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Epidemiology and Social

Incident HIV among pregnant and breast-feeding women in sub-Saharan Africa: a systematic review and meta-analysis

Graybill, Lauren A.a; Kasaro, Margaretb; Freeborn, Kelliec; Walker, Jennifer S.d; Poole, Charlesa; Powers, Kimberly A.a; Mollan, Katie R.a,e; Rosenberg, Nora E.f; Vermund, Sten H.g; Mutale, Wilbroadh; Chi, Benjamin H.c

Author Information
doi: 10.1097/QAD.0000000000002487

Abstract

Introduction

HIV acquisition among pregnant and breast-feeding women increases risk of maternal morbidity and mortality, and accounts for a significant, and growing, proportion of pediatric HIV infections globally [1]. A meta-analysis of 19 studies conducted between 1980 and 2012 estimated an average HIV incidence rate of 3.8/100 person-years [95% confidence interval (CI): 3.0--4.6] among pregnant and breast-feeding women in sub-Saharan Africa (SSA) [2]. Although this estimate is above the World Health Organization's (WHO) threshold for substantial risk of HIV acquisition [3], the rapidly evolving HIV prevention and treatment landscape since publication of this review may have important implications for maternal HIV incidence.

In 2013, the WHO updated HIV treatment guidelines, expanding antiretroviral therapy (ART) eligibility to CD4+ ≤ 500 cells/μl [4], and in 2015, it recommended universal treatment for HIV [5]. These changes, together with increased uptake of HIV testing and counseling and medical male circumcision [6–8], coincided with a 30% decline in the estimated number of new adult HIV infections in SSA between 2010 and 2017 [9]. Similar temporal trends in HIV incidence have been observed in three population-based cohort studies in SSA [10–12], with more gradual declines observed among women than among men [11,12]. Although combination HIV prevention and treatment interventions may not directly target pregnant and breast-feeding women, these populations may experience downstream benefits in HIV prevention. In at least one study [13], maternal HIV incidence was considerably lower in a cohort of pregnant and breast-feeding women participating in a community-based HIV prevention program than estimates of maternal incidence from the previous review [2].

Although the previous review observed evidence of heterogeneity among study-specific estimates of the incidence rate and the association between pregnancy and risk of HIV acquisition, their investigation into the underlying factors contributing to this variability was limited [2]. A better understanding of features contributing to variation in estimates is critical for guiding future research and policy, and for developing efficient strategies to reduce horizontal and vertical HIV transmission during pregnancy and breast-feeding.

In this updated review of literature from SSA between 1980 and 2018, we sought to summarize estimates of HIV incidence among pregnant and breast-feeding women; summarize estimates of the associations between pregnancy and risk of maternal HIV acquisition and between breast-feeding and risk of HIV acquisition; and identify population and methodological characteristics contributing to variation in study-specific estimates of incidence and association.

Methods

This review is registered with PROSPERO (CRD42017079577) and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Guidelines [14].

Study selection and data abstraction

We searched PubMed, Embase, PsycInfo, and the Cochrane Library for relevant literature published between 1 January 1980 and 1 December 2018 (Table S1, http://links.lww.com/QAD/B657). We also searched online abstract archives from HIV Research for Prevention Conference (2014–2018), Conference of Retroviruses and Opportunistic Infections (2014–2018), and International AIDS Society Conferences (2001–2018) using the terms (‘pregnant’, ‘pregnancy’, or ‘postpartum’) and (‘incident’, ‘incidence’, or ‘seroconvert’).

We screened resulting titles and abstracts to identify publications that referred to HIV incidence among women or to pregnancy/breast-feeding and HIV. We conducted a full text review of included publications to identify primary research reports with estimates of (or sufficient information to derive) the incidence rate of HIV among pregnant and breast-feeding women, the incidence rate ratio (IRR) or hazard ratio contrasting HIV incidence between pregnant and nonpregnant periods, and/or the IRR or hazard ratio contrasting HIV incidence between breast-feeding and non-breast-feeding periods. Included studies were restricted to those published in English and conducted in SSA. We requested additional information from authors when publications contained relevant but insufficient information, and reviewed the bibliographies of included publications for relevant references.

Two investigators reviewed each publication at screening and full-text review; disagreements were resolved by consensus. Data on outcomes and exposures of interest and key population and methodological features of each study were abstracted into standardized tables by one reviewer and checked by two others. When more than one publication reported the same outcome from the same study population over the same period, we included the report considered most complete.

Outcome and exposure definitions

HIV incidence, the primary outcome, was defined as the number of new HIV infections per 100 person-years. Pregnancy and breast-feeding represented periods of interest in studies contributing incidence rate estimates, and represented exposures of interest in studies estimating the IRR or hazard ratio. We accepted all definitions in our primary analyses. In a sensitivity analysis, we excluded studies where the breast-feeding period exceeded 24 months postpartum [15].

Statistical approach

We used inverse-variance-weighted random-effects meta-analysis to estimate natural log-transformed measures of the average HIV incidence rate among pregnant and breast-feeding women, the average association between pregnancy and risk of HIV acquisition, the average association between breast-feeding and risk of HIV acquisition, and 95% prediction intervals around summary estimates. The 95% prediction intervals convey the estimated spread of the random-effects distribution, and can be informally interpreted as 95% CI for the true rate or association to be estimated in a randomly selected study population [16–18]. When zero seroconversions were reported, we applied a half-integer continuity correction to prevent the estimate from being omitted. As IRRs roughly approximate hazard ratios [19], we pooled these estimates for meta-analysis and assumed approximate collapsibility since HIV acquisition is rare [20]. Summary estimates and 95% prediction intervals were exponentiated for interpretability.

