SUMMARY
Background:
Safer conception strategies empower individuals trying to conceive to minimize HIV transmission risk to partners and potential children, however effectiveness data are scarce. We assess adoption of safer conception methods and HIV and pregnancy outcomes from Sakh’umndeni, a novel safer conception service in South Africa.
Methods:
The Sakh’umndeni clinical cohort at Witkoppen Clinic in Johannesburg prospectively enrolled adults trying to conceive and in relationships with an HIV-positive partner. Participants received safer conception care by a nurse, including antiretroviral therapy (ART) for HIV-positive partners, pre-exposure prophylaxis (PrEP) for HIV-negative partners, counseling around timed condomless sex, and/or self-insemination. We estimated time-to-first pregnancy using Kaplan-Meier curves; pregnancy and HIV incidence were estimated as events per person-years of risk.
Findings:
Between July 16, 2013-April 5, 2017, 526 individuals (334 women/192 men) from 334 partnerships enrolled. Couples were serodifferent (n=162/334, 48%), seroconcordant (n=149/334, 45%), or in relationships with an unknown status partner (n=23/334, 7%). At enrollment, 61% (n=176/287) of HIV-positive women and 46% (n=60/131) of HIV-positive men were virally suppressed (<50 copies/mL). Adoption of safer conception strategies ranged from 92% for ART (n=73/80) to 28% for PrEP (n=28/101). A total of 2,719 follow-up visits were completed and 99 pregnancies observed in 89 women. Pregnancy incidence was 41·2/100 person-years (95%CI:33·4–50·7); 25 pregnancies miscarried. Pregnancy incidence was 79·0/100 person-years [95%CI:49·8–125·4] among HIV-negative women and 36·7/100 person-years (95%CI:29·1–46·3) among HIV-positive women. At time of pregnancy, viral suppression among women was high (68/78 [87%] <50 and 77/78 [99%] <1000 copies/mL). No horizontal or vertical HIV transmission events were observed.
Interpretation:
Safer conception strategies empowered couples to safely conceive. Pregnancy incidence among service users was high, though sub-fertility was also common. Integration of safer conception counseling may promote HIV prevention and linkage to care.
Funding:
United States Agency for International Development (USAID); UJMT Consortium/Fogarty International Center, National Institutes of Health (NIH); Johns Hopkins University Center for AIDS Research (NIH).
Keywords: HIV, safer conception, pregnancy, discordant couples, prevention of mother-to-child transmission, antiretroviral therapy, pre-exposure prophylaxis, Sub-Saharan Africa
INTRODUCTION
Women and men living with HIV frequently desire to have children.1 Given the potential horizontal HIV transmission risk to partners while trying to become pregnant and vertical transmission risk to babies if pregnancy is achieved, there has been a call for the expansion of safer conception services in high HIV burden countries.2–4 Safer conception strategies build off the treatment as prevention evidence which demonstrated that viral suppression under antiretroviral therapy (ART) eliminates HIV transmission risk (Undetectable=Untransmittable).5–7 For couples in which the partner with HIV is not yet on treatment or not yet virally suppressed, pre-exposure prophylaxis (PrEP) for the HIV-negative partner can offer a bridging strategy to reduce HIV transmission risks.8 Safer conception strategies also optimize preconception health for couples including sexually transmitted infection (STI) screening and treatment, repeat HIV testing to avoid conception in the context of an undiagnosed infection, monitoring of viral load, education around home-based self-insemination as a risk-free option for couples in which the male partner is HIV-negative, and fertility awareness education to limit timed condomless sex to days of peak fertility.6 Frequent pregnancy testing and early referral to antenatal care as well as recommended discontinuation of condomless sex during pregnancy are also part of a safer conception package. For seroconcordant couples, preconception STI and viral load management are important to reduce HIV vertical transmission risks. Other options, such as sperm-washing and intrauterine insemination or in-vitro fertilization are safe but costly, and it is not clear that that they are more beneficial than the low-cost options.9
Studies have demonstrated a demand for safer conception services, need for improved provider knowledge around safer conception counseling, and limited population-level knowledge of safer conception strategies among individuals living with HIV.10–14 Yet there remains a lack of evidence of the real-world effectiveness of safer conception services to achieve HIV prevention and pregnancy goals in low- and middle-income settings. Poor adoption or adherence to safer conception strategies or implementation challenges may undermine the utility of safer conception services. The goals of this study were to assess the effectiveness of safer conception services at achieving pregnancy and HIV prevention goals in a resource-limited setting, as well as client adoption and sustained engagement in safer conception services.
METHODS
Study design, population and procedures
Women and men enrolled into the Sakh’umndeni safer conception prospective cohort at Witkoppen Clinic, a comprehensive primary healthcare center in northern Johannesburg, South Africa. Sakh’umndeni (“building a family” in Zulu) was established as a demonstration project to gain effectiveness data from an HIV prevention and reproductive health intervention to optimize HIV and pregnancy outcomes among couples living with HIV.
