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Induction of second trimester abortion (12–20 weeks) with mifepristone and misoprostol: a review of 386 consecutive cases
Contraception 73 (2006) 516 – 519
Original research article
Induction of second trimester abortion (12–20 weeks) with mifepristone and misoprostol: a review of 386 consecutive cases Sin Ee Goh, Kok Joo Thong4 Edinburgh Fertility and Reproductive Endocrine Centre, Royal Infirmary of Edinburgh, Little France, EH16 4SA Edinburgh, UK Received 16 September 2005; revised 22 November 2005; accepted 13 December 2005
Abstract Design: A retrospective analysis of 386 women who underwent termination of pregnancy between 12 and 24 weeks’ gestation. Methods: Each woman received 200 mg mifepristone orally followed by vaginal misoprostol 800 Ag 36 to 48 h later. Three hours after the initial misoprostol administration, 400-Ag doses of vaginal misoprostol were administered every 3 h, to a maximum of four doses in 24 h. If abortion failed, 200 mg mifepristone is given again 3 h after the last misoprostol dose, followed by 12 h of rest before vaginal misoprostol administration is repeated as per previous course of treatment. Results: Overall, 97.9% and 99.5% of the women aborted within 24 and 36 h, respectively. The median induction-to-abortion interval was 6.7 h (range: 1.4–73.8 h), and nulliparous women took significantly longer time to abort (6.0 h in multiparous women compared to 7.6 h in nulliparous women; p b .0001). One woman failed to abort within 48 h. Surgical evacuation of the uterus was performed in 5% of women for incomplete abortion or retained placenta. Multiparous women were less likely to need analgesic administration for pain relief, and to experience vomiting and diarrhea, than nulliparous women. Conclusion: The combination of 200 mg mifepristone and vaginally administered misoprostol is a safe, effective and noninvasive regimen for termination of pregnancy between 12 and 20 weeks. D 2006 Elsevier Inc. All rights reserved. Keywords: Mifepristone; Misoprostol; Second trimester; Labour induction abortion
1. Introduction For more than two decades, prostaglandins or their analogues have been used frequently for medical abortion. This method has proved to be a safe alternative to surgical termination of pregnancy [1]. There are different types of prostaglandin analogues that can be used for second trimester medical abortion. The two most commonly used prostaglandin analogues, gemeprost and misoprostol, have both been shown to be safe and effective when combined with mifepristone [2–5]. Since only the former was licensed for the purpose of medical abortion, it was more widely used in the past. However, as compared to misoprostol, gemeprost is expensive and requires specific conditions for storage and transfer [6].
4 Corresponding author. Tel.: +44 131 242 2443/6; fax: +44 131 242 2447. E-mail address: [email protected] (K.J. Thong). 0010-7824/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2005.12.004
Therefore, in recent years, there is a trend to use misoprostol for second trimester abortion. Misoprostol is a synthetic analogue of naturally occurring prostaglandin E1. It is used for prophylaxis and treatment of gastroduodenal ulcers [7]. Due to its uterotonic effect, it is contraindicated in pregnancy. Unlike gemeprost, it can be taken orally and is associated with fewer gastrointestinal side effects [8]. The use of mifepristone, a progesterone receptor blocker, prior to second trimester abortion with prostaglandin has been shown to significantly reduce the time between the first administration of a prostaglandin to expulsion of the fetus [9,10]. This antigestagen targets cells of the endometrium and myometrium and sensitizes the pregnant uterus to exogenous prostaglandin. It has been demonstrated that a dose of 200 mg mifepristone is sufficient for this purpose without the loss of efficacy [8,11]. It has been reported previously that the combination of oral mifepristone 200 mg followed by vaginally and orally administered misoprostol provides a noninvasive and
S.E. Goh, K.J. Thong / Contraception 73 (2006) 516 – 519