Because of the potential for publication bias, we drew funnel plots and analyzed them with the symmetry test of Egger et al. and with Duval and Tweedie's trim-and-fill imputation method [21,22]. We analyzed overall heterogeneity using 95% prediction intervals and the P value for Cochrane's Q statistic. We used stratified analyses and univariate random-effects meta-regression to analyze heterogeneity further by comparing average rates and associations by population characteristics of included studies. Meta-regression was also used to explore associations between estimates and methodological aspects related to study quality [23,24]. When a single study contributed information to more than one stratum of a variable, we used robust variances to account for correlation [25]. Given the large number of studies contributing estimates of the incidence rate, we also constructed separate multivariable models for each potential source of heterogeneity of the incidence rate. Each model adjusted for region, years of study implementation, and calendar time to account for differences in HIV prevalence and ART coverage. All analyses were conducted using the Metafor package in R, version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria) [26].

Sources of heterogeneity

Characteristics related to underlying HIV risk – region, calendar time, age, membership of a high-risk population, and participant enrollment in an HIV-prevention clinical trial – may be associated with estimates of incidence and association. As studies contributing estimates of the association had limited variability in calendar time, and did not provide age-stratified results, these features were only evaluated as sources of heterogeneity of the incidence rate.

We defined region using the World Bank's classifications, and calendar time based on mid-year of study implementation. We examined calendar time continuously, as a quadratic function, and categorically with three periods: precombination HIV prevention (before 2010), early adoption (2010–2014), and program expansion (after 2014). These periods correspond to important updates to WHO HIV treatment and prevention recommendations [4,5,27,28], and their implementation across SSA [6–8]. We defined age groups based on the most commonly reported categorization in the literature: less than 20, 20–24, 25–29, and at least 30. Other age group categorizations were considered in sensitivity analyses. We used a binary variable to distinguish between studies that enrolled a ‘high-risk’ cohort (e.g. HIV-discordant couples or female sex workers) and those that did not. We stratified by type of ‘high-risk’ group in sensitivity analyses. Studies were also classified according to whether participants were enrolled in a clinical trial evaluating an HIV prevention intervention.

The following features related to the measurement of incident infections and person-time may also be associated with estimates of incidence and association: study design, use of results from repeat HIV testing to identify seroconversions, reproductive periods observed over follow-up, use of HIV DNA/RNA PCR in the HIV-testing algorithm, and method for estimating date of HIV infection. As all studies contributing estimates of the association used repeat HIV testing and observed all reproductive periods over follow-up, these features were only evaluated as sources of heterogeneity of the incidence rate.

Finally, estimates of the IRR or hazard ratio may be related to the inclusion of breast-feeding-exposed periods in the reference group, adjustment for confounders, and adjustment for time-varying measures of condom use and intercourse frequency.

Results

Our search yielded 5186 nonduplicate abstracts (Fig. 1). Screening resulted in 202 publications for full-text review, of which 57 met inclusion criteria. After excluding 20 publications because of overlapping cohorts and outcomes, 37 publications remained (Table 1    ). Thirty-four contributed estimates of the HIV incidence rate [13,29–61], and 10 contributed estimates of either the IRR or hazard ratio [55–64]. Follow-up ranged from 45 person-years to 57 240 person-years. Most studies were conducted in southern Africa (n = 20) [13,29,30,32,34,35,39–44,48,51,52,54,55,60,61,64]. The mid-point of follow-up occurred before 2010 in 26 studies [29,32,34–36,38–44,48,50,52–64], between 2010 and 2014 in eight [30,31,33,37,46,47,49,55], and after 2014 in three [13,45,51]. Two studies reported results stratified by calendar time [55,56]. In seven studies, participants were enrolled in an HIV prevention trial [32,43,54,60–62,64]. Four studies enrolled high-risk study populations [54,57,62,63], and two studies reported results stratified by risk-group [58,59]. Eight studies reported estimates of incidence stratified by age [13,30,38,39,44,48,55,58].

Fig. 1
Fig. 1:
Study selection flowchart.
Table 1
Table 1:
Description of studies meeting inclusion criteria.
Table 1 (Continued)
Table 1 (Continued):
Description of studies meeting inclusion criteria.
Table 1 (Continued)
Table 1 (Continued):
Description of studies meeting inclusion criteria.
Table 1 (Continued)
Table 1 (Continued):
Description of studies meeting inclusion criteria.
Table 1 (Continued)
Table 1 (Continued):
Description of studies meeting inclusion criteria.