Sakh’umndeni provided a comprehensive safer conception package.15 Sakh’umndeni providers counselled individuals and couples trying to become pregnant and affected by HIV in safer conception strategies to optimize preconception health and minimize HIV transmission risks. Key aspects included STI screening and treatment (rapid plasma reagin testing for syphilis, alongside syndromic management for other STIs), viral load monitoring for patients with HIV (at baseline, two months later if not virally suppressed, then 6-monthly and at pregnancy diagnosis), ART initiation for all participants living with HIV not on treatment, repeat HIV testing for HIV-negative participants, on-site PrEP for HIV-negative participants, provision of plastic syringes for home-based self-insemination (aimed at serodifferent couples with an HIV-negative male partner), and fertility awareness education to limit condomless intercourse to peak fertility windows. Women were provided preconception folate vitamins and cervical cancer screening, trained to complete menstrual cycle diaries which were used by providers to identify peak days, offered contraception until clinically ready (see definition below), and tested for pregnancy at enrollment and each subsequent visit. HIV-negative men were offered voluntary male medical circumcision on-site. Disclosure counseling was provided to participants with HIV who had not yet disclosed to their partners. Clients received information on sperm-washing and assisted reproductive technologies, though services were not provided. Counseling was given in a confidential setting by a safer conception counselor and a professional nurse licensed in ART management. To create a one-stop shop, other primary healthcare services to manage chronic conditions, STIs, and any temporary contraception were provided by the nurse.
We enrolled safer conception clients from July 16, 2013 to April 5, 2017. Posters and flyers at Witkoppen Clinic and surrounding primary health clinics, outreach campaigns at malls, taxi ranks and other community gathering places, as well as media campaigns (e.g. Facebook, radio, television and newspaper spotlights) were used to raise awareness of services. Couples or individuals in partnerships with at least one HIV-positive partner and who wanted to become pregnant within six months were eligible to use the service if they were not pregnant at enrollment, not previously diagnosed as infertile, and at least 18 years of age. Although we encouraged patients to attend as couples, individuals attending alone were also eligible. All clients were provided with an HIV combination prevention package tailored to their situation. The choice of which option(s) to adopt was client-driven and could change over time.
Safer conception counseling and participant follow-up for pregnancy incidence were completed in December 5, 2017. Pregnancy, HIV, and infant outcomes were followed through October 1, 2018. Couples were requested to attend Sakh’umndeni monthly to review menstrual cycles, clinical readiness for conception and pregnancy incidence. Frequent visits were intended to reduce delays around clinical optimization. Clearance to start trying to conceive was given by the nurse-clinician once risk reduction had been achieved, including treatment of STIs, viral suppression of all partners with HIV, stable PrEP uptake, or self-insemination if the male partner was HIV-negative. Clients were followed through pregnancy or for six months post clinical optimization if they did not become pregnant, at which time they were referred to a public fertility clinic for further assessment. If conception was achieved, a viral load was taken at conception and women were immediately linked to antenatal care available on-site. Throughout pregnancy women attended follow-up visits at Sakh’umndeni. Pregnancy loss was monitored, and couples assisted in subsequent conception in the event of miscarriage or referred for additional care if associated fertility problems were suspected. Infants were enrolled after birth and birth outcomes assessed, including 6-week HIV testing.
Clinical, reproductive, and sexual health histories, alongside physical examinations and urine-based (hCG) pregnancy testing were conducted at enrollment and updated across follow-up visits. Laboratory testing (HIV viral load, CD4 count, syphilis, pap smears) was conducted at enrollment and subsequently per national guidelines. Sociodemographic, clinical, laboratory and safer conception strategy adoption (choices) were recorded on standardized case report forms and entered in REDCap™ (Vanderbilt, Tennessee). When only the female partner attended, partner and couple-level characteristics were reported by the female partner.
This study was approved by the Human Research Ethics Committee at the University of the Witwatersrand (M130467) and the institutional review board at the University of North Carolina (13–2138). Written informed consent was obtained for all participants.
Outcomes
The primary study outcomes were pregnancy incidence and HIV transmission to partners and infants. Secondary outcomes included adoption and sustained engagement in safer conception care, achievement of clinical readiness for conception, HIV prevention indicators (repeat HIV testing uptake, viral suppression at pregnancy, PrEP uptake), and pregnancy outcomes. Secondary outcomes assessing sub-fertility and correlates thereof will be published separately.
Statistical analysis
Sakh’umndeni client characteristics and secondary outcomes were assessed using descriptive statistics. Predictors of missing pregnancy outcome data (loss-to-follow up [LTFU]) were assessed in a modified robust Poisson regression model, as the outcome was common and the log-binomial model failed to converge; covariates were assessed in univariable models based on a priori hypotheses of their relationship to LTFU and were retained in the multivariable model if p<0.20 in the univariable analysis.16 For the primary outcome of pregnancy incidence, women contributed time-at-risk to first pregnancy from safer conception enrollment until the estimated first conception date, mortality, transfer out, no longer trying to conceive, last visit date (LTFU), exit from the service (referral to infertility services), or study end, whichever occurred first. In a secondary analysis assessing time-to-first pregnancy after clinical readiness, all women in partnerships not clinically ready during follow-up and women conceiving prior to receiving clinical clearance were excluded. For time-to-first pregnancy outcomes, Kaplan-Meier cumulative incidence functions (complement of survival curves) were plotted, and log-rank tests used to assess time-to-first-pregnancy across sub-groups. We estimated pregnancy incidence rates based on the events per person-years at risk. HIV incidence among HIV-negative partners was described using events observed over person-years of risk observed. Cox Proportional Hazards models were used to compare differences in time-to-pregnancy according by female partner HIV-status and safer conception method choice, adjusting for age. The proportional hazards assumption was assessed using Schoenfeld’s residuals. All analyses were conducted in Stata 14·2 (College Station, Texas).
