- Email: [email protected]
Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis,
Contraception xxx (xxxx) xxx
Contents lists available at ScienceDirect
Contraception journal homepage: www.elsevier.com/locate/con
Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis q,qq Erica P. Cahill a,⇑, Andrea Henkel a, Jonathan G. Shaw a,b, Kate A. Shaw a a b
Department of Obstetrics and Gynecology, Division of Family Planning Services and Research, Stanford University School of Medicine, United States Department of Medicine, Division of Primary Care and Population Health, Stanford University School of Medicine, United States
a r t i c l e
i n f o
Article history: Received 6 March 2019 Received in revised form 26 August 2019 Accepted 15 September 2019 Available online xxxx MeSH Terms: Abortion, Induced Abortion, Therapeutic Abortifacient Agents, Nonsteroidal Misoprostol
a b s t r a c t Objective: To understand effect of adjunct misoprostol on cervical preparation with overnight osmotic dilators for dilation and evacuation after 16 weeks gestation. Methods: We searched on-line reference databases using search terms for second trimester, abortion, misoprostol, and dilators. Randomized controlled trials of cervical preparation for second trimester D&E using overnight osmotic dilators comparing adjunct misoprostol to placebo were included. Weighted mean with standard deviation (SD) and pooled binary outcomes were compared. Results: Among 84 articles identified, three met inclusion criteria (n = 457 subjects) adjunct misoprostol did not significantly decrease mean procedure times (8.5 ± 4.6 vs 9.6 ± 5.8 min, p = 0.78) or manual dilation (18% vs 28%, p = 0.23) when compared to placebo. There was no difference in total complications (p = 0.61), major complications (p = 0.44), or cervical lacerations (p = 0.87). Conclusion: Current limited evidence suggests adjunct misoprostol with osmotic dilators after 16 weeks does not affect procedure time or need for manual dilation. Implications: Further research is needed to determine the effect of adjunct misoprostol on major complications and blood loss. Ó 2019 Elsevier Inc. All rights reserved.
1. Introduction In the United States, nearly 700,000 legal abortions are performed every year, making abortion one of the most common surgical procedures [1]. The Center for Disease Control (CDC) reports that the vast majority (>90%) occur prior to 13 weeks; safe abortion in the second trimester remains an important option for women with barriers to accessing earlier abortion or with fetal anomalies not discovered until the second trimester ultrasound. Dilation and evacuation (D&E) is a safe procedure and complications are rare. However, the risk of complication from D&E increases disproportionately with gestational age; approximately two-thirds of all q Declaration of Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. qq Funding: Some of this research was reported as a poster abstract at the National Abortion Federation (NAF) Conference (April 2018) and the International Federation of Obstetrics and Gynecology (FIGO) Conference in Sao Paolo, Brazil (October 2018). ⇑ Corresponding author. E-mail address: [email protected] (E.P. Cahill).
abortion complications occur during second trimester abortions [2]. Adequate cervical preparation reduces the risk of these complications and has been the focus of recent research. At this time, there is insufficient evidence to define a strict cervical preparation protocol for patients desiring abortion in the mid to late second trimester. Current clinical practice and expert opinion for cervical dilation in the mid to late second trimester include osmotic dilators overnight, often two sets of dilators for later gestations. Several studies have investigated adding adjunctive medications to osmotic dilators to improve cervical dilation without extending the days required for cervical preparation [3–5]. The medications most commonly used are mifepristone, a progesterone receptor modulator, and misoprostol, a synthetic prostaglandin. While mifepristone is a valuable tool in cervical preparation, it is both expensive and has limited access [4]. Misoprostol has several important advantages for clinical use: it is widely available, stable at room temperature, and inexpensive. Buccal misoprostol has similar efficacy as a vaginal route [6]. Current Society of Family Planning Guidelines suggest adjunct misoprostol may be helpful in improving cervical dilation though it is
https://doi.org/10.1016/j.contraception.2019.09.005 0010-7824/Ó 2019 Elsevier Inc. All rights reserved.
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
2
E.P. Cahill et al. / Contraception xxx (xxxx) xxx
unclear if it decreases patient risks [7]. Since the publication of these guidelines over ten years ago, several studies have evaluated adjunct misoprostol for cervical preparation for mid to late second trimester dilation and curettage. However, they are all relatively small studies and not powered for more than their primary outcomes. Our aim was to systematically review currently available data to determine the potential benefits and risks of use of misoprostol as an adjunct to osmotic dilators for mid to late second trimester D&E procedures. 2. Materials and methods 2.1. Data sources and searches We searched PubMed database, MEDLINE, ClinicalTrials.gov, Cochrane Register for Controlled Trials, and POPLINE from inception through 2019 with search terms including abortion, cervical preparation, misoprostol, and second trimester. For example, our PubMed Search strategy was: ((((((((‘‘Abortion, Induced” [Mesh]) OR ‘‘Abortion, Therapeutic” [Mesh])) AND ((‘‘Abortifacient Agents, Nonsteroidal” [Mesh]) AND ‘‘Misoprostol” [Mesh])) AND cervical) NOT labor, labor, induced, induction)) NOT first). The search was limited to English-language trials. From all sources, a total of 84 articles were identified. 2.2. Study selection criteria We reviewed titles as well as abstracts to identify studies examining adjunctive misoprostol with osmotic dilators. Criteria for inclusion in the analysis were 1) data including D&E procedures performed at 16 weeks or later, 2) use of overnight osmotic dilators, 3) randomized, blinded trial comparing adjunctive misoprostol to placebo. 2.3. Data extraction and quality assessment Two authors independently reviewed each study to determine if it met inclusion criteria and assessed its quality. Of the 84 articles initially identified, three met inclusion criteria. The meta-analysis therefore includes a total of 457 patients who had osmotic dilators placed overnight. Of these, 228 patients received adjunctive misoprostol and 229 patients received placebo. All data included were from randomized placebo-controlled trials and were judged to be of high quality by Cochrane Review risk of bias tools for RCT based on appropriate randomization, blinding of providers and subjects, and consideration of confounders. 2.4. Data synthesis and analysis We were interested in three major effects of adjunctive misoprostol: 1) effect on procedure time and ease of procedure, 2) effect on complication rates, specifically complications caused by lack of cervical dilation, 3) side effect profile including timing and duration. Individual data were not available, therefore the summary data from each study were used for meta-analysis. The results from the three trials were pooled and weighted by the number of participants to calculate crude summary statistics (Table 3). We used RevMan Software [8] to perform meta-analysis (Table 4, Fig. 1). For the meta-analysis we used a random effects model weighted by inverse variance to account for variance in our pooled measures. We used the I2 statistic to evaluate for heterogeneity (0–100%) and considered I2 values of <60% to be evidence of mild to moderate heterogeneity. We also used descriptive analysis for side-effect
Fig. 1. Forest plots of meta-analysis outcomes for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion.
