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Safety of efavirenz in first- trimester of pregnancy Systematic review and meta-analysis of outcomes from observational cohorts Nathan Ford, MSF/UCT Lynne.

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Presentation on theme: "Safety of efavirenz in first- trimester of pregnancy Systematic review and meta-analysis of outcomes from observational cohorts Nathan Ford, MSF/UCT Lynne."— Presentation transcript:

1 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 Alexandra Calmy, Geneva University Hospital

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

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 :

7 Systematic review Primary endpoint -Birth defects of any kind Primary analysis - 1 st Trimester EFV vs 1 st 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 1 st trimster vs 2 nd /3 rd trimster -Prevalence of secondary outcomes -GRADE assessment of quality of evidence

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

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 StudySettingDescriptionSize pregnancy cohort Birth defect data MTCT-PlusMultisiteProspective cohort495No (other outcome) WestreichS AfricaProspective cohort81Yes APRMultisiteBirth registry11,867Yes BeraS AfricaProspective cohort851Yes TownsendUKPopulation based surveillance7,135Yes CoffieCote d’IvoireProspective cohort in trial168Yes LaherS AfricaRetrospective cohort117No (other outcome) MachadoBrazilProspective cohort696Yes Gonzales- Tome SpainProspective cohort619Yes RossouwS AfricaRetrospective cohort37Yes BussmanBotswanaProspective cohort71Yes FloridiaItalyNational surveillance study334Yes JoaoBrazilRetrospective cohort90Yes JeantilsFranceRetrospective cohort12Yes PatelEuropeProspective cohort1,973Yes BatallanFranceRetrospective cohort9Yes

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12 Primary outcomes –Pooled RR for EFV vs non EFV: 0.85 (95% CI , p=0.47) Low heterogeneity (I 2 =0; 95% CI %, p=0.85) –Prevalence of birth defects: 2.9% (95% CI %) similar ranges reported in the general population in the US (2.7%) France (2-5%) and South Africa ( %) –Prevalence neural tube defect s (1/1301): 0.08% (95% CI %) similar to ranges in general population in the UK (0.14%) and South Africa (0.36%)

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14 Secondary outcomes RR 1 st vs 2 nd /3 rd trimester EFV =0.91 (95% CI = ) Prevalence of stillbirth, spontaneous abortion and pre-term within range of general population Termination of pregnancy –5.3% (CI %) to 33.7% (CI %). –Soweto: RR EFV vs non-EFV 5.73 (CI )

15 CONCLUSIONS: I No increased risk of overall birth defects among women exposed to EFV during 1 st 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%)

16 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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