There was limited variability in how studies measured incidence after accounting for study design (Table S2, http://links.lww.com/QAD/B658). Prospective cohort studies (n = 24) enrolled HIV-seronegative women and retested them over follow-up to identify changes in HIV serostatus. Twenty-one prospective cohort studies contributed estimates of the incidence rate among pregnant and breast-feeding women [13,29,30,32,37–40,42–44,48–50,52,54,58–61], and eight contributed estimates of the IRR or hazard ratio [57–64]. Eleven cross-sectional studies contributed estimates of the incidence rate among pregnant and breast-feeding women [31,33–36,41,45–47,51,53]. In these studies, HIV status at the time of the first antenatal visit was retrospectively assessed at the time of enrollment, which occurred in the third trimester [31,41,46,47], at delivery [33–35,51], or in the postpartum period [36,45,53]. Women classified as HIV-negative in pregnancy were enrolled and current HIV serostatus was assessed to identify new HIV infections. Finally, two studies nested within large population-based surveillance studies contributed estimates of both the incidence rate and the hazard ratio [55,56]. These studies used prospectively collected data from HIV surveillance assessments to assess changes in serostatus over time.

HIV incidence during pregnancy and breast-feeding

Studies contributing estimates of incidence during pregnancy typically captured the period between the first antenatal visit and delivery, while studies contributing estimates of incidence during breast-feeding captured the period from delivery up to 24 months postpartum depending on length of follow-up (Table 1    ).

Thirty-four studies contributed 100 758 person-years of follow-up and generated 44 estimates of HIV incidence among pregnant and/or breast-feeding women. Ten studies reported stratified estimates of incidence during pregnancy and during breast-feeding [13,37,39,44,54–59]. Using all available estimates, we observed little difference in the average HIV incidence rate during pregnancy only (n = 22, 3.4/100 person-years, 95% prediction interval: 1.1--10.4), breast-feeding only (n = 17, 3.1/100 person-years, 95% prediction interval: 1.0--9.5), and pregnancy and breast-feeding combined (n = 5, 4.6/100 person-years, 95% prediction interval: 1.4--15.4). We, therefore, combined estimates into a single HIV incidence rate during ‘pregnancy and breast-feeding’ for subsequent analyses. The estimated average of the HIV incidence rates during pregnancy and breast-feeding was 3.6 per 100 person-years (95% prediction interval: 1.2--11.1; Figure S1, http://links.lww.com/QAD/B653). Our results were unchanged after excluding one study with follow-up exceeding 24 months postpartum [48]. There was no visual or statistical evidence of funnel plot asymmetry (P = 0.3). Cochrane's Q statistic indicated evidence of heterogeneity (P < 0.001), which was consistent with the wide 95% prediction interval.

The average HIV incidence rate among pregnant and breast-feeding women was associated with age, calendar time, study design, and method of estimating the timing of HIV infection (Table 2). Average HIV incidence rates were lower among women at least 30 years old than among women less than 20 years old (ratio of average incidence rates: 0.5, 95% CI: 0.3--0.7), and this inverse relationship was robust to different categorizations of age (Table S3, http://links.lww.com/QAD/B659). HIV incidence appeared to have an inverted u-shaped association with calendar time (Figure S2, http://links.lww.com/QAD/B654). After adjusting for region and length of study, the average incidence rate for studies conducted after 2014 was 0.4 times the average rate for studies conducted prior to 2010 (95% CI: 0.2--0.7). Incidence was also associated with study design. Average rates were the highest among cross-sectional studies (4.7/100 person-years, 95% prediction interval: 1.6--13.5), followed by prospective cohort studies (3.4/100 person-years, 95% prediction interval: 1.2--9.4) and surveillance studies (2.2/100 person-years, 95% prediction interval: 0.6--7.4). Studies that defined the date of seroconversion as the date of the first positive HIV test observed higher incidence rates than studies that used a date between the last negative and first positive HIV test (ratio of average incidence rates: 4.3, 95% CI: 1.4--13.2).

Table 2
Table 2:
Stratified analysis and meta-regression of the incidence rate of HIV during pregnancy and breast-feeding.

After stratifying by type of high-risk population, we observed higher estimated incidence rates among pregnant and breast-feeding women with known HIV-positive partners than rates estimated in a more general study population (ratio of average incidence rates: 4.7, 95% CI: 2.2--10.2; Table S4, http://links.lww.com/QAD/B660).

Pregnancy and HIV acquisition

Ten studies contributed estimates of the association between pregnancy and HIV acquisition. In four, nonpregnant, non-breast-feeding periods served as the referent [55,56,58,59]; in six, nonpregnant periods (which included breast-feeding) were defined as the referent [57,60–64]. There were variability definitions of ‘nonpregnant’ and ‘nonpregnant/non-breast-feeding’ because of heterogeneous definitions of pregnancy and breast-feeding (Table 1    ). All studies used methods that allowed women to contribute person-time to both exposed and unexposed periods.

The average hazard ratio estimating the association between pregnancy and risk of HIV acquisition was 0.9 (95% prediction interval: 0.2--3.8; Figure S3, http://links.lww.com/QAD/B655). Although we observed statistical evidence of funnel plot asymmetry (P = 0.05), results were largely unchanged after using a trim-and-fill analysis to impute one possibly missing result (average hazard ratio: 1.0, 95% prediction interval: 0.3--3.3). We also observed evidence of heterogeneity among study-specific estimates of the association (P < 0.001), which was consistent with the wide 95% prediction interval spanning the null. Stratified analyses and meta-regression revealed limited evidence of associations between the average hazard ratios and the measured characteristics of contributing studies (Table 3). Two estimates were generated by studies with partially overlapping cohorts [61,64]; exclusion of either did not change these results substantially (Tables S5, http://links.lww.com/QAD/B661 and S6, http://links.lww.com/QAD/B662).