profiles, as these were described differently in the three studies. As each paper discussed estimated blood loss differently, this data was unable to be pooled for analysis.
3. Results Our search strategy identified 84 abstracts that were screened, with three full-text manuscripts meeting all inclusion criteria: Edelman (2006) [9], Drey (2014) [10], and Goldberg (2015) [11] for a total of 457 patients. All included studies were randomized controlled trials using osmotic dilators combined with either placebo or misoprostol for cervical preparation for D&E after 16 weeks gestation (Table 1). The study protocols in our analysis varied in several significant ways including by gestational age of patients, type of osmotic dilator used, and procedure location [9–11]. All studies used buccal misoprostol 400 mcg for dosing and route, but with variation in timing from 90 minutes to three hours prior to procedure [9–11]. The protocols also varied in the type of osmotic dilator used; two used laminaria whereas in the final, largest study, providers used both laminaria and DilapanÒ. Each study reported procedure times and initial dilation (Table 2). Procedure times in minutes were shorter with adjunctive misoprostol than placebo by approximately one and a half minutes. Additional manual dilation was high in both groups, with
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
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E.P. Cahill et al. / Contraception xxx (xxxx) xxx Table 1 Individual study characteristics and misoprostol timing for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion. Author, year
Gest Age (weeks)
n
Groups
N per group
Timing: miso to procedure
Timing: dilators to procedure
Primary Outcome
Procedure Setting(s)
Edelman, 2006
16–20 6/7
63
L+M L+P
31 32
60–90 min
1 day prior
Initial Dilation
Urban surgical center
19–20 6/7
29
Drey, 2014
21–23 1/7
196
L+M L+P L+M
12 17 98
3–4 h
1 day prior
Procedure Time
Urban hospital-based abortion clinic
Goldberg, 2015
16–18 6/7
102
L+P D+P+M D+P+P
98 51 51
3 h ± 30 min
1 day prior
Procedure Time
Multiple urban stand-alone abortion clinics, hospital-based abortion clinics and hospital operating rooms
19–23 6/7
96
D+P+M D+P+P
48 48
Legend: L = Laminaria, D = osmotic Dilators of any type, P = Placebo, M = Misoprostol.
Table 2 Individual study procedure characteristics for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion. Author, year
Gest Age, weeks
N
Groups
Mean Procedure Time, minutes mean ± SD
p
Pre-Op Cervical Dilation, mm mean ± SD Median (IQR)
p
Additional Dilation n (%)
p
Edelman, 2006
16–20 6/7
63
L+M
7.5 ± 3.2
0.65
17 ± 1.9
0.16
19 (61%)
0.79
L+P
7.8 ± 2.6
16.3 ± 1.7
21 (65%)
19–20 6/7
29
L+M
8.5 ± 3.3
0.85
18 ± 1.8
0.01
6 (50%)
0.44
Drey, 2014
21–23 1/7
196
L+P L+M
8.3 ± 2.5 10.6 ± 4.9
0.02
16 ± 1.7 25 (23.7–26.3)
0.04
11 (64%) 9 (8%)
1
Goldberg, 2015
16–18 6/7
102
L+P D+P+M
13.1 ± 8.1 8.26 ± 5.9
0.33
24.3 (22.3–25.7) 24 ± 10
0.02
10 (8%) 5 (10%)
0.03
D+P+P
8.19 ± 5.9
D+P+M
10.35 ± 7.9
D+P+P
13.39 ± 8.5
19–23 6/7
98
20 ± 4.0 0.01
25 ± 8.0 24 ± 5.0
18 (35%) 0.19
4 (8%)
0.34
8 (17%)
Legend: L = Laminaria, D = osmotic Dilators of any type, P = Placebo, M = Misoprostol.
more subjects who received placebo requiring manual dilation (16.2% vs 24.9%). We pooled results and reported overall crude summary statistics, weighted by number of participants (Table 3). When we weighted by inverse variance, no outcome was statistically significant in the meta-analysis (Table 4).
Table 3 Pooled analysis of procedure characteristics and complications for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion.
