European Journal of Obstetrics & Gynecology and Reproductive Biology 171 (2013) 291–294
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European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
A pilot study on the combined use of letrozole, mifepristone and misoprostol in termination of first trimester pregnancy up to 9 weeks’ gestation Joyce Chai *, Pak-Chung Ho Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong Special Administrative Region
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 June 2013 Received in revised form 20 August 2013 Accepted 16 September 2013
Objective: To assess the feasibility of adding letrozole to the standard regimen of mifepristone and misoprostol for termination of pregnancy up to 63 days. Study design: We recruited 50 subjects who had requested legal termination of pregnancy up to 63 days. Medical abortion was performed with a singe dose of 200 mg mifepristone and 10 mg of letrozole daily for 3 days followed by 800 mcg vaginal misoprostol. Results: The complete abortion rate was 98% (95% CI: 94–100%). The median induction-to-abortion interval of the regimen was 5.1 h (range 1.2–56 h). No serious adverse effects were reported. Conclusions: The results of this pilot study suggest that a regimen of mifepristone, letrozole and misoprostol is associated with a high complete abortion rate without major adverse events. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Letrozole Mifepristone Misoprostol Termination of pregnancy
1. Introduction After mifepristone was approved by the United States Food and Drug Administration in 2000, the combination of mifepristone and vaginal use of misoprostol became almost a standard of care in early medical abortion up to 63 days of gestation [1,2]. Misoprostol, a synthetic analogue of naturally occurring prostaglandin E1, has a uterotonic effect and it can stimulate myometrial contraction and cause cervical ripening and dilatation. Progesterone maintains the uterus in a quiescent state by inducing hyperpolarization of the membrane of the myometrial cells, and a greater change in electric potential is necessary before contractions can occur [3]. Mifepristone is an anti-progestin that binds to the progesterone receptors and prevents endogenous progesterone from exerting its effects [4]. It can also increase the sensitivity of the uterus to prostaglandins. The complete abortion rate achieved with this sequential regimen has been found to be up to 93–95% [5,6], which is higher than the rate achieved with either mifepristone or misoprostol alone. Oestrogen is another important hormone for the maintenance of pregnancy. Albrecht et al. showed that 50% of baboons miscarried when maternal oestrogen synthesis was suppressed
* Corresponding author at: Department of Obstetrics and Gynaecology, 6/F., Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong Special Administrative Region. Tel.: +852 22554518. E-mail address: [email protected] (J. Chai). 0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2013.09.017
using aromatase inhibitors whereas all maintained their pregnancy when concomitant estradiol was given [7]. Letrozole is a thirdgeneration aromatase inhibitor which suppresses the production of oestrogen; at clinical doses there is no effect on basal levels of cortisol and aldosterone [8]. Shi et al. found that a combination of anti-progestin with aromatase inhibitor acted synergistically to induce a 100% abortion rate in rats, while there was little effect when the antiprogestin or aromatase inhibitor was administered alone [9]. Recently, the effect of pretreatment with letrozole prior to misoprostol was studied for early medical abortion. The efficacy was 80% and 86.9% when 7.5 mg letrozole was given for 2 days before treatment with 800 mcg vaginal misoprostol and 10 mg for 3 days before treatment with 800 mcg misoprostol respectively [10,11]. When 10 mg letrozole was given for 7 days followed by 800 mcg vaginal misoprostol, the complete abortion rate increased to 95% [12]. Letrozole probably facilitates medical termination by suppressing the synthesis of oestradiol, which is an important factor in the maintenance of early pregnancy. Although the combination of mifepristone and misoprostol is highly effective, complete abortion rates are lower with pregnancies more than 7 weeks. It is postulated that by combining both letrozole and mifepristone, together with misoprostol, a synergistic effect will be exerted as the depleted oestrogen and progesterone level will be insufficient to support the pregnancy, and the uterotonic effect of misoprostol will hasten the abortion process, hence improving the complete abortion rate. As the combination of these three drugs has not been used before, it is uncertain whether this regimen will lead to