Table 3
Table 3:
Stratified analysis and meta-regression of the association between pregnancy and risk of HIV acquisition.

Breast-feeding and HIV acquisition

Four studies compared the risk of HIV acquisition during breast-feeding to risk during nonpregnant and non-breast-feeding periods. The average hazard ratio estimating the association between breast-feeding and risk of HIV acquisition was 1.0 (95% prediction interval: 0.6--1.6; Figure S4, http://links.lww.com/QAD/B656). We did not observe statistical evidence of funnel plot asymmetry (P = 0.2). Compared with estimates of the association between pregnancy and risk of HIV acquisition, estimates of the association between breast-feeding and risk of HIV acquisition were more tightly clustered around the null. We observed little evidence of heterogeneity between the study-specific hazard ratio estimates (P = 0.6), and our analyses revealed limited evidence of associations between the average hazard ratios and the measured characteristics of contributing studies (Table 4).

Table 4
Table 4:
Stratified analysis and meta-regression of the association between breast-feeding and risk of HIV acquisition.

Discussion

In this meta-analysis update -- which included 15 new studies and over 77 000 additional person-years of follow-up -- the estimated average HIV incidence rate among pregnant and breast-feeding women was above the ‘substantial risk’ threshold described by the WHO [3], whereas the estimated average associations between pregnancy and risk of HIV acquisition, and breast-feeding and risk of HIV acquisition, were close to the null. Prediction intervals around each of our summary estimates were wide, highlighting the variability of HIV incidence across populations of pregnant and breast-feeding women in SSA.

Our results were consistent with findings from a previous meta-analysis that reported high average HIV incidence during pregnancy and breast-feeding [2]. Hormonal changes during pregnancy may increase susceptibility to HIV through changes in the vaginal epithelial thickness, microbiome, and CCR5 coreceptor expression [65,66]. Pregnancy activates the innate immune system, increasing inflammation and concentration of dendritic cells in the female genital tract, while suppressing the adaptive immune response [67,68]. Such immunologic changes may increase risk of HIV acquisition [69–71], and can last for several months postpartum [72,73]. Behavioral changes occurring during pregnancy may also influence risk of HIV acquisition. Couples may be more likely to engage in unprotected sex during pregnancy [34,58,74], and male partners may be more likely to seek extra-partnership sexual liaisons during extended periods of pregnancy-related or breast-feeding-related abstinence [34,75–77].

Substantial heterogeneity of the incidence rates, however, cautions us from interpreting the average HIV incidence rate estimated in this study as the incidence rate among pregnant and breast-feeding women in SSA. Our results suggest maternal HIV incidence rates may lower among older compared with younger pregnant and breast-feeding women, and higher among women in HIV serodiscordant relationships. Additionally, we observed changes in average HIV incidence over calendar time that follow temporal trends observed in the region since the 1980s: a steady rise in HIV incidence until the early 2000s [78], largely driven by increasing HIV prevalence without viral suppression [79], followed by a slow decline that may be attributed to expanded HIV testing and counseling, medical male circumcision, and ART services. Inverted u-shaped trends in HIV incidence over time have been observed in large population-based cohorts in SSA [10–12], with reported associations between HIV incidence and community-level coverage of ART and medical male circumcision. Models predict that integrated behavioral and biomedical interventions will reduce HIV incidence generally [80,81], and among pregnant women specifically [82], and two cluster randomized trials of combination HIV prevention with universal ART demonstrated some reductions in community-wide HIV incidence [83,84]. Although we expect that HIV-negative pregnant and breast-feeding women may serve as beneficiaries of expanded combination HIV prevention, impact will likely vary across sub-groups.

Prediction intervals around estimates of the average association between pregnancy and risk of HIV acquisition and between breast-feeding and risk of HIV acquisition, were wide with lower and upper bounds on either side of the null. This variability is not unexpected; pregnancy and breast-feeding are periods marked by significant biological and behavioral changes that may have different effects on risk of HIV. For example, the potential increased risk of HIV arising from the pregnancy-induced physiological changes described earlier may be offset by a reduction in sexual intercourse that frequently occurs during late pregnancy and early breast-feeding [34,54,58,74]. The direction of the observed association between pregnancy or breast-feeding and risk of HIV acquisition may, therefore, depend on both study context and analytical decisions regarding covariate measurement and adjustment [85]. Furthermore, as the physiological and behavioral changes that accompany pregnancy and breast-feeding are dynamic, decisions regarding how to define pregnancy, breast-feeding, and the referent state may influence the direction of the observed association. For example, the inclusion of breast-feeding in the referent group may produce estimates closer to the null as incidence rates during breast-feeding appear similar to those during pregnancy, whereas single categories for pregnancy and breast-feeding may obscure periods during pregnancy or breast-feeding when risk is truly elevated or suppressed. Work by Thomson et al.[54] suggests that physiological changes during pregnancy increase susceptibility to HIV, particularly in late pregnancy and early breast-feeding. However, additional work is needed to better understand the interaction between biological susceptibility and behavioral changes on risk of HIV acquisition among pregnant and breast-feeding women in different SSA contexts.

