International Journal of Gynecology and Obstetrics 124 (2014) 38–41

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International Journal of Gynecology and Obstetrics

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CLINICAL ARTICLE

Efficacy of mifepristone for cervical priming for second-trimester surgicaltermination of pregnancy

Leigh Searle a,⁎, John Tait b, Fali Langdana a,c, Dushyant Maharaj a,c

a Department of Obstetrics and Gynecology, Capital and Coast District Health Board, Wellington, New Zealandb Department of Women’s and Children’s Health and Surgery, Capital and Coast District Health Board, Wellington, New Zealandc Department of Obstetrics and Gynecology, University of Otago, Dunedin, New Zealand

⁎ Corresponding author at: 15 Puriri Terrace, PalmersTel.: +64 27 3253991.

E-mail address: leigh.searle@trainee.ranzcog.edu.au (L

0020-7292/$ – see front matter © 2013 International Fedehttp://dx.doi.org/10.1016/j.ijgo.2013.05.029

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 23 February 2013Received in revised form 30 May 2013Accepted 18 September 2013

Keywords:CervixInduced abortionLaminariaMidtrimesterMifepristone

Objective: To determine whether mifepristone plus misoprostol was as effective as misoprostol with or withoutlaminaria (depending on gestational age) for cervical preparation for second-trimester termination of pregnancy.Methods: A retrospective cohort study was carried out among women who underwent surgical termination be-tween 14 and 19 + 6 weeks of pregnancy. Those who received preoperative mifepristone were compared withthose who did not. The study group receivedmifepristone plus misoprostol before dilation and evacuation of theuterus betweenMay 2008 and September 2011. The comparison (non-mifepristone) group receivedmisoprostolwith or without laminaria between January 2005 and April 2008. Results: There was no difference between thegroups in terms of difficulty of cervical dilation, with an overall relative risk for moderate–difficult dilation inthemifepristone group of 0.91 (95% confidence interval, 0.49–1.68). Therewas no difference between the groupswith regard to complications arising from the procedure. Conclusion:Mifepristone is effective for cervical priming

prior to second-trimester dilation and evacuation in both multiparous and primiparous women, without an in-crease in complication rates.© 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Mifepristone is a synthetic steroid compound that acts as a compet-itive antagonist at progesterone receptors. In addition to being anantiprogestogen, mifepristone has antiglucocorticoid and antiandro-gen activity.

The effects of mifepristone include reversible blockade of proges-terone receptors on the endometrium and cervix [1]. Progesteroneprevents cervical ripening and maintains uterine quiescence duringpregnancy, and is regarded as a key hormone inmaintaining a pregnan-cy [2]. It has been shown that the need for surgical dilation of the cervixin first-trimester surgical termination of pregnancy can be avoidedwithmifepristone [3,4]; however, very few data exist regarding its use insecond-trimester termination of pregnancy.

Second-trimester termination of pregnancy—which can be carriedout either medically or surgically—accounts for 10%–15% of all termina-tions performed worldwide [5]. Surgical termination of pregnancy after15 weeks via dilation and evacuation (D&E) preceded by cervical prep-aration is safe and effective when performed by a sufficiently skilled op-erator [6]. A retrospective cohort study found that medical terminationof pregnancy had significantly higher rates of complications comparedwith D&E (29% vs 4%) [7], and a 2008 Cochrane review concluded that

ton North 4414, New Zealand.

. Searle).