RESULTS
A total of 526 individuals, including 334 women and 192 men enrolled in Sakh’umndeni. Among the 334 couples represented, 57% (n=192/334) of male partners attended the service. Characteristics of safer conception clients at enrollment are summarized in Table 1. Overall, 87% (n=291/334) of women and 69% of men (n=133/192) were HIV-positive; 61% (n=176/330) of women and under half of men (n=60/190, 46%) with HIV were virally suppressed per national treatment guidelines (<50 copies/mL, viral loads missing for n=6). Median viral loads among women and men with detectable viral load were 358 copies/mL [IQR 121–1,058] and 453 copies/mL [IQR 106–8,540] respectively (mean 7,463 copies/mL [sd:21,365] among women and 24,181 copies/mL [sd:65,450] among men).
Table 1:
Baseline characteristics of Sakh’umndeni Safer Conception Service Clients Enrolled at Witkoppen Clinic, Johannesburg, South Africa, 2013–2017 (n=526)
| Client Characteristics | Women (n=334) |
Men (n=192) |
|---|---|---|
| Demographics | ||
| Age, median (IQR) | 34 (30–38) | 38 (33–42) |
| Employed, n (%) | 216 (65%) | 162 (84%) |
| Average monthly income, median USD (IQR) | 320 (200–480) | 320 (200–560) |
| Education, n (%) | ||
| Primary or below | 64 (19%) | 47 (25%) |
| Some secondary school | 157 (47%) | 66 (34%) |
| Matriculated secondary school | 113 (34%) | 79 (41%) |
| Nationality, n (%) | ||
| South African | 200 (60% | 123 (64%) |
| Non-native South African | 134 (40%) | 69 (36%) |
| Reproductive History | ||
| Ever been pregnant, n (%) | 256 (77%) | -- |
| Number of living children, median (IQR) | 1 (0–1) | 1 (0–2) |
| Number of living children, n (%) | ||
| None | 135 (40%) | 56 (29%) |
| One | 136 (41%) | 61 (32%) |
| Two or more | 63 (19%) | 75 (39%) |
| Clinical characteristics | ||
| BMI, median (IQR)1 | 26·2 (23·2–31·1) | 25·2 (22·6–27·6) |
| Syndromically treated STI at enrollment, n (%) | 11 (3·3%) | 5 (2·6%) |
| Syphilis diagnosis, n (%) | 3 (1·4%) | 1 (1·8%) |
| Circumcised, n (%) | ||
| Not circumcised | -- | 95 (49%) |
| Medically circumcised | -- | 32 (17%) |
| Traditionally circumcised | -- | 65 (34%) |
| HIV status, n (%) | ||
| HIV positive | 291 (87%) | 133 (69%) |
| HIV negative | 43 (13%) | 58 (30%) |
| Unknown (refused testing) | 1 (0%) | |
| On antiretroviral therapy, n (%)3 | 243 (84%) | 101 (76%) |
| Baseline viral load undetectable, n (%)4 | 176 (61%) | 60 (46%) |
| Baseline CD4 Count Strata, n (%)5 | ||
| 0–200 cells/μL | 24 (8%) | 20 (15%) |
| 201–350 cells/μL | 61 (21%) | 37 (28%) |
| 351–500 cells/μL | 70 (24%) | 31 (24%) |
| >500 cells/μL | 133 (46%) | 43 (33%) |
IQR=interquartile range; BMI=body mass index; STI=sexually transmitted infection;
BMI available for n=394;
Rapid plasma reagin syphilis testing completed for n=219 women and n=57 men;
Among HIV positive clients;
Baseline viral loads missing for n=4 women and n=2 men;
Baseline CD4 counts missing for n=3 women and n=2 men.
Almost half of participating couples (48% n=162/334) were in serodifferent relationships (one partner HIV-positive, one partner HIV-negative), 45% (n=149/334) were in HIV-positive seroconcordant relationships, and 7% (n=23/334) were couples with an HIV-positive woman and an unknown status male partner (Table 2).
Table 2:
Baseline characteristics of Couples Represented at Sakh’umndeni Safer Conception Service, at Witkoppen Clinic, Johannesburg, South Africa, 2013–2017 (n=334)
| HIV status within the partnership | n (%) |
| HIV seroconcordant | 149 (45%) |
| HIV serodifferent | 162 (48%) |
| HIV status of one partner unknown | 23 (7%) |
| Reproductive History | n (%) |
| Ever been pregnant together | 126 (38%) |
| Ever had a live birth together1 | 85 (26%) |
| Trying to conceive prior to attendance | 239 (72%) |
| Sexual History | Median (IQR) |
| Relationship duration, years | 5 (2–10) |
| Number times having vaginal sex in past 30 days | 8 (4–12) |
| Number of times having condomless sex in the past 30 days | 6 (1–11) |
Missing for n=5
Participant follow-up and reasons for exit are detailed in Figure 1. A total of 2,719 follow-up visits were completed, including 2,178 by women and 541 by men. The median number of follow-up visits were 6 [IQR 2–10] and 2 [IQR 1–4] among women and men respectively. Most women (88%, n=293/334) and men (80%, n=153/192) completed ≥1follow-up visits. During follow-up one woman and her infant died, one enrolled man and one unenrolled male partner died. All four deaths were determined to be unrelated to the study. Independent predictors of LTFU included being in a serodifferent relationship (vs. seroconcordant) and trying to conceive for >12 months prior to enrollment (Supplemental Table 1).
