In Swaziland, a small country located in southern Africa, 41% of pregnant women are HIV-infected . Voluntary use of contraception by HIV-infected women currently prevents more HIV-infected births – and at a lower cost – than antiretroviral (ARV) regimens . Providing effective contraception is an essential part of Swaziland's prevention of mother-to-child transmission (PMTCT) program.
In 2006, Baylor College of Medicine's International Pediatric AIDS Initiative opened a clinical Center of Excellence (COE) in Mbabane, Swaziland. The clinic's contraceptive options include male and female condoms, the norethisterone enanthate injection, oral contraceptive pills, and the Jadelle implant (Bayer Schering Pharma, Berlin-Wedding, Germany) . The Jadelle implant is a progestin-only contraceptive device that is inserted subdermally. It consists of two sterile silicon rods, each with 75 mg of levonorgestrel and provides contraceptive protection for 5 years with annual pregnancy rates of 0–0.8% . At the COE, skilled nurses who have attended a 1-day training on the procedure place the implants. Thirty seven percent of all female patients ages 16–49 chose the Jadelle implant, making it is the most commonly used form of hormonal contraception.
We conducted a retrospective chart review using the Baylor College of Medicine's International Pediatric AIDS Initiative-Swaziland COE electronic medical record system. Informed consent was waived and approval for de-identified data collection and analysis was obtained at the time of patient enrollment. Institutional review boards from the Baylor College of Medicine Children's Foundation-Swaziland, Baylor College of Medicine in Houston, Texas, and the Swaziland Scientific and Ethics Committee granted approval. No funds were received for this study.
Data from patient records were entered into a de-identified, de-linked database for statistical analysis, which included all women who had the implant placed between September 2010 and May 2012. Data end points were pregnancy, transfer out of clinic, implant removal, and death. Other recorded data included ARV regimen, condom use, and history of tuberculosis treatment. Patients were excluded if there was missing documentation or, if based on estimated date of conception, they were presumed to have been pregnant prior to Jadelle implant insertion.
Parametric data were reported using mean and standard deviation and compared with a Student's t-test. Categorical data were compared using a global Pearson's χ2 test; when the global test was significant, post-hoc pair-wise comparisons were made using individual χ2 or Fisher's exact tests, with α adjusted by Bonferroni's correction for multiple variable levels. Only P values less than the adjusted α were considered significant.
Of the 576 women who had the implant inserted during the study period, two were presumed pregnant prior to implant insertion and, therefore, excluded from further analysis. Two additional women were excluded due to missing documentation and two others because they were HIV-uninfected. In total, 570 women were included in the analysis, and 16 (2.8%) became pregnant while using the Jadelle implant. Among the 570 women using the Jadelle implant, 347 (61%) were taking ARVs at the time of implant insertion. Of these 347 women, 208 were on nevirapine (NVP)-based regimens, 121 were on efavirenz (EFV)-based regimens, and 18 were on lopinavir/ritonavir (LPV/r)-based regimens (Table 1). Fifteen of the 16 women (one woman had not yet initiated ARVs) who became pregnant while taking ARVs and using the implant were on EFV-based regimens. None of the women taking NVP or LPV/r became pregnant while using the Jadelle implant.
For the 16 pregnant women, the mean time elapsed between implant insertion and pregnancy was 16.4 months (SD 5.5; data not shown). The ARV regimen at the time of pregnancy was the only factor that correlated with pregnancy outcomes (P <0.001; Table 1). Age, CD4+ cell count, reported condom use, and the providers placing the implant were not significantly different between the two groups.
In Swaziland, a once-daily, fixed-dose, EFV-based ARV regimen (tenofovir DF, lamivudine and EFV: TDF/3TC/EFV) is available as first-line therapy for many HIV-infected individuals. Until recently, however, it was not recommended for women of childbearing age . The 121 women who were taking EFV were likely prescribed it for a variety of reasons. Some were taking EFV for the simplified fixed-drug combination that allows once-daily dosing. Others were on EFV because of past coadministration of antituberculosis therapy (ATT) and ARVs. Three of the 16 women who became pregnant had received ATT at some point since the implant was placed (P = 0.064; Table 1). The study, however, was not sufficiently powered to detect a significant difference in these women. Only one woman was actually on ATT at the time of pregnancy and ARVs had not been initiated for this patient. Notably, the Jadelle implant package insert cautions that women on ATT may require dual contraception as the implant's efficacy may be compromised. In general, the women who became pregnant were 3.4 times as likely to have received ATT since the implant was inserted. Further studies are needed to reach a more definitive conclusion on the effects of ATT on the Jadelle implant.
A recent study has show that, within a group of HIV-infected women who took levonorgesterol (Plan B), those also taking EFV had lower levels of levonorgesterol than those not taking EFV . In addition, it has been shown that EFV, but not NVP, when used with combined oral contraceptive pills, resulted in decreased levels of both progesterone and EFV . Currently, these findings are limited to case reports . The practical implications of this interaction for women on EFV using the Jadelle implant have yet to be determined and no warning currently exists on the Jadelle implant package insert. In our cohort of 570 HIV-infected women in Swaziland, 12.4% of those taking EFV while using the Jadelle implant became pregnant. The risk of EFV cotherapy was the only variable that significantly (P <0.001) correlated with pregnancy outcomes. The data from this study strongly suggest an increased risk of pregnancy in HIV-infected women taking EFV when using the Jadelle implant for family planning.
The Jadelle implant is widely used in sub-Saharan Africa. New 2013 WHO guidelines suggest moving toward TDF/3TC/EFV as first-line treatment for all women of childbearing age. As countries incorporate these recommendations, further investigation of the interactions on all family planning choices, in both larger cohorts and with different family planning options, is essential to making informed policy decisions.
This work was made possible with assistance from the Baylor International Pediatric AIDS Initiative-Swaziland and Texas Children's Hospital. Employees or trainees of the above-mentioned groups did all of the data collection and analysis for this study.
This research was approved in entirety by the internal review boards (IRBs) of the Baylor College of Medicine (BCM) Children's Foundation-Swaziland, BCM in Houston, Texas and the Swaziland Scientific and Ethics Committee.
Conflicts of interest
There are no conflicts of interest.
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