Total Participants, N Procedure Time (min) Mean ± SD Additional Dilation Required N (%) All complications* N (%) Major Complications** N (%) Cervical Lacerations N (%)
Misoprostol
Placebo
228 8.3 ± 4.6
229 9.6 ± 5.9
37 (16.2%)
57 (24.9%)
25 (11%)
26 (12%)
10 (4.4%)
16 (7.0%)
13 (5.7%)
9 (3.9%)
*All complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics alone, cervical laceration, re-aspiration. **Major complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics.
For the meta-analysis, data from each study were pooled and weighted by the inverse variance from each study (Table 4, Fig. 1). None of our outcomes of interest were statistically significant (Fig. 1). Most studies reported the most commonly known complications of D&E including cervical laceration, uterine perforation, hemorrhage, delivery prior to procedure as well as a total complication score. In all studies, complications were rare. Comparing adjunctive misoprostol to placebo, there was no statistical difference in total complications (p = 0.61), major complications (p = 0.44), or cervical lacerations specifically (p = 0.87). The highest total complication rate (23% in misoprostol group, 16% in placebo group) was reported in the study of women 21– 23 weeks and was mainly cervical lacerations (13% in misoprostol group, 6% in placebo group). The authors attribute much of this to lower uterine segment pressure, defined as a subjective sensation by the surgeon of the fetal parts compressing against the lower uterine segment and making it difficult to pass instruments. They suggest that the contractions caused by the misoprostol may make this sensation more likely. Lower uterine segment pressure was not reported in any of the other studies, making comparison difficult. We also compared side effects in the misoprostol versus placebo groups, specifically cramping. Each study had different metrics for evaluating and reporting side effects making a
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
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E.P. Cahill et al. / Contraception xxx (xxxx) xxx
Table 4 Summary of weighted meta-analysis outcomes for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion. Outcome
Total Participants, n
% (CI) IV, random effect
I2
p
Procedure Time Only > 19 weeks Additional Dilation Required Only > 19 weeks Pre-Operative Cervical Dilation# All Complications*,^ Major Complications**,^ Cervical Lacerations^
457 321 457 321 165 457 457 457
0.32 ( 2.53, 1.89) 1.66 ( 3.64, 0.32) 0.68 (0.36, 1.28) 0.75 (0.47, 1.21) 2.04 ( 1.14, 5.21) 0.61 (0.09, 4.13) 0.47 (0.07, 3.20) 0.81 (0.06, 10.49)
88% 52% 67% 0% 77% 83% 67% 66%
0.78 0.10 0.23 0.24 0.21 0.61 0.44 0.87
*All complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics alone, cervical laceration, re-aspiration. **Major complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics. #Does not include Drey et al. as no mean (SD) of dilation was reported. ^Does not include Edelman et al. as no RR could be calculated due to 0 complications reported in either group.
meta-analysis of this data impossible. For example, Edelman et al. asked women about cramping and found a higher frequency in women who received misoprostol compared with placebo (81% vs 50%, p = 0.02). Drey et al. used a four-point scale (0–4) for assessing pain before, during, and after procedure. Women who received adjunctive misoprostol were more likely to report severe or unbearable pain before the procedure (52% vs 11% p < 0.001) but there was no difference in pain after procedure. Goldberg et al. report the percentage of women experiencing ‘‘unacceptable or very unacceptable” pain levels prior to procedure was higher in misoprostol group (37% vs 9%, p < 0.001), but the authors do not report on pain during or after procedure. Regardless of metric used, all studies found that women who received misoprostol reported more pain after administration of medication and before procedure than women who received placebo.
4. Discussion We found that adjunctive misoprostol did not significantly decrease procedure time or the need for additional dilation when compared with placebo in a weighted meta-analysis. There was insufficient data, even with three pooled studies, to definitively demonstrate differences in complication rates or blood loss. Both of these outcomes are important and further studies should be done with the aim of investigating these outcomes. One concern some have with use of misoprostol is greater potential for cervical lacerations due to a more softened cervix. Indeed, in one study there were significantly more cervical lacerations in the adjunctive misoprostol group [10]. The authors of this study suggest that increased lower uterine segment pressure was a potential cause for this increase in lacerations. This increase in cervical lacerations in the misoprostol group was not demonstrated in the two other studies. In a different study evaluating adjunctive misoprostol with same-day osmotic dilators (excluded from our meta-analysis), a decrease in cervical lacerations was noted in the misoprostol group compared with placebo [12]. In all studies included in this analysis, overall complication rates including cervical lacerations were very low and we did not have adequate statistical power to evaluate in this analysis, or to evaluate differences in techniques that may confound this risk. However, given the large difference in complication rates between sites, it is possible that different techniques of D&E may lend themselves to different risks of cervical laceration and perforation. For example, given the mechanism of misoprostol, the uterus is more likely to contract down and push pregnancy tissue into lower uterine segment. This may reduce the risk of perforation as pregnancy tissue is farther from fundus. However, it can be more difficult to compress in this part of the uterus. To reduce the risk of cervical laceration, we sug-
gest no force be applied to ring forceps on cervical lip as pregnancy tissue is removed. Instead, counter traction with pressure on speculum during removal and using only gentle traction can decrease risk of cervical lacerations. Misoprostol is a prostaglandin analog that acts on receptors to soften the cervix. This may expedite the procedure and reduce complications as additional dilation is not as likely to be needed. It also causes uterine contractions, which may serve to expedite the procedure, as pregnancy may be in the process of expulsion. It also may explain the potential for a reduction in blood loss as bleeding is reduced when the uterus contracts down more quickly. We were unable to explore adjunctive misoprostol’s effect on blood loss in this analysis due to differences in reporting of this outcome between the studies. Recent work demonstrates that estimated blood loss may severely underestimate actual blood loss in D&E, particularly at later gestational ages [13]. Further research to evaluate the impact of misoprostol on blood loss is needed. Misoprostol has many advantages for use for cervical preparation, including it is inexpensive, stable at room