OBJECTIVE: To investigate the adjunctive use of mifepristone in second-trimester induction abortions using misoprostol 1 day after feticidal digoxin.
METHODS: This is a randomized, placebo-controlled, double-blind trial of mifepristone in second-trimester induction termination using misoprostol after feticidal digoxin. Women seeking abortion between 18 and 23 weeks of gestation were offered enrollment. At the time of digoxin amnioinfusion, participants received a randomly allocated, identical-appearing capsule containing either mifepristone, 200 mg, or placebo. Patients returned the following day for induction with buccal misoprostol. The primary outcome was the time interval from the first misoprostol dose to abortion. Analysis utilized survival curves with log-rank testing.
RESULTS: Of 64 women, 32 received mifepristone and 32 received placebo. The groups did not differ by ethnicity, age, parity, reason for termination, or gestational age. Median procedure time was significantly shorter for those who received mifepristone, 10 hours (95% confidence interval [CI] 8–12), than those who did not, 18 hours (95% CI 15–22), P<.01, and those parous, 10 hours (95% CI 9–14), compared with nulliparous, 16 hours (95% CI 12–22, P=.02). Other findings in the mifepristone compared with placebo group included rates of placental retention, 3.1% compared with 6.3% (P=.61), length of hospitalization, 0.66 days compared with 0.8 days (P=.23), and analgesic requirements, 27.2 mg compared with 39.3 mg morphine (P=.22). Side effects during induction were similar between groups.
CONCLUSION: Addition of mifepristone in second-trimester termination inductions using misoprostol significantly reduces the abortion time interval.
CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT00382538
LEVEL OF EVIDENCE: I
Addition of mifepristone in second-trimester termination inductions using misoprostol after feticidal digoxin significantly reduces the abortion time interval and misoprostol dose needed to complete abortion.
From the 1Department of Obstetrics and Gynecology, Boston University School of Medicine, Boston, Massachusetts.
Presented at the Reproductive Health 2007, a joint meeting of the Association of Reproductive Health Professionals, Planned Parenthood Federation of America, Society for the Advancement of Reproductive Care, and Society of Family Planning, Minneapolis, Minnesota, September 26-29, 2007.
Supported by an anonymous foundation.
The authors thank Howard Cabral for his statistical assistance.
Corresponding author: Nathalie Kapp, MD, MPH, World Health Organization, Department of Reproductive Health and Research, 20 Avenue Appia, Geneva-27, Switzerland CH-1201; e-mail: firstname.lastname@example.org.
Financial Disclosure The authors have no potential conflicts of interest to disclose.
Mifepristone is an artificial steroidal drug with antiprogesterone and antiglucocorticoid actions. It has demonstrated efficacy for medical abortions in the first and second trimesters1 and has been used for cervical preparation before labor induction in term patients.2 Given its pharmacology, it most likely affects the cervix as well as the uterus favorably for termination3 and augments uterine sensitivity to the prostaglandin analogue, misoprostol.4,5
Misoprostol’s efficacy, favorable side effect profile, and low cost, in comparison with other prostaglandin analogues, have made it a common inductive agent for second-trimester use.6–9 Use of misoprostol as a singular inductive agent in second-trimester terminations demonstrate median induction times ranging from 10 to 19 hours.6,8,10–13 A number of studies of second-trimester induction abortion demonstrate median abortion times, from the start of induction to delivery, of 10 hours or less with use of gemeprost or misoprostol when mifepristone is given 36 hours before the inductive agent.14–18 Its beneficial effect on induction, in one study, was a 50% estimated reduction in time to completed abortion compared with abortions performed without adjunctive mifepristone.16
In the United States, feticidal agents such as digoxin may be used with second-trimester labor induction abortions.8,19 Whether mifepristone further increases the efficacy of abortion protocols that employ intraamniotic digoxin followed by misoprostol has not been reported.
At Boston Medical Center, dilation and evacuation for pregnancy termination in the second trimester is utilized up to 18 weeks of gestation while more advanced pregnancies require termination using an induction procedure. Approximately 100 terminations are performed each year from 18 to 23 weeks of gestation, using misoprostol for induction 1 day after feticidal digoxin amnioinfusion. To investigate the adjunctive use of mifepristone in this setting, we conducted a randomized trial of mifepristone versus placebo administered at the time of digoxin instillation for women in the second trimester requesting termination of pregnancy.
MATERIALS AND METHODS
The Institutional Review Board of Boston University School of Medicine approved the trial protocol. Women presenting to Boston Medical Center for termination of pregnancy between 18 weeks 0 days and 23 weeks 0 days of gestation with the ability to give informed consent were invited to participate. Exclusion criteria included a known allergy to mifepristone, misoprostol, or prostaglandins; preexisting intrauterine fetal demise; premature preterm rupture of membranes; intrauterine device in place; history of chronic adrenal failure; porphyrias; or concurrent long-term corticosteroid treatment. Women who declined study entry underwent induction without mifepristone, and data were not collected on these women.