effective regimen for first and mid-trimester termination of pregnancy [3,12]. The purpose of this study is to report the effectiveness and safety of this regimen in clinical practice over a period of 2.5 years in Edinburgh. 2. Materials and methods Three-hundred and eighty-six consecutive women admitted to the Edinburgh Royal Infirmary for abortion with gestational age of 12–20 weeks’ gestation between February 2002 and August 2004 were studied. A database was set up to collect the data of all women undergoing termination of pregnancy during this study period. Abortion was carried out under the conditions of the 1967 United Kingdom Abortion Act. Women admitted were either referred by their general practitioners, the family planning unit or Caledonian Youth. The gestational age was determined by menstrual history and clinical examination, and ultrasound was performed only if necessary as judged by the attending doctor. After the decision to terminate the pregnancy was made, the women were referred to the Medical Termination Unit in the hospital where they were counselled prior to the abortion. Since the combined use of mifepristone and misoprostol is not licensed for use in termination of pregnancy, women were required to sign a consent form for the procedure. The women were given a single dose of 200 mg oral mifepristone in the Medical Termination Unit. After the mifepristone administration, they were then allowed home and were admitted to the unit 36 to 48 h later when 800 Ag of misoprostol (four tablets) was inserted into the posterior vaginal fornix. Subsequently, 400 Ag of vaginal misoprostol was administered every 3 h for a maximum of four doses in 24 h. If abortion had not occurred, a second course of treatment was to be started. In this course, an oral dose of 200 mg mifepristone was given again 3 h after the last dose of misoprostol (i.e., 15 h after the first dose of misoprostol), and the women were allowed to rest for 12 h before repeating misoprostol administration as per the first course. That is, an initial dose of 800 Ag vaginal misoprostol, and 3 h later, 400 Ag misoprostol at 3-h intervals, up to a maximum dose of four doses for that day. If a woman has significant vaginal bleeding (hemorrhagic shock or requiring blood transfusion) before the administration of misoprostol, dilatation and evacuation would have to be carried out in accordance with the Centre’s protocol. Alternatively, if a woman failed to expel the conceptus after the two courses of treatment, we will discuss with her the alternative use of mifepristone and gemeprost (further dose of mifepristone 200 mg and subsequent use of gemeprost 1 mg [2]) for abortion. This will commence after an agreed interval of 48 h after the last administered dose of misoprostol. Analgesia [intramuscular (im) diamorphine 10 mg 3- to 4-hourly] was given if required. Antiemetic drugs for vomiting (metoclopramide 10 mg 8-hourly or cyclizine
517
50 mg 8-hourly) and diarrhea (codeine phosphate 30 mg) were also administered as required. Successful termination was defined as abortion occurring within 48 h of administration of the first dose of misoprostol. The expelled fetus and placenta were examined by the attending nurse for completeness. Surgical evacuation of the uterus was carried out if there was clinical evidence of retained placenta tissue or suspicion of incomplete abortion. It is our policy to carry out surgical evacuation if blood loss was more than 500 ml at the time of expulsion of the fetus/placenta. The program GraphPad Prism 4.0 for Windows was used for statistical analysis of continuous variables using the Mann–Whitney U test. Chi-square tests were used for the analysis of noncontinuous variables. A pb .05 was considered significant. 3. Results Table 1 shows the characteristics of the 386 women who underwent second trimester abortion, and Table 2 shows the treatment outcomes for these women. Two women (0.5%) aborted after 200 mg mifepristone without misoprostol. One of them was a nulliparous woman (33 years old) at 14 weeks of gestation, and the other woman (20 years old), at 15 weeks of gestation, had a previous delivery and two previous abortions. Neither of them had excessive bleeding, and curettage was not performed. Following the first administration of misoprostol, 43.2% and 63.8% of women aborted within 6 and 8 h, and 86.2% and 97.9% aborted within 12 and 24 h, respectively. Only two women (0.5%) did not abort within 36 h. One woman failed to abort within 48 h after administration of the first dose of misoprostol. She was 14 weeks pregnant and had two previous vaginal deliveries. She was given 6000 Ag of misoprostol over a period of 72 h and was subsequently given two doses of 1 mg gemeprost. The placenta was expelled after 73.8 h after the administration of the first dose of misoprostol, and she required a surgical evacuation. In this study, the treatment outcomes of women (n =93) who underwent termination between 12 and 14 weeks’ gestation were analysed. There is no significant difference in the dose of misoprostol used, induction–abortion time and need for surgical evacuation of the uterus between nulliparous (n = 40) women and multiparous (n =53) women undergoing Table 1 Characteristics of the women who underwent mid-trimester abortion Characteristics
Median age in years (range) Median gestational age in weeks (range)
Parity
Total (N = 386)
Nulliparous (n = 193)
Multiparous (n = 193)
204 (13–42)
264 (16–44)
22 (13–44)
16 (12–20)
15 (13–20)
16 (12–20)