temperature, and widely available. While mifepristone has been shown to have a similar efficacy to an additional day of osmotic dilators and to be better tolerated than misoprostol, it is not widely available; therefore alternative options are clinically important [4]. Misoprostol is already widely used for cervical preparation in early second trimester abortion alone or with osmotic dilators. A recent retrospective study of 274 women evaluated cervical preparation with same-day osmotic dilators plus misoprostol for D&E by highly skilled surgeons from 18 to 21 + 6 weeks gestation [14]. All procedures were completed the same day with a mean procedure time of 10 min (SD 4.2), which is within the range of the procedure times found in this meta-analysis. The authors found only two immediate complications (one cervical laceration, one extramural delivery) occurred. While this was retrospective and not compared with placebo, this study does demonstrate feasibility of one-day cervical preparation with adjunctive misoprostol for mid-second trimester procedures. Particularly for women living in states where they have to travel far distances to obtain a safe abortion in the mid to late second trimester, who may have to miss work, pay for childcare, as well as lodging in the area while undergoing an abortion procedure, any regimen that improves ability to obtain a safe abortion in the fewest days possible will increase access and ease. Our study includes all available data on a randomized comparison of adjunctive misoprostol compared with placebo for cervical preparation for mid to late second trimester abortion to date. It provides an important foundation for conducting further research on adjunctive misoprostol and provides a framework for future studies. The biggest limitation is the heterogeneity of the studies in terms of gestational ages included, administration of misoprostol,
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
E.P. Cahill et al. / Contraception xxx (xxxx) xxx
osmotic dilator type, and outcomes investigated. In the outcomes analyzed, the I2 statistic, a measure of heterogeneity ranged from 0% to 88%, with all outcomes >60%, signifying greater than moderate heterogeneity. Despite being the only studies that met our inclusion criteria, they differed in very significant ways, including gestational age, procedure setting, osmotic dilators used, timing of misoprostol, and outcome measurements. However, this is the only data we have available at this time. Meta-analyses remind us of the importance of standardizing outcome measurements, particularly reports of pain and blood loss, in order to draw conclusions about optimal cervical preparation. All studies had high rates of manual dilation ranging from 8% to over 60%, with over 50% of patients in the Edelman study requiring additional dilation in all groups (Table 2). In that study, the mean number of laminaria placed was just over two in the over 19-week gestation group, whereas all participants in the Drey et al. study had at least eight laminaria placed and the participants in the Goldberg study had over seven dilators placed, on average. The primary outcome in two of these studies is procedure time, which is perhaps not the most clinically relevant outcome, despite being considered a surrogate for time spent managing complications. More clinically relevant outcomes have been suggested including ability to complete the procedure the same day (compared to two-day dilators) and complication rates, including blood loss or cervical lacerations. Additionally, even pooling this data did not provide adequate power to detect differences in such small rates of complications. While second trimester abortion remains uncommon, it is increasingly more common for women to have to travel distances to access care. This has increased the importance of finding methods that decrease cervical preparation time without increasing procedure time or complication rates. The findings of this meta-analysis do not demonstrate a clear benefit of adjunctive misoprostol with overnight osmotic dilators. Further research is needed to definitively determine if adjunctive misoprostol has an effect on blood loss and rate of complications.
5
References [1] Jatlaoui TC, Boutot ME, Mandel MG, Whiteman MK, Ti A, Petersen E, et al. Abortion surveillance - United States, 2015. MMWR Surveill Summ. 2018;67 (13):1–45. [2] Lohr PA, Hayes JL, Gemzell-Danielsson K. Surgical versus medical methods for second trimester induced abortion. Cochrane Database Syst. Rev. 2008;1: CD006714. [3] Patel A, Talmont E, Morfesis J, Pelta M, Gatter M, Momtaz MR, et al. Adequacy and safety of buccal misoprostol for cervical preparation prior to termination of second-trimester pregnancy. Contraception 2006;73(4):420–30. [4] Shaw KA, Shaw JG, Hugin M, Velasquez G, Hopkins FW, Blumenthal PD. Adjunct mifepristone for cervical preparation prior to dilation and evacuation: a randomized trial. Contraception 2015;91(4):313–9. [5] Wilson LC, Meyn LA, Creinin MD. Cervical preparation for surgical abortion between 12 and 18 weeks of gestation using vaginal misoprostol and DilapanS. Contraception 2011;83(6):511–6. [6] Al R, Yapca O. Vaginal misoprostol compared with buccal misoprostol for termination of second-trimester pregnancy: a randomized controlled trial. Obstet. Gynecol. 2015;126(3):593–8. [7] Newmann S, Dalve-Endres A, Drey EA, Society of Family P. Clinical guidelines. Cervical preparation for surgical abortion from 20 to 24 weeks’ gestation. Contraception 2008;77(4):308–14. [8] Review Manager (RevMan) Version 5.3. ed. Copenhagen: The Nordic Cochrane Centre: The Cochrane Collaboration; 2014. [9] Edelman AB, Buckmaster JG, Goetsch MF, Nichols MD, Jensen JT. Cervical preparation using laminaria with adjunctive buccal misoprostol before second-trimester dilation and evacuation procedures: a randomized clinical trial. Am. J. Obstet. Gynecol. 2006;194(2):425–30. [10] Drey EA, Benson LS, Sokoloff A, Steinauer JE, Roy G, Jackson RA. Buccal misoprostol plus laminaria for cervical preparation before dilation and evacuation at 21–23 weeks of gestation: a randomized controlled trial. Contraception 2014;89(4):307–13. [11] Goldberg AB, Fortin JA, Drey EA, Dean G, Lichtenberg ES, Bednarek PH, et al. Cervical preparation before dilation and evacuation using adjunctive misoprostol or mifepristone compared with overnight osmotic dilators alone: a randomized controlled trial. Obstet. Gynecol. 2015;126(3):599–609. [12] Boraas CM, Achilles SL, Cremer ML, Chappell CA, Lim SE, Chen BA. Synthetic osmotic dilators with adjunctive misoprostol for same-day dilation and evacuation: a randomized controlled trial. Contraception 2016;94(5):467–72. [13] Serapio ET, Pearlson GA, Drey EA, Kerns JL. Estimated versus measured blood loss during dilation and evacuation: an observational study. Contraception 2018;97(5):451–5. [14] Lyus R, Lohr PA, Taylor J, Morroni C. Outcomes with same-day cervical preparation with Dilapan-S osmotic dilators and vaginal misoprostol before dilatation and evacuation at 18 to 21+6 weeks’ gestation. Contraception 2013;87(1):71–5.
