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Effects of Depot Medroxyprogesterone Acetate Injection Timing on Medical Abortion Efficacy and Repeat Pregnancy

A Randomized Controlled Trial

Raymond, Elizabeth G. MD, MPH; Weaver, Mark A. PhD; Louie, Karmen S. MS, MPH; Tan, Yi-Ling MPH; Bousiéguez, Manuel MBA; Aranguré-Peraza, Ana Gabriela MD; Lugo-Hernández, Elba M. MD; Sanhueza, Patricio MD; Goldberg, Alisa B. MD, MPH; Culwell, Kelly R. MD, MPH; Kaplan, Clair MSN, ARPN; Memmel, Lisa MD, MS; Sonalkar, Sarita MD, MPH; Jamshidi, Roxanne MD, MPH; Winikoff, Beverly MD, MPH

doi: 10.1097/AOG.0000000000001627
Contents: Original Research
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OBJECTIVE: To evaluate the effects of timing of depot medroxyprogesterone acetate injection on medical abortion outcome and risk of repeat pregnancy within the subsequent 6 months.

METHODS: In a multinational randomized trial, we assigned women undergoing medical abortion who wanted depot medroxyprogesterone acetate to administration either with mifepristone (Quickstart group) or after the abortion (Afterstart group). We ascertained abortion outcome, pregnancies, and contraception use over 7 months.

RESULTS: From August 2013 to March 2015, we enrolled 461 participants with pregnancy durations of 75 days or less. Of participants included in the abortion outcome analyses, 14 of 220 (6.4%) and 12 of 226 (5.3%) in the Quickstart and Afterstart groups, respectively, had surgery to complete the abortion; the upper 90% confidence limit on this difference was 4.9%, within our prestipulated 5% noninferiority margin. Ongoing pregnancy after initial abortion treatment was significantly more common in the Quickstart group (8/220 [3.6%]) than in the Afterstart group (2/226 [0.9%]); the difference was 2.7% (90% confidence interval 0.4–5.6%). By 6 months, 5 of 213 (2.3%) and 7 of 217 (3.2%) in the Quickstart and Afterstart groups, respectively, became pregnant (exact log-rank test, P=.64). Use of highly effective contraceptives was significantly more common in the Quickstart group at 31 days (P<.001), but no difference was apparent at 6 months. The Quickstart group was significantly more satisfied with group assignment.

CONCLUSION: Depot medroxyprogesterone acetate administration with mifepristone did not appreciably increase the risk of surgery after medical abortion but did increase the risk of ongoing pregnancy. It enhanced patient satisfaction, but we found no evidence that it decreased 6-month risk of repeat pregnancy.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01902485.

Our data indicate that timing of depot medroxyprogesterone acetate injection does not substantially increase surgery risk after medical abortion and may not reduce repeat pregnancy.

Gynuity Health Projects, New York, New York; the Departments of Medicine and Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; the Secretariat of Health, Mexico City, Mexico; Planned Parenthood League of Massachusetts, Boston, Massachusetts; Planned Parenthood of the Pacific Southwest, San Diego, California; Planned Parenthood of Southern New England, New Haven, Connecticut; Planned Parenthood Northern California, San Rafael, California; the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Johns Hopkins University, Baltimore, Maryland.

Corresponding author: Elizabeth G. Raymond, MD, MPH, Gynuity Health Projects, 15 East 26th Street, Suite 801, New York, NY 10010; e-mail: eraymond@gynuity.org.

Financial support provided by an anonymous donor. The funder had no role in the development of the study question or the study design or in the collection, storage, or analysis of data.

Financial Disclosure Dr. Jamshidi is a Nexplanon trainer (Merck). The other authors reported no potential conflicts of interest.

Presented at the 2015 National Abortion Federation Annual Meeting, April 18–21, 2015, Baltimore, Maryland; the XXI FIGO World Congress of Obstetrics and Gynecology, October 4–9, 2015, Vancouver, Canada; the Fifth Research Meeting on Unwanted Pregnancy and Unsafe Abortion: Public Health Challenges in Latin America and the Caribbean, September 28–30, 2015, Mexico City, Mexico; the North American Forum on Family Planning, November 14–16, 2015, Chicago, Illinois; and the 3rd International Congress on Women's Health and Unsafe Abortion, January 26–29, 2016, Bangkok, Thailand.