Figure 1:
Sakh’umndeni Safer Conception Service Consort Diagram
Safer conception strategy adoption and implementation outcomes are illustrated (Figure 2). Among participants presenting as serodifferent or unknown, the service diagnosed eight individuals as HIV-positive (two women and six men) at baseline HIV testing for a yield of 7% (n=8/107); four additional men tested positive at other clinics per female partner report). Of those newly diagnosed, 6/8 (75%) initiated ART. PrEP adoption was higher among women (n=22/43, 51%) than men (n=6/58, 10%, Fisher’s exact p-value<0·0001). Among those electing PrEP, 21/28 (75%) had partners on ART, 7/21 (33%) of whom were virally suppressed. Among the 21 HIV-negative women electing not to use PrEP, 18/21 (86%) had partners on ART at enrollment, though only 4/18 (22%) were known to be virally suppressed. Among HIV-negative men not using PrEP, 32/52 (62%) elected self-insemination.
Figure 2:
Adoption of safer conception strategies among clients of the Sakh’umndeni safer conception clinic, Johannesburg, South Africa, 2013–2017.
Across serodynamic relationship types, Sakh’umndeni initiated 14% (n=73/526) of the total cohort on ART, including 92% of women (n=44/48) not on ART and 91% of men (n=29/32). Adoption of strategies varied by serodynamics, with 101/162 (62%) of serodifferent couples electing timed self-insemination, 126/149 (85%) of seroconcordant couples choosing timed condomless sex and condomless sex without timing favored among sero-unknown couples (16/23, 70%, X2 comparison across groups: p<0·0001). Overall, 84/293 (29%) of dyads with follow-up changed strategies at least once. Four women (4/334, 1%) chose to use oral contraception until clinically ready to conceive.
In terms of safer conception attempts, among the 334 couples enrolled, 66% (n=222) received provider indication of clinical readiness for safer conception, while 7% (n=22/334) conceived prior to clinical readiness and 27% (n=90/334) stopped attending the service prior to clinical readiness. Among clients receiving the provider go-ahead, the median time-to-readiness was 3·5 months [IQR 1·3–6·8]. Time-to-readiness was shorter among HIV-negative women than HIV-positive women (2·4 months [IQR: 1·3–6·8] vs. 4·0 months [IQR: 1·6–7·3], Wilcoxon rank test, p=0·02). During follow-up, HIV-negative women reported a mean of 5.2 (sd:4.5) condomless sex acts per month compared to 4.5 (sd: 5.0) among HIV-positive women (p-value=0.22, accounting for within person clustering).
We observed 99 pregnancies among 89 women. Prior to the time-of-first-pregnancy, 67/89 (75%) of women received provider indication of clinical readiness. Kaplan-Meier cumulative incidence curves representing time-to-pregnancy since enrollment and time-to-pregnancy after clinical readiness are depicted (Figure 3a,b)). Women with HIV experienced significantly longer times-to-pregnancy (Figure 3c and 3d).
Figure 3: Time to pregnancy among women enrolled in a safer conception clinic, Johannesburg, South Africa 2013–2017.
(A) Time to pregnancy from enrollment, censored at 30 months. (B) Time to pregnancy from clinical readiness to attempt pregnancy as determined by health care provider, censored at 18 months. (C) Time to pregnancy by woman’s HIV status from enrollment, censored at 30 months. (D) Time to pregnancy by woman’s HIV status from clinical readiness to attempt pregnancy as determined by health care provider, censored at 18 months.
Pregnancy incidence rates are presented in Table 3. The overall pregnancy incidence rates following enrollment and clinical readiness were 41·2/100 woman-years (95% CI 33·4, 50·7) and 62·6/100 woman-years (95% CI 48·3, 80·9), respectively. Per Sakh’umndeni protocol, women were to be referred for fertility work-up six months after clinical readiness. In practice clients were at times retained longer.
Table 3:
Pregnancy Incidence Among Women Attending the Sakh’umndeni Safer Conception Clinic (n=334)
| Analysis Time | Incident Pregnancy | Person-time (years) | Incidence Rate per 100 person-years [95% CI] |
Hazard Ratio [95% CI] |
|---|---|---|---|---|
| From enrollment | 89 | 216·2 | 41·2 [33·4–50·7] | |
| HIV positive women | 71 | 193·4 | 36·7 [29·1–46·3] | 0·56 [0·33–0·96] |
| HIV negative women | 18 | 22·8 | 79·0 [49·8–125·4] | REF |
| From clinical readiness | 58 | 92·7 | 62·5 [48·3–80·9] | |
| HIV positive women | 41 | 79·3 | 51·7 [38·1–70·2] | 0·50 [0·27–0·90] |
| HIV negative women | 17 | 13·4 | 126·2 [78·5–200·3] | REF |
CI=Confidence interval; Note there were 99 pregnancies in total among 89 women. Incidence rates reflect person-time accrued until first pregnancy. Hazard ratios estimated through Cox Proportional Hazards models inclusive of age (<35 vs. 35+ years) and safer conception method (timed condomless sex, self-insemination, condomless sex without limits).
In terms of conception method, 11/21 (51%) HIV-negative women who conceived were on PrEP at time of conception. Most women (83%, n=74/89) conceived through timed condomless sex, 17% (n=15) via self-insemination. Conception by safer conception method was similar among couples initially electing to use self-insemination vs. timed condomless sex (Figure 4; log-rank test p=0·689).
