Our GRADE assessment rated the quality of studies as being low. The main limitations were that the majority of studies failed to consider potential threats to validity; five studies considered sources of bias and only three studies adjusted for potential confounders. Most studies were also limited by a small sample size and low event rate that resulted in low statistical confidence around the point estimate.
Our systematic review of the available evidence to date found no increased risk of overall birth defects among women exposed to efavirenz during the first trimester of pregnancy compared with exposure to other antiretroviral drugs. The incidence of overall birth defects with first trimester efavirenz use (2.9%) was similar to the ranges reported in the general population; 2.7% in the United States , 2–5% in France , and 2.5–8% in South Africa . Only one case of a neural tube defect was reported across all cohorts reporting congenital birth defects among first-trimester exposed women (1256 women with live births), giving a point prevalence (0.08%) that is within the range reported among the general population in the United Kingdom (0.14%)  and South Africa (0.36%) . Although these data should provide reassurance to health providers confronted with women who become pregnant while on efavirenz, the low incidence of neural tube defects in the general population means that a larger sample size is still needed to be able to definitively rule out an increased risk of this specific defect. The range in prevalence of secondary outcomes is an effect of both variability in the sample size of individual studies and the diversity of settings included in the review, resulting in differing background rates of these outcomes in the general population. Pooled estimates are not provided for secondary outcomes for this reason.
Strengths of this review include a broad search strategy that identified a number of studies not yet published in the literature and the inclusion of updated data for several cohorts. In addition, our primary analysis was limited to data that were derived from prospective studies, which are less subject to reporting bias than retrospective reports. Nevertheless, there may be a publication bias towards reporting birth defects when a women is on efavirenz and but not reporting birth outcomes if no birth defects occur. Such a publication bias would be expected to lead to an overestimation of the risk of efavirenz compared with other antiretroviral drugs.
An important limitation is that few studies reported on risk of bias or attempted to control for potential confounders, and we were therefore not able to assess the potential effect of these in this review. In particular, women on efavirenz may differ from those not on efavirenz; the latter group may comprise more women who planned their pregnancies and so were more likely to be exposed to protective factors (such as folate supplementation) and reduced risk factors (such as smoking and poor diet). Consideration of confounding is all the more important given that it would not be ethically acceptable to conduct a randomized trial to assess risk. Nevertheless, such differences are unlikely to affect our results importantly, and moreover would be expected to result in an overestimation of the relative risk of birth defects in the efavirenz group.
The main limitation to this review is the limited sample size. Despite calls for more systematic recording of birth outcomes from women receiving antiretroviral drugs during pregnancy , such data remains persistently under-reported, and while there has been a rapid increase in women of childbearing age receiving efavirenz in Africa in recent years, we were only able to identify one registry report from Africa. The few prospective cohorts that do provide reports are inconsistent in reporting of birth outcomes beyond overall birth defects.
Our review provides several directions for research and practice. First, the establishment of prospective birth registries should be supported, particularly in African countries where the majority of first-trimester exposures occur. A number of treatment cohorts contacted during the conduct of this review stated that first-trimester efavirenz exposures were not uncommon, but that such data were not routinely captured. This represents an important missed opportunity. Second, there is a need to support the standardized collection of birth outcome data such that meaningful comparisons can be made with respect not only to rates of birth defects but also other important outcomes such as termination of pregnancy and spontaneous abortions, stillbirths, and preterm deliveries. Third, women in childbearing age represent a substantial proportion of the total number of people infected with HIV in developing countries , and healthcare providers will continue to be faced with women presenting with unintended pregnancies while taking efavirenz. The high rate of termination of pregnancy reported in some cohorts points to a need for improved counseling for women inadvertently exposed during pregnancy. Fourth, periconceptional provision of high-dose folates have proven efficacy in preventing neural tube defects among women with prior risk and could be considered for women of childbearing age who are receiving efavirenz and are likely to become pregnant in settings where folate supplementation is not provided . Finally, efforts must continue to support HIV-positive women to seek care early in their pregnancy.
We would like to thank Musaed Abrahams, Elaine Abrams, Emrahim Bera, Marco Floridia, Didier Ekouevi, Fatima Laher, Elizabeth Machado, Claire Townsend, Patrick A Coffie, and Xavier Anglaret for providing additional data, and Gary Maartens and D. Heather Watts for helpful comments on an earlier draft.
There are no conflicts of interest.
The conclusions and opinions expressed in this article are those of the authors and do not necessarily reflect those of their respective organizations.
N.F. and A.C. conceived the study. N.F., L.M. and K.K., undertook searches, extracted data, and conducted authors for additional data. N.F. performed the statistical analyses and wrote the first draft. All authors supported the interpretation of results, provided comments on subsequent drafts and approved the final version.
1. Fundaro C, Genovese O, Rendeli C, Tamburrini E, Salvaggio E. Myelomeningocele in a child with intrauterine exposure to efavirenz
. AIDS 2002; 16:299–300.