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
Contents lists available at ScienceDirect
Contraception journal homepage: www.elsevier.com/locate/con
Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis q,qq Erica P. Cahill a,⇑, Andrea Henkel a, Jonathan G. Shaw a,b, Kate A. Shaw a a b
Department of Obstetrics and Gynecology, Division of Family Planning Services and Research, Stanford University School of Medicine, United States Department of Medicine, Division of Primary Care and Population Health, Stanford University School of Medicine, United States
a r t i c l e
i n f o
Article history: Received 6 March 2019 Received in revised form 26 August 2019 Accepted 15 September 2019 Available online xxxx MeSH Terms: Abortion, Induced Abortion, Therapeutic Abortifacient Agents, Nonsteroidal Misoprostol
a b s t r a c t Objective: To understand effect of adjunct misoprostol on cervical preparation with overnight osmotic dilators for dilation and evacuation after 16 weeks gestation. Methods: We searched on-line reference databases using search terms for second trimester, abortion, misoprostol, and dilators. Randomized controlled trials of cervical preparation for second trimester D&E using overnight osmotic dilators comparing adjunct misoprostol to placebo were included. Weighted mean with standard deviation (SD) and pooled binary outcomes were compared. Results: Among 84 articles identified, three met inclusion criteria (n = 457 subjects) adjunct misoprostol did not significantly decrease mean procedure times (8.5 ± 4.6 vs 9.6 ± 5.8 min, p = 0.78) or manual dilation (18% vs 28%, p = 0.23) when compared to placebo. There was no difference in total complications (p = 0.61), major complications (p = 0.44), or cervical lacerations (p = 0.87). Conclusion: Current limited evidence suggests adjunct misoprostol with osmotic dilators after 16 weeks does not affect procedure time or need for manual dilation. Implications: Further research is needed to determine the effect of adjunct misoprostol on major complications and blood loss. Ó 2019 Elsevier Inc. All rights reserved.
1. Introduction In the United States, nearly 700,000 legal abortions are performed every year, making abortion one of the most common surgical procedures [1]. The Center for Disease Control (CDC) reports that the vast majority (>90%) occur prior to 13 weeks; safe abortion in the second trimester remains an important option for women with barriers to accessing earlier abortion or with fetal anomalies not discovered until the second trimester ultrasound. Dilation and evacuation (D&E) is a safe procedure and complications are rare. However, the risk of complication from D&E increases disproportionately with gestational age; approximately two-thirds of all q Declaration of Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. qq Funding: Some of this research was reported as a poster abstract at the National Abortion Federation (NAF) Conference (April 2018) and the International Federation of Obstetrics and Gynecology (FIGO) Conference in Sao Paolo, Brazil (October 2018). ⇑ Corresponding author. E-mail address: [email protected] (E.P. Cahill).
abortion complications occur during second trimester abortions [2]. Adequate cervical preparation reduces the risk of these complications and has been the focus of recent research. At this time, there is insufficient evidence to define a strict cervical preparation protocol for patients desiring abortion in the mid to late second trimester. Current clinical practice and expert opinion for cervical dilation in the mid to late second trimester include osmotic dilators overnight, often two sets of dilators for later gestations. Several studies have investigated adding adjunctive medications to osmotic dilators to improve cervical dilation without extending the days required for cervical preparation [3–5]. The medications most commonly used are mifepristone, a progesterone receptor modulator, and misoprostol, a synthetic prostaglandin. While mifepristone is a valuable tool in cervical preparation, it is both expensive and has limited access [4]. Misoprostol has several important advantages for clinical use: it is widely available, stable at room temperature, and inexpensive. Buccal misoprostol has similar efficacy as a vaginal route [6]. Current Society of Family Planning Guidelines suggest adjunct misoprostol may be helpful in improving cervical dilation though it is
https://doi.org/10.1016/j.contraception.2019.09.005 0010-7824/Ó 2019 Elsevier Inc. All rights reserved.
