In the United States, 55% of the 1.3 million abortions per year occur before 9 completed weeks of gestation. An additional 34% of abortions occur in women who are 10–12 weeks pregnant.1 In the United States vacuum aspiration abortion has proven to be a very safe and effective method during this period of pregnancy. However, in many countries, including the United States, surgical abortion may not be available due to the lack of trained providers. Establishing an effective and acceptable medication alternative would be important in expanding women's access to abortion services and, world-wide, could reduce morbidity and mortality associated with unsafe procedures. Surgical methods for pregnancies in the late first trimester, including dilatation and curettage and vacuum aspiration, continue to have a high rate of complications in many countries. According to the World Health Organization, unsafe abortions lead to between 70,000 and 80,000 maternal deaths each year worldwide.2
Successful medical termination of pregnancy with mifepristone followed by misoprostol up to 9 weeks of gestation has been well documented.3–6 During the past 25 years, several options for nonsurgical termination of pregnancy in the second trimester (beyond 12 weeks of gestation) have been developed. The combination of mifepristone and misoprostol has advantages over other current nonsurgical options, such as hypertonic saline or prostaglandin only, due to shorter induction to abortion intervals and a reduced risk of severe complications.7
The evidence supports mifepristone and misoprostol for early first trimester abortion and second trimester abortion. Gouk and colleagues8 demonstrated a success rate of 96% in 253 women at 9 weeks to 12 weeks of gestation. Ashok and colleagues9 demonstrated a success rate of 95% using a regimen of 200 mg oral mifepristone and 800 mcg vaginal misoprostol in 120 women at 9 weeks to 13 weeks of gestation. Cheng and colleagues10 demonstrated successful medical abortions using mifepristone and misoprostol in 2,007 women at 10–16 weeks of gestation. A study published in 2002 by Ashok and colleagues11 compared medical abortion with vacuum aspiration for abortions at 10 weeks and 13 weeks of gestation and found an overall efficacy of 94.6% in the medical abortion group, which varied slightly although not significantly with gestational age. More recent studies have also shown a similar overall efficacy with the number of misoprostol doses and induction-to-abortion interval increasing with gestation.12–13 The objective of this study was to investigate the efficacy of mifepristone and misoprostol for the termination of pregnancies in the late first trimester in three different clinical settings.
MATERIALS AND METHODS
This was a prospective study of 321 women seeking termination of pregnancy with gestations from 64 to 84 days (±3 days) by vaginal ultrasonography. Between May 2002 and June 2005, women were enrolled at three sites: University of Rochester Reproductive Health Program in Rochester, New York; Hung Vuong Hospital in Ho Chi Minh City, Vietnam; and K.E.M. Hospital in Pune, India. The enrollment period varied among the three sites (Rochester was May 2002–January 2005; Pune was: July 2002–June 2005; Ho Chi Minh City was June 2003–December 2004). The original protocol projected a total sample size of 450 women (Pune 100, Ho Chi Minh City 200, Rochester 150). However, abortion case loads were smaller than projected at Pune and Rochester, resulting in a slow rate of enrollment. In Pune, many eligible women elected not to join the study because they desired a tubal ligation at the time of their abortion and thus elected a surgical procedure. Due to funding constraints, the study team elected to stop the study before reaching full enrollment.
Inclusion criteria included an intrauterine pregnancy from 64 days to 84 days (±3 days) by vaginal ultrasonography, eligible for and interested in medical abortion, general good health, and willingness to participate in the study. The formula used for calculating gestational age was 42 plus crown rump length in mm. Maximal crown rump length was 42 plus 3 mm. Women were excluded if they had a confirmed or suspected ectopic pregnancy; an intrauterine device in place; chronic renal failure; concurrent long-term corticosteroid therapy; history of allergy to mifepristone, misoprostol, or other prostaglandin; hemorrhagic disorders or concurrent anticoagulant therapy; inherited porphyrias; or other serious physical or mental health conditions. Eligible women learned of the study when they presented for surgical terminations (Pune and Ho Chi Minh City) or called to schedule an appointment for a surgical termination (Rochester). The Population Council's Institutional Review Board and the ethics committees at K.E.M. Hospital, Pune, the University of Rochester, and Hung Vuong Hospital approved the study protocol. All the women gave their informed consent.