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therewere fewer adverse events and less painwithD&E thanwithmed-ical termination of pregnancy [7]. For gynecologists lacking the skillsand caseload for D&E, medical terminationwithmifepristone andmiso-prostol is recommended [6]. Cervical priming is recommended prior toD&E after 9 weeks and is essential when performed after 14 weeks, inorder to minimize the risk of cervical and uterine trauma [8]. Cervicalpreparation methods include laminaria tents (dried compressed sea-weed that absorbs fluid and gradually expands); Dilapan (GynotechIndustries, Middlesex, NJ, USA), which is a hydrophilic polymer rodhygroscopic dilator; Lamicel (Medtronic Xomed, CT, USA), which is apolyvinyl alcohol sponge impregnated with magnesium sulfate; andprostaglandins (of which the analog misoprostol is the most commonlyused) [8]. Cervical laceration is the most commonly reported complica-tion of D&E, and use of laminaria tents has significantly reduced this risk[9]. Use of mifepristone sensitizes the action of subsequently adminis-tered prostaglandins [1]. A randomized controlled trial by Carbonellet al. [10] compared mifepristone plus misoprostol with misoprostolonly prior to D&E between 12 and 20 weeks of pregnancy. The authorsreported that womenwho receivedmifepristone had increased cervicalcompliance at the timeof surgery, although thiswas not significant [10].

Mifepristonewas approved in New Zealand in 2001 for 4 uses: earlymedical termination of pregnancy; priming the cervix before surgicaltermination; second-trimester medical termination of pregnancy; andinduction of labor in cases of intrauterine fetal death [11].

The aim of the present study was to determine whether mifepris-tone plus misoprostol was as effective as misoprostol with or without

ublished by Elsevier Ireland Ltd. All rights reserved.

Table 2Patient variables.a

Mifepristone Non-mifepristone P value

39L. Searle et al. / International Journal of Gynecology and Obstetrics 124 (2014) 38–41

laminaria (depending on gestational age) for cervical preparation forsecond-trimester termination of pregnancy, in addition to comparingthe complication rates between the methods.

Total women who underwenttermination

202 312

Total women included 199 309Parity 0.0013

Primiparous 54 127Multiparous 145 182

Previous terminations 0.890 117 1921 47 702 28 353 5 84 2 35 0 1

Gestational age attermination, wk

0.000028

14 8 (4) 18 (6)15 28 (14) 98 (32)16 76 (38) 123 (40)17 39 (20) 34 (11)18 39 (20) 29 (9)19 9 (4) 7 (2)

a Values are given as number or number (percentage) unless otherwise indicated.

2. Materials and methods

A retrospective cohort study was conducted involving women whounderwent second-trimester D&E between 14 and 19 + 6 weeks ofpregnancy. Women who received mifepristone prior to surgical termi-nation of pregnancy were compared with women who received theprevious standard treatment of misoprostol with or without laminariaat Wellington Regional Hospital, Wellington, New Zealand. The mifep-ristone group included all women who underwent second-trimestertermination of pregnancy between May 1, 2008, and September 30,2011. The non-mifepristone group included all womenwho underwentsurgical termination between January 1, 2005, and April 30, 2008: be-fore the introduction of mifepristone use. Table 1 shows the 2 groups,including the medications given at each gestational age. Both groupsof women received preoperative misoprostol 1–2 hours prior to D&E,in addition to mifepristone or laminaria.

Primiparouswomen at 17–19 weeks of pregnancywere not givenmi-fepristone at the study institution owing to the lack of evidence that itwould provide adequate cervical preparation at these gestational ages;laminaria is the proven method for cervical preparation in these women[12,13]. At the study center, laminaria is inserted on the day prior toD&E. This involves a pelvic examination, which can be quite uncomfort-able. Mifepristone is given orally 24–48 hours before the procedure.

Approval was obtained from the Capital and Coast District HealthBoardAudit Committee prior to reviewing patient notes. Because the re-view conformed to the standards established by theNational Health andMedical Research Council of Australia for ethical quality review [14],ethics approval was not sought. All second-trimester D&E procedureswere performed under general anesthesia, with 5 units of oxytocin ad-ministered at completion. Two obstetrics and gynecology consultantsperformed second-trimester D&E over the study period. Difficulty ofcervical dilation—a subjective measurement—was recorded routinelyby the operating surgeon in the operative record of women undergoingD&E. Women did not undergo further cervical dilation preoperatively ifdilation was inadequate. The following data were collected: gestationalage, parity, and number of previous terminations. The primary outcomewasdifficulty of cervical dilation. The secondary outcomewas complica-tions (excessive bleeding requiring oxytocin infusion, admission over-night, perforation of the uterus, and retained products of conceptionproven on ultrasound examination). It was also documented whetherthe fetus was passed prior to scheduled D&E.

