Wing confounders of the effect of pregnancy on death (or AIDS and death), based on previous literature and plausible biological mechanism. Confounders measured at Hypericin baseline (HAART initiation) included age, ethnicity, employment status, current tuberculosis, calendar date of HAART initiation, and WHO stage. Confounders measured over time included weight, body mass index, hemoglobin, CD4 count and CD4 percent, drug regimen, and drug adherence estimated from pharmacy visit data. We didPregnancy and Clinical Response to HAARTFigure 2. Effect of pregnancy on time to (A) 
death, (B) death or new stage 4 AIDS, or (C) death or new stage 3 or 4 AIDS. Curves are inverse, weighted, extended Kaplan-Meier curves. doi:10.1371/journal.pone.0058117.gnot control for baseline or time-updated viral load because of the high proportion of missingness, but included a sensitivity analysis in which viral load was imputed. We used restricted four-knot cubic splines to flexibly control for age, body mass index, CD4 count, and time-on-study.combined death and new stage 3 or 4 clinical AIDS events [33]. Missing data led to approximately 18 missing observations in the final analysis, so we also conducted a multiple imputation analysis to account for missing baseline data [40]. In all analyses, longitudinal data were carried forward from the most recent observed value.Sensitivity Analysis and Missing 3PO DataTo test analytic assumptions, we performed three sensitivity analyses in addition to the main analysis; these sensitivity analyses addressed issues in definitions of the population, exposure, and outcome, as well as technical decisions in the modeling. The most critical sensitivity analyses were in exploring alternate outcome definitions. These analyses included 1) a combined outcome of death and new stage 4 clinical AIDS events and (separately) 2)Role of the Funding SourceThe funding sources had no involvement in the design or conduct of the study, in the collection, management, analysis, or interpretation of the data, in the preparation, writing, review or approval of this manuscript, or in the decision to submit this manuscript for publication.Pregnancy and Clinical Response to HAARTFigure 3. Effect of pregnancy on time to drop-out, displayed as weighted inverse extended Kaplan-Meier curves. doi:10.1371/journal.pone.0058117.gResultsThe initial study population comprised 7,534 non-pregnant, ?ART-naive women ages 18?5, who contributed a total of 249,754 person-months, or 20,813 person-years of follow-up to this analysis, of which 2,472 (12 ) person-years were exposed (occurring coincident with or subsequent to an incident pregnancy). Mean follow-up in all women was 2.7 years, and median (interquartile range) for follow-up was 2.1 (0.8, 4.3) years. Baseline characteristics of the 7,534 women and characteristics of their contributed follow-up time are described in Table 1. The typical woman was 33 years old at initiation of HAART with a body mass index below 25 kg/m2 (and often below 18.5 kg/m2), low hemoglobin (median [IQR] 10.9 [9.5, 12.3] g/dL), and a CD4 count below 100 cells/mm3. Among the 19 of women who had a viral load taken at baseline, most (81 ) had a viral load above 10,000 copies/ml. Over follow-up, most person-time was virally suppressed and at a CD4 counts above 200 cells/mm3. A total of 918 women (12 ) experienced at least one pregnancy during follow-up, at a median of 14 (IQR 7, 26; mean 19) months after initiation of HAART. Younger women (18?5 years.Wing confounders of the effect of pregnancy on death (or AIDS and death), based on previous literature and plausible biological mechanism. Confounders measured at baseline (HAART initiation) included age, ethnicity, employment status, current tuberculosis, calendar date of HAART initiation, and WHO stage. Confounders measured over time included weight, body mass index, hemoglobin, CD4 count and CD4 percent, drug regimen, and drug adherence estimated from pharmacy visit data. We didPregnancy and Clinical Response to HAARTFigure 2. Effect of pregnancy on time to (A) death, (B) death or new stage 4 AIDS, or (C) death or new stage 3 or 4 AIDS. Curves are inverse, weighted, extended Kaplan-Meier curves. doi:10.1371/journal.pone.0058117.gnot control for baseline or time-updated viral load because of the high proportion of missingness, but included a sensitivity analysis in which viral load was imputed. We used restricted four-knot cubic splines to flexibly control for age, body mass index, CD4 count, and time-on-study.combined death and new stage 3 or 4 clinical AIDS events [33]. Missing data led to approximately 18 missing observations in the final analysis, so we also conducted a multiple imputation analysis to account for missing baseline data [40]. In all analyses, longitudinal data were carried forward from the most recent observed value.Sensitivity Analysis and Missing DataTo test analytic assumptions, we performed three sensitivity analyses in addition to the main analysis; these sensitivity analyses addressed 
issues in definitions of the population, exposure, and outcome, as well as technical decisions in the modeling. The most critical sensitivity analyses were in exploring alternate outcome definitions. These analyses included 1) a combined outcome of death and new stage 4 clinical AIDS events and (separately) 2)Role of the Funding SourceThe funding sources had no involvement in the design or conduct of the study, in the collection, management, analysis, or interpretation of the data, in the preparation, writing, review or approval of this manuscript, or in the decision to submit this manuscript for publication.Pregnancy and Clinical Response to HAARTFigure 3. Effect of pregnancy on time to drop-out, displayed as weighted inverse extended Kaplan-Meier curves. doi:10.1371/journal.pone.0058117.gResultsThe initial study population comprised 7,534 non-pregnant, ?ART-naive women ages 18?5, who contributed a total of 249,754 person-months, or 20,813 person-years of follow-up to this analysis, of which 2,472 (12 ) person-years were exposed (occurring coincident with or subsequent to an incident pregnancy). Mean follow-up in all women was 2.7 years, and median (interquartile range) for follow-up was 2.1 (0.8, 4.3) years. Baseline characteristics of the 7,534 women and characteristics of their contributed follow-up time are described in Table 1. The typical woman was 33 years old at initiation of HAART with a body mass index below 25 kg/m2 (and often below 18.5 kg/m2), low hemoglobin (median [IQR] 10.9 [9.5, 12.3] g/dL), and a CD4 count below 100 cells/mm3. Among the 19 of women who had a viral load taken at baseline, most (81 ) had a viral load above 10,000 copies/ml. Over follow-up, most person-time was virally suppressed and at a CD4 counts above 200 cells/mm3. A total of 918 women (12 ) experienced at least one pregnancy during follow-up, at a median of 14 (IQR 7, 26; mean 19) months after initiation of HAART. Younger women (18?5 years.