After determining eligibility and obtaining written informed consent, an Rh determination was performed. If found to be Rh negative, the subject was given anti-D immune globulin. A baseline hemoglobin measurement was performed only if there was a previous history of anemia. Mifepristone 200 mg orally was administered, and an appointment was made to return to the clinic in 1–2 days. Upon returning to the clinic for the second visit, 800 mcg misoprostol was inserted vaginally. At Rochester and Ho Chi Minh City, vaginal insertion was by the subject with dry misoprostol tablets. At the India site, vaginal insertion was done by the clinician with dry tablets. The misoprostol dose was repeated (400 mcg vaginally, or, if bleeding had begun, orally) every 3 hours for a maximum of two additional doses, as needed, for a maximal total dose of 1,600 mcg over an 8-hour period.
Women remained in the clinic until the pregnancy had passed and vaginal bleeding was minimal or the woman underwent an aspiration curettage. In Rochester and Ho Chi Minh City, if a woman had not aborted by approximately 10 hours after the first dose, she was given a suction aspiration. In Pune, women were held in the hospital overnight for observation and those who had not completed the abortion process at 8:00 AM on day 4 or 5 were given the option of continuing their treatment and receiving an additional 400 mcg dose of misoprostol (orally) and another dose (400 mcg orally) 3 to 4 hours later. Women at the Pune site received a surgical aspiration if the abortion was not completed on the afternoon of day 4 or 5.
At all three sites, products of conception were identified by visual inspection. Vaginal ultrasonography was used on an as-needed basis for the diagnosis of incomplete and ongoing pregnancies. In Rochester and Ho Chi Minh City, women received ibuprofen 800 mg every 4 hours as needed and combined acetaminophen 300 mg and codeine 30 mg two tablets every 4 hours as needed for pain relief. In Pune, women received ibuprofen 800 mg or Parvon Forte (Jagson Pharma, Shahpur Jat Delhi, New Delhi, India) (dextropropoxyphene plus paracetamol 500 mg) for pain relief.
Women were carefully monitored, and pain, adverse effects, and time of expulsion were noted by the provider on an in-clinic diary card. Before discharge on day 3 or day 4, an interview was conducted to assess acceptability, method preferences, and pain. Women were asked to rate their experience on a categorical five-point scale from very satisfied to very unsatisfied. Women were also asked to rate the severity of the pain during the medical abortion procedure using a visual analogue scale with circles of increasing size numbered from one to seven. The smallest circle (1) represented no pain at all and the largest circle (7) represented the worst pain imaginable.
All the women were also provided with a home study card on which they were asked to record adverse effects, bleeding, and cramping experienced and pain medication required. The cards also contained reminder instructions about what to expect during the abortion process, an emergency telephone number, and the date and time of the follow-up appointment. Women were instructed that they could return to the clinic at any time if they had concerns about the process or experienced very heavy bleeding.
Women returned on day 15 for follow-up care. Abortion status was assessed by physical examination and ultrasonography. An exit interview was conducted to assess acceptability, adverse effects, and bleeding history. Staff attempted to contact by phone or home visit women who failed to show up for the follow-up visit. Women were considered lost to follow-up if the final visit was not completed by the end of the study.
Data were analyzed using the Statistics Package for Social Sciences (SPSS) 13.0 (SPSS Inc., Chicago, IL). Analysis was done on an intent-to-treat basis, and only women who were completely lost to follow-up were excluded from the analysis. Primary outcome measures included the rate of successful termination and patient satisfaction with the regimen. A successful termination was defined as complete abortion without uterine aspiration, ie, surgical intervention. Continuous variables (gestational age, age, and time to expulsion) were normally distributed and reported as means. Independent t tests were used for continuous variables. The χ2 or Fisher exact test, as appropriate, was used for independent nominal data. Confidence intervals were used where appropriate and statistical significance was defined as a P value of <.05.
In total, 321 women participated in the study (Ho Chi Minh City 200, Rochester 70, and Pune 51). Five women from the Ho Chi Minh City site who agreed to participate in the study did not return for misoprostol administration. Of these five women, four women required a surgical completion. The outcome of the fifth woman is unknown. One woman from the Rochester site administered the first dose of misoprostol orally rather than vaginally and subsequently experienced a successful medical abortion. Analysis was conducted on an intent-to-treat basis. Only one woman with unknown abortion outcome was excluded from the analysis.