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J. Chai, P.-C. Ho / European Journal of Obstetrics & Gynecology and Reproductive Biology 171 (2013) 291–294
untoward side effects or complications. Therefore, we conducted a pilot study to assess the profile of side effects and the complete abortion rate of vaginal misoprostol when given with mifepristone and letrozole for termination of first trimester pregnancy up to 9 weeks’ gestation. 2. Materials and methods We conducted this pilot study at Queen Mary Hospital, Hong Kong. Ethical approval was obtained from the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Written consent was obtained from all participants before participation in the study. A total of 50 pregnant women aged 18 years or older with gestation up to 63 days requesting legal termination of pregnancy were recruited. The medical history was obtained, and a clinical examination including gynaecological and breast examination was performed by the gynaecologist. The research nurse recruited suitable women at the outpatient clinic after assessment by the medical staff. Exclusion criteria included (i) any contraindications or allergies to letrozole, mifepristone or misoprostol; (ii) an intrauterine contraceptive device in utero; (iii) breastfeeding; (iv) abnormal baseline liver/renal function tests or (v) multiple pregnancy. Following recruitment at the outpatient clinic, blood was taken for haemoglobin and liver/renal function tests. An ultrasound examination was performed to confirm the duration of pregnancy. After admission into the study, all women were given 200 mg of mifepristone (Hua Lian Parmaceutical Co., Shanghai, China) and 10 mg of letrozole orally in the presence of medical or nursing staff. This was designated as day 1 of the study. Women were instructed to return on day 2 for a second dose of 10 mg of letrozole. On day 3 the patient was admitted into the hospital in accordance with our local laws. After admission the patient was given the third dose of 10 mg of letrozole, and 800 mcg of misoprostol (Cytotec; Pfizer, New York, USA) was given vaginally. Women stayed in the hospital for 4 h. Temperature, blood pressure and pulse rate were recorded hourly by a nurse. Women were interviewed by a nurse at the end of 4 h regarding the side effects experienced. Vaginal examination was done at the end of 4 h. If a woman did not have heavy bleeding or severe pain, she was allowed to go home with a diary card to record the days of vaginal bleeding. The women came back on day 7 for clinical assessment, ultrasound examination of the pelvis and blood sampling for haemoglobin level. The intention was to determine whether the abortion was complete and to review the bleeding pattern. If the pelvic ultrasound examination showed the presence of an ongoing pregnancy, vacuum aspiration would be arranged without a further attempt with misoprostol. If the pelvic ultrasound examination showed that there was incomplete abortion or missed abortion, the woman would be observed unless there was heavy bleeding. The women were followed up again on day 43 for duration of bleeding and return of menses. If no vacuum aspiration was necessary during the period up to the first menstruation, the outcome was classified as complete abortion. The primary outcome measures were the proportion of complete abortion and the induction-to-abortion interval. Secondary outcome measures included the incidence of side effects and the duration of bleeding. 3. Results Fifty-four women were invited to this pilot study. Four were not eligible due to two cases of silent miscarriage, and two cases of abnormal liver function tests.
Table 1 Baseline demographics of the study population. Study group (n = 50) Age (years) Weight (kg) Height (cm) Gestational age by ultrasound (days) Previous pregnancy Previous abortion (s) Parity
34.1 (6.8) 57.1 (10.0) 159.4 (4.6) 51.1 (6.0) 42 (84) 13 (26) 38 (76)
Data are expressed as n (%) or mean (SD).
Table 2 Abortion outcomes of the study population. Study group (n = 46)a Median induction-to-abortion interval in hours (range) Success rate in 4 h (%) Success rate in 8 h (%) Success rate in 12 h (%) Success rate in 16 h (%) Success rate in 20 h (%) Success rate in 24 h (%) Success rate in >48 h (%) Mean haemoglobin level, g/dl (SD) Before After Median duration of bleeding in days (range) a
5.1 (1.2–56) 9 (19.6) 39 (84.8) 44 (95.7) 44 (95.7) 44 (95.7) 44 (95.7) 46 (100) 12.3 (1.0) 12.5 (0.9) 14 (7–33)
4 women were unsure of the timing.