4 Significant difference by Mann–Whitney U test, p b .0001.
518
S.E. Goh, K.J. Thong / Contraception 73 (2006) 516 – 519
Table 2 Treatment outcomes by parity Parity
Median dose of misoprostol in micrograms (range) Median induction– abortion time, in hours (range) Surgical evacuation of uterus (%)
Total (N = 386)
p
Nulliparous (n = 193)
Multiparous (n = 193)
1600 (800–4400)
1200 (800–4000)
1500 (800–4400)
7.6 (1.5–38.2)
6.0 (1.4–73.8)
6.7 (1.4–73.8)
b .0001
7 (3.6)
13 (6.7)
19 (5.0)
V .20
.0004
this regime. One hundred percent of nulliparous women and 96.2% of multiparous women in this gestation group aborted within 24 h of misoprostol administration. Overall, 3.2% (n = 3) of these women needed surgical evacuation of the uterus and 97.8% (n = 91) of them aborted within 24 h. Data on analgesic use were recorded for 383 women. Of these patients, 76.2% needed diamorphine for pain relief. Significantly less multiparous women required diamorphine administration than nulliparous women (63.9% vs. 88.5%; p b.001). Ten women (5.2%) required more than two doses of 10 mg i.m. diamorphine administration in the nulliparous group, as compared to only four women in the multiparous group (2.1%). Since two women aborted before the administration of misoprostol, they were excluded in the data analysis for side effects. The incidence of vomiting was higher than that of diarrhea for this regimen (37.8% for vomiting compared to 2.7% for diarrhea). Multiparous women had significantly less gastrointestinal side effects than nulliparous women, with the percentages of both vomiting and diarrhea lower than those of nulliparous women (25.5% vs. 50.0% for vomiting, pb .001; and 1.0% vs. 4.7% for diarrhea, p b.05, respectively). 4. Discussion This study confirms the efficacy of this combination of mifepristone and misoprostol regimen for termination of pregnancy between 12 and 20 weeks’ gestation. The median induction-to-abortion interval (6.7 h) is comparable to previous studies using this combination [3,6,11]. The complete abortion rate of 95.0% in this study is comparable to previous studies using mifepristone and misoprostol (95.7%) [11]. The regimen used in our study is similar to a previous study by Ashok and Templeton [3] in Aberdeen except that we gave four doses of 400 Ag misoprostol in the second course of treatment, whereas the former gave five doses in their study. In a previous study reported from our center, surgical evacuation of the uterus following second trimester abortion may be needed in up to 80% of women [10]. In this study, only 5.0% of the women required surgical evacuation of the
uterus for incomplete abortion or retained placenta tissue. This is lower than that reported in other reports that adopted a similar regimen (9.4%) [3] or with mifepristone and gemeprost (33% and 11%, respectively) [2,13]. Our rationale for surgical evacuation of retained placenta tissue is to reduce the potential risk of prolonged or major haemorrhage and endometritis if a large piece of placenta is not removed. In our centre, we now base the diagnosis of retained placenta tissue or incomplete abortion on clinical grounds, and more women underwent evacuation of uterus in the past when scanning was carried out. In accordance with previous reports, the response of multiparous women was different from nulliparous women following treatment with mifepristone and a prostaglandin analogue [2]. The induction-to-abortion interval was significantly shorter in multiparous women (6.0 h) than in nulliparous women (7.6 h). They also require a significantly lower dose of misoprostol compared to nulliparous women. This can be explained by the difference in the compliance of the cervix in the two groups. In contrast, multiparous women (6.7%) had a higher incidence of surgical evacuation than nulliparous women (3.6%). The reason for this is unknown, but this observation was reported in another study of second trimester termination of pregnancy using gemeprost carried out in our center [13]. A possible reason for this might be the more efficient establishment of pregnancy in multiparous women [14]. The high percentage of successful abortion within 24 h (97.9%) and low incidence of surgical evacuation (3.2%) for women between 12 and 14 weeks’ gestation show that this regimen is effective for abortion for women of this gestational age. Our hospital is the main tertiary center for gynecological emergencies in our catchment area, and if these women had any complications, they would have been readmitted. The use of mifepristone and misoprostol is therefore a safe alternative for dilatation and evacuation of second trimester pregnancy if there is lack of skilled personnel to carry out the dilatation and evacuation. This study also demonstrated a higher incidence of vomiting in nulliparous (50%) women than in multiparous women (25.5%) as