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
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E.P. Cahill et al. / Contraception xxx (xxxx) xxx
unclear if it decreases patient risks [7]. Since the publication of these guidelines over ten years ago, several studies have evaluated adjunct misoprostol for cervical preparation for mid to late second trimester dilation and curettage. However, they are all relatively small studies and not powered for more than their primary outcomes. Our aim was to systematically review currently available data to determine the potential benefits and risks of use of misoprostol as an adjunct to osmotic dilators for mid to late second trimester D&E procedures. 2. Materials and methods 2.1. Data sources and searches We searched PubMed database, MEDLINE, ClinicalTrials.gov, Cochrane Register for Controlled Trials, and POPLINE from inception through 2019 with search terms including abortion, cervical preparation, misoprostol, and second trimester. For example, our PubMed Search strategy was: ((((((((‘‘Abortion, Induced” [Mesh]) OR ‘‘Abortion, Therapeutic” [Mesh])) AND ((‘‘Abortifacient Agents, Nonsteroidal” [Mesh]) AND ‘‘Misoprostol” [Mesh])) AND cervical) NOT labor, labor, induced, induction)) NOT first). The search was limited to English-language trials. From all sources, a total of 84 articles were identified. 2.2. Study selection criteria We reviewed titles as well as abstracts to identify studies examining adjunctive misoprostol with osmotic dilators. Criteria for inclusion in the analysis were 1) data including D&E procedures performed at 16 weeks or later, 2) use of overnight osmotic dilators, 3) randomized, blinded trial comparing adjunctive misoprostol to placebo. 2.3. Data extraction and quality assessment Two authors independently reviewed each study to determine if it met inclusion criteria and assessed its quality. Of the 84 articles initially identified, three met inclusion criteria. The meta-analysis therefore includes a total of 457 patients who had osmotic dilators placed overnight. Of these, 228 patients received adjunctive misoprostol and 229 patients received placebo. All data included were from randomized placebo-controlled trials and were judged to be of high quality by Cochrane Review risk of bias tools for RCT based on appropriate randomization, blinding of providers and subjects, and consideration of confounders. 2.4. Data synthesis and analysis We were interested in three major effects of adjunctive misoprostol: 1) effect on procedure time and ease of procedure, 2) effect on complication rates, specifically complications caused by lack of cervical dilation, 3) side effect profile including timing and duration. Individual data were not available, therefore the summary data from each study were used for meta-analysis. The results from the three trials were pooled and weighted by the number of participants to calculate crude summary statistics (Table 3). We used RevMan Software [8] to perform meta-analysis (Table 4, Fig. 1). For the meta-analysis we used a random effects model weighted by inverse variance to account for variance in our pooled measures. We used the I2 statistic to evaluate for heterogeneity (0–100%) and considered I2 values of <60% to be evidence of mild to moderate heterogeneity. We also used descriptive analysis for side-effect
Fig. 1. Forest plots of meta-analysis outcomes for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion.
profiles, as these were described differently in the three studies. As each paper discussed estimated blood loss differently, this data was unable to be pooled for analysis.
3. Results Our search strategy identified 84 abstracts that were screened, with three full-text manuscripts meeting all inclusion criteria: Edelman (2006) [9], Drey (2014) [10], and Goldberg (2015) [11] for a total of 457 patients. All included studies were randomized controlled trials using osmotic dilators combined with either placebo or misoprostol for cervical preparation for D&E after 16 weeks gestation (Table 1). The study protocols in our analysis varied in several significant ways including by gestational age of patients, type of osmotic dilator used, and procedure location [9–11]. All studies used buccal misoprostol 400 mcg for dosing and route, but with variation in timing from 90 minutes to three hours prior to procedure [9–11]. The protocols also varied in the type of osmotic dilator used; two used laminaria whereas in the final, largest study, providers used both laminaria and DilapanÒ. Each study reported procedure times and initial dilation (Table 2). Procedure times in minutes were shorter with adjunctive misoprostol than placebo by approximately one and a half minutes. Additional manual dilation was high in both groups, with
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
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E.P. Cahill et al. / Contraception xxx (xxxx) xxx Table 1 Individual study characteristics and misoprostol timing for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion. Author, year
Gest Age (weeks)
n
Groups
N per group
Timing: miso to procedure
Timing: dilators to procedure
Primary Outcome
Procedure Setting(s)
Edelman, 2006
16–20 6/7
63
L+M L+P
31 32
60–90 min
1 day prior
Initial Dilation
Urban surgical center
19–20 6/7
29
Drey, 2014
21–23 1/7
196
L+M L+P L+M
12 17 98
3–4 h
1 day prior
Procedure Time
Urban hospital-based abortion clinic
Goldberg, 2015
16–18 6/7
102
L+P D+P+M D+P+P
98 51 51
3 h ± 30 min
1 day prior
Procedure Time
Multiple urban stand-alone abortion clinics, hospital-based abortion clinics and hospital operating rooms
19–23 6/7
96
D+P+M D+P+P
48 48
Legend: L = Laminaria, D = osmotic Dilators of any type, P = Placebo, M = Misoprostol.