The baseline demographics of the study group are presented in Table 1. The characteristics of the abortion process are shown in Table 2. Forty-nine women (98%) had complete abortion (95% confidence interval: 94–100%). One woman had incomplete abortion requiring emergency vacuum aspiration due to heavy bleeding. She was a 42-year-old nulliparous woman with a history of one spontaneous miscarriage. Dating ultrasound confirmed a gestational age of 59 days on day 1 of the study. Bleeding started at 4 h after the administration of misoprostol and a piece of tissue was expelled an hour later. Ongoing bleeding was noted 2 h after expulsion of the tissue mass with total blood loss of 400 ml. On examination the cervical os was open with continuous bleeding from the uterine cavity. Emergency suction evacuation was arranged for incomplete abortion, and haemostasis was achieved at the end of operation. Histology of the tissue mass and uterine evacuates both confirmed products of gestation. The median induction-to-abortion interval (defined as the interval between the administration of misoprostol and the abortion) was 5.1 h (1.2–56 h). Of the 46 women who noted the timing of passage of products of gestation, 44 (95.7%) aborted within 12 h of misoprostol administration. The incidence of side effects after the administration of medications is shown in Table 3. The incidence of side effects after mifepristone and letrozole were comparable to those of baseline, while bleeding, diarrhoea, abdominal pain, and fever developed after misoprostol administration in most women. 4. Comments Medical abortion became an alternative method of abortion with the availability of prostaglandin analogues in the early 1970s and the anti-progestin mifepristone in the 1980s. The most common early first-trimester medical abortion regimen consisted of mifepristone in combination with administration of misoprostol [1,2]. The complete abortion rate was up to 95% in gestations up to 63 days [5,6].
J. Chai, P.-C. Ho / European Journal of Obstetrics & Gynecology and Reproductive Biology 171 (2013) 291–294
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Table 3 Side effects profile. Side effect
During pregnancy n (%)
24 h after mifepristone and first dose of letrozole n (%)
After 3 days of letrozole before administration of misoprostol n (%)
Nausea Vomiting Diarrhoea Abdominal pain Fever Bleeding
37 13 1 10 0 0
32 7 0 11 0 3
31 11 0 14 0 7
(74) (26) (2) (20) (0) (0)
(64) (14) (0) (22) (0) (6)
(62) (22) (0) (28) (0) (14)
Side effect
1 h after misoprostol n (%)
2 h after misoprostol n (%)
3 h after misoprostol n (%)
4 h after misoprostol n (%)
Nausea Vomiting Diarrhoea Abdominal pain Fever Bleeding
6 0 0 21 0 11
6 1 3 30 1 18
9 1 5 39 3 36
5(10) 0 (0) 6 (12) 47 (94) 7 (14) 41 (82)
(12) (0) (0) (42) (0) (22)
(12) (2) (6) (60) (2) (36)
Both progesterone and oestrogen are important hormones in maintaining early pregnancy. Progesterone is the dominant hormone controlling uterine contractility [3]. The importance of maintaining estrogen levels has been shown in studies where letrozole, an anti-oestrogen, induced miscarriage in baboons in up to 50% of the animals treated while it had no effect on progesterone [7]. It is therefore logical to postulate that the combination of letrozole and mifepristone, together with misoprostol, will hasten the abortion process and improve the complete abortion rate. In this pilot study, we explored the feasibility of a new regimen of medication termination using 800 mcg vaginal misoprostol following pretreatment with 200 mg mifepristone and three days of 10 mg letrozole. With this novel regimen we achieved an overall complete abortion rate of 98% and there was no ongoing pregnancy in the entire series. As this is only a pilot study without a control group, we are uncertain whether this regimen is more effective than the standard regimen with mifepristone and misoprostol. Since the standard regimen is already highly effective, with a complete abortion rate of 95%, the slight increase in complete abortion rate may not be clinically significant. A post hoc power analysis showed that a study of more than 1200 participants would be required to show whether this difference is statistically significant. We chose to use 10 mg letrozole for 3 days in our study as a previous study combining this dosage with misoprostol achieved a complete abortion rate of 86.9% without any serious adverse events [10]. Although increasing the duration of letrozole to 7 days prior to misoprostol administration improved the complete abortion rate to 95%, it significantly prolonged the abortion process [12]. Future studies may be conducted to assess whether this new combination of letrozole, mifepristone and misoprostol can improve the complete abortion rate by further increasing the dosage or duration of letrozole. The safety profile