Patients were identified from coding records of pregnancy termina-tion between 14 and 19 weeks at Wellington Regional Hospital. Noteswere then reviewed to include the patients in each group that fulfilledthe study criteria, and clinical records were checked for complicationsarising from the procedure.

Table 1The 2 study groups.

Gestational age, wk Mifepristonea

Primiparous Multiparous

14 Mifepristone + misoprostol15 Mifepristone + misoprostol Mifepristone + m16 Mifepristone + misoprostol Mifepristone + m17 Mifepristone + m18 Mifepristone + m19 Mifepristone + m

a Mifepristone + misoprostol refers tomifepristone 200 mg 24–48 hours prior to procedureday of surgery.

b Laminaria + misoprostol refers to laminaria inserted into cervix 48 hours prior to proceduthe day of surgery.

Epi Info 7.0.8.0 (Centers for Disease Control and Prevention, Atlanta,GA, USA) was used for statistical analysis. The χ2 test was used to com-pare patient variables for differences between groups. The relative riskfor moderate–difficult cervical dilation was calculated using 95% confi-dence intervals (CIs) and P values obtained from the χ2 test. The rateof complications was compared with the relative risk, and the Fisherexact test was used to calculate P values because these numbers weresmall. P b 0.05 was considered to be statistically significant.

3. Results

Notes were reviewed for 99% of all patients who underwent termi-nation of pregnancy between January 2005 and September 2011 (309/312 in the non-mifepristone arm and 199/202 in the mifepristone armof the study). Patient characteristics are shown in Table 2. There was asignificant difference in the proportion of primiparous and multiparouswomen between the groups. There was no significant difference in par-ity amongmultiparous women or in the number of previous pregnancyterminations between the groups. There was a significant difference ingestational age at termination between the groups, with earlier gesta-tional age in the non-mifepristone group compared with the mifepris-tone group.

Difficulty in cervical dilation—the primary outcome—is shown inTable 3. The overall relative risk for moderate–difficult cervical dilationfor women who received mifepristone was 0.91 (95% CI, 0.49–1.68),showing no difference in cervical dilation difficulty between the groups.There was no difference in relative risk even when the results were

Non-mifepristoneb

Primiparous Multiparous

Misoprostolisoprostol Misoprostol Misoprostolisoprostol Laminaria + misoprostol Laminaria + misoprostolisoprostol Laminaria + misoprostolisoprostol Laminaria + misoprostolisoprostol Laminaria + misoprostol

plusmisoprostol 600 μg for primiparouswomen or 400 μg formultiparouswomen on the

re plus misoprostol 600 μg for primiparous women or 400 μg for multiparous women on

Table 3Cervical dilation.

Cervical dilation Mifepristone Non-mifepristone Relative risk for moderate–difficult dilation(95% confidence interval)

P value

Easy Moderate–difficult Easy Moderate–difficult

All women 182 15 278 25 0.91 (0.49–1.68) 0.77All women stratified 1.06 (0.55–2.04 0.21

Primiparous 49 5 109 17 0.68 (0.27–1.77) 0.42Multiparous 135 10 175 8 1.58 (0.64–3.90) 0.32

40 L. Searle et al. / International Journal of Gynecology and Obstetrics 124 (2014) 38–41

stratified for parity (given that there were proportionally more primip-arouswomen in the non-mifepristone group): 1.06 (95% CI, 0.55–2.04).

There was no difference in the rate of complications between thegroups (Table 4). The relative risk of all complications in the mifepris-tone group was 0.71 (95% CI, 0.34–1.46). There were no significant dif-ferences between the groups for any of the complications documented.The relative risk of the fetus being delivered prior to theater in themifepristone group was 1.55, which was not statistically significant.

4. Discussion

The present study showed thatmifepristone plusmisoprostolwas aseffective for cervical preparation for D&E in the second trimester astreatment with misoprostol with or without laminaria, depending ongestational age. There was also no difference in complication ratesbetween the groups.