Figure 4:
Time to pregnancy by safer conception strategy chosen at baseline censored at 30 months of follow-up.
In an age-adjusted Cox proportional hazards model comparing time-to-pregnancy by HIV status and safer conception strategy, HIV-positive women had a 44% lower risk of conception as compared to HIV-negative women [aHR:0·56, 95% CI: 0·33–0·96]; compared to timed condomless sex, neither self-insemination [aHR:0·94, 95% CI: 0·60–1·47] nor untimed condomless sex [aHR:0·60, 95% CI: 0·26–1·41] were associated with time-to-pregnancy. Findings were similar in the time-since-clinical readiness analysis.
Outcomes of the 99 pregnancies are presented in Table 4.
Table 4:
Pregnancy outcomes among Sakh’umndeni incident pregnancies (n=99)
| Pregnancy outcomes | n (%) |
|---|---|
| Live birth | 64 (65%) |
| Miscarriage | 21 (21%) |
| Ectopic pregnancy | 4 (4%) |
| Unable to ascertain outcome | 10 (10%) |
| Transferred out to clinic outside of Johannesburg | 6 |
| Transferred out to another clinic in Johannesburg | 2 |
| Unknown | 2 |
Regarding HIV transmission and outcomes, at pregnancy, 67/78 (87%) women with HIV were virally suppressed (<50 copies/mL) and 77/78 (99%) had viral loads <1000 copies/mL. Among HIV-exposed infants, 42/47 (89%) had a 6-week infant HIV polymerase chain reaction (PCR) test result, all of which were HIV-negative (Table 5).
Table 5:
HIV Transmission Outcomes
| Prevention of Vertical Transmission1 | |
| Virally suppressed <50 copies/ml at pregnancy | 68/78 (87%) |
| Virally suppressed <1000 copies/ml at pregnancy | 77/78 (99%) |
| Infant testing results available (HIV-exposed infants) | |
| Confirmed PCR for baby of HIV positive mom | 42/47 (89%) |
| Results unknown, mother transferred out to another clinic2 | 4/47 (9%) |
| Not applicable3 | 1/47 (2%) |
| Infant HIV Incidence | |
| HIV infections among babies observed | 0/42 (0%) |
| Prevention of Horizontal Transmission | |
| Serodifferent HIV− men / HIV+ women conceiving | |
| Female partner viral loads available at time of pregnancy | 30/30 (100%) |
| Female partner virally suppressed <50 copies/ml at pregnancy | 25/30 (83%) |
| Female partner virally suppressed <1000 copies/ml at pregnancy | 30/30 (100%) |
| Serodifferent HIV+ men / HIV− women conceiving | |
| Male partner viral loads available at time of pregnancy | 16/18 (89%) |
| Male partner virally suppressed <50 copies/ml at pregnancy | 14/16 (88%) |
| Male partner virally suppressed <1000 copies/ml at pregnancy | 16/16 (100%) |
| HIV repeat testing | |
| Proportion of HIV negative partners re-tested during study follow-up4 | 81/101 (80%) |
| Average number of times HIV negative partners were re-tested during study follow-up5 | |
| Overall | 3 [1–6] |
| Men | 2 [1–3] |
| Women | 6 [3–8] |
| Adult HIV Incidence | |
| Person-years of risk observed among HIV negative clients | 76·1 PY |
| HIV seroconversions observed among HIV negative clients | 0 |
| HIV incidence4 | 0·0% [0·0–3·9%] |
Among pregnancies of women with HIV (n=78);
All 4 mothers were virally suppressed at time of pregnancy diagnosis.
One mother died due to complications during child birth and her infant died at 1-week, prior to 6-week PCR testing.
Among n=101 HIV negative partners at baseline;
Among n=81 HIV negative partners with follow-up testing.
HIV-negative clients had a median of three [IQR 1–6] post-enrollment HIV tests. Retesting was higher among women than men (median 6 [IQR 3–8] vs. 2 [IQR 1–3], Wilcoxon rank test p-value <0·0001). No HIV seroconversions were observed (incidence 0·0% [95% CI: 0·0–3·9) during the 76·1 person-years of follow-up among HIV-negative participants.
DISCUSSION
The Sakh’umndeni cohort achieved excellent safer conception effectiveness in real-world, resource-limited conditions. Men commonly engaged in the intervention and 85% of clients returned for post-enrollment follow-up care. Adoption of safer conception strategies, including HIV testing, ART, PrEP, timed condomless sex, and self-insemination were high. At enrollment 39% of women and 54% of men with HIV were not virally suppressed despite high ART coverage. By the time of conception, lack of viral suppression was reduced to 13% of women. Not a single case of onward transmission to infants or partners was observed.