of this regimen was reassuring. There were no serious adverse events reported. Fourteen percent of women started vaginal bleeding before the administration of misoprostol but none aborted before misoprostol administration. The side effects reported during the misoprostol administration were not higher than the previous large study with the usage of mifepristone and misoprostol together [13]. While bleeding is an expected side effect of medical abortion, excessive bleeding requiring transfusion or surgical evacuation to achieve haemostasis is uncommon. One woman (2%) in our study required suction evacuation to treat excessive bleeding, and this risk was not higher than that reported in a multicenter trial involving 2121 women [14]. Our study showed a median duration of bleeding of 14 days (7–33 days). The duration of vaginal bleeding following medical abortion with mifepristone and misoprostol varies among studies, with a mean of
(18) (2) (10) (78) (6) (72)
duration of bleeding of 13–17 days [14,15]. It would be difficult to compare the duration of bleeding with the standard regimen without a proper randomized controlled trial. The addition of letrozole did not appear to shorten the induction-to-abortion interval. The median induction-to-abortion interval was 5.1 h in our cohort, compared to a previous reported interval of around 4 h using a combination of mifepristone and misoprostol. It is well understood, however, that in very early pregnancies it may not always be possible to identify the time of expulsion. The exact mechanism of action of letrozole as an abortifacient remains unclear. Kallner et al. showed that letrozole did not affect uterine contractility or increase the sensitivity to misoprostol of the uterine myometrium [16]. It has been demonstrated that letrozole markedly suppressed serum oestradiol (E2) concentration while it had no effect on the progesterone level [7,12]. Oestradiol induces differentiation of cytotrophoblasts into syncytiotrophoblasts through oestrogen receptors [17,18]. The letrozole-induced reduction of E2 may suppress trophoblast differentiation leading to delayed placental development. Another possible mechanism is through its effect on vascular endothelial growth factor and Ang-1 expression [19,20]. Further laboratory studies would be necessary to allow better understanding of the exact underlying mechanism. In conclusion, the present regimen of using mifepristone, letrozole and misoprostol achieved a complete abortion rate of 98% without serious adverse effects. Its efficacy and side-effect profile will have to be further validated by future prospective randomized controlled trials with adequate power. Acknowledgement This project was funded by the Committee on Research and Conference Grants of University of Hong Kong. References [1] ACOG. ACOG Practice Bulletin. Clinical management guidelines of obstetrician-gynecologists. Number 67, October 2005. Medical management of abortion. Obstet Gynecol 2005;106:871–2. [2] Royal College of Obstetricians and Gynaecologists. The care of women requesting induced abortion. Evidence-based Clinical Guideline No. 7. London (UK): RCOG Press; 2004. [3] Baird DT. Mode of action of medical methods of abortion. J Am Med Women’s Assoc 2000;55:121–6. [4] Van Look PFA, Bygdeman M. Antiprogesterone steroids: a new dimension in human fertility regulation. Oxford Rev Reprod Biol 1989;1:1–60. [5] Ashok PW, Penney GC, Flett GM, Templeton A. An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum Reprod 1998; 13:2962–5.
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[6] Schaff EA, Eisinger SH, Stadalius LS, Franks P, Gore BZ, Poppema S. Low-dose mifepristone 200 mg and vaginal misoprostol for abortion. Contraception 1999;59:1–6. [7] Albrecht ED, Aberdeen GW, Pepe GJ. The role of estrogen in the maintenance of primate pregnancy. Am J Obstet Gynecol 2000;182:432–8. [8] Bisagni G, Cocconi G, Scaglione F, Fraschini F, Pfister CH, Trunet PF. Letrozole, a new oral non-steroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study. Ann Oncol 1996;7: 99–102. [9] Shi L, Shi SQ, Given RL, Von Hertzen H, Garfield RE. Synergistic effects of antiprogestins and iNOS or aromatase inhibitors on establishment and maintenance of pregnancy. Steroids 2003;68:1077–84. [10] Lee CYV, Ng EHY, Yeung WSB, Ho PC. Misoprostol with or without letrozole pretreatment for termination of pregnancy: a randomized controlled trial. Obstet Gynecol 2011;117:317–23. [11] Lee CYV, Tang OS, Ng HYE, Yeung SBW, Ho PC. A pilot study on the use of letrozole with either misoprostol or mifepristone for termination of pregnancy up to 63 days. Contraception 2011;83:62–7. [12] Yeung TW, Lee VC, Ng EH, Ho PC. A pilot study on the use of a 7-day course of letrozole followed by misoprostol for the termination of early pregnancy up to 63 days. Contraception 2012;86:763–9.