compared to a previous study with gemeprost [10]. It has been reported that vomiting is unlikely to be due to the administration of prostaglandin alone, but may also be related to the diamorphine administration [2]. This could possibly explain the higher incidence of vomiting in nulliparous women, as a higher proportion was administered diamorphine for pain relief. In nulliparous women (4.7%), the incidence of diarrhea was higher than in multiparous women (1.0%). This is most likely to be due to the use of higher dose of prostaglandin for termination of pregnancy. The incidence of diarrhea (2.7%) is lower than that using gemeprost (5%) [2]. A weakness in this retrospective study is that we did not follow up 100% of all our patients. However, in the United Kingdom, individual patients are registered under general practitioners (physicians in the community) who work
S.E. Goh, K.J. Thong / Contraception 73 (2006) 516 – 519
closely with our centre. If there were serious complications, the general practitioners would contact us as our centre is the only centre in our catchment area of 1 million carrying out mid-trimester abortion. It is recognized that second trimester abortion is an important problem in developing countries, where access to medical services and resources is limited, and the skill and expertise to carry out safe dilatation and evacuation may not always be available. The availability of a medical treatment using agents that do not incur a high cost in storage and transport makes provision of safe abortion feasible in Third World countries [3,6,15]. The regimen described is a costeffective method for second trimester termination of pregnancy as compared to the previous regimen adopted using gemeprost. This is because the latter is more expensive (o21.00 per milligram) and requires cold storage. Misoprostol, on the other hand, is less expensive (approximately o0.80 for 800 Ag) and can be administered orally, which may be preferred by some women and cultures. In conclusion, the combination of oral mifepristone 200 mg followed by vaginally administered misoprostol is a safe, effective and noninvasive regimen termination of pregnancy between 12 and 20 weeks’ gestation. Acknowledgment We would like to thank the medical and nursing staff at the Bruntsfield Suite in the New Royal Infirmary of Edinburgh for their help in this study. We would also like to thank Dr. A Colin Duncan and Dr. Nirmala Mary for their statistical support. References [1] Karim SMM, Filshie GM. Therapeutic abortion using PCF2a. Lancet 1970;I:157 – 9.
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[2] Thong KJ, Baird DT. Induction of second trimester abortion with mifepristone and gemeprost. Br J Obstet Gynaecol 1993;100: 758 – 61. [3] Ashok PW, Templeton A. Nonsurgical mid-trimester termination of pregnancy: a review of 500 consecutive cases. Br J Obstet Gynaecol 1999;106:706 – 10. [4] Gemzell-Danielsson K, Ostlund E. Termination of second trimester pregnancy with mifepristone and gemeprost. The clinical experience of 197 cases. Acta Obstet Gynaecol Scand 2000;79:702 – 6. [5] El-Refaey H, Hinshaw K, Templeton A. The abortifacient effect of misoprostol in the second trimester. Hum Reprod 1993;8:1744 – 6. [6] El-Refaey H, Templeton A. Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: a randomized comparison between two misoprostol regimens. Hum Reprod 1995;10:475 – 8. [7] Collins PW. Misoprostol: discovery, development, and clinical applications. Med Res Rev 1990;10:149 – 72. [8] McKinley C, Thong KJ, Baird DT. The effect of dose of mifepristone and gestation on the efficacy of medical abortion with mifepristone and misoprostol. Hum Reprod 1993;8:1502 – 5. [9] Urquhart DR, Templeton A. The use of mifepristone prior to prostaglandin induced mid-trimester termination. Hum Reprod 1990;5:883 – 6. [10] Rodger MT, Baird DT. Pre-treatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. Br J Obstet Gynaecol 1990;97:41 – 5. [11] Webster D, Penney GC, Templeton A. A comparison of 600 and 200 mg mifepristone prior to second trimester abortion with prostaglandin misoprostol. Br J Obstet Gynaecol 1996;103:706 – 9. [12] Thong KJ, Baird DT. Induction of abortion with mifepristone and misoprostol in early pregnancy. Br J Obstet Gynaecol 1992;99: 1004 – 7. [13] Tang OS, Thong KJ, Baird DT. Second trimester medical abortion with mifepristone and gemeprost: a review of 956 cases. Contraception 2001;64:29 – 32. [14] Bartley J, Tong S, Everington D, Baird DT. Parity is a major determinant of success rate in medical abortion: a retrospective analysis of 3161 consecutive cases of early medical abortion treated with reduced doses of mifepristone and vaginal gemeprost. Contraception 2000;62:297 – 303. [15] Ashok PW, Penney GC, Flett GMM, Templeton A. An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum Reprod 1998;13:2962 – 5.