The sociodemographic characteristics of all study participants are described in Table 1. Women were on average 25 years old (range 16–44 years) and had slightly more than 9 years of education (range 0–18 years). There was a significant difference in the sociodemographic profile of women from the three sites, with women from the Rochester and Pune sites significantly more educated than women from Ho Chi Minh City (P<.001). Women recruited in Ho Chi Minh City and Pune were also significantly more likely to be married than women from Rochester (Ho Chi Minh City 64.5%, Rochester 12.9%, and Pune: 98.0%).
For almost one half of women (46.0%) from the Ho Chi Minh City site, this was their first pregnancy as compared with only about one fifth of women (18.6%) from Rochester and only 6% of women from Pune (P<.001). For most (70.4%) women in the study, this was their first abortion. However, women recruited at the Ho Chi Minh City and Pune sites were significantly more likely to have no history of abortion compared with women from Rochester (Ho Chi Minh City 73.5 %, Rochester: 50.0%, and Pune 86.4%, P<.001). The mean gestational age for women in the study was 71.62 days (standard deviation [SD] 6.58; range 61–87 days) and there was no statistically significant difference in gestational age among the three study sites.
Abortion outcomes are detailed in Table 2. Eighty-nine percent of women who completed the study successfully terminated their pregnancies. There was no statistical difference in the success rates among the three study sites (Ho Chi Minh City 88.9%, Rochester 87.1%, and Pune 92.2%).
More than one half (n=19) of the 35 failures were due to an incomplete abortion. Of the remaining 16 cases, 10 women required a surgical abortion to control bleeding, five women requested a surgical completion, and one woman required a surgical procedure to terminate an ongoing pregnancy. One woman from the Rochester site received a blood transfusion and required hospitalization due to excessive bleeding on day 21 of the study.
After the initial 800 mcg vaginal misoprostol dose, one half (51.4%) of all women received two additional doses of 400 mcg oral misoprostol for a total dose of 1,600 mcg (Fig. 1). There was a statistically significant association between total dose and study site, with more women from Pune and Ho Chi Minh City receiving two or more misoprostol doses than their counterparts in Rochester. (P=.001).
Among all women with a complete abortion, the mean time from the first dose of misoprostol to the passing of the products of conception was approximately 335 minutes (range 75–690 minutes) (data not shown). Although women recruited at the Ho Chi Minh City and Pune sites received a significantly larger misoprostol dose, the mean time to complete abortion was significantly shorter among women recruited in Pune compared with Ho Chi Minh City and Rochester (Ho Chi Minh City 361.9 minutes, range 150–690 minutes; Rochester 312.7 minutes, range 75–600 minutes; and Pune 263.9 minutes, range 110–580 minutes).
Table 3 shows the bleeding and adverse effects recorded by women on their take-home diaries. Women reported on average 9.6 days of any bleeding (including light, normal, and heavy bleeding) (range 0–19 days) with only 2.0 days of heavy bleeding (range 0–11 days). Most women also reported some cramping (mean 3.1 days; range 0–16 days) and nausea (mean 0.87 days; range: 0–9). There were significant differences in reports of almost all adverse effects among study sites. For example, women from Rochester reported significantly longer durations of heavy bleeding, cramps, and nausea than women from the other two sites.
Patient acceptability of adverse effects was assessed both on day 3 or 4 and day 15. At the conclusion of the misoprostol visit, most women found the amount of bleeding very acceptable (13.3%) or acceptable (74.6%). There was a significant difference in acceptability among study sites: 14 of the 18 women who were dissatisfied with the bleeding associated with the procedure were from the Pune site. Women reported a similar assessment at the follow-up visit on day 15, with most women reporting that the bleeding was very acceptable (12.0%) or acceptable (74.7%).
Similarly, at the end of day 3 or 4, most women also found the amount of cramping acceptable (68.6%) or very acceptable (12.4%). When asked again at the follow-up visit, most women also found the cramping very acceptable (15.7%) or acceptable (65.5%) At both visits, women recruited from the Rochester site were more likely then their counterparts in Pune or Ho Chi Minh City to find the amount of cramping unacceptable; 20 of the 36 women who were dissatisfied with the level of cramping on day 3 or 4 were recruited at the Rochester site. Among all three sites, it was equally divided how women reported cramping, ie, less than expected (35.6%), the same as expected (28.6%), or more than expected (35.2%). Again, these reports did not vary from day 3 or 4 to the follow-up visit on day 15.