[13] von Hertzen H, Huong NT, Piaggio G, et al. Misoprostol dose and route after mifepristone for early medical abortion: a randomized controlled noninferiority trial. BJOG 2010;117:1186–96. [14] Spitz IM, Bardin CW, Benton L, et al. Early pregnancy termination with mifepristone and misoprostol in the United States. N Engl J Med 1998;338:1241–7. [15] Schaff EA, Eisinger SH, Stadalius LS, et al. Low dose mifepristone 200 mg and vaginal misoprostol for abortion. Contraception 1999;59:1–6. [16] Kallner HK, Ho PC, Gemzell-Danielsson K. Effect of letrozole on uterine tonus and contractility: a randomized controlled trial. Contraception 2012;86:419–24. [17] Billiar RB, Pepe GJ, Albrecht ED. Immunocytochemical identification of the oestrogen receptor in the nuclei of cultured human placental syncytiotrophoblasts. Placenta 1997;18:365–70. [18] Rama S, Peutrusz, Rao AJ. Hormonal regulation of human trophoblast differentiation: a possible role for 17-beta-estradiol and GnRH. Mol Cell Endocrinol 2004;218:79–94. [19] Albrecht E, Robb VA, Pepe GJ. Regulation of placental vascular endothelial growth/permeability factor expression and angiogenesis by estrogen during early baboon pregnancy. J Clin Endocrinol Metab 2004;89:5803–9. [20] Albrecht ED, Babischkin JS, Pepe GJ. Regulation of placental villous angiopoietin-1 and -2 expression by estrogen during baboon pregnancy. Mol Reprod Dev 2008;75:504–11.
Contents lists available at ScienceDirect
European Journal of Obstetrics & Gynecology and Reproductive Biology journal homepage: www.elsevier.com/locate/ejogrb
A pilot study on the combined use of letrozole, mifepristone and misoprostol in termination of first trimester pregnancy up to 9 weeks’ gestation Joyce Chai *, Pak-Chung Ho Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong Special Administrative Region
A R T I C L E I N F O
A B S T R A C T
Article history: Received 14 June 2013 Received in revised form 20 August 2013 Accepted 16 September 2013
Objective: To assess the feasibility of adding letrozole to the standard regimen of mifepristone and misoprostol for termination of pregnancy up to 63 days. Study design: We recruited 50 subjects who had requested legal termination of pregnancy up to 63 days. Medical abortion was performed with a singe dose of 200 mg mifepristone and 10 mg of letrozole daily for 3 days followed by 800 mcg vaginal misoprostol. Results: The complete abortion rate was 98% (95% CI: 94–100%). The median induction-to-abortion interval of the regimen was 5.1 h (range 1.2–56 h). No serious adverse effects were reported. Conclusions: The results of this pilot study suggest that a regimen of mifepristone, letrozole and misoprostol is associated with a high complete abortion rate without major adverse events. ß 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Letrozole Mifepristone Misoprostol Termination of pregnancy
1. Introduction After mifepristone was approved by the United States Food and Drug Administration in 2000, the combination of mifepristone and vaginal use of misoprostol became almost a standard of care in early medical abortion up to 63 days of gestation [1,2]. Misoprostol, a synthetic analogue of naturally occurring prostaglandin E1, has a uterotonic effect and it can stimulate myometrial contraction and cause cervical ripening and dilatation. Progesterone maintains the uterus in a quiescent state by inducing hyperpolarization of the membrane of the myometrial cells, and a greater change in electric potential is necessary before contractions can occur [3]. Mifepristone is an anti-progestin that binds to the progesterone receptors and prevents endogenous progesterone from exerting its effects [4]. It can also increase the sensitivity of the uterus to prostaglandins. The complete abortion rate achieved with this sequential regimen has been found to be up to 93–95% [5,6], which is higher than the rate achieved with either mifepristone or misoprostol alone. Oestrogen is another important hormone for the maintenance of pregnancy. Albrecht et al. showed that 50% of baboons miscarried when maternal oestrogen synthesis was suppressed
* Corresponding author at: Department of Obstetrics and Gynaecology, 6/F., Professorial Block, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong Special Administrative Region. Tel.: +852 22554518. E-mail address: [email protected] (J. Chai). 0301-2115/$ – see front matter ß 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejogrb.2013.09.017