Table 2 Individual study procedure characteristics for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion. Author, year
Gest Age, weeks
N
Groups
Mean Procedure Time, minutes mean ± SD
p
Pre-Op Cervical Dilation, mm mean ± SD Median (IQR)
p
Additional Dilation n (%)
p
Edelman, 2006
16–20 6/7
63
L+M
7.5 ± 3.2
0.65
17 ± 1.9
0.16
19 (61%)
0.79
L+P
7.8 ± 2.6
16.3 ± 1.7
21 (65%)
19–20 6/7
29
L+M
8.5 ± 3.3
0.85
18 ± 1.8
0.01
6 (50%)
0.44
Drey, 2014
21–23 1/7
196
L+P L+M
8.3 ± 2.5 10.6 ± 4.9
0.02
16 ± 1.7 25 (23.7–26.3)
0.04
11 (64%) 9 (8%)
1
Goldberg, 2015
16–18 6/7
102
L+P D+P+M
13.1 ± 8.1 8.26 ± 5.9
0.33
24.3 (22.3–25.7) 24 ± 10
0.02
10 (8%) 5 (10%)
0.03
D+P+P
8.19 ± 5.9
D+P+M
10.35 ± 7.9
D+P+P
13.39 ± 8.5
19–23 6/7
98
20 ± 4.0 0.01
25 ± 8.0 24 ± 5.0
18 (35%) 0.19
4 (8%)
0.34
8 (17%)
Legend: L = Laminaria, D = osmotic Dilators of any type, P = Placebo, M = Misoprostol.
more subjects who received placebo requiring manual dilation (16.2% vs 24.9%). We pooled results and reported overall crude summary statistics, weighted by number of participants (Table 3). When we weighted by inverse variance, no outcome was statistically significant in the meta-analysis (Table 4).
Table 3 Pooled analysis of procedure characteristics and complications for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion.
Total Participants, N Procedure Time (min) Mean ± SD Additional Dilation Required N (%) All complications* N (%) Major Complications** N (%) Cervical Lacerations N (%)
Misoprostol
Placebo
228 8.3 ± 4.6
229 9.6 ± 5.9
37 (16.2%)
57 (24.9%)
25 (11%)
26 (12%)
10 (4.4%)
16 (7.0%)
13 (5.7%)
9 (3.9%)
*All complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics alone, cervical laceration, re-aspiration. **Major complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics.
For the meta-analysis, data from each study were pooled and weighted by the inverse variance from each study (Table 4, Fig. 1). None of our outcomes of interest were statistically significant (Fig. 1). Most studies reported the most commonly known complications of D&E including cervical laceration, uterine perforation, hemorrhage, delivery prior to procedure as well as a total complication score. In all studies, complications were rare. Comparing adjunctive misoprostol to placebo, there was no statistical difference in total complications (p = 0.61), major complications (p = 0.44), or cervical lacerations specifically (p = 0.87). The highest total complication rate (23% in misoprostol group, 16% in placebo group) was reported in the study of women 21– 23 weeks and was mainly cervical lacerations (13% in misoprostol group, 6% in placebo group). The authors attribute much of this to lower uterine segment pressure, defined as a subjective sensation by the surgeon of the fetal parts compressing against the lower uterine segment and making it difficult to pass instruments. They suggest that the contractions caused by the misoprostol may make this sensation more likely. Lower uterine segment pressure was not reported in any of the other studies, making comparison difficult. We also compared side effects in the misoprostol versus placebo groups, specifically cramping. Each study had different metrics for evaluating and reporting side effects making a
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
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E.P. Cahill et al. / Contraception xxx (xxxx) xxx
Table 4 Summary of weighted meta-analysis outcomes for overnight dilators with adjunctive misoprostol compared to placebo for second trimester abortion. Outcome
Total Participants, n
% (CI) IV, random effect
I2
p
Procedure Time Only > 19 weeks Additional Dilation Required Only > 19 weeks Pre-Operative Cervical Dilation# All Complications*,^ Major Complications**,^ Cervical Lacerations^
457 321 457 321 165 457 457 457
0.32 ( 2.53, 1.89) 1.66 ( 3.64, 0.32) 0.68 (0.36, 1.28) 0.75 (0.47, 1.21) 2.04 ( 1.14, 5.21) 0.61 (0.09, 4.13) 0.47 (0.07, 3.20) 0.81 (0.06, 10.49)
88% 52% 67% 0% 77% 83% 67% 66%
0.78 0.10 0.23 0.24 0.21 0.61 0.44 0.87
*All complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics alone, cervical laceration, re-aspiration. **Major complications: uterine perforation, hospitalization, hemorrhage requiring more intervention than uterotonics. #Does not include Drey et al. as no mean (SD) of dilation was reported. ^Does not include Edelman et al. as no RR could be calculated due to 0 complications reported in either group.
meta-analysis of this data impossible. For example, Edelman et al. asked women about cramping and found a higher frequency in women who received misoprostol compared with placebo (81% vs 50%, p = 0.02). Drey et al. used a four-point scale (0–4) for assessing pain before, during, and after procedure. Women who received adjunctive misoprostol were more likely to report severe or unbearable pain before the procedure (52% vs 11% p < 0.001) but there was no difference in pain after procedure. Goldberg et al. report the percentage of women experiencing ‘‘unacceptable or very unacceptable” pain levels prior to procedure was higher in misoprostol group (37% vs 9%, p < 0.001), but the authors do not report on pain during or after procedure. Regardless of metric used, all studies found that women who received misoprostol reported more pain after administration of medication and before procedure than women who received placebo.