To our knowledge, this report presents the first published outcomes data from a safer conception service for couples trying to conceive in low or middle-income countries. Findings from Uganda, Kenya and South Africa have highlighted that knowledge and adoption of safer conception practices among HIV-affected couples is low in the absence of specific safer conception service delivery.13,14,17 Randomized trials have assessed the HIV prevention efficacy of ‘treatment for all’ and PrEP, but these studies were not designed to assess effectiveness in couples trying to conceive, nor to optimize pregnancy outcomes.8,18 The Partners Demonstration Project offered ART and/or PrEP to serodifferent couples and monitored fertility intentions, though <10% of couples (n=70) in the study were trying to conceive.19 Their study reported pregnancy rates among women actively trying to conceive consistent with our “clinical readiness” analysis. Published data from services in Europe largely mirror ours. In Switzerland and Spain, no horizontal transmissions were observed amongst 62 and 46 serodifferent couples respectively, though one vertical transmission was observed in the Spanish study.20,21
While our study explicitly embraces Undetectable=Untransmissable,7 we found that viral suppression among patients on ART should not be presumed and viral load monitoring needs to be a core component of safer conception service delivery, particularly given the potential transmission risks that couples undergo when trying to conceive if not virally suppressed. Data from Zambia reinforce this point, as HIV-negative women and men in serodifferent partnerships with positive fertility intentions had twice the HIV acquisition risk as compared to couples without fertility intentions; overall HIV incidence rates were 7.4/100 couple-years in men-to-women (M+F-) and 5.9/100 couples-years from women-to-men (M-F+).22 Our data also highlight the potential role of PrEP-especially among women-for bridging interim risk periods when male partners are not virally suppressed.
Despite the successes of Sakh’umndeni at preventing HIV transmission, time-to-pregnancy was long, with times extended as couples wait for clinical readiness. Many women did not conceive through the service and pregnancy incidence among women with HIV retained in safer conception services was half that among HIV-negative women after accounting for age and safer conception method, highlighting potential underlying fertility issues in this population. The purpose of this analysis was descriptive and differences in pregnancy incidence by HIV status may be explained by many biological and behavioral factors which warrant further exploration, as does the high burden of sub-fertility. Nevertheless, the pregnancy incidence rate observed was about twice as high as those reported in other studies assessing both intended and unintended pregnancy in the context of HIV.19,23–25 Unfortunately, pregnancy loss among women conceiving was high (28%), though in line with reports from other studies closely monitoring pregnancy outcomes in HIV-positive women.25–27
While the positive results advocate for roll-out, a key element for consideration of the Sakh’umndeni results is scalability. A stand-alone monthly safer conception service is resource-intensive. Alternative approaches, such as safer conception integration into routine HIV and primary care may have comparable benefits and require fewer resources. Integrated care may also reach more clients (as well as more fertile clients)-given that documented demand for services far exceeds observed uptake of this standalone service and couples newly initiating conception may not perceive a need for specialty services.12 Though preferred implementation strategies may differ across settings, models to test scale-up approaches such as facility-level safer conception ‘champions’ or utilization of counselors and/or peers as the primary provider with clinical support form a nurse should be evaluated. Successful service delivery will require training and mentoring for healthcare providers as knowledge to counsel around methods is limited and stigma to planned pregnancy in the context of HIV frequently exists.28,29 Clients were uncomfortable engaging in condomless sex, and provider and client training in peak fertility methods will be necessary.
This study has several limitations. As an implementation study, safer conception strategies were not randomized. This study was thus not designed to assess the efficacy of one safer conception strategy versus another, but rather the general adoption of strategies and overall effectiveness of the safer conception package at achieving HIV prevention and pregnancy. Furthermore, while the protocol stipulated referrals to outside fertility services following 6-months of attempted conception, clinicians sometimes allowed the clients to utilize the service for longer, particularly if one partner was traveling or away or insistent upon returning. These challenges are not uncommon in a real-world setting and likely reduced pregnancy incidence. Additionally, LTFU prior to exiting Sakh’umndeni was common. LTFU was higher among serodifferent couples and those who had tried to conceive for >12 months; it is possible that many of these couples stopped trying to conceive, in which case they exited the risk-set and results would be unbiased. However, others may have continued trying–if they were less likely to conceive, we may have overestimated pregnancy incidence among all couples initially represented. Our results should thus be interpreted as pregnancy incidence rates among those retained in the service. The extent to which safer conception services benefit those who acquire knowledge and leave is important, however our data cannot answer that question. Finally, we were unable to ascertain the outcomes of all pregnancies nor the HIV status of all babies and HIV-negative partners. Thus, we cannot rule out that a transmission event occurred and was unobserved, though all women were on ART or PrEP when last engaged.
Empowering couples with HIV to achieve their reproductive goals while optimizing the health of the family is an essential component of promoting reproductive rights and is long overdue. Sakh’umndeni results demonstrate that services to optimize pregnancy and HIV outcomes can be implemented in a real-world, resource-limited primary care setting, that clients adopt the strategies, and that favorable outcomes with absence of transmission events to partners and infants can be achieved. These results build on U=U by ensuring that couples achieve and maintain the ‘Undetectable’ and thus ‘Untransmittable’ state prior to attempted conception and pregnancy. Future research should assess optimal models for integration and scale-up of safer conception services.
Supplementary Material
RESEARCH IN CONTEXT.
Evidence before this study
Prior to commencement of this study in 2013, implementation data on the uptake of safer conception strategies and services were not available from the sub-Saharan Africa context. Studies published at that time were largely qualitative, focusing on provider and patient attitudes around fertility desires and preferences for services. However, data outside of safer conception research were emerging which documented the effectiveness of antiretroviral therapy (HPTN 052) and pre-exposure prophylaxis (Partners PrEP) for HIV prevention in serodifferent heterosexual couples. Though these interventions were not focused on couples trying to conceive, these data formed the backbone of the Sakh’umndeni Safer Conception study design. To assess the existing literature on safer conception effectiveness in sub-Saharan Africa, we searched PubMed before 1 February 2019 using key words “safer conception” or “safe pregnancy” or “pregnancy planning” or “fertility planning” AND “HIV”. A 2018 systematic review by Davey et al. on safer conception strategies to inform evidence-based interventions reported feasibility and acceptability data, however still at this time no effectiveness data from implementation of safer conception services were available.