Our results should be interpreted in light of possible limitations. It is unclear if contributing studies enrolled representative cohorts of women, so the extent to which our estimates generalize to all pregnant and breast-feeding women in SSA is unknown. It is possible that investigators targeted clinics in areas of elevated HIV incidence, which may bias estimates of incidence upwards. Few estimates of the incidence rate captured the first trimester of pregnancy, and given the variability of risk over the course of pregnancy [54,58,62], this may bias estimates of incidence. The directionality of this bias is unclear; two studies report higher incidence during early compared with late pregnancy [58,62], whereas one reports the reverse [54]. For this reason, misclassification of early or late pregnancy-exposed periods as nonpregnant person-time may also bias estimates of the association in unknown directions. Finally, our analyses were restricted by the number of studies and the information provided by each study. The small number of estimates may have limited our power to detect associations between estimates and underlying sources of heterogeneity. Differences in populations and methodological features of contributing studies may not have been adequately captured by variables used in meta-regression models, and several important population features were unmeasured by contributing studies.

Although many countries in SSA have placed considerable focus on identifying and treating HIV-infected pregnant and breast-feeding women, HIV-uninfected women have received considerably less attention in antenatal and postnatal settings. Our results support the expansion of bio-behavioral HIV prevention interventions and repeat testing throughout pregnancy and breast-feeding to women at high risk of HIV acquisition. Further work is needed to identify risk factors for HIV acquisition during pregnancy and breast-feeding to facilitate targeted prevention interventions in antenatal and postnatal settings. Offering female-controlled strategies, such as tenofovir-based oral preexposure prophylaxis, and promoting couple-based prevention approaches in these settings, are important next steps that may reduce the risk of HIV-related maternal morbidity and mortality, and ensure continued progress towards the elimination of mother-to-child transmission of HIV.

Acknowledgements

This study was supported in part by the National Institutes of Health (R01 AI131060, R00 MH104154, K24 AI120796, P30 AI050410, D43 TW009340).

All authors met the criteria for authorship as established by the International Committee of Medical Journal Editors. Contributions were as follows: study concept and design: L.A.G., M.K., K.A.P., W.M., B.H.C.; literature search: L.A.G., J.S.W.; literature review: L.A.G., M.K., K.F., B.H.C.; data abstraction: L.A.G., K.F., B.H.C.; statistical analysis: L.A.G., C.P., K.R.M., K.A.P.; data interpretation: L.A.G., C.P., K.A.P., K.R.M., N.E.R., S.H.V., W.M., B.H.C.; drafting of manuscript: L.A.G., K.F., B.H.C.; critical revisions of manuscript: all authors.

Sources of funding: This study was supported in part by the National Institutes of Health (R01 AI131060, R00 MH104154, K24 AI120796, P30 AI050410, D43 TW009340).

Disclaimer: The funders of this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Duplicate Publication: Results have not been published previously. Results were presented as a research poster at the 11th International Workshop on HIV Paediatrics (abstract number 109) and the 10th International AIDS Society Conference (abstract number TUPEC475).

Conflicts of interest

There are no conflicts of interest.