After consent and study enrollment, participants were assigned to their treatment group by a sequentially distributed study number in an allocation ratio of 1:1. The randomization scheme used permuted blocks of eight, selected by a random number generator created using SAS V.9.3 (SAS Institute, Inc., Cary, NC). Mifepristone, 200 mg, and placebo (vitamin C, 250 mg) were placed in identical gelatin capsules by the pharmacy.20 The pharmacy dispensed the study medication based on the randomization scheme, thus maintaining blinding to study allocation for participants, clinicians, and researchers.
All participants underwent an ultrasound-guided amniocentesis with intraamniotic injection of 1.5 mg of digoxin. Immediately after the injection, study participants received a study capsule, and its ingestion was witnessed by an investigator. Women returned to the hospital the following morning, approximately 20–24 hours after receiving the study capsule, for admission to the gynecology floor and misoprostol induction. Induction was achieved using an initial 400 mcg of misoprostol, followed by 200 mcg every 6 hours, with all doses administered buccally. Buccal administration consisted of instructing the women to place the tablets between the inside of their cheek and gums for 30 minutes, then to swallow any remaining residue. All women received morphine patient-controlled analgesia. After fetal expulsion, spontaneous placental delivery was allowed, unless bleeding occurred or at least 4 hours had elapsed without spontaneous expulsion. In these cases, surgical intervention to remove the placenta was performed using local anesthesia, usually in an adjacent treatment room.
For clinically stable women, discharge from the hospital depended on the time of the completed abortion; for those who delivered in the afternoon or evening, discharge was the same day, excepting those who had difficulties arranging transportation. Those who delivered during the night were discharged the following morning.
The primary outcome of the trial was the median interval from first misoprostol dose to fetal expulsion. Secondary outcomes included the proportion of women delivering within 24 hours, the proportion of women with a complete delivery requiring additional treatment for retained placenta, the amount of required pain medication and length of hospital stay between the two groups. Data on demographics, side effects, and adverse events were collected.
Statistical analysis was accomplished using SAS. Sample size was calculated for the primary outcome using a survival analysis power formula, with an alpha level of 0.05 and a power of 80%.21 We used data from our institution,8,22 which estimated a median misoprostol induction time of 12.5 hours, and then estimated a likely delta (time difference between the two treatment groups) of 35%. The number needed in each group using this calculation was 32 per group. Loss to follow-up was not anticipated, as women were enrolled at the time of feticide, then hospitalized during their induction. The analytic plan for the study included the use of Kaplan-Meier survival curves23,24 for the analysis of the induction-to-delivery interval with log-rank testing of the null hypothesis. Chi square analysis was utilized to analyze differences in the incidence of placental retention and need for transfusion, and t tests for comparison of pain medication utilization. We planned to analyze the data as intent-to-treat if losses or dropouts occurred in the study.
From August 2005 to November 2006, we enrolled 64 of 114 women undergoing induction termination (Fig. 1). Demographically the two treatment groups were similar in all important respects (Table 1). The mean gestational age in the study was 19 weeks and 4 days (standard deviation 1.2 weeks). The mean interval between administration of the study drug and the first dose of misoprostol was 21.2±1.6 hours (range 17.9–26.7 hours) and did not differ by group (P=.14). Women received the study medication after digoxin administration within 5.04±1.9 and 5.22±1.7 minutes in the mifepristone and placebo groups, respectively (P=.83). All women received their allocated medication.
Median time to abortion was significantly different for those who received mifepristone, 10 hours (95% confidence interval [CI] 8–12), from those in the placebo group,18 hours (95% CI 15–22, P<.01) (Fig. 2). Time to expulsion also differed by parity; women with a previous delivery had median induction times of 10 hours (95% CI 9–14) while those without had longer inductions times, 16 hours (95% CI 12–22, P=.02) (Fig. 3). Within the groups defined by parity, nulliparous women receiving mifepristone had shorter induction times than nulliparous women who did not receive mifepristone. The same pattern was seen for parous women. The median abortion times for parous and nulliparous women receiving mifepristone demonstrated a narrower range of values, 9 hours (95% CI 7–10) and 12 hours (95% CI 10–14, P=.03), whereas those receiving placebo, 17 hours (95% CI 11–20) and 20 hours (95% CI 18–25, P=.17), respectively, were more variable (Fig. 4). Other covariates (gestational age, demographic variables, reason for termination or side effects including symptoms on admission) did not significantly affect the induction time interval in bivariate analyses.
The proportion of women with completed inductions in 24 hours was 97% for those who received mifepristone and 72% in the placebo group (P<.01). The mean dose of misoprostol required for completed abortion differed significantly by group: 925±48 mcg compared with 1412±101 mcg in the mifepristone and placebo groups, respectively (P<.01).
