Comparative safety and effectiveness of perinatal antiretroviral therapies for HIV-infected women and their children: Systematic review and network meta-analysis including different study designs

PLoS One. 2018 Jun 18;13(6):e0198447. doi: 10.1371/journal.pone.0198447. eCollection 2018.


Background: Nearly all newly infected children acquire Human Immunodeficiency virus (HIV) via mother-to-child transmission (MTCT) during pregnancy, labour or breastfeeding from untreated HIV-positive mothers. Antiretroviral therapy (ART) is the standard care for pregnant women with HIV. However, evidence of ART effectiveness and harms in infants and children of HIV-positive pregnant women exposed to ART has been largely inconclusive. The aim of our systematic review and network meta-analysis (NMA) was to evaluate the comparative safety and effectiveness of ART drugs in children exposed to maternal HIV and ART (or no ART/placebo) across different study designs.

Methods: We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (inception until December 7, 2015). Primary outcomes were any congenital malformations (CMs; safety), including overall major and minor CMs, and mother-to-child transmission (MTCT; effectiveness). Random-effects Bayesian pairwise meta-analyses and NMAs were conducted. After screening 6,468 citations and 1,373 full-text articles, 90 studies of various study designs and 90,563 patients were included.

Results: The NMA on CMs (20 studies, 7,503 children, 16 drugs) found that none of the ART drugs examined here were associated with a significant increase in CMs. However, zidovudine administered with lamivudine and indinavir was associated with increased risk of preterm births, zidovudine administered with nevirapine was associated with increased risk of stillbirths, and lamivudine administered with stavudine and efavirenz was associated with increased risk of low birth weight. A NMA on MTCT (11 studies, 10,786 patients, 6 drugs) found that zidovudine administered once (odds ratio [OR] = 0.39, 95% credible interval [CrI]: 0.19-0.83) or twice (OR = 0.43, 95% CrI: 0.21-0.68) was associated with significantly reduced risk of MTCT.

Conclusions: Our findings suggest that ART drugs are not associated with an increased risk of CMs, yet some may increase adverse birth events. Some ART drugs (e.g., zidovudine) effectively reduce MTCT.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Abnormalities, Drug-Induced / epidemiology
  • Alkynes
  • Anti-HIV Agents / adverse effects*
  • Anti-HIV Agents / economics
  • Benzoxazines / adverse effects
  • Benzoxazines / economics
  • Child
  • Congenital Abnormalities
  • Cyclopropanes
  • Drug Therapy, Combination / adverse effects
  • Drug Therapy, Combination / economics
  • Female
  • HIV Infections / drug therapy*
  • Humans
  • Infant
  • Infant, Low Birth Weight
  • Infant, Newborn
  • Infectious Disease Transmission, Vertical / prevention & control
  • Infectious Disease Transmission, Vertical / statistics & numerical data*
  • Lamivudine / adverse effects
  • Lamivudine / economics
  • Network Meta-Analysis
  • Nevirapine / adverse effects
  • Nevirapine / economics
  • Perinatal Care / economics*
  • Pregnancy
  • Pregnancy Complications, Infectious / drug therapy*
  • Stavudine / adverse effects
  • Stavudine / economics
  • Stillbirth / epidemiology
  • Zidovudine / adverse effects
  • Zidovudine / economics


  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Lamivudine
  • Zidovudine
  • Nevirapine
  • Stavudine
  • efavirenz