Added value of this study
This study reports prospective findings on the effectiveness outcomes – including pregnancy incidence and HIV transmission -- from a safer conception cohort in South Africa. These are the first longitudinally followed and reported pregnancy and HIV outcomes from a specific safer conception service in Sub-Saharan Africa. Findings from the Sakh’umndeni cohort suggest effectiveness of the service for both pregnancy optimization and HIV prevention goals and further present implementation outcomes including adoption of safer conception strategies and sustained engagement in safer conception care.
Implications of all the available evidence
Safer conception strategies are acceptable to patients and will be adopted when sufficient patient and provider training in safer conception methods have occurred – including timed condomless sex, menstrual cycle charting and peak fertility identification, PrEP counseling, manual self-insemination, and information around more resource-intensive assisted reproductive options. Safer conception can effectively promote reproductive and HIV prevention goals through enhancing viral suppression prior to attempted conception and offering bridging strategies for risk reduction until viral suppression is achieved. Women living with HIV, even those on antiretroviral therapy, experience lower pregnancy rates and providers should be aware of associated prolonged transmission risks if women living with HIV in serodifferent relationships are trying to conceive and not virally suppressed. Future research should emphasize models for service delivery scale-up in HIV high burden, low-resource settings.
Acknowledgments
We are grateful to the Witkoppen Health and Welfare Centre team and students who have supported the study in various ways, and most importantly to the women and men who participated in the study and made it possible. This work was supported through the President’s Emergency Plan for AIDS Relief (PEPFAR) through United States Agency for International Development (USAID) under the terms of AID-674-A-12–00033, the UJMT Consortium/Fogarty International Center of the National Institutes of Health (R25TW009340), and the Johns Hopkins University Center for AIDS Research through the National Institutes of Health (P30AI094189). The contents are the sole responsibility of Witkoppen Health and Welfare Centre and the authors and do not necessarily reflect the views of USAID, NIH or the United States Government.
Role of the funding source
This work was supported through the President’s Emergency Plan for AIDS Relief through United States Agency for International Development, the UJMT Consortium/Fogarty International Center of the National Institutes of Health, and the Johns Hopkins University Center for AIDS Research through the National Institutes of Health. The funding source did not influence the study design, analysis or write-up of the results. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Footnotes
Declaration of interests
The authors have no conflicts of interest to declare.
The final publication is available at https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(19)30144-4/fulltext
REFERENCES
- 1.Nattabi B, Li J, Thompson SC, et al. A systematic review of factors influencing fertility desires and intentions among people living with HIV/AIDS: implications for policy and service delivery. AIDS and behavior 2009;13(5):949–68. doi: 10.1007/s10461-009-9537-y [published Online First: 2009/03/31] [DOI] [PubMed] [Google Scholar]
- 2.Mmeje O, Titler MG, Dalton VK. A call to action for evidence-based safer conception interventions for HIV-affected couples desiring children in Sub-Saharan Africa. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics 2014. doi: 10.1016/j.ijgo.2014.07.034 [published Online First: 2014/10/07] [DOI] [PubMed] [Google Scholar]
- 3.Black V, Davies N, Williams BG, et al. Establishing conception intentions and safer conception services for eliminating the vertical, and reducing the horizontal, transmission of HIV. BJOG : an international journal of obstetrics and gynaecology 2016;123(10):1585–8. doi: 10.1111/1471-0528.14156 [DOI] [PubMed] [Google Scholar]
- 4.Mantell JE, Smit JA, Stein ZA. The right to choose parenthood among HIV-infected women and men. J Public Health Policy 2009;30(4):367–78. doi: 10.1057/jphp.2009.35 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Matthews LT, Smit JA, Cu-Uvin S, et al. Antiretrovirals and safer conception for HIV-serodiscordant couples. Current opinion in HIV and AIDS 2012;7(6):569–78. doi: 10.1097/COH.0b013e328358bac9 [published Online First: 2012/10/04] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Cohan D, Weber S, Goldschmidt R. Safer conception options for HIV-serodiscordant couples. American journal of obstetrics and gynecology 2012;206(1):e21; author reply e21–2. doi: 10.1016/j.ajog.2011.08.014 [DOI] [PubMed] [Google Scholar]
- 7.The Lancet H. U=U taking off in 2017. The lancet HIV 2017;4(11):e475. doi: 10.1016/S2352-3018(17)30183-2 [DOI] [PubMed] [Google Scholar]