Two women required a dilation and evacuation (D&E) during their induction: one woman had a low-lying fibroid that seemed to obstruct passage of the fetus after 36 hours of misoprostol, and one woman experienced heavy bleeding, without passage of the fetus. Both women were in the placebo group. They contributed data to the time of D&E in the survival analysis, after which their data were censored, as they did not proceed to the primary outcome of interest.
The rates of placental retention requiring surgical removal were 6.3% in the placebo group and 3.1% in the mifepristone group (P=.61). The median time to spontaneous placental delivery after fetal expulsion was 1.5 hours for both treatment groups (P=.31).
In the interval after digoxin amnioinfusion and administration of the study drug, and before misoprostol initiation, 28.1% of the women in the mifepristone group reported nausea, which was not significantly different from the 9.4% of those who received placebo (P=.11). Rates of cramping during the same time interval were reported by 46% and 31% of the women, respectively (P=.20). During induction, the amounts of morphine used by women in the mifepristone and the placebo groups were 27.2 mg and 39.3 mg, respectively (P=.22). Nausea during induction did not differ by treatment group, occurring in 56% of women in the mifepristone group and 49.9% in the placebo group (P=.27). Vomiting occurred in 42% and 40% of women, respectively (P=.67).
Women in the mifepristone group spent less than a day (0.66 days, 95% CI 0.89–0.52) in the hospital, as did the women in the placebo group (0.8 days, 95% CI 1.05–0.46) (P=.23).
Complications of heavy bleeding occurred twice during the course of the study. One woman in the placebo group required a D&E for treatment before fetal delivery. The other woman, who was in the mifepristone arm, experienced heavy bleeding after fetal delivery, during placental separation. Intervention to remove her placenta was delayed. With assisted removal of her placenta, the bleeding stopped; however, she required transfusion. There were no other serious complications, including no occurrences of uterine rupture.
Our findings demonstrate a beneficial effect of mifepristone on the induction time interval for second-trimester termination. This trial intended to investigate whether mifepristone would show a decrease in induction time intervals when misoprostol was used in conjunction with feticide. In our population, with gestational ages of 18–23 weeks, we found a 45% decrease in induction time. The magnitude of the decrease is similar to that described for induction with misoprostol without feticide.
Although median induction times of 7 hours have been reported with pretreatment with mifepristone, gestational ages in these studies are much earlier than in our population, primarily between 15 and 16 weeks.14,17,18 As induction times have decreased with the use of more efficacious prostaglandins and their analogues, gestational age has become an important predictor of induction time, with higher gestational ages correlating to slower induction times. An additional independent factor is that of parity, which is demonstrated again in our study; nulliparous women have longer induction times than those with previous vaginal or cesarean deliveries.17,18 However, administration of mifepristone appears to mitigate the time difference of the abortion interval between parity groups.
The need for surgical intervention for removal of the placenta is low in our study. There are several studies showing rates of placental retention of 5–11% after use of the combined regimen of misoprostol and mifepristone without an increase in adverse events reported.14,17,18 Our findings are corroborative; although we had one adverse event awaiting the placenta, this was avoidable. We did not demonstrate a difference in placental intervention rates between the two groups. Although cases of uterine rupture in second-trimester terminations have been reported in the literature, no cases occurred in our series despite the inclusion of women with previous hysterotomies.25–27
Strengths of our study include its double-blinded randomized design, which increases the validity of our findings by reducing the likelihood of confounding and bias. Additionally, our findings are more generalizable than many studies of its type as we enrolled women seeking second-trimester terminations in our racially diverse institution, regardless of the history of a previous hysterotomy. Our study also offers some safety information on the use of digoxin as an intraamniotic feticidal agent, as we collected information on women’s side effects after its administration until hospital admission, 24 hours later. There were no serious side effects or events that occurred between digoxin administration and hospital admission. Additionally, we report a low rate of nausea before induction in women who received digoxin without mifepristone.
Our findings are limited by the fact that we used buccal administration of misoprostol, which restricts its comparability to other studies. Although its use has not been reported in second-trimester inductions, the effect on the uterus is similar to vaginal dosing.28 In our institution, buccal misoprostol is preferred over vaginal administration by our staff as it may be given very efficiently as it does not require a vaginal examination or presence of a physician, thereby allowing more same-day procedures. We demonstrate a median induction time of 18 hours for all buccal dosing, which is longer than our institution’s historical data using vaginal dosing, but is similar to other reports for second-trimester terminations using misoprostol as a singular inductive agent.11,29–31
In conclusion, induction terminations remain an important method of second-trimester abortion, particularly where D&E is not available. The addition of mifepristone to induction regimens using misoprostol decreases the induction time interval by up to 45%, when used in conjunction with feticidal digoxin.
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