI 1.05-1.87), p=0.04, and head and neck defects AOR 1.96 (95% CI 1.2-3.21), p=0.03. Dr Sibiude noted that these were only by MACDP classification and mostly minor.
In conclusion Dr Sibiude suggested that in countries where this is possible recommendations to avoid efavirenz in pregnancy should be maintained, stressing the need for surveillance where it is used routinely. The association between AZT and heart defects needs further detailed investigation to clarify the mechanism, she added.
Overall she concluded: “However, the potential risk of birth defects has to be balanced with the major success of current PMTCT strategies.”
EFV in pregnancy has courted controversy since neural tube defects were reported in three of twenty in utero exposed monkeys during preclinical studies.  Subsequent human data have been reassuring including that from a meta-analysis, which found no association between EFV exposure and birth defects. [3, 4]
Upcoming WHO 2013 guidelines recommend EFV-based regimens as the preferred first line ART (including for pregnant women). Many national guidelines, including BHIVA, also recommend its use in pregnancy.
Although the EPF is the largest prospective cohort to date, when these data on neurological events are considered in the context of all available data, the estimated prevalence of birth defects overall (<3%) and neural tube defects (<0.01%) remains unchanged. 
It is notable that none of the events reported were neural tube defects and the findings were only significant using one classification system.
Elevated risk of heart defects associated with AZT exposure was reported previously in a retrospective analysis – which also found higher prevalence of EFV associated defects than other cohorts – but not in the Antiretroviral Pregnancy Registry (APR). [6, 7, 8]
APR data to July 2012 on 6388 live births with first trimester exposure shows 18/702 defects for EFV, prevalence 2.6 (95% CI 1.5-4.0) and 127/3864 for AZT, prevalence 3.3 (2.7 to 3.9). EFV defects include a single case of myelomeningocele and a single case of anophthalmia with severe facial clefts and amniotic binding. It is unfortunate that these data were not submitted to the APR.
- 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. 14th CROI. Atlanta, GA. 3-6 March 2013. Oral abstract 81.
- Nightingale SL. From the food and drug administration. JAMA 1998; 280: 1472.
- Ford N et al. Safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. AIDS 2011, 25:2301–2304.
- World Health Organisation. Technical update on treatment optimisation: use of efavirenz during pregnancy, a public health perspective. June 2013.
- Personal communication Nathan Ford, HIV/AIDS Department of the World Health Organization. June 2013.
- Brogly SB et al. Birth Defects among Children Born to Human Immunodeficiency Virus-infected Women: Pediatric AIDS Clinical Trials Protocols 219 and 219C. Pediatr Infect Dis J.2010;28(8):721-727.
- Clayden P. Retrospective analysis finds higher prevalence of birth defects associated with efavirenz than previously reported. HTB. 1 October 2010.
- The Antiretroviral Pregnancy Registry.