2. De Santis M, Carducci B, De Santis L, Cavaliere A, Straface G. Periconceptional exposure to efavirenz
and neural tube defects. Arch Intern Med 2002; 162:355.
3. Lewis-Hall FC. Important Change in SUSTIVA (efavirenz) Package Insert – Change from Category C to D. Bristol-Myers Squibb Company 2005
. [Accessed 31 December 2009]
4. Antiretroviral Pregnancy
Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2009.
Wilmington, NC: Registry Coordinating Center; 2009. www.APRegistry.com
. [Accessed 31 December 2009]
5. Townsend C, Willey B, Cortina-Borja M, Peckham C, Tookey P. Antiretroviral therapy and congenital abnormalities
in infants born to HIV-infected women in the UK and Ireland, 1990–2007. AIDS 2009; 23:519–524.
6. World Health Organization. Rapid advice: antiretroviral therapy for HIV infection in adults and adolescents – November 2009.
World Health Organization, Geneva, Switzerland, 2009. http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf
. [Accessed 31 December 2009]
7. Perinatal HIV Guidelines Working Group. Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
, April 29, 2009; 1–90. http://aidsinfo.nih.gov/ContentFiles/PerinatalGL.pdf
. [Accessed 31 December 2009]
9. Baroncelli S, Tamburrini E, Ravizza M, Dalzero S, Tibaldi C, Ferrazzi E, et al
. Antiretroviral treatment in pregnancy
: a six-year perspective on recent trends in prescription patterns, viral load suppression, and pregnancy
outcomes. AIDS Patient Care STDS 2009; 23:513–520.
10. De Clercq E. Anti-HIV drugs: 25 compounds approved within 25 years after the discovery of HIV. Int J Antimicrob Agents 2009; 334:307–320.
11. Bera E, McCausland K, Nonkwelo R, Mgudlwa B, Chacko S, Majeke B. Birth defects
following exposure to efavirenz
-based antiretroviral therapy during pregnancy
: a study at a regional South African hospital. AIDS 2010; 24:283–289.
12. Nachega JB, Hislop M, Dowdy DW, Gallant JE, Chaisson RE, Regensberg L, Maartens G. Efavirenz
versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS 2008; 22:2117–2125.
13. Boulle A, Van Cutsem G, Cohen K, Hilderbrand K, Mathee S, Abrahams M, et al
. Outcomes of nevirapine- and efavirenz
-based antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. JAMA 2008; 300:530–539.
14. Guyatt G, Oxman A, Vist G, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al
. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336:924–926.
15. Meade MO, Guyatt GH, Cook RJ, Groll R, Kachura JR, Wigg M, et al
. Agreement between alternative classifications of acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 163:490–493.
16. Fleiss JL. The statistical basis of meta-analysis. Stat Methods Med Res 1993; 2:121–145.
17. Sheehe P. Combination of log relative risk in retrospective studies of disease. Am J Pub Health 1966; 56:1745–1750.
18. Joao EC, Calvet GA, Krauss MR, Freimanis Hance L, Ortiz J, Ivalo SA, et al
. NISDI Perinatal Study Group. Maternal antiretroviral use during pregnancy and infant congenital anomalies: the NISDI perinatal study
. J Acquir Immune Defic Syndr
19. Fernandez Ibieta M, Ramos Amador J, Bellon Cano J, González-Tomé M, Guillén Martín S, Navarro Gómez M, et al
. Malformaciones congenitas en una cohorte de ninos no infectados, hijos de madres infectadas por el virus de la inmunodeficiencia humana. An Pediatr(Barc) 2009; 70:253–264.
20. Saitoh A, Hull AD, Franklin P, Spector SA. Myelomeningocele in an infant with intrauterine exposure to efavirenz
. J Perinatol 2005; 25:555–556.
21. Watts DH, Li D, Handelsman E, Tilson H, Paul M, Foca M, et al
. Assessment of birth defects
according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr 2007; 44:299–305.
22. Conway J, Scott G, Muenz D, Brogly S, Knapp K, Talbot J, et al
. Prevalence of Congenital Anomalies in Infants with in Utero Exposure to Antiretrovirals: IMPAACT P1025. 17th Conference on Retroviruses and Opportunistic Infections
, San Franciso, 2010. Abstract 923.
23. Bussmann H, Wester CW, Wester CN, Lekoko B, Okezie O, Thomas AM, et al
rates and birth outcomes among women on efavirenz
-containing highly active antiretroviral therapy in Botswana. J Acquir Immune Defic Syndr 2007; 45:269–277.
24. Coffie P, Moh R, Tonwe-Gold B, Amani-Bosse C, Messou E, Gabillard D, et al. Issues des grossesses chez des femmes exposées à l'efavirenz à Abidjan, Côte d'Ivoire
. 5ème Conférence Francophone sur le VIH/Sida, Casablanca, Morocco
, 28-31 March 2010: Abstract no. 448/73P
25. Patel D, Thorne C, Fiore S, Newell ML, European Collaborative Study. Does highly active antiretroviral therapy increase the risk of congenital abnormalities
in HIV-infected women. J Acquir Immune Defic Syndr 2005; 40:116–118.