The authors thank the following personnel who were instrumental in collecting study data: Teresa López Flores and Maribel Martínez-Jiménez, Secretariat of Health, Mexico City; L. Fields, D. Freedman-Shara, G. Ward, J. Wilder, and S. Dobson, Planned Parenthood of Southern New England; Planned Parenthood of the Pacific Southwest Chula Vista Health Center; Jessica McClusky, Boston Medical Center; Jennifer Fortin and Sarah McKetta, Planned Parenthood League of Massachusetts; Margarita Avelar and Mariela Garcia, Planned Parenthood Northern California; and Torri Ross, Bayview Medical Center. The authors also thank Jennifer Britton, who managed study data at Gynuity.

The findings and conclusions in this article are those of the authors and do not necessarily represent the views of Planned Parenthood Federation of America, Inc.

Allowing women undergoing medical abortion to initiate their chosen contraceptive method at the time of mifepristone administration—an approach called “quickstart”1—has been proposed as a strategy for facilitating contraceptive uptake in this population.2–7 We recently reported results of a randomized trial that compared quickstart of etonogestrel implants with the more standard approach of delaying initiation until after the medical abortion was complete.8 We found no evidence that quickstart significantly reduced the 6-month pregnancy rate, but participants strongly preferred this option. Importantly, our data refuted the concern that administration of the progestin-based implants concurrently with the antiprogestin mifepristone would reduce the abortifacient efficacy of the mifepristone. Based on our results, we recommended that quickstart of implants should be routinely offered in medical abortion practice.

Depot medroxyprogesterone acetate (DMPA) has advantages over implants: it is much less expensive than implants and can be administered by personnel not trained in implant insertion. In 2006–2010, DMPA was used by more than 2.5 times as many women in the United States as implants.9 Therefore, in parallel with the implant study, we conducted a trial of DMPA at the same sites using the same protocol. Our primary objectives were to evaluate whether initiating DMPA on the same day as mifepristone rather than requiring women to delay the injection until after the abortion was complete would affect 1) the risk of having surgery to complete abortion and 2) the probability of pregnancy during the subsequent 6 months. Here we report the results of this trial.

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MATERIALS AND METHODS

The trial was approved by the Chesapeake institutional review board, Boston University Medical Center institutional review board, Johns Hopkins Medicine institutional review board, and the Comisión de Ética en Investigación de la Secretaría de Salud del Distrito Federal. Detailed information about the trial methods has been reported previously.8 Below is a summary.

We conducted the trial at clinics managed by seven organizations in the United States and Mexico between 2013 and 2015. Women who met sites' criteria for outpatient medical abortion with mifepristone and misoprostol and desired DMPA for contraception were eligible for enrollment. Enrollment rates in the Mexico sites were capped for administrative reasons; U.S. sites enrolled without restriction. The abortifacient regimen was 200 mg mifepristone orally followed 1–2 days later by 800 micrograms misoprostol buccally.10

Each participant provided signed informed consent and baseline information. Randomization was administered using sequentially numbered, opaque, sealed envelopes. Participants in the Quickstart group received 150 mg DMPA intramuscularly shortly after ingesting mifepristone. Participants in the Afterstart group took the mifepristone in the clinic but were required to wait until the abortion was complete before initiating any hormonal contraceptive. Follow-up data were collected within 1 month and at 4 and 7 months after enrollment. Participants received compensation after completing each scheduled contact. Participants were charged for the abortion and all contraceptives as if they were not in the study. The Mexico sites routinely provided all contraceptives free to all patients. These sites normally stocked norethindrone enanthate rather than DMPA for injectable contraception; during the study, DMPA was available to study participants. A clinician blinded to group assignment reviewed records from participants who received any abortifacient treatment in addition to the initially dispensed drugs to assess need for that treatment. The expert's judgments were not used in analyses, however.

We calculated that 380 participants would provide 80% power to allow us to conclude with 95% confidence that the surgery rate was no more than 5 percentage points higher in the Quickstart group than in the Afterstart group, assuming 4% true rates in both groups.11 Expecting 20% loss to follow-up, we aimed to enroll 475 women.