using aromatase inhibitors whereas all maintained their pregnancy when concomitant estradiol was given [7]. Letrozole is a thirdgeneration aromatase inhibitor which suppresses the production of oestrogen; at clinical doses there is no effect on basal levels of cortisol and aldosterone [8]. Shi et al. found that a combination of anti-progestin with aromatase inhibitor acted synergistically to induce a 100% abortion rate in rats, while there was little effect when the antiprogestin or aromatase inhibitor was administered alone [9]. Recently, the effect of pretreatment with letrozole prior to misoprostol was studied for early medical abortion. The efficacy was 80% and 86.9% when 7.5 mg letrozole was given for 2 days before treatment with 800 mcg vaginal misoprostol and 10 mg for 3 days before treatment with 800 mcg misoprostol respectively [10,11]. When 10 mg letrozole was given for 7 days followed by 800 mcg vaginal misoprostol, the complete abortion rate increased to 95% [12]. Letrozole probably facilitates medical termination by suppressing the synthesis of oestradiol, which is an important factor in the maintenance of early pregnancy. Although the combination of mifepristone and misoprostol is highly effective, complete abortion rates are lower with pregnancies more than 7 weeks. It is postulated that by combining both letrozole and mifepristone, together with misoprostol, a synergistic effect will be exerted as the depleted oestrogen and progesterone level will be insufficient to support the pregnancy, and the uterotonic effect of misoprostol will hasten the abortion process, hence improving the complete abortion rate. As the combination of these three drugs has not been used before, it is uncertain whether this regimen will lead to
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untoward side effects or complications. Therefore, we conducted a pilot study to assess the profile of side effects and the complete abortion rate of vaginal misoprostol when given with mifepristone and letrozole for termination of first trimester pregnancy up to 9 weeks’ gestation. 2. Materials and methods We conducted this pilot study at Queen Mary Hospital, Hong Kong. Ethical approval was obtained from the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. Written consent was obtained from all participants before participation in the study. A total of 50 pregnant women aged 18 years or older with gestation up to 63 days requesting legal termination of pregnancy were recruited. The medical history was obtained, and a clinical examination including gynaecological and breast examination was performed by the gynaecologist. The research nurse recruited suitable women at the outpatient clinic after assessment by the medical staff. Exclusion criteria included (i) any contraindications or allergies to letrozole, mifepristone or misoprostol; (ii) an intrauterine contraceptive device in utero; (iii) breastfeeding; (iv) abnormal baseline liver/renal function tests or (v) multiple pregnancy. Following recruitment at the outpatient clinic, blood was taken for haemoglobin and liver/renal function tests. An ultrasound examination was performed to confirm the duration of pregnancy. After admission into the study, all women were given 200 mg of mifepristone (Hua Lian Parmaceutical Co., Shanghai, China) and 10 mg of letrozole orally in the presence of medical or nursing staff. This was designated as day 1 of the study. Women were instructed to return on day 2 for a second dose of 10 mg of letrozole. On day 3 the patient was admitted into the hospital in accordance with our local laws. After admission the patient was given the third dose of 10 mg of letrozole, and 800 mcg of misoprostol (Cytotec; Pfizer, New York, USA) was given vaginally. Women stayed in the hospital for 4 h. Temperature, blood pressure and pulse rate were recorded hourly by a nurse. Women were interviewed by a nurse at the end of 4 h regarding the side effects experienced. Vaginal examination was done at the end of 4 h. If a woman did not have heavy bleeding or severe pain, she was allowed to go home with a diary card to record the days of vaginal bleeding. The women came back on day 7 for clinical assessment, ultrasound examination of the pelvis and blood sampling for haemoglobin level. The intention was to determine whether the abortion was complete and to review the bleeding pattern. If the pelvic ultrasound examination showed the presence of an ongoing pregnancy, vacuum aspiration would be arranged without a further attempt with misoprostol. If the pelvic ultrasound examination showed that there was incomplete abortion or missed abortion, the woman would be observed unless there was heavy bleeding. The women were followed up again on day 43 for duration of bleeding and return of menses. If no vacuum aspiration was necessary during the period up to the first menstruation, the outcome was classified as complete abortion. The primary outcome measures were the proportion of complete abortion and the induction-to-abortion interval. Secondary outcome measures included the incidence of side effects and the duration of bleeding. 3. Results Fifty-four women were invited to this pilot study. Four were not eligible due to two cases of silent miscarriage, and two cases of abnormal liver function tests.