Original research article
Induction of second trimester abortion (12–20 weeks) with mifepristone and misoprostol: a review of 386 consecutive cases Sin Ee Goh, Kok Joo Thong4 Edinburgh Fertility and Reproductive Endocrine Centre, Royal Infirmary of Edinburgh, Little France, EH16 4SA Edinburgh, UK Received 16 September 2005; revised 22 November 2005; accepted 13 December 2005
Abstract Design: A retrospective analysis of 386 women who underwent termination of pregnancy between 12 and 24 weeks’ gestation. Methods: Each woman received 200 mg mifepristone orally followed by vaginal misoprostol 800 Ag 36 to 48 h later. Three hours after the initial misoprostol administration, 400-Ag doses of vaginal misoprostol were administered every 3 h, to a maximum of four doses in 24 h. If abortion failed, 200 mg mifepristone is given again 3 h after the last misoprostol dose, followed by 12 h of rest before vaginal misoprostol administration is repeated as per previous course of treatment. Results: Overall, 97.9% and 99.5% of the women aborted within 24 and 36 h, respectively. The median induction-to-abortion interval was 6.7 h (range: 1.4–73.8 h), and nulliparous women took significantly longer time to abort (6.0 h in multiparous women compared to 7.6 h in nulliparous women; p b .0001). One woman failed to abort within 48 h. Surgical evacuation of the uterus was performed in 5% of women for incomplete abortion or retained placenta. Multiparous women were less likely to need analgesic administration for pain relief, and to experience vomiting and diarrhea, than nulliparous women. Conclusion: The combination of 200 mg mifepristone and vaginally administered misoprostol is a safe, effective and noninvasive regimen for termination of pregnancy between 12 and 20 weeks. D 2006 Elsevier Inc. All rights reserved. Keywords: Mifepristone; Misoprostol; Second trimester; Labour induction abortion
1. Introduction For more than two decades, prostaglandins or their analogues have been used frequently for medical abortion. This method has proved to be a safe alternative to surgical termination of pregnancy [1]. There are different types of prostaglandin analogues that can be used for second trimester medical abortion. The two most commonly used prostaglandin analogues, gemeprost and misoprostol, have both been shown to be safe and effective when combined with mifepristone [2–5]. Since only the former was licensed for the purpose of medical abortion, it was more widely used in the past. However, as compared to misoprostol, gemeprost is expensive and requires specific conditions for storage and transfer [6].
4 Corresponding author. Tel.: +44 131 242 2443/6; fax: +44 131 242 2447. E-mail address: [email protected] (K.J. Thong). 0010-7824/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2005.12.004
Therefore, in recent years, there is a trend to use misoprostol for second trimester abortion. Misoprostol is a synthetic analogue of naturally occurring prostaglandin E1. It is used for prophylaxis and treatment of gastroduodenal ulcers [7]. Due to its uterotonic effect, it is contraindicated in pregnancy. Unlike gemeprost, it can be taken orally and is associated with fewer gastrointestinal side effects [8]. The use of mifepristone, a progesterone receptor blocker, prior to second trimester abortion with prostaglandin has been shown to significantly reduce the time between the first administration of a prostaglandin to expulsion of the fetus [9,10]. This antigestagen targets cells of the endometrium and myometrium and sensitizes the pregnant uterus to exogenous prostaglandin. It has been demonstrated that a dose of 200 mg mifepristone is sufficient for this purpose without the loss of efficacy [8,11]. It has been reported previously that the combination of oral mifepristone 200 mg followed by vaginally and orally administered misoprostol provides a noninvasive and
S.E. Goh, K.J. Thong / Contraception 73 (2006) 516 – 519
effective regimen for first and mid-trimester termination of pregnancy [3,12]. The purpose of this study is to report the effectiveness and safety of this regimen in clinical practice over a period of 2.5 years in Edinburgh. 