All analyses maintained participants in their randomly assigned groups. The primary medical abortion outcome analyses excluded participants without known abortion outcomes, those in the Afterstart group who initiated hormonal contraceptives within 6 days after mifepristone ingestion, and those in the Quickstart group who did not receive DMPA at enrollment. The main analysis tested the null hypothesis that the proportion in the Quickstart group who had surgery to complete the abortion was at least 5% higher than the proportion in the Afterstart group compared with the alternative that the difference would be less than 5% by estimating the difference with an exact two-sided 90% confidence interval (corresponding to one-sided α=0.05). Intention-to-treat sensitivity analyses included all randomized participants with worst-case imputation for those with missing outcomes. Secondary analyses similarly estimated differences between groups in the proportion who received any extra treatment to complete the abortion and who had ongoing pregnancy after initial treatment.

We used an exact log-rank test at the two-sided 5% significance level to compare 6-month pregnancy probabilities between groups. We defined a participant as having “evidence of nonpregnancy” at 6 months if she had a negative pregnancy test at 197 days or later, had a first reported pregnancy conceived later than 183 days after enrollment, or was using sterilization, implants, an intrauterine device (IUD), or an injectable method at 183 days. We considered her to be using implant or IUD at 183 days if she received the method within 183 days and reported no removal or expulsion earlier than 184 days. We considered her to be using an injectable method if she received DMPA 78–183 days after enrollment or of norethindrone enanthate 109–183 days after enrollment. Otherwise, we considered a participant who was followed for at least 183 days without a reported pregnancy to have “no evidence of pregnancy.”

We compared the use of highly effective contraceptives (defined as DMPA, implants, IUDs, or female sterilization) and other outcomes in the two groups using χ2 tests or nonparametric Wilcoxon rank-sum tests. We tested interactions by country, when possible, using Breslow-Day tests for homogeneity.

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RESULTS

We enrolled 461 participants with pregnancy durations of 75 days or less between August 2013 and March 2015 (Table 1); we terminated recruitment at that point because of slow accrual. All participants met study eligibility criteria. One woman at a U.S. site declined DMPA after assignment to the Quickstart group; she was subsequently lost to follow-up. Mexican participants were more likely than those in the United States to have gestations of greater than 63 days (15.4% compared with 4.5%, respectively) and to have had less than 12 years of education (at least 47.4% compared with 4.5%, respectively), and they were less likely to have previously used DMPA (1.1% compared with 60.4%, respectively) and to have had a prior abortion (34.6% compared with 56.8%; P<.05 for all four comparisons).

Table 1.

Table 1.

Of the three participants in the Afterstart group excluded from the medical abortion outcome analyses who had known abortion outcomes (Fig. 1), one had surgery to complete the abortion, one had extra misoprostol, and one had a complete pregnancy termination without additional treatment. Of the 446 included participants, 86% in the Quickstart group and 91% in the Afterstart group had ultrasonography to assess abortion outcome. These outcomes are presented in Table 2.

Fig. 1.

Fig. 1.

Table 2.

Table 2.

The upper 90% confidence limit around the difference between groups in the proportion who had surgery to complete the abortion (Table 3) was below our prespecified noninferiority margin of 5%, providing 95% confidence that our null hypothesis should be rejected. However, our sensitivity analysis found that, if only one of the excluded participants in the Quickstart group with unknown abortion outcomes had surgery, the null hypothesis would not have been rejected. The lower 90% confidence limit around the difference between groups in the proportion of women who had ongoing pregnancy after initial treatment was greater than 0, providing 95% confidence that the proportion was higher in the Quickstart group than in the Afterstart group. The independent reviewer confirmed that 11 of 14 surgeries in the Quickstart group, 6 of 12 surgeries in the Afterstart group, and 1 of 13 extra drug treatments in the Afterstart group were definitely or probably needed.

Table 3.

Table 3.

Abortion outcomes did not differ appreciably by country, but the median pain score, the duration of bleeding, and the proportion of participants with heavy bleeding were all significantly higher in Mexico (P<.02 for all three comparisons). We found no significant interactions between group and country with regard to postabortion bleeding, pain, or extra clinic visits (P>.1 for each outcome). The difference in satisfaction at follow-up (Table 4) was significantly greater in the United States than in Mexico (P=.008).

Table 4.

Table 4.

Pregnancy rates through 6 months did not differ significantly by group (Table 5). The difference between groups in the proportion of participants who were documented to have received DMPA, implants, IUDs, or sterilization by 31 days after enrollment was significantly greater in the United States than in Mexico (P<.001); in the Afterstart group, the proportion of participants who were not using one of these methods by 31 days was 23% in the United States and 15% in Mexico. Of these women (n=39), 12 (31%) cited logistic difficulties in getting to the clinic, three preferred another method, one wanted to wait until she had stopped bleeding, one was still pregnant, and 22 did not provide a reason. Among participants with data at 6 months, the proportion using these methods did not differ significantly between countries.

