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Nathan Ford, MSF/UCT Lynne Mofenson, NIH Katarina Krazner, LSHTM

Safety of efavirenz in first-trimester of pregnancy Systematic review and meta-analysis of outcomes from observational cohorts. Nathan Ford, MSF/UCT Lynne Mofenson, NIH Katarina Krazner, LSHTM Lisa Frigati, Red Cross Children Hospital Edward Mills, University of Ottawa

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Nathan Ford, MSF/UCT Lynne Mofenson, NIH Katarina Krazner, LSHTM

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  1. Safety of efavirenz in first-trimester of pregnancySystematic review and meta-analysis of outcomes from observational cohorts Nathan Ford, MSF/UCT Lynne Mofenson, NIH Katarina Krazner, LSHTM Lisa Frigati, Red Cross Children Hospital Edward Mills, University of Ottawa Alexandra Calmy, Geneva University Hospital

  2. WHY DO THE STUDY? • Incidence of neural tube defects varies according to ethnic, geographic, and nutritional factors: 0.14% (UK) - 0.36% (South Africa) • Risk data for EFV unclear: case reports contradicted by subsequent cohorts

  3. RISK DATA I: ANIMAL STUDIES • 20 pregnant cynomolgus monkeys dosed during pregnancy with EFV and compared with 20 controls. • 3/20 EFV-exposed monkeys had neural-tube like defects • But: only 2% of animal teratogens (30/1200) are teratogenic in humans

  4. RISK DATA II: RETROSPECTIVE CASE REPORTS • Italy, 2002: 3 NTDs, inc. 1 myelomeningocele • Italy, 2002: 1 myelomeningocele • USA 2005: 1 myelomeningocele But: unsystematic retrospective observations give no indication of risk • 2 retrospective cases of NTDs reported for other ARVs

  5. CONFLICTING RECOMMENDATIONS Conflicting guidelines - US/WHO : recommend against use in first trimester - EU/SA: recommend against use throughout pregnancy Conflicting drug labels - BMS: “Fetal harm can occur when administered to a pregnant women during the first trimester” - Aspen: “Use of Aspen efavirenz in pregnancy is not recommended”

  6. Systematic review • Databases MEDLINE via PubMed, EMBASE, Cochrane CENTRAL, CINAHL, PsycInfo, LILACS, Current Controlled Trials (www.controlled-trials.com) and US National Institutes of Health • Conference abstracts All International AIDS Society conferences (up to Cape Town, July 2009) All Conferences on Retroviruses and Opportunitistic Infections (up to Montreal, February 2009) • Pregnancy registry Antiretroviral Pregnancy Registry (apregistry.com/) • Cohorts ART-LINC, ART-CC, ECS, IeDEA-SA, MSF, MTCT+, NISDI, PENTA, PHRU, RHRU Ford et al, AIDS 2010.24: 1461-70

  7. Systematic review Primary endpoint • Birth defects of any kind Primary analysis - 1st Trimester EFV vs 1st Trimester non-EFV ART Secondary outcomes • Spontaneous abortions, termination of pregnancy, stillbirths, pre-term delivery Secondary analyses: • Sensitivity analyses: location, duration of exposure, publication status • EFV risk 1st trimster vs 2nd /3rd trimster • Prevalence of secondary outcomes • GRADE assessment of quality of evidence

  8. Identification process for eligible studies 1098 articles screened by title and abstract 1008 Papers excluded (not relevant) 90 full text papers reviewed 8 additional articles identified through bibliographies 72 Papers excluded 19 reviews or commentaries 9 duplicate reports 45 Not relevant 26 studies considered eligible for inclusion 10 studies excluded Data not disaggregated by trimester; outcome data not available unsystematic observational studies; duplicate reports 16 included in analysis

  9. Results I: Study Characteristics 16 studies • 11 prospective cohorts • 5 retrospective cohorts • 9 MLIC: SA, Botswana, Brazil, Ivory Coast, multisite) • 7 HIC: Europe and US

  10. Primary outcomes • Pooled RR for EFV vs non EFV: 0.85 (95% CI 0.60-1.21, p=0.47) • Low heterogeneity (I2 =0; 95% CI 0-56.3%, p=0.85) • Prevalence of birth defects: 2.9% (95% CI 2.1-4.0%) • similar ranges reported in the general population in the US (2.7%) France (2-5%) and South Africa (2.5 - 8%) • Prevalence neural tube defect s (1/1301): 0.08% (95% CI 0.02-0.43%) • similar to ranges in general population in the UK (0.14%) and South Africa (0.36%)

  11. Secondary outcomes • RR 1st vs 2nd/3rd trimester EFV =0.91 (95% CI = 0.46-1.79) • Prevalence of stillbirth, spontaneous abortion and pre-term within range of general population • Termination of pregnancy • 5.3% (CI95 0.64-17.7%) to 33.7% (CI95 23.7-44.9%). • Soweto: RR EFV vs non-EFV 5.73 (CI95 1.45- 22.75)

  12. CONCLUSIONS: I • No increased risk of overall birth defects among women exposed to EFV during 1st trimester compared to exposure to non-EFV regimens • can exclude a 2-fold increase in overall birth defects • Only 1 NTD reported for 1301 live births, giving a prevalence (0.08%) • Point prevalence within range of general population • Fragile data (upper CI95% = 0.43%)

  13. CONCLUSIONS: II • High rates of TOP point to need for careful counselling • Birth registries should be supported • Need for standardized birth outcome data collection • Data exist but not collected/reported

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