Table 1 Baseline demographics of the study population. Study group (n = 50) Age (years) Weight (kg) Height (cm) Gestational age by ultrasound (days) Previous pregnancy Previous abortion (s) Parity
34.1 (6.8) 57.1 (10.0) 159.4 (4.6) 51.1 (6.0) 42 (84) 13 (26) 38 (76)
Data are expressed as n (%) or mean (SD).
Table 2 Abortion outcomes of the study population. Study group (n = 46)a Median induction-to-abortion interval in hours (range) Success rate in 4 h (%) Success rate in 8 h (%) Success rate in 12 h (%) Success rate in 16 h (%) Success rate in 20 h (%) Success rate in 24 h (%) Success rate in >48 h (%) Mean haemoglobin level, g/dl (SD) Before After Median duration of bleeding in days (range) a
5.1 (1.2–56) 9 (19.6) 39 (84.8) 44 (95.7) 44 (95.7) 44 (95.7) 44 (95.7) 46 (100) 12.3 (1.0) 12.5 (0.9) 14 (7–33)
4 women were unsure of the timing.
The baseline demographics of the study group are presented in Table 1. The characteristics of the abortion process are shown in Table 2. Forty-nine women (98%) had complete abortion (95% confidence interval: 94–100%). One woman had incomplete abortion requiring emergency vacuum aspiration due to heavy bleeding. She was a 42-year-old nulliparous woman with a history of one spontaneous miscarriage. Dating ultrasound confirmed a gestational age of 59 days on day 1 of the study. Bleeding started at 4 h after the administration of misoprostol and a piece of tissue was expelled an hour later. Ongoing bleeding was noted 2 h after expulsion of the tissue mass with total blood loss of 400 ml. On examination the cervical os was open with continuous bleeding from the uterine cavity. Emergency suction evacuation was arranged for incomplete abortion, and haemostasis was achieved at the end of operation. Histology of the tissue mass and uterine evacuates both confirmed products of gestation. The median induction-to-abortion interval (defined as the interval between the administration of misoprostol and the abortion) was 5.1 h (1.2–56 h). Of the 46 women who noted the timing of passage of products of gestation, 44 (95.7%) aborted within 12 h of misoprostol administration. The incidence of side effects after the administration of medications is shown in Table 3. The incidence of side effects after mifepristone and letrozole were comparable to those of baseline, while bleeding, diarrhoea, abdominal pain, and fever developed after misoprostol administration in most women. 4. Comments Medical abortion became an alternative method of abortion with the availability of prostaglandin analogues in the early 1970s and the anti-progestin mifepristone in the 1980s. The most common early first-trimester medical abortion regimen consisted of mifepristone in combination with administration of misoprostol [1,2]. The complete abortion rate was up to 95% in gestations up to 63 days [5,6].
J. Chai, P.-C. Ho / European Journal of Obstetrics & Gynecology and Reproductive Biology 171 (2013) 291–294
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Table 3 Side effects profile. Side effect
During pregnancy n (%)
24 h after mifepristone and first dose of letrozole n (%)
After 3 days of letrozole before administration of misoprostol n (%)
Nausea Vomiting Diarrhoea Abdominal pain Fever Bleeding
37 13 1 10 0 0
32 7 0 11 0 3
31 11 0 14 0 7
(74) (26) (2) (20) (0) (0)
(64) (14) (0) (22) (0) (6)
(62) (22) (0) (28) (0) (14)
Side effect
1 h after misoprostol n (%)
2 h after misoprostol n (%)
3 h after misoprostol n (%)
4 h after misoprostol n (%)
Nausea Vomiting Diarrhoea Abdominal pain Fever Bleeding
6 0 0 21 0 11
6 1 3 30 1 18
9 1 5 39 3 36
5(10) 0 (0) 6 (12) 47 (94) 7 (14) 41 (82)
(12) (0) (0) (42) (0) (22)
(12) (2) (6) (60) (2) (36)
Both progesterone and oestrogen are important hormones in maintaining early pregnancy. Progesterone is the dominant hormone controlling uterine contractility [3]. The importance of maintaining estrogen levels has been shown in studies where letrozole, an anti-oestrogen, induced miscarriage in baboons in up to 50% of the animals treated while it had no effect on progesterone [7]. It is therefore logical to postulate that the combination of letrozole and mifepristone, together with misoprostol, will hasten the abortion process and improve the complete abortion rate. In this pilot study, we explored the feasibility of a new regimen of medication termination using 800 mcg vaginal misoprostol following pretreatment with 200 mg mifepristone and three days of 10 mg letrozole. With this novel regimen we achieved an overall complete abortion rate of 98% and there was no ongoing pregnancy in the entire series. As this is only a pilot study without a control group, we