At the end of the misoprostol visit, women reported a mean pain score of 4.21 (range 1–7). There were no significant differences in the pain levels reported among the three study sites. However, nulligravid women reported experiencing significantly more pain than their multigravid counterparts (nulligravid mean pain 4.68, SD 1.36; multigravid mean pain 3.98 SD 1.58; P=.001). Women were not asked to assess the acceptability of the pain during the procedure on day 15.
The use of pain medications, however, did differ significantly among the three sites. All women from Rochester took analgesics compared with only slightly less than one third (29.7%) of women in Ho Chi Minh City and about one half (48%) of women in Pune. Use of analgesics was not significantly associated with gravidity or gestational age.
At the end of day 3 or 4, women were asked to assess their satisfaction and method preferences (Table 4). Most women were either satisfied (64.8%) or very satisfied (28.6%) with their experiences. Of the 10 women who found the method either unsatisfactory or very unsatisfactory, six women required a surgical intervention before the end of the study.
Almost all (94.6%) women reported that they would recommend the procedure to a friend and also agreed (90.4%) that they would request a medical abortion if they required another abortion at this gestational age. Fewer women in Rochester reported that they would repeat the procedure when compared with their counterparts in Pune and Ho Chi Minh City (Ho Chi Minh City 94.4%; Rochester 72.5%; Pune 96.1%; P=.001).
Women were also asked to compare the acceptability of this procedure with previous abortion procedures. Among those women with a history of abortion (n=95), most (72.6%) found the procedure better than their previous experience. There was, however, a significant association between the study site and women's preferences: 14 of the 16 women who found the procedure worse than their previous experience were from the Rochester site (P 0.001).
The study found a high level of efficacy of medical abortion at 64 to 84 days of gestation. Most (90.2%) women successfully terminated their pregnancies. Other studies have demonstrated a similar efficacy rate with a comparable protocol at later gestational ages.8,9 This study found a slight although not statistically significant difference in efficacy among the three sites (Ho Chi Minh City 88.9%; Rochester 87.1%; Pune 92.2%). These differences may be attributed to differences in the number of misoprostol doses administered at each site, ie, women recruited at the Rochester site were less likely to receive a second or third dose of misoprostol, whereas women recruited at the Pune site were more likely to receive the third additional dose of misoprostol. In Rochester, women were monitored closely by ultrasonography because the machine was readily available, and women who passed the pregnancy were not given an additional dose. Women recruited at the Pune site were kept at the clinic overnight for observation and thus more likely to receive an additional dose of misoprostol to control bleeding.
In general, most women found the level of bleeding and cramping associated with the procedure acceptable. There were, however, significant differences among the three study sites regarding the acceptability of specific adverse effects such as bleeding and cramping. Although there was no significant association between recruitment site and reports of pain, pain reports of nulligravida compared with multigravida did differ significantly. Other studies have also found that women with a previous live birth were significantly less likely to use analgesia.14 Our study, however, did not find a significant association between parity and use of analgesia. Rather study site was a better predictor of the use of analgesia than any specific sociodemographic characteristics such as parity, gestational age, or age. A recent literature review on treatment of pain during medical abortion also found that differences in use of analgesics during medical abortion were likely to be due to differences in policies for offering medication rather than differences in patient characteristics.15
Overall, most women were satisfied with the method and would recommend the procedure to a friend or choose the same method again if they required another abortion at this gestational age. However, women who participated in this study were not randomly assigned but elected to participate by virtue of their interest in a medical pregnancy abortion. Previous studies have found that women who are able to choose the method of termination are more likely to be satisfied with their procedure, regardless of the type of procedure selected.16 That said, as shown in previous studies of medical abortion at earlier gestational ages, we found a significant association between method failure and acceptability.17 Even if women are allowed to select their method of pregnancy termination, their assessment of the acceptability of a procedure will be greatly determined by the method's effectiveness.
In conclusion, our study has shown that mifepristone and misoprostol in repeated doses at 24–48 hours later, is an acceptable and effective means of abortion in the late first trimester. This procedure offers women and health care providers a valuable alternative to surgical abortion, further decreasing the need for surgery and anesthesia.
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