Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11).
BACKGROUND
Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used.


RESULTS
The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines. We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%-4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3-3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1-10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1-13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1-8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7-5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication.


CONCLUSIONS
We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV. Please see later in the article for the Editors' Summary.
Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France; Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Le Kremlin-Bicêtre, France.
Jeanne
J
Sibiude
Hôpital Louis Mourier, Assistance Publique-Hôpitaux de Paris, Colombes, France; Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Le Kremlin-Bicêtre, France; Université Paris Diderot-Paris 7, Paris, France.
Laurent
L
Mandelbrot
Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris, France; EA 3620, Université Paris Descartes 5, Paris, France.
Stéphane
S
Blanche
Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Le Kremlin-Bicêtre, France; Institut National d'Etudes Démographiques, Paris, France.
Jérôme
J
Le Chenadec
Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Le Kremlin-Bicêtre, France.
Naima
N
Boullag-Bonnet
Université Paris Diderot-Paris 7, Paris, France; Hôpital Robert Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.
Albert
A
Faye
Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France.
Catherine
C
Dollfus
Hôpital Pitié Salpétrière, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U943, Paris, France.
Roland
R
Tubiana
Pediatric Cardiology, M3C Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France.
Damien
D
Bonnet
INSERM UMR S953, Université Paris 6, Paris, France.
Nathalie
N
Lelong
INSERM UMR S953, Université Paris 6, Paris, France.
Babak
B
Khoshnood
Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Le Kremlin-Bicêtre, France; Institut National d'Etudes Démographiques, Paris, France; Université Paris Sud, Le Kremlin-Bicêtre, France.
Josiane
J
Warszawski
D019380:Anti-HIV Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D000013:Congenital Abnormalities / Q000453:epidemiology / Q000209:etiology*; D005260:Female; D005602:France / Q000453:epidemiology; D015658:HIV Infections / Q000188:drug therapy*; D006330:Heart Defects, Congenital / Q000139:chemically induced* / Q000453:epidemiology; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000453:epidemiology*; D015995:Prevalence; D011446:Prospective Studies
D019380:Anti-HIV Agents