To the Editor—We read with interest the article by Theron et al [1] on their post hoc analysis of the Promoting Maternal and Infant Survival Everywhere (PROMISE) 1077BF/1077FF trials. They found an increased incidence of low-birth-weight (LBW) infants (<2500 g) and adverse pregnancy outcomes in women who conceived while on antiretroviral therapy (ART) compared with those who restarted ART after pregnancy was diagnosed. Their study adds an important data point to the limited, and sometimes contradictory, evidence regarding safety of ART in pregnancy and its relationship with adverse pregnancy outcomes [2].
We recently completed 2 studies on sexually transmitted infections (STIs) in pregnant women living with human immunodeficiency virus (HIV) in Pretoria [3] and Cape Town [4], South Africa. (Ethical approval for those studies was provided by the institutional review boards at the University of Cape Town’s Faculty of Health Sciences Research Ethics Committee, University of Pretoria’s Faculty of Health Sciences Research Ethics Committee, and the University of California, Los Angeles.
In both studies, we detected Chlamydia trachomatis and Neisseria gonorrhoeae infection at the first antenatal care (ANC) visit. We examined the combined dataset of 416 women living with HIV with live births for the effect of ART at conception on birth outcomes. Overall, 190 (46%) women were on ART at the time of conception and 226 (54%) women initiated ART during pregnancy. There was no significant difference between these groups with regard to maternal age, gestational age at enrollment, gravidity, and ART regimen (mostly tenofovir disoproxil fumarate, emtricitabine, and efavirenz). The prevalence of STIs was high (30%); STIs were less common among women who conceived while on ART than those who initiated ART during pregnancy (25% vs 34%; P = .063); most likely this reflects increased engagement with healthcare.
ART at conception and STI at first ANC visit were not associated with LBW in our combined cohort (after adjustment for maternal age and gestational age at enrollment). After stratification by presence of an STI, there was a clear association of ART at conception with LBW infants among women with an STI detected at the first ANC visit (Table 1). This was not the case for women who tested STI-negative. In women with an STI, birthweight was significantly lower among those on ART at conception compared with those who initiated ART during pregnancy (3000 g vs 3140 g; P = .034). This association was absent in women without an STI (3060 g vs 3070 g; P = .97).
Table 1.
Relationship Between Antiretroviral Therapy at Time of Conception and Low Birth Weight in Pregnant Women Living With Human Immunodeficiency Virus With and Without a Sexually Transmitted Infection in South Africa
| Participant group | Time of ART Initiation | Low Birth Weight (n = 59) | Normal Birth Weight (n = 357) | OR (95% CI) | P Value |
|---|---|---|---|---|---|
| Total cohort | ART at conception | 30 (16%) | 160 (84%) | 1.3 (.74–2.2) | .39 |
| ART initiated during pregnancy | 29 (13%) | 197 (87%) | |||
| Low Birth Weight (n = 19) | Normal Birth Weight (n = 105) | OR (95% CI) | P Value | ||
| STI detected at first ANC visita | ART at conception | 12 (25%) | 36 (75%) | 3.3 (1.2–9.1) | .017 |
| ART initiated during pregnancy | 7 (9.2%) | 69 (91%) | |||
| Low Birth Weight (n = 40) | Normal Birth Weight (n = 252) | OR (95% CI) | P Value | ||
| No STI detected at first ANC visita | ART at conception | 18 (13%) | 124 (87%) | 0.85 (.43–1.7) | .62 |
| ART initiated during pregnancy | 22 (15%) | 128 (85%) |
Data are presented as number with row proportion. Low birth weight is defined as <2500 g.
Abbreviations: ANC, antenatal care; ART, antiretroviral therapy; CI, confidence interval; OR, odds ratio; STI, sexually transmitted infection.
aThe Xpert CT/NG assay was performed on vaginal swabs to detect Chlamydia trachomatis and Neisseria gonorrhoea; 94 women had a positive test for C. trachomatis, 9 for N. gonorrhoeae, and 21 for both.
It is unclear why STIs may modify the effect of ART on birth weight. Methodological bias cannot be ruled out. Several pathogenic mechanisms may account for associations between ART and adverse pregnancy outcomes, including modulation of the Th1 to Th2 immune shift, which is associated with pregnancy, and changes in placental cytokine expression [5]. Chlamydia trachomatis and N. gonorrhoeae infection are associated with elevated genital tract cytokine concentrations and substantial changes in cytokine profile with upregulation of proinflammatory cytokines [6]. Possibly, combined alterations in cytokine expression related to ART and STIs might explain our observation.
Adverse pregnancy outcomes, STIs, and living with HIV are overlapping disease burdens in sub-Saharan Africa where the benefits of ART on maternal health and for prevention of mother-to-child transmission are unquestioned. We therefore agree with the authors that continuous monitoring of any adverse effects of ART on pregnancy outcomes is warranted. Future studies should explore the potential role of STIs and inflammatory pathway changes.
Notes
Acknowledgment.
Financial support. Research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH) under award R21HD084274-01A1 to A. M.-M. and J. K. and by the President’s Emergency Plan for AIDS Relief through the US Agency for International Development under the terms of Cooperative Agreement AID 674-A-12–00017 (to A. M.-M.). D. J. D. received funding from the NIH and Fogarty International Center (K01TW011187). D. J. D. and L. M. received funding from the National Institute of Mental Health (R01MH116771). R. P., J. K. and A. M. were supported through the National Institute for Allergy and Infectious Diseases (award number R01AI149339).
Potential conflicts of interest. The authors received a donation of STI Xpert assays from Cepheid (California). J. K. reports personal fees from Cepheid during the conduct of the study and personal fees from Danaher outside the submitted work. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
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