References

1. Johnson LF, Stinson K, Newell ML, Bland RM, Moultrie H, Davies MA, et al. The contribution of maternal HIV seroconversion during late pregnancy and breastfeeding to mother-to-child transmission of HIV. J Acquir Immune Defic Syndr 2012; 59:417–425.
2. Drake AL, Wagner A, Richardson B, John-Stewart G. Incident HIV during pregnancy and postpartum and risk of mother-to-child HIV transmission: a systematic review and meta-analysis. PLoS Med 2014; 11:e1001608.
3. World Health Organization (WHO). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. 2nd ed.Geneva, Switzerland: WHO; 2016.
4. World Health Organization (WHO). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva, Switzerland: WHO; 2013.
5. World Health Organization (WHO). Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. Geneva, Switzerland: WHO; 2015.
6. World Health Organization (WHO). Global update on the health sector response to HIV, 2014. Geneva, Switzerland: WHO; 2014.
7. Joint United Nations Programme on HIV/AIDS (UNAIDS). Prevention gap report. Geneva, Switzerland: UNAIDS; 2016.
8. World Health Organization (WHO). Treat all: policy adoption and implementation status in countries. Geneva, Switzerland: WHO; 2017.
9. Joint United Nations Programme on HIV/AIDS (UNAIDS). UNAIDS data 2018. Geneva, Switzerland: UNAIDS; 2018.
10. Borgdorff MW, Kwaro D, Obor D, Otieno G, Kamire V, Odongo F, et al. HIV incidence in western Kenya during scale-up of antiretroviral therapy and voluntary medical male circumcision: a population-based cohort analysis. Lancet HIV 2018; 5:e241–e249.
11. Vandormael A, Akullian A, Siedner M, de Oliveira T, Bärnighausen T, Tanser F. Declines in HIV incidence among men and women in a South African population-based cohort. Nat Commun 2019; 10:5482.
12. Grabowski MK, Serwadda DM, Gray RH, Nakigozi G, Kigozi G, Kagaayi J, et al. Rakai Health Sciences Program. HIV prevention efforts and incidence of HIV in Uganda. N Engl J Med 2017; 377:2154–2166.
13. Fatti G, Grimwood A, Egbujie B, Mothibi E, Shaikh N, Jackson D, et al. Low HIV incidence in South African pregnant women receiving a prevention intervention. Topics in Antiviral Medicine 2017; 25:324s–325s.
14. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6:e1000097.
15. World Health Organization (WHO). Infant and young child feeding. Geneva, Switzerland: WHO; 2018.
16. Higgins JPT, Thompson SG, Spiegelhalter DJ. A re-evaluation of random-effects meta-analysis. J R Stat Soc Ser A Stat Soc 2009; 172:137–159.
17. Riley RD, Higgins JPT, Deeks JJ. Interpretation of random effects meta-analyses. BMJ 2011; 342:d549.
18. IntHout J, Ioannidis JPA, Rovers MM, Goeman JJ. Plea for routinely presenting prediction intervals in meta-analysis. BMJ open 2016; 6:e010247.
19. Hernan MA. The hazards of hazard ratios. Epidemiology 2010; 21:13–15.
20. VanderWeele TJ. Unmeasured confounding and hazard scales: sensitivity analysis for total, direct, and indirect effects. Eur J Epidemiol 2013; 28:113–117.
21. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56:455–463.
22. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315:629–634.
23. Greenland S, O’Rourke K. On the bias produced by quality scores in meta-analysis, and a hierarchical view of proposed solutions. Biostatistics 2001; 2:463–471.
24. Jüni P, Witschi A, Bloch R, Egger M. The hazards of scoring the quality of clinical trials for meta-analysis. JAMA 1999; 282:1054–1060.
25. Tipton E. Small sample adjustments for robust variance estimation with meta-regression. Psychol Methods 2015; 20:375–393.
26. Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw 2010; 39:1–48.
27. World Health Organization (WHO). Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach - 2010 revision. Geneva, Switzerland: WHO; 2010.
28. World Health Organization (WHO). Guidance on couples HIV testing and counseling including antiretroviral therapy for treatment and prevention in serodiscordant couples: recommendations for a public health approach. Geneva, Switzerland: WHO; 2012.
29. De Schacht C, Hoffman HJ, Mabunda N, Lucas C, Alons CL, Madonela A, et al. High rates of HIV seroconversion in pregnant women and low reported levels of HIV testing among male partners in Southern Mozambique: results from a mixed methods study. PloS One 2014; 9:e115014.
30. De Schacht C, Mabunda N, Ferreira OC Jr, Ismael N, Calú N, Santos I, et al. High HIV incidence in the postpartum period sustains vertical transmission in settings with generalized epidemics: A cohort study in Southern Mozambique. J Int AIDS Soc 2014; 17:18808.
31. Egbe TO, Tazinya RM, Halle-Ekane GE, Egbe EN, Achidi EA. Estimating HIV incidence during pregnancy and knowledge of prevention of mother-to-child transmission with an ad hoc analysis of potential cofactors. J Pregnancy 2016; 2016:7397695.
32. Humphrey JH, Hargrove JW, Malaba LC, Iliff PJ, Moulton LH, Mutasa K, et al. ZVITAMBO Study Group. HIV incidence among post-partum women in Zimbabwe: risk factors and the effect of vitamin A supplementation. AIDS 2006; 20:1437–1446.
33. Imade GE, Sagay AS, Musa J, Ocheke AN, Adeniyi DS, Idighri M, et al. Declining rate of infection with maternal human immunodeficiency virus at delivery units in north-central Nigeria. Afr J Reprod Health 2013; 17 ((4 Spec No)):138–145.
34. Keating MA, Hamela G, Miller WC, Moses A, Hoffman IF, Hosseinipour MC. High HIV incidence and sexual behavior change among pregnant women in Lilongwe, Malawi: implications for the risk of HIV acquisition. PloS One 2012; 7:e39109.
