Effect of HIV Infection and Antiretroviral Treatment on Pregnancy Rates in the Western Cape Province of South Africa

Background: Previous studies suggest that untreated human immunodeficiency virus (HIV) infection is associated with a reduced incidence of pregnancy, but studies of the effect of antiretroviral treatment (ART) on pregnancy incidence have been inconsistent. Methods: Routine data from health services in the Western Cape province of South Africa were linked to identify pregnancies during 2007-2017 and maternal HIV records. The time from the first (index) pregnancy outcome date to the next pregnancy was modeled using Cox proportional hazards models. Results: During 2007-2017, 1 042 647 pregnancies were recorded. In all age groups, pregnancy incidence rates were highest in women who had started ART, lower in HIV-negative women, and lowest in ART-naive HIV-positive women. In multivariable analysis, after controlling for the most recent CD4+ T-cell count, pregnancy incidence rates in HIV-positive women receiving ART were higher than those in untreated HIV-positive women (adjusted hazard ratio, 1.63; 95% confidence interval, 1.59-1.67) and those in HIV-negative women. Conclusion: Among women who have recently been pregnant, receipt of ART is associated with high rates of second pregnancy. Better integration of family planning into HIV care services is needed. The Western Cape Government Health Department maintains a number of electronic record systems for the purpose of managing hospital and primary care administration, drug dispensing, and laboratory data [24]. Records for individual patients are linked across systems through a unique patient identifier, which was initially introduced in hospitals and has been rolled out to primary care clinics since 2007. This linkage process is managed by the Provincial Health Data Centre, which provided the data for this analysis. A pregnancy is identified if there is an antenatal clinic visit; a rhesus antibody test; an International Classification of Diseases, Tenth Revision, code indicating pregnancy or an abortive outcome of pregnancy; drugs dispensed for a termination of pregnancy; or a birth recorded on the birth register. Based on these data sources, a pregnancy outcome and pregnancy outcome date are inferred for each woman. In a substantial fraction of cases, it is not possible to determine a pregnancy outcome (Table 1), and a pregnancy confidence score is calculated to measure the degree of confidence that the evidence truly indicates a pregnancy. In the main analysis, all possible pregnancy events are considered, but in a sensitivity analysis we restrict the analysis to those pregnancies with a pregnancy confidence score of 0.7 or higher (termed “probable pregnancies”). These pregnancies had at least 1 evidence that was considered to be high confidence and indicative of pregnancy on its own (eg, rhesus antibody testing) or multiple moderate-confidence evidences (eg, antenatal clinic visits); further details are provided in the Supplementary Materials. For pregnancies with no outcome recorded, in most cases the outcome date is predicted to be 41 weeks after the first evidence of pregnancy. In cases where additional data are available, the outcome date is inferred by using the last menstrual period date, estimated delivery date, or gestational age. Baseline Characteristics For analysis 1, characteristics of all pregnancies in the database are presented. For analysis 2, characteristics are presented only for the index pregnancy (ie, the first pregnancy in the database), and we exclude HIV-positive women with no CD4+ T-cell count measurements and women whose estimated pregnancy end date is after the end of 2017. Abbreviations: ART, antiretroviral therapy; HIV, human immunodeficiency virus. aIn analysis 1, pregnancies are only classified as involving HIV-positive women if there is evidence of HIV before the pregnancy outcome date; in analysis 2, pregnancy intervals are classified as HIV positive if there is any evidence of HIV (ie, evidence before or after the index pregnancy outcome date). A woman is identified as HIV positive if there is a positive enzyme-linked immunosorbent assay (ELISA), a CD4+ T-cell count, a viral load test result, a record that combination ART was dispensed, or registration on the TIER.net or equivalent database (ie, databases for the management of HIV-positive patients). The date of ART initiation is taken as the earlier of the first recorded date on which ART was dispensed and the recorded date of ART initiation. As rapid diagnostic test results are not electronically recorded, exact dates of diagnosis cannot be inferred in most cases. Analysis is restricted to women who had evidence of at least one pregnancy, with the first pregnancy outcome date occurring between 1 January 2007 and 31 December 2017. Women were excluded if they were aged <15 or >49 years at the first pregnancy outcome date. In the analysis of times to conception after the first conception, the analysis was further limited to women whose first pregnancy outcome date was 9 months prior to the end of 2017, in order to exclude women who were unlikely to have had a second pregnancy outcome before the end of 2017. The total number of pregnancies in the Western Cape public health sector in each year was compared to estimates of the Thembisa model (version 4.1), a combined demographic and HIV model fitted to Western Cape data [23]. The model is calibrated to antenatal and household survey HIV prevalence data, as well as to reported numbers of HIV-positive patients receiving ART in the Western Cape, and is the official source of Joint United Nations Programme on HIV/AIDS (UNAIDS) estimates for South Africa. Consistent with the approach adopted in several previous evaluations of the effect of HIV on fertility [8, 9], we then assessed factors associated with the time from the first pregnancy outcome date to the second pregnancy conception date (estimated as 270 days before the second pregnancy outcome date), using Cox proportional hazards models. Follow-up was censored at the earlier of the second pregnancy conception date and 31 March 2017. ART and CD4+ T-cell count were treated as time-varying covariates. Women with no evidence of HIV infection in the database were assumed to be HIV negative for the entire follow-up, while women whose first date of HIV evidence occurred after their first pregnancy date were included in the follow-up only from the date of their first CD4+ T-cell count. Because of concern that women who died or migrated out of the province might be incorrectly classified as residing in the Western Cape during follow-up, a sensitivity analysis was conducted in which women were censored 2 years after their last date of contact with the health system, if this occurred before the original censoring date of 31 March 2017 (HIV-positive women could be censored later, 270 days before the date of their last HIV-related laboratory test, if this occurred before the original censoring date). Because it was anticipated that hazards in different covariate categories would not be proportional, Cox proportional hazard models were also fitted separately for the following 4 durations after the index pregnancy: 0–1, 2–3, 4–5 and 6 or more years. All statistical analyses were performed using Stata, version 15.1 (StataCorp, College Station, TX). The analysis was undertaken as part of a broader evaluation of the impact of expanded access to ART in pregnancy, approved by the Human Research Ethics Committee at the University of Cape Town (HREF 541/2015). Informed consent was not sought, as the data were collected through routine health services and anonymized before they were shared with the researchers.