2. Materials and methods Three-hundred and eighty-six consecutive women admitted to the Edinburgh Royal Infirmary for abortion with gestational age of 12–20 weeks’ gestation between February 2002 and August 2004 were studied. A database was set up to collect the data of all women undergoing termination of pregnancy during this study period. Abortion was carried out under the conditions of the 1967 United Kingdom Abortion Act. Women admitted were either referred by their general practitioners, the family planning unit or Caledonian Youth. The gestational age was determined by menstrual history and clinical examination, and ultrasound was performed only if necessary as judged by the attending doctor. After the decision to terminate the pregnancy was made, the women were referred to the Medical Termination Unit in the hospital where they were counselled prior to the abortion. Since the combined use of mifepristone and misoprostol is not licensed for use in termination of pregnancy, women were required to sign a consent form for the procedure. The women were given a single dose of 200 mg oral mifepristone in the Medical Termination Unit. After the mifepristone administration, they were then allowed home and were admitted to the unit 36 to 48 h later when 800 Ag of misoprostol (four tablets) was inserted into the posterior vaginal fornix. Subsequently, 400 Ag of vaginal misoprostol was administered every 3 h for a maximum of four doses in 24 h. If abortion had not occurred, a second course of treatment was to be started. In this course, an oral dose of 200 mg mifepristone was given again 3 h after the last dose of misoprostol (i.e., 15 h after the first dose of misoprostol), and the women were allowed to rest for 12 h before repeating misoprostol administration as per the first course. That is, an initial dose of 800 Ag vaginal misoprostol, and 3 h later, 400 Ag misoprostol at 3-h intervals, up to a maximum dose of four doses for that day. If a woman has significant vaginal bleeding (hemorrhagic shock or requiring blood transfusion) before the administration of misoprostol, dilatation and evacuation would have to be carried out in accordance with the Centre’s protocol. Alternatively, if a woman failed to expel the conceptus after the two courses of treatment, we will discuss with her the alternative use of mifepristone and gemeprost (further dose of mifepristone 200 mg and subsequent use of gemeprost 1 mg [2]) for abortion. This will commence after an agreed interval of 48 h after the last administered dose of misoprostol. Analgesia [intramuscular (im) diamorphine 10 mg 3- to 4-hourly] was given if required. Antiemetic drugs for vomiting (metoclopramide 10 mg 8-hourly or cyclizine
517
50 mg 8-hourly) and diarrhea (codeine phosphate 30 mg) were also administered as required. Successful termination was defined as abortion occurring within 48 h of administration of the first dose of misoprostol. The expelled fetus and placenta were examined by the attending nurse for completeness. Surgical evacuation of the uterus was carried out if there was clinical evidence of retained placenta tissue or suspicion of incomplete abortion. It is our policy to carry out surgical evacuation if blood loss was more than 500 ml at the time of expulsion of the fetus/placenta. The program GraphPad Prism 4.0 for Windows was used for statistical analysis of continuous variables using the Mann–Whitney U test. Chi-square tests were used for the analysis of noncontinuous variables. A pb .05 was considered significant. 3. Results Table 1 shows the characteristics of the 386 women who underwent second trimester abortion, and Table 2 shows the treatment outcomes for these women. Two women (0.5%) aborted after 200 mg mifepristone without misoprostol. One of them was a nulliparous woman (33 years old) at 14 weeks of gestation, and the other woman (20 years old), at 15 weeks of gestation, had a previous delivery and two previous abortions. Neither of them had excessive bleeding, and curettage was not performed. Following the first administration of misoprostol, 43.2% and 63.8% of women aborted within 6 and 8 h, and 86.2% and 97.9% aborted within 12 and 24 h, respectively. Only two women (0.5%) did not abort within 36 h. One woman failed to abort within 48 h after administration of the first dose of misoprostol. She was 14 weeks pregnant and had two previous vaginal deliveries. She was given 6000 Ag of misoprostol over a period of 72 h and was subsequently given two doses of 1 mg gemeprost. The placenta was expelled after 73.8 h after the administration of the first dose of misoprostol, and she required a surgical evacuation. In this study, the treatment outcomes of women (n =93) who underwent termination between 12 and 14 weeks’ gestation were analysed. There is no significant difference in the dose of misoprostol used, induction–abortion time and need for surgical evacuation of the uterus between nulliparous (n = 40) women and multiparous (n =53) women undergoing Table 1 Characteristics of the women who underwent mid-trimester abortion Characteristics
Median age in years (range) Median gestational age in weeks (range)
Parity
Total (N = 386)
Nulliparous (n = 193)
Multiparous (n = 193)
204 (13–42)
264 (16–44)
22 (13–44)
16 (12–20)
15 (13–20)
16 (12–20)