There has been 1 other study comparing mifepristone plus miso-prostolwithmisoprostol alone for cervical preparation in the second tri-mester [10]. In that study, women who were 12–20 weeks pregnantwere randomized to either vaginal or sublingual misoprostol plusmifepristone compared with vaginal or sublingual misoprostol only.Women were assessed on the day of surgery, and if inadequate cervicaldilation was achieved with mifepristone Dilapan tents were insertedinto the cervix. Therewas a significant reduction in the need for Dilapantent use among women who received mifepristone: 30% versus 53% inthe misoprostol-only group (P b 0.01). The study did not find a signifi-cant difference in cervical dilation between the groups and there wereno cases of retained products; 3 women were admitted with hemor-rhage but it was not stated in which group they were included. Therewere no cervical lacerations in the present study, compared with 4 cer-vical tears in the study by Carbonell et al. [10] (1 in the mifepristonegroup and 3 in the misoprostol-only group). In the study by Carbonellet al. [10], expulsion of the conceptus occurred in 2 cases in the mifep-ristone group prior to misoprostol administration (0.5% of women inthat group), compared with 1% in the present study. However, therewas a 0.6% incidence of gestational expulsion prior to D&E in the lami-naria group in the present study. There was a low rate of patient exclu-sion owing to notes beingunavailable in the present study (1% in each ofthe groups), whereas in the study by Carbonell et al. [10] 3% of womendropped out or did not have available results.

Table 4Complications.

Mifepristone Non-mif

ComplicationsAll women 10 22All women stratifiedPrimiparous 1 11Multiparous 9 11

Complication typeHeavy bleeding 8 12Retained products of conception 1 3Uterine perforation 1 3Delivery prior to theater 2 2

In the present study, complications of D&Ewere rare in both groups;therefore, a much larger number of patients would be needed to detecta difference in complications between groups. Given that some of thepatients came from different district health boards, some late complica-tionsmight have beenmissed. The studyunit follows-up on late compli-cations of patients by requesting a report from the referring hospital ifa complication occurs; however, this system may not ensure that allcomplications are recorded by the unit. Themeasurement of cervical di-lation was a subjective one. However, because there were only 2 opera-tors carrying out the procedures, it is likely to be reproducible. Previousstudies in this area documented dilation by using the largest Hegardilator that the cervix allowed without resistance and documentedthe consistency and permeability of the cervix after cervical preparation[10], or used a force measurement to document difficulty of cervicaldilation [15]. Using one of these methods would have given a moreobjective measurement of cervical resistance.

The present study was limited by its small size, which probablycontributed to the lack of significant differences between the groups.The unit does not currently use mifepristone for primiparous womenat 17–19 weeks for termination of pregnancy; however, it should beconsidered given its success in multiparous women at this gestationalage and based on the study by Carbonell et al. [10].

Mifepristone is likely to be much more acceptable to patients be-cause it involves taking a tablet rather than the pelvic examinationthat is required to insert laminaria rods into the cervical os. The samenumber of visits to the clinic would be required because mifepris-tone is given 24–48 hours prior to D&E (laminaria is inserted theday before surgery).

In conclusion, mifepristone plusmisoprostol for cervical preparationbefore D&E in the second trimester is as effective as laminaria, with noincrease in complications. A randomized controlled trialwill be requiredto determine its efficacy for termination of pregnancy among primipa-rous women.

Conflict of interest

J.T. is a founding director of ISTAR, which is a not-for-profit pharma-ceutical company that supplies mifepristone in New Zealand. He wasnot involved in extracting data from patient notes. The other authorshave no conflicts of interest.

epristone Relative risk for moderate–difficultdilation (95% confidence interval)

P value

0.71 (0.34–1.46) 0.450.70 (0.33–1.50) 0.460.21 (0.03–1.6) 0.161.03 (0.43–2.4) 0.99

1.04 (0.43–2.49) 0.990.20 (0.02–1.70) 0.220.52 (005–4.94) 0.981.55 (0.22–10.93) 0.99

41L. Searle et al. / International Journal of Gynecology and Obstetrics 124 (2014) 38–41

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