35. Kieffer MP, Nhlabatsi B, Mahdi M, Hoffman HJ, Kudiabor K, Wilfert CM. Improved detection of incident HIV infection and uptake of PMTCT services in labor and delivery in a high HIV prevalence setting. J Acquir Immune Defic Syndr 2011; 57:e85–e91.
36. Kinuthia J, Kiarie JN, Farquhar C, Richardson B, Nduati R, Mbori-Ngacha D, John-Stewart G. Cofactors for HIV-1 incidence during pregnancy and postpartum period. Curr HIV Res 2010; 8:510–514.
37. Kinuthia J, Drake AL, Matemo D, Richardson BA, Zeh C, Osborn L, et al. HIV acquisition during pregnancy and postpartum is associated with genital infections and partnership characteristics. AIDS 2015; 29:2025–2033.
38. Leroy V, Van De Perre P, Lepage P, Saba J, Nsengumuremyi F, Simonon A, et al. Seroincidence of HIV-1 infection in African women of reproductive age: a prospective cohort study in Kigali, Rwanda, 1988–1992. AIDS 1994; 8:983–986.
39. Mbizvo MT, Kasule J, Mahomed K, Nathoo K. HIV-1 seroconversion incidence following pregnancy and delivery among women seronegative at recruitment in Harare, Zimbabwe. Cent Afr J Med 2001; 47:115–118.
40. Miotti P, Canner J, Chiphangwi J, Liomba G, Saah A, Dallabetta G. Preparations for AIDS vaccine evaluations. Rate of new HIV infection in a cohort of women of childbearing age in Malawi. AIDS Res Hum Retroviruses 1994; 10: (Suppl 2): S239–S241.
41. Moodley D, Esterhuizen TM, Pather T, Chetty V, Ngaleka L. High HIV incidence during pregnancy: compelling reason for repeat HIV testing. AIDS 2009; 23:1255–1259.
42. Moodley D, Esterhuizen T, Reddy L, Moodley P, Singh B, Ngaleka L, Govender D. Incident HIV infection in pregnant and lactating women and its effect on mother-to-child transmission in South Africa. J Infect Dis 2011; 203:1231–1234.
43. Moodley D, Moodley P, Sebitloane M, Soowamber D, McNaughton-Reyes HL, Groves AK, Maman S. High prevalence and incidence of asymptomatic sexually transmitted infections during pregnancy and postdelivery in KwaZulu Natal, South Africa. Sex Transm Dis 2015; 42:43–47.
44. Munjoma MW, Mhlanga FG, Mapingure MP, Kurewa EN, Mashavave GV, Chirenje MZ, et al. The incidence of HIV among women recruited during late pregnancy and followed up for six years after childbirth in Zimbabwe. BMC Public Health 2010; 10:668.
45. Nikuze A, Wanjala S, Ben-Farhat J, Omwoyo W, Oyiengo L, Szumilin E, et alHIV incidence, cascade, and testing among mothers in Western Kenya. 24th Conference on Retroviruses and Opportunistic Infections. Seattle, United States: CROI 2017; 2017.
46. Rogers AJ, Akama E, Weke E, Blackburn J, Owino G, Bukusi EA, et al. Implementation of repeat HIV testing during pregnancy in southwestern Kenya: progress and missed opportunities. J Int AIDS Soc 2017; 20:e25036.
47. Tabu F, Ngonzi J, Mugyenyi G, Bajunirwe F, Mayanja R, Morten S. Prevalence of HIV infection among parturients with a negative primary test during the antenatal period at Mbarara Regional Referral Hospital, Uganda. BJOG 2013; 120:13.
48. Taha TE, Dallabetta GA, Hoover DR, Chiphangwi JD, Mtimavalye LAR, Liomba GN, et al. Trends of HIV-1 and sexually transmitted diseases among pregnant and postpartum women in urban Malawi. AIDS 1998; 12:197–203.
49. Traore C. Evaluation of HIV incidence during pregnancy in Ouagadougou, Burkina Faso. 19th International AIDS Conference. Washington DC, United States: International AIDS Society; 2012.
50. Van de Perre P, Hitimana DG, Simonon A, Dabis F, Msellati PEK, et al. Postnatal transmission of HIV-1 associated with breast abscess. Lancet 1992; 339:1490–1491.
51. Phiri S, Manda E, Tweya H, Rosenberg N, Gugsa S, Chiwoko J, et alComparison of HIV testing yield rates for pregnant and lactating women towards zero new paediatric HIV infection: experiences from Bwaila District Hospital, Lilongwe, Malawi. 21st International AIDS Conference. Durban, South Africa: International AIDS Society; 2016.
52. Mepham S, Bland R, Ndirangu J, Newell ML. HIV incidence and associated socio-economic factors in a prospective cohort of pregnant women in rural, northern KwaZulu-Natal, South Africa. 5th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention. Cape Town, South Africa: International AIDS Society; 2009.
53. John F, Chung M, Kinuthia J, Richardson B, Farquhar C, John-Stewart G, et al. HIV-1 incidence after antenatal counselling and testing. 16th International AIDS Conference. Toronto, Canada: International AIDS Society; 2006.
54. Thomson KA, Hughes J, Baeten JM, John-Stewart G, Celum C, Cohen CR, et al. Partners in Prevention HSV/HIV Transmission Study and Partners PrEP Study Teams. Increased risk of HIV acquisition among women throughout pregnancy and during the postpartum period: a prospective per-coital-act analysis among women with HIV-infected partners. J Infect Dis 2018; 218:16–25.
55. Chetty T, Vandormael A, Thorne C, Coutsoudis A. Incident HIV during pregnancy and early postpartum period: a population-based cohort study in a rural area in KwaZulu-Natal, South Africa. BMC Pregnancy Childbirth 2017; 17:248.
56. Marston M, Newell ML, Crampin A, Lutalo T, Musoke R, Gregson S, et al. Is the risk of HIV acquisition increased during and immediately after pregnancy? A secondary analysis of pooled HIV community-based studies from the ALPHA network. PloS One 2013; 8:e82219.
57. Braunstein SL, Ingabire CM, Kestelyn E, Uwizera AU, Mwamarangwe L, Ntirushwa J, et al. High human immunodeficiency virus incidence in a cohort of Rwandan female sex workers. Sex Transm Dis 2011; 38:385–394.