4 Significant difference by Mann–Whitney U test, p b .0001.
518
S.E. Goh, K.J. Thong / Contraception 73 (2006) 516 – 519
Table 2 Treatment outcomes by parity Parity
Median dose of misoprostol in micrograms (range) Median induction– abortion time, in hours (range) Surgical evacuation of uterus (%)
Total (N = 386)
p
Nulliparous (n = 193)
Multiparous (n = 193)
1600 (800–4400)
1200 (800–4000)
1500 (800–4400)
7.6 (1.5–38.2)
6.0 (1.4–73.8)
6.7 (1.4–73.8)
b .0001
7 (3.6)
13 (6.7)
19 (5.0)
V .20
.0004
this regime. One hundred percent of nulliparous women and 96.2% of multiparous women in this gestation group aborted within 24 h of misoprostol administration. Overall, 3.2% (n = 3) of these women needed surgical evacuation of the uterus and 97.8% (n = 91) of them aborted within 24 h. Data on analgesic use were recorded for 383 women. Of these patients, 76.2% needed diamorphine for pain relief. Significantly less multiparous women required diamorphine administration than nulliparous women (63.9% vs. 88.5%; p b.001). Ten women (5.2%) required more than two doses of 10 mg i.m. diamorphine administration in the nulliparous group, as compared to only four women in the multiparous group (2.1%). Since two women aborted before the administration of misoprostol, they were excluded in the data analysis for side effects. The incidence of vomiting was higher than that of diarrhea for this regimen (37.8% for vomiting compared to 2.7% for diarrhea). Multiparous women had significantly less gastrointestinal side effects than nulliparous women, with the percentages of both vomiting and diarrhea lower than those of nulliparous women (25.5% vs. 50.0% for vomiting, pb .001; and 1.0% vs. 4.7% for diarrhea, p b.05, respectively). 4. Discussion This study confirms the efficacy of this combination of mifepristone and misoprostol regimen for termination of pregnancy between 12 and 20 weeks’ gestation. The median induction-to-abortion interval (6.7 h) is comparable to previous studies using this combination [3,6,11]. The complete abortion rate of 95.0% in this study is comparable to previous studies using mifepristone and misoprostol (95.7%) [11]. The regimen used in our study is similar to a previous study by Ashok and Templeton [3] in Aberdeen except that we gave four doses of 400 Ag misoprostol in the second course of treatment, whereas the former gave five doses in their study. In a previous study reported from our center, surgical evacuation of the uterus following second trimester abortion may be needed in up to 80% of women [10]. In this study, only 5.0% of the women required surgical evacuation of the
uterus for incomplete abortion or retained placenta tissue. This is lower than that reported in other reports that adopted a similar regimen (9.4%) [3] or with mifepristone and gemeprost (33% and 11%, respectively) [2,13]. Our rationale for surgical evacuation of retained placenta tissue is to reduce the potential risk of prolonged or major haemorrhage and endometritis if a large piece of placenta is not removed. In our centre, we now base the diagnosis of retained placenta tissue or incomplete abortion on clinical grounds, and more women underwent evacuation of uterus in the past when scanning was carried out. In accordance with previous reports, the response of multiparous women was different from nulliparous women following treatment with mifepristone and a prostaglandin analogue [2]. The induction-to-abortion interval was significantly shorter in multiparous women (6.0 h) than in nulliparous women (7.6 h). They also require a significantly lower dose of misoprostol compared to nulliparous women. This can be explained by the difference in the compliance of the cervix in the two groups. In contrast, multiparous women (6.7%) had a higher incidence of surgical evacuation than nulliparous women (3.6%). The reason for this is unknown, but this observation was reported in another study of second trimester termination of pregnancy using gemeprost carried out in our center [13]. A possible reason for this might be the more efficient establishment of pregnancy in multiparous women [14]. The high percentage of successful abortion within 24 h (97.9%) and low incidence of surgical evacuation (3.2%) for women between 12 and 14 weeks’ gestation show that this regimen is effective for abortion for women of this gestational age. Our hospital is the main tertiary center for gynecological emergencies in our catchment area, and if these women had any complications, they would have been readmitted. The use of mifepristone and misoprostol is therefore a safe alternative for dilatation and evacuation of second trimester pregnancy if there is lack of skilled personnel to carry out the dilatation and evacuation. This study also demonstrated a higher incidence of vomiting in nulliparous (50%) women than in multiparous women (25.5%) as compared to a previous study with gemeprost [10]. It has been