are uncertain whether this regimen is more effective than the standard regimen with mifepristone and misoprostol. Since the standard regimen is already highly effective, with a complete abortion rate of 95%, the slight increase in complete abortion rate may not be clinically significant. A post hoc power analysis showed that a study of more than 1200 participants would be required to show whether this difference is statistically significant. We chose to use 10 mg letrozole for 3 days in our study as a previous study combining this dosage with misoprostol achieved a complete abortion rate of 86.9% without any serious adverse events [10]. Although increasing the duration of letrozole to 7 days prior to misoprostol administration improved the complete abortion rate to 95%, it significantly prolonged the abortion process [12]. Future studies may be conducted to assess whether this new combination of letrozole, mifepristone and misoprostol can improve the complete abortion rate by further increasing the dosage or duration of letrozole. The safety profile of this regimen was reassuring. There were no serious adverse events reported. Fourteen percent of women started vaginal bleeding before the administration of misoprostol but none aborted before misoprostol administration. The side effects reported during the misoprostol administration were not higher than the previous large study with the usage of mifepristone and misoprostol together [13]. While bleeding is an expected side effect of medical abortion, excessive bleeding requiring transfusion or surgical evacuation to achieve haemostasis is uncommon. One woman (2%) in our study required suction evacuation to treat excessive bleeding, and this risk was not higher than that reported in a multicenter trial involving 2121 women [14]. Our study showed a median duration of bleeding of 14 days (7–33 days). The duration of vaginal bleeding following medical abortion with mifepristone and misoprostol varies among studies, with a mean of
(18) (2) (10) (78) (6) (72)
duration of bleeding of 13–17 days [14,15]. It would be difficult to compare the duration of bleeding with the standard regimen without a proper randomized controlled trial. The addition of letrozole did not appear to shorten the induction-to-abortion interval. The median induction-to-abortion interval was 5.1 h in our cohort, compared to a previous reported interval of around 4 h using a combination of mifepristone and misoprostol. It is well understood, however, that in very early pregnancies it may not always be possible to identify the time of expulsion. The exact mechanism of action of letrozole as an abortifacient remains unclear. Kallner et al. showed that letrozole did not affect uterine contractility or increase the sensitivity to misoprostol of the uterine myometrium [16]. It has been demonstrated that letrozole markedly suppressed serum oestradiol (E2) concentration while it had no effect on the progesterone level [7,12]. Oestradiol induces differentiation of cytotrophoblasts into syncytiotrophoblasts through oestrogen receptors [17,18]. The letrozole-induced reduction of E2 may suppress trophoblast differentiation leading to delayed placental development. Another possible mechanism is through its effect on vascular endothelial growth factor and Ang-1 expression [19,20]. Further laboratory studies would be necessary to allow better understanding of the exact underlying mechanism. In conclusion, the present regimen of using mifepristone, letrozole and misoprostol achieved a complete abortion rate of 98% without serious adverse effects. Its efficacy and side-effect profile will have to be further validated by future prospective randomized controlled trials with adequate power. Acknowledgement This project was funded by the Committee on Research and Conference Grants of University of Hong Kong. References [1] ACOG. ACOG Practice Bulletin. Clinical management guidelines of obstetrician-gynecologists. Number 67, October 2005. Medical management of abortion. Obstet Gynecol 2005;106:871–2. [2] Royal College of Obstetricians and Gynaecologists. The care of women requesting induced abortion. Evidence-based Clinical Guideline No. 7. London (UK): RCOG Press; 2004. [3] Baird DT. Mode of action of medical methods of abortion. J Am Med Women’s Assoc 2000;55:121–6. [4] Van Look PFA, Bygdeman M. Antiprogesterone steroids: a new dimension in human fertility regulation. Oxford Rev Reprod Biol 1989;1:1–60. [5] Ashok PW, Penney GC, Flett GM, Templeton A. An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum Reprod 1998; 13:2962–5.
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