4. Discussion We found that adjunctive misoprostol did not significantly decrease procedure time or the need for additional dilation when compared with placebo in a weighted meta-analysis. There was insufficient data, even with three pooled studies, to definitively demonstrate differences in complication rates or blood loss. Both of these outcomes are important and further studies should be done with the aim of investigating these outcomes. One concern some have with use of misoprostol is greater potential for cervical lacerations due to a more softened cervix. Indeed, in one study there were significantly more cervical lacerations in the adjunctive misoprostol group [10]. The authors of this study suggest that increased lower uterine segment pressure was a potential cause for this increase in lacerations. This increase in cervical lacerations in the misoprostol group was not demonstrated in the two other studies. In a different study evaluating adjunctive misoprostol with same-day osmotic dilators (excluded from our meta-analysis), a decrease in cervical lacerations was noted in the misoprostol group compared with placebo [12]. In all studies included in this analysis, overall complication rates including cervical lacerations were very low and we did not have adequate statistical power to evaluate in this analysis, or to evaluate differences in techniques that may confound this risk. However, given the large difference in complication rates between sites, it is possible that different techniques of D&E may lend themselves to different risks of cervical laceration and perforation. For example, given the mechanism of misoprostol, the uterus is more likely to contract down and push pregnancy tissue into lower uterine segment. This may reduce the risk of perforation as pregnancy tissue is farther from fundus. However, it can be more difficult to compress in this part of the uterus. To reduce the risk of cervical laceration, we sug-
gest no force be applied to ring forceps on cervical lip as pregnancy tissue is removed. Instead, counter traction with pressure on speculum during removal and using only gentle traction can decrease risk of cervical lacerations. Misoprostol is a prostaglandin analog that acts on receptors to soften the cervix. This may expedite the procedure and reduce complications as additional dilation is not as likely to be needed. It also causes uterine contractions, which may serve to expedite the procedure, as pregnancy may be in the process of expulsion. It also may explain the potential for a reduction in blood loss as bleeding is reduced when the uterus contracts down more quickly. We were unable to explore adjunctive misoprostol’s effect on blood loss in this analysis due to differences in reporting of this outcome between the studies. Recent work demonstrates that estimated blood loss may severely underestimate actual blood loss in D&E, particularly at later gestational ages [13]. Further research to evaluate the impact of misoprostol on blood loss is needed. Misoprostol has many advantages for use for cervical preparation, including it is inexpensive, stable at room temperature, and widely available. While mifepristone has been shown to have a similar efficacy to an additional day of osmotic dilators and to be better tolerated than misoprostol, it is not widely available; therefore alternative options are clinically important [4]. Misoprostol is already widely used for cervical preparation in early second trimester abortion alone or with osmotic dilators. A recent retrospective study of 274 women evaluated cervical preparation with same-day osmotic dilators plus misoprostol for D&E by highly skilled surgeons from 18 to 21 + 6 weeks gestation [14]. All procedures were completed the same day with a mean procedure time of 10 min (SD 4.2), which is within the range of the procedure times found in this meta-analysis. The authors found only two immediate complications (one cervical laceration, one extramural delivery) occurred. While this was retrospective and not compared with placebo, this study does demonstrate feasibility of one-day cervical preparation with adjunctive misoprostol for mid-second trimester procedures. Particularly for women living in states where they have to travel far distances to obtain a safe abortion in the mid to late second trimester, who may have to miss work, pay for childcare, as well as lodging in the area while undergoing an abortion procedure, any regimen that improves ability to obtain a safe abortion in the fewest days possible will increase access and ease. Our study includes all available data on a randomized comparison of adjunctive misoprostol compared with placebo for cervical preparation for mid to late second trimester abortion to date. It provides an important foundation for conducting further research on adjunctive misoprostol and provides a framework for future studies. The biggest limitation is the heterogeneity of the studies in terms of gestational ages included, administration of misoprostol,
Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005
E.P. Cahill et al. / Contraception xxx (xxxx) xxx
osmotic dilator type, and outcomes investigated. In the outcomes analyzed, the I2 statistic, a measure of heterogeneity ranged from 0% to 88%, with all outcomes >60%, signifying greater than moderate heterogeneity. Despite being the only studies that met our inclusion criteria, they differed in very significant ways, including gestational age, procedure setting, osmotic dilators used, timing of misoprostol, and outcome measurements. However, this is the only data we have available at this time. Meta-analyses remind us of the importance of standardizing outcome measurements, particularly reports of pain and blood loss, in order to draw conclusions about optimal cervical preparation. All studies had high rates of manual dilation ranging from 8% to over 60%, with over 50% of patients in the Edelman study requiring additional dilation in all groups (Table 2). In that study, the mean number of laminaria placed was just over two in the over 19-week gestation group, whereas all participants in the Drey et al. study had at least eight laminaria placed and the participants in the Goldberg study had over seven dilators placed, on average. The primary outcome in two of these studies is procedure time, which is perhaps not the most clinically relevant outcome, despite being considered a surrogate for time spent managing complications. More clinically relevant outcomes have been suggested including ability to complete the procedure the same day (compared to two-day dilators) and complication rates, including blood loss or cervical lacerations. Additionally, even pooling this data did not provide adequate power to detect differences in such small rates of complications. While second trimester abortion remains uncommon, it is increasingly more common for women to have to travel distances to access care. This has increased the importance of finding methods that decrease cervical preparation time without increasing procedure time or complication rates. The findings of this meta-analysis do not demonstrate a clear benefit of adjunctive misoprostol with overnight osmotic dilators. Further research is needed to definitively determine if adjunctive misoprostol has an effect on blood loss and rate of complications.
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Please cite this article as: E. P. Cahill, A. Henkel, J. G. Shaw et al., Misoprostol as an adjunct to overnight osmotic dilators prior to second trimester dilation and evacuation: A systematic review and meta-analysis, Contraception, https://doi.org/10.1016/j.contraception.2019.09.005