reported that vomiting is unlikely to be due to the administration of prostaglandin alone, but may also be related to the diamorphine administration [2]. This could possibly explain the higher incidence of vomiting in nulliparous women, as a higher proportion was administered diamorphine for pain relief. In nulliparous women (4.7%), the incidence of diarrhea was higher than in multiparous women (1.0%). This is most likely to be due to the use of higher dose of prostaglandin for termination of pregnancy. The incidence of diarrhea (2.7%) is lower than that using gemeprost (5%) [2]. A weakness in this retrospective study is that we did not follow up 100% of all our patients. However, in the United Kingdom, individual patients are registered under general practitioners (physicians in the community) who work
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closely with our centre. If there were serious complications, the general practitioners would contact us as our centre is the only centre in our catchment area of 1 million carrying out mid-trimester abortion. It is recognized that second trimester abortion is an important problem in developing countries, where access to medical services and resources is limited, and the skill and expertise to carry out safe dilatation and evacuation may not always be available. The availability of a medical treatment using agents that do not incur a high cost in storage and transport makes provision of safe abortion feasible in Third World countries [3,6,15]. The regimen described is a costeffective method for second trimester termination of pregnancy as compared to the previous regimen adopted using gemeprost. This is because the latter is more expensive (o21.00 per milligram) and requires cold storage. Misoprostol, on the other hand, is less expensive (approximately o0.80 for 800 Ag) and can be administered orally, which may be preferred by some women and cultures. In conclusion, the combination of oral mifepristone 200 mg followed by vaginally administered misoprostol is a safe, effective and noninvasive regimen termination of pregnancy between 12 and 20 weeks’ gestation. Acknowledgment We would like to thank the medical and nursing staff at the Bruntsfield Suite in the New Royal Infirmary of Edinburgh for their help in this study. We would also like to thank Dr. A Colin Duncan and Dr. Nirmala Mary for their statistical support. References [1] Karim SMM, Filshie GM. Therapeutic abortion using PCF2a. Lancet 1970;I:157 – 9.
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[2] Thong KJ, Baird DT. Induction of second trimester abortion with mifepristone and gemeprost. Br J Obstet Gynaecol 1993;100: 758 – 61. [3] Ashok PW, Templeton A. Nonsurgical mid-trimester termination of pregnancy: a review of 500 consecutive cases. Br J Obstet Gynaecol 1999;106:706 – 10. [4] Gemzell-Danielsson K, Ostlund E. Termination of second trimester pregnancy with mifepristone and gemeprost. The clinical experience of 197 cases. Acta Obstet Gynaecol Scand 2000;79:702 – 6. [5] El-Refaey H, Hinshaw K, Templeton A. The abortifacient effect of misoprostol in the second trimester. Hum Reprod 1993;8:1744 – 6. [6] El-Refaey H, Templeton A. Induction of abortion in the second trimester by a combination of misoprostol and mifepristone: a randomized comparison between two misoprostol regimens. Hum Reprod 1995;10:475 – 8. [7] Collins PW. Misoprostol: discovery, development, and clinical applications. Med Res Rev 1990;10:149 – 72. [8] McKinley C, Thong KJ, Baird DT. The effect of dose of mifepristone and gestation on the efficacy of medical abortion with mifepristone and misoprostol. Hum Reprod 1993;8:1502 – 5. [9] Urquhart DR, Templeton A. The use of mifepristone prior to prostaglandin induced mid-trimester termination. Hum Reprod 1990;5:883 – 6. [10] Rodger MT, Baird DT. Pre-treatment with mifepristone (RU 486) reduces interval between prostaglandin administration and expulsion in second trimester abortion. Br J Obstet Gynaecol 1990;97:41 – 5. [11] Webster D, Penney GC, Templeton A. A comparison of 600 and 200 mg mifepristone prior to second trimester abortion with prostaglandin misoprostol. Br J Obstet Gynaecol 1996;103:706 – 9. [12] Thong KJ, Baird DT. Induction of abortion with mifepristone and misoprostol in early pregnancy. Br J Obstet Gynaecol 1992;99: 1004 – 7. [13] Tang OS, Thong KJ, Baird DT. Second trimester medical abortion with mifepristone and gemeprost: a review of 956 cases. Contraception 2001;64:29 – 32. [14] Bartley J, Tong S, Everington D, Baird DT. Parity is a major determinant of success rate in medical abortion: a retrospective analysis of 3161 consecutive cases of early medical abortion treated with reduced doses of mifepristone and vaginal gemeprost. Contraception 2000;62:297 – 303. [15] Ashok PW, Penney GC, Flett GMM, Templeton A. An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum Reprod 1998;13:2962 – 5.