- 8.Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. The New England journal of medicine 2012;367(5):399–410. doi: 10.1056/NEJMoa1108524 [published Online First: 2012/07/13] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zafer M, Horvath H, Mmeje O, et al. Effectiveness of semen washing to prevent human immunodeficiency virus (HIV) transmission and assist pregnancy in HIV-discordant couples: a systematic review and meta-analysis. Fertility and sterility 2016;105(3):645–55 e2. doi: 10.1016/j.fertnstert.2015.11.028 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Matthews LT, Bajunirwe F, Kastner J, et al. “I Always Worry about What Might Happen Ahead”: Implementing Safer Conception Services in the Current Environment of Reproductive Counseling for HIV-Affected Men and Women in Uganda. BioMed research international 2016;2016:4195762. doi: 10.1155/2016/4195762 [published Online First: 2016/04/07] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mmeje O, Njoroge B, Akama E, et al. Perspectives of healthcare providers and HIV-affected individuals and couples during the development of a Safer Conception Counseling Toolkit in Kenya: stigma, fears, and recommendations for the delivery of services. AIDS care 2016;28(6):750–7. doi: 10.1080/09540121.2016.1153592 [published Online First: 2016/03/11] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Schwartz SR, Mehta SH, Taha TE, et al. High pregnancy intentions and missed opportunities for patient-provider communication about fertility in a South African cohort of HIV-positive women on antiretroviral therapy. AIDS and behavior 2012;16(1):69–78. doi: 10.1007/s10461-011-9981-3 [published Online First: 2011/06/10] [DOI] [PubMed] [Google Scholar]
- 13.Wagner GJ, Goggin K, Mindry D, et al. Correlates of Use of Timed Unprotected Intercourse to Reduce Horizontal Transmission Among Ugandan HIV Clients with Fertility Intentions. AIDS and behavior 2014. doi: 10.1007/s10461-014-0906-9 [published Online First: 2014/10/05] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Steiner RJ, Black V, Rees H, et al. Low Receipt and Uptake of Safer Conception Messages in Routine HIV Care: Findings From a Prospective Cohort of Women Living With HIV in South Africa. J Acquir Immune Defic Syndr 2016;72(1):105–13. doi: 10.1097/QAI.0000000000000945 [published Online First: 2016/02/09] [DOI] [PubMed] [Google Scholar]
- 15.Schwartz SR, Bassett J, Sanne I, et al. Implementation of a safer conception service for HIV-affected couples in South Africa. AIDS 2014;28 Suppl 3:S277–85. doi: 10.1097/QAD.0000000000000330 [published Online First: 2014/07/06] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Zou G A modified poisson regression approach to prospective studies with binary data. American journal of epidemiology 2004;159(7):702–6. [published Online First: 2004/03/23] [DOI] [PubMed] [Google Scholar]
- 17.Hancuch K, Baeten J, Ngure K, et al. Safer conception among HIV-1 serodiscordant couples in East Africa: understanding knowledge, attitudes, and experiences. AIDS care 2018:1–9. doi: 10.1080/09540121.2018.1437251 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. The New England journal of medicine 2011;365(6):493–505. doi: 10.1056/NEJMoa1105243 [published Online First: 2011/07/20] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Heffron R, Thomson K, Celum C, et al. Fertility Intentions, Pregnancy, and Use of PrEP and ART for Safer Conception Among East African HIV Serodiscordant Couples. AIDS and behavior 2018;22(6):1758–65. doi: 10.1007/s10461-017-1902-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Barreiro P, del Romero J, Leal M, et al. Natural pregnancies in HIV-serodiscordant couples receiving successful antiretroviral therapy. J Acquir Immune Defic Syndr 2006;43(3):324–6. doi: 10.1097/01.qai.0000243091.40490.fd [published Online First: 2006/09/28] [DOI] [PubMed] [Google Scholar]
- 21.Vernazza PL, Graf I, Sonnenberg-Schwan U, et al. Preexposure prophylaxis and timed intercourse for HIV-discordant couples willing to conceive a child. AIDS 2011;25(16):2005–8. doi: 10.1097/QAD.0b013e32834a36d0 [published Online First: 2011/07/01] [DOI] [PubMed] [Google Scholar]
- 22.Joseph Davey DL, Wall KM, Kilembe W, et al. Difficult decisions: Evaluating individual and couple-level fertility intentions and HIV acquisition among HIV serodiscordant couples in Zambia. PloS one 2018;13(1):e0189869. doi: 10.1371/journal.pone.0189869 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Myer L, Carter RJ, Katyal M, et al. Impact of antiretroviral therapy on incidence of pregnancy among HIV-infected women in Sub-Saharan Africa: a cohort study. PLoS medicine 2010;7(2):e1000229. doi: 10.1371/journal.pmed.1000229 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Ngure K, Heffron R, Mugo NR, et al. Contraceptive method and pregnancy incidence among women in HIV-1-serodiscordant partnerships. AIDS 2012;26(4):513–8. doi: 10.1097/QAD.0b013e32834f981c [published Online First: 2011/12/14] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Schwartz SR, Rees H, Mehta S, et al. High incidence of unplanned pregnancy after antiretroviral therapy initiation: findings from a prospective cohort study in South Africa. PloS one 2012;7(4):e36039. doi: 10.1371/journal.pone.0036039 [published Online First: 2012/05/05] [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Cates JE, Westreich D, Edmonds A, et al. The Effects of Viral Load Burden on Pregnancy Loss among HIV-Infected Women in the United States. Infectious diseases in obstetrics and gynecology 2015;2015:362357. doi: 10.1155/2015/362357 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Gibb DM, Kizito H, Russell EC, et al. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS medicine 2012;9(5):e1001217. doi: 10.1371/journal.pmed.1001217 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Joseph Davey D, West S, Umutoni V, et al. A Systematic Review of the Current Status of Safer Conception Strategies for HIV Affected Heterosexual Couples in Sub-Saharan Africa. AIDS and behavior 2018;22(9):2916–46. doi: 10.1007/s10461-018-2170-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Davies NE, Matthews LT, Crankshaw TL, et al. Supporting HIV prevention and reproductive goals in an HIV-endemic setting: taking safer conception services from policy to practice in South Africa. Journal of the International AIDS Society 2017;20(Suppl 1):21271. doi: 10.7448/IAS.20.2.21271 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.