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Timing of Initiation of Antiretroviral Therapy and Risk of Preterm Birth in Studies of HIV-infected Pregnant Women: The Role of Selection Bias

Stoner, Marie C., D.; Cole, Stephen, R.; Price, Joan; Winston, Jennifer; Stringer, Jeffrey S., A.

doi: 10.1097/EDE.0000000000000772
Infectious diseases
Video Abstract

Background: Women who initiate antiretroviral therapy (ART) during pregnancy are reported to have lower risk of preterm birth compared with those who enter pregnancy care already receiving ART. We hypothesize this association can be largely attributed to selection bias.

Methods: We simulated a cohort of 1000 preconceptional, HIV-infected women, where half were randomly allocated to receive immediate ART and half to delay ART until their presentation for pregnancy care. Gestational age at delivery was drawn from population data unrelated to randomization group (i.e., the true effect of delayed ART was null). Outcomes of interest were preterm birth (<37 weeks), very preterm birth (<32 weeks), and extreme preterm birth (<28 weeks). We analyzed outcomes in 2 ways: (1) a prospectively enrolled clinical trial, where all women were considered (the intent-to-treat (ITT) analysis); and (2) an observational study, where women who deliver before initiating ART were excluded (the naïve analysis). We explored the impact of later ART initiation and gestational age measurement error on our findings.

Results: Preconception ART initiation was not associated with preterm birth in ITT analyses. Risk ratios (RRs) for the effect of preconception ART initiation were RR = 1.10 (preterm), RR = 1.41 (very preterm), and RR = 5.01 (extreme preterm) in naïve analyses. Selection bias increased in the naïve analysis with advancing gestational age at ART initiation and with introduction of gestational age measurement error.

Conclusions: Analyses of preterm birth that compare a preconception exposure to one that occurs in pregnancy are at risk of selection bias. See video abstract at,

From the University of North Carolina at Chapel Hill, Chapel Hill, NC.

Submitted January 5, 2017; accepted October 12, 2017.

Code for replication and creation of the simulated dataset is available as a supplementary file.

The authors report no conflicts of interest.

Supported by Grant T32 5T32AI007001 from National Institutes of Health.

Supplemental digital content is available through direct URL citations in the HTML and PDF versions of this article (

Correspondence: Marie C. D. Stoner, 135 Dauer Drive, 2101 McGavran-Greenberg Hall, Chapel Hill, NC 27599. E-mail:

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