58. Gray RH, Li X, Kigozi G, Serwadda D, Brahmbhatt H, Wabwire-Mangen F, et al. Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study. Lancet 2005; 366:1182–1188.
59. Morrison CS, Wang J, Van Der Pol B, Padian N, Salata RA, Richardson BA. Pregnancy and the risk of HIV-1 acquisition among women in Uganda and Zimbabwe. AIDS 2007; 21:1027–1034.
60. Reid SE, Dai JY, Wang J, Sichalwe BN, Akpomiemie G, Cowan FM, et al. Pregnancy, contraceptive use, and HIV acquisition in HPTN 039: relevance for HIV prevention trials among African women. J Acquir Immune Defic Syndr 2010; 53:606–613.
61. Teasdale CA, Abrams EJ, Chiasson MA, Justman J, Blanchard K, Jones HE. Incidence of sexually transmitted infections during pregnancy. PloS One 2018; 13:e0197696.
62. Mugo NR, Heffron R, Donnell D, Wald A, Were EO, Rees H, et al. Partners in Prevention HSV/HIV Transmission Study Team. Increased risk of HIV-1 transmission in pregnancy: a prospective study among African HIV-1-serodiscordant couples. AIDS 2011; 25:1887–1895.
63. Vandepitte J, Weiss HA, Bukenya J, Nakubulwa S, Mayanja Y, Matovu G, et al. Alcohol use, mycoplasma genitalium, and other STIs associated with HIV incidence among women at high risk in Kampala, Uganda. J Acquir Immune Defic Syndr 2013; 62:119–126.
64. Wand H, Ramjee G. Combined impact of sexual risk behaviors for HIV seroconversion among women in Durban, South Africa: implications for prevention policy and planning. AIDS Behav 2011; 15:479–486.
65. Sheffield JS, Wendel GD Jr, McIntire DD, Norgard MV. The effect of progesterone levels and pregnancy on HIV-1 coreceptor expression. Reprod Sci 2009; 16:20–31.
66. Hapgood JP, Kaushic C, Hel Z. Hormonal contraception and HIV-1 acquisition: biological mechanisms. Endocr Rev 2018; 39:36–78.
67. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and infection. N Engl J Med 2014; 370:2211–2218.
68. Robinson DP, Klein SL. Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis. Horm Behav 2012; 62:263–271.
69. Asin SN, Eszterhas SK, Rollenhagen C, Heimberg AM, Howell AL. HIV type 1 infection in women: increased transcription of HIV type 1 in ectocervical tissue explants. J Infect Dis 2009; 200:965–972.
70. Masson L, Passmore JA, Liebenberg LJ, Werner L, Baxter C, Arnold KB, et al. Genital inflammation and the risk of HIV acquisition in women. Clin Infect Dis 2015; 61:260–269.
71. Kahle EM, Bolton M, Hughes JP, Donnell D, Celum C, Lingappa JR, et al. Partners in Prevention HSV/HIV Transmission Study Team. Plasma cytokine levels and risk of HIV type 1 (HIV-1) transmission and acquisition: a nested case-control study among HIV-1-serodiscordant couples. J Infect Dis 2015; 211:1451–1460.
72. Groer MW, El-Badri N, Djeu J, Williams SN, Kane B, Szekeres K. Suppression of natural killer cell cytotoxicity in postpartum women: time course and potential mechanisms. Biol Res Nurs 2014; 16:320–326.
73. Groer ME, Jevitt C, Ji M. Immune changes and dysphoric moods across the postpartum. Am J Reprod Immunol 2015; 73:193–198.
74. Teasdale CA, Abrams EJ, Chiasson MA, Justman J, Blanchard K, Jones HE. Sexual risk and intravaginal practice behavior changes during pregnancy. Arch Sex Behav 2017; 46:539–548.
75. Onah HE, Iloabachie GC, Obi SN, Ezugwu FO, Eze JN. Nigerian male sexual activity during pregnancy. Int J Gynaecol Obstet 2002; 76:219–223.
76. Lawoyin TO, Larsen U. Male sexual behaviour during wife's pregnancy and postpartum abstinence period in Oyo State, Nigeria. J Biosoc Sci 2002; 34:51–63.
77. Awusabo-Asare K, Anarfi JK. Postpartum sexual abstinence in the era of AIDS in Ghana: prospects for change. Health Transit Rev 1997; 7: (Suppl): 257–270.
78. GBD 2015 HIV Collaborators. Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015. The lancet HIV 2016; 3:e361–e387.
79. Tanser F, Bärnighausen T, Grapsa E, Zaidi J, Newell M-L. High coverage of ART associated with decline in risk of HIV acquisition in rural KwaZulu-Natal, South Africa. Science 2013; 339:966–971.
80. Anderson SJ, Cherutich P, Kilonzo N, Cremin I, Fecht D, Kimanga D, et al. Maximising the effect of combination HIV prevention through prioritisation of the people and places in greatest need: a modelling study. Lancet 2014; 384:249–256.
81. Jones A, Cremin I, Abdullah F, Idoko J, Cherutich P, Kilonzo N, et al. Transformation of HIV from pandemic to low-endemic levels: a public health approach to combination prevention. Lancet 2014; 384:272–279.
82. Powers KA, Orroth K, Rosenberg NE, Graybill LA, Kumwenda A, Mtande T, et alA mathematical modeling analysis of combination HIV prevention in antenatnal clinics. 26th Conference on Retroviruses and Opportunistic Infections. Seattle, United States: CROI 2019; 2019.
83. Makhema MJ, Wirth K, Pretorius Holme M, Gaolathe T, Mmalane M, Kadima E, et al. Impact of prevention and treatment interventions on population HIV incidence: primary results of the community-randomized Ya Tsie Botswana prevention project. J Int AIDS Soc 2018; 21 (S6):e25148.
84. Hayes R, Donnell D, Floyd S, Mandla N, Bwalya J, Sabapathy K, et al. Effect of universal testing and treatment on HIV incidence - HPTN 071 (PopART). N Engl J Med 2019; 381:207–218.
85. Rothman K, Greenland S, Lash T. Modern epidemiology. 3rd ed.Philadelphia, PA: Lippincott Williams & Wilkins; 2008.
Keywords:

adolescent; breast-feeding; HIV; incidence; pregnancy; sub-Saharan Africa; women

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