26. Machado ES, Hofer CB, Costa TT, Nogueira SA, Oliveira RH, Abreu TF, et al
outcome in women infected with HIV-1 receiving combination antiretroviral therapy before versus after conception. Sex Transm Infect 2009; 85:82–87.
27. Gonzalez-Tome M, Fernandez-Ibieta M, Ramos Amador J, MuñozGalligo E, Rojo C, Nieto O, et al. The Spanish cohort of HIV-infected mother -infant pairs. Efavirenz in pregnancy: maternal characteristics of women who become pregnant on EFV-containing regimen and neonatal effects. XVII International AIDS Conference, 3-8 August 2008
, Mexico City, Mexico: Abstract no. CDB0207.
28. Floridia M, Tamburrini E, Ravizza M, Tibaldi C, Bucceri A, Maccabruni A, et al
. Antiretroviral therapy at conception in pregnant women with HIV in Italy: wide range of variability and frequent exposure to contraindicated drugs. Antivir Ther 2006; 11:941–946.
29. Westreich D, Robel D, MacDonald P, Majuba P, Maskew M, Nagar S, Jaffray I, MacPhail Abstract P, Cole S, Sanne I. Pregnancy, Efavirenz, and Birth Outcomes in Johannesburg. 17th Conference on Retroviruses and Opportunistic Infections,
San Franciso, 2010. Abstract 922.
30. Laher F, Forrest J, Mohapi L, Gray G. Efavirenz Conceptions in Soweto, South Africa. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 19-22 July 2009
, Cape Town, South Africa: Abstract TUPEC047.
31. Rossouw T. Quantifying antiretroviral risk in pregnancy
. S Afr Med J 2007; 97:1016–1016.
32. Joao E, Calvet G, Cunha C, Menezes J, Martins E, Medeiros A, et al. Pregnancy outcome in women exposed to efavirenz. XVI International AIDS Conference
, 13-18 August 2006, Toronto, Canada: Abstract no. CDB0698.
33. Batallan A, Moreau G, Levine M, Longuet P, Bodard M, Legac S, et al. In utero exposure to efavirenz: evaluation in children born alive. 2nd IAS Conference on HIV Pathogenesis and Treatment, 13-16 July 2003
, Paris, France: Abstract no. 1100.
34. Jeantils V, Khuong MA, Delassus JL, Honoré P, Taverne B, Uzan M, Tassi S. [Efavirenz
(Sustiva) in pregnancy
: a study about 12 HIV patients]. Gynecol Obstet Fertil 2006; 34:593–596.
35. Joao E, Calvet G, Sidi L, Cruz L, Cardoso C, Cunha C, et al. Increased incidence of spontaneous abortion during first trimester exposure to efavirenz. 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 22–25 July 2007
, Sydney, Australia: Abstract TUPEB113.
36. Shepard TH. Catalog of teratogenic agents. 6th ed. Baltimore: Johns Hopkins University Press; 1989.
37. Correa A, Cragan J, Kucik J, Alverson C, Gilboa S, Balakrishnan R, et al
. Metropolitan Atlanta Congenital Defects Program 40th Anniversary Edition Surveillance Report: Reporting Birth Defects
Surveillance Data 1968–2003. Birth Defects
Research (Part A) Clin Mol Teratol 2007; 79:65–93.
38. Goujard J, de Vigan C, Vodovar V, Verite V, Dehe S. Douze années d'enrégistrement des malformations congénitales à Paris (1985–1996). Med Foetale 1999; 39:20–28.
39. Human Genetics Policy Guidelines for the Management and Prevention of Genetic Disorders, Birth Defects
and Disabilities. Pretoria, South Africa: Sub-Directorate, Human Genetics, National Department of Health 2008. www.doh.gov.za
. [Accessed 31 December 2009]
40. Rankin J, Pattenden S, Abramsky L, Boyd P, Jordan H, Stone D, et al
. Prevalence of congenital anomalies in five British regions, 1991–99. Arch Dis Child Fetal Neonatol Ed 2005; 90:F374–F379.
41. Venter PA, Christianson AL, Hutamo CM, Makhura MP, Gericke GS. Congenital anomalies in rural black South African neonates: a silent epidemic? S Afr Med J 1995; 85:15–20.
42. Chersich MF, Urban MF, Venter FW, et al
use during pregnancy
and for women of child-bearing potential. AIDS Res Ther 2006; 7:11.
43. ART-LINC Collaboration of International Databases to Evaluate AIDS (IeDEA), Keiser O, Anastos K, et al. Antiretroviral therapy in resource-limited settings 1996 to 2006: patient characteristics, treatment regimens and monitoring in sub-Saharan Africa, Asia and Latin America. Trop Med Int Health
44. UK MRC Vitamin Study Research Group. Lancet