Table 5.

Table 5.

Two serious adverse events were reported in each study group. Three were postabortion hemorrhages managed in hospitals, and one was appendicitis.

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DISCUSSION

The data from this randomized trial suggest that concurrent intramuscular injection of 150 mg DMPA may decrease mifepristone efficacy in medical abortion. The primary analyses of abortion outcome provided 95% confidence that quickstart did not increase the risk of having surgery to complete the abortion by more than 5%. But sensitivity analyses found that even one additional surgical procedure in the Quickstart group could have negated this conclusion. Moreover, the incidence of ongoing pregnancy after treatment was significantly higher in the Quickstart group (3.6%) than in the Afterstart group (0.9%).

These results contrast with those of our parallel trial of quickstart of implants conducted using the same protocol at the same sites.8 That trial showed convincingly that quickstart of etonogestrel implants did not appreciably increase the rates of surgery, receipt of any extra treatment, or ongoing pregnancy after medical abortion treatment. We are unable to find published data directly comparing the pharmacologic properties of the two contraceptive preparations within the few days after initiation, but the proposition that they may interact differently with mifepristone is certainly plausible.

Notably, though, our study did not demonstrate conclusively that quickstart of DMPA had clinically important adverse effects on abortion outcome. Our estimate of the difference between the ongoing pregnancy rates in the two groups was imprecise, and our data are consistent with only a very small (0.4%) increase resulting from quickstart. In both groups, more than 93% of participants had complete abortions without surgery, and in more than 96%, the treatment terminated the ongoing pregnancy. Quickstart did not adversely reduce in-person follow-up after the abortion.

Furthermore, the quickstart approach had several valuable benefits. Although we did not find evidence that it reduced the pregnancy rate over the next 6 months or increased use of DMPA or other highly effective methods at 6 months, it did substantially increase uptake of these methods within the first month after the abortion, thus reducing gaps in contraceptive coverage. Participants strongly preferred quickstart, particularly in the United States, where 88% of women in the Quickstart group said after the abortion that they were pleased at the timing of DMPA provision compared with only 23% in the Afterstart group. Based on these findings, we recommend that women undergoing medical abortion who desire DMPA should be offered the quickstart option with full information.

Our study used 150 mg DMPA administered intramuscularly. The alternate subcutaneous preparation containing 104 mg is absorbed more slowly and produces a lower peak serum level of hormone than the intramuscular preparation.12 The degree to which these pharmacokinetic differences might temper any interaction with mifepristone is unknown.

We ascertained abortion outcome for more than 96% of enrolled participants and 6-month pregnancy status for more than 95%. These figures were substantially higher than the 80% that we had anticipated when we designed the trial, and thus we were able to terminate enrollment before reaching the target sample size without sacrificing power. Nevertheless, possible bias resulting from loss to follow-up is a limitation of our study. As noted in our prior article,8 lack of blinding and reliance on participant report of outcomes could also have caused bias or misclassification. Payment for completion of interim contacts could have influenced participants' likelihood of receiving repeat DMPA injections, but because 96% of postabortion contacts earlier than 6 months after enrollment were conducted by phone, we believe that this effect was minimal.

Although nearly all study participants stated that avoiding pregnancy was “very important,” only about half in either group were using DMPA or another highly effective contraceptive method 6 months later. In contrast, in our parallel trial of implants,8 the corresponding proportion was more than 91% in both groups. This difference was not attributable primarily to differential contraceptive uptake within the month of the abortion but rather to higher subsequent discontinuation in the DMPA study. From this perspective, to maximize long-term contraceptive coverage after medical abortion, which method a woman chose was more important than when it was administered. Notably, in the U.S. sites, where enrollment was not restricted by the central study management, the enrollment rate was 30% faster in the DMPA study than in the implant study, suggesting that patients favored DMPA over implants. Unfortunately, we collected no data on the reasons for this preference; cost may have been a factor, because the study did not provide the contraceptives free of charge. Enabling patients to obtain contraceptive implants should be a priority for facilities providing medical abortion.

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© 2016 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved.