Prior Uterine Evacuation of Pregnancy As Independent Risk Factor

Home , Dilation and curettage, Dilation and evacuation

Systematic Review ajog.org Prior uterine evacuation of pregnancy as independent risk factor for preterm birth: a systematic review and metaanalysis Gabriele Saccone, MD; Lisa Perriera, MD; Vincenzo Berghella, MD

reterm birth (PTB) is the number BACKGROUND: Preterm birth (PTB) is the number one cause of perinatal mortality. Prior P one cause of perinatal mortality in surgery on the cervix is associated with an increased risk of PTB. History of uterine many countries, including the United evacuation, by either induced termination of pregnancy (I-TOP) or spontaneous abortion States.1,2 Defining risk factors for pre- (SAB), which involve mechanical and/or osmotic dilatation of the cervix, has been diction of PTB is an important goal for associated with an increased risk of PTB in some studies but not in others. several reasons. First, identifying women OBJECTIVE: The objective of the study was to evaluate the risk of PTB among women at risk allows initiation of risk-specific with a history of uterine evacuation for I-TOP or SAB. treatment.3,4 Second, it may define a DATA SOURCES: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, EMBASE, population useful for studying particular and Sciencedirect) were searched from their inception until January 2015 with no limit interventions. Finally, it may provide for language. important insights into the mechanisms STUDY ELIGIBILITY CRITERIA: We included all studies of women with prior uterine leading to PTB. evacuation for either I-TOP or SAB, compared with a control group without a history of Prior surgery on the cervix, such as uterine evacuation, which reported data about the subsequent pregnancy. cone biopsy and loop electrosurgical STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcome was the inci- excision procedure, is associated with an dence of PTB < 37 weeks. Secondary outcomes were incidence of low birthweight (LBW) increased risk of spontaneous PTB.5-7 and small for gestational age (SGA). We planned to assess the primary and the secondary A history of uterine evacuation, by outcomes in the overall population as well as in studies on I-TOP and SAB separately. The either induced termination of pregnancy pooled results were reported as odds ratio (OR) with 95% confidence interval (CI). (I-TOP) or treatment of spontaneous RESULTS: We included 36 studies in this metaanalysis (1,047,683 women). Thirty-one abortion (SAB) by suction dilation and studies reported data about prior uterine evacuation for I-TOP, whereas 5 studies re- curettage or by dilation and evacuation ported data for SAB. In the overall population, women with a history of uterine evacuation for (D&E), which may involve mechanical either I-TOP or SAB had a significantly higher risk of PTB (5.7% vs 5.0%; OR, 1.44, 95% CI, and/or osmotic dilatation of the cervix, 1.09e1.90), LBW (7.3% vs 5.9%; OR, 1.41, 95% CI, 1.22e1.62), and SGA (10.2% vs has been associated with an increased 9.0%; OR, 1.19, 95% CI, 1.01e1.42) compared with controls. Of the 31 studies on I-TOP, risk of PTB in some studies but not in 28 included 913,297 women with a history of surgical I-TOP, whereas 3 included 10,253 others.8-10 women with a prior medical I-TOP. Women with a prior surgical I-TOP had a significantly Some studies have also postulated that higher risk of PTB (5.4% vs 4.4%; OR, 1.52, 95% CI, 1.08e2.16), LBW (7.3% vs 5.9%; OR, the method of uterine evacuation may 1.41, 95% CI, 1.22e1.62), and SGA (10.2% vs 9.0%; OR, 1.19, 95% CI, 1.01e1.42) influence the association (or not) with compared with controls. Women with a prior medical I-TOP had a similar risk of PTB PTB.9,10 Moreover, with recent increases compared with those who did not have a history of I-TOP (28.2% vs 29.5%; OR, 1.50, 95% in the use of medications (misoprostol CI, 1.00e2.25). Five studies, including 124,133 women, reported data about a subsequent and mifepristone), it would be impor- pregnancy in women with a prior SAB. In all of the included studies, the SAB was surgically tant to assess outcomes in subsequent managed. Women with a prior surgical SAB had a higher risk of PTB compared with those pregnancies after medical termination of who did not have a history of SAB (9.4% vs 8.6%; OR, 1.19, 95% CI, 1.03e1.37). pregnancy as the element of cervical CONCLUSION: Prior surgical uterine evacuation for either I-TOP or SAB is an independent trauma is minimized with these risk factor for PTB. These data warrant caution in the use of surgical uterine evacuation techniques.11 and should encourage safer surgical techniques as well as medical methods. The aim of this metaanalysis was to evaluate the risk of PTB among women Key words: abortion, delivery, miscarriage, preterm termination of pregnancy with a history of uterine evacuation for either I-TOP or SAB.

From the Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy (Dt Saccone), and Division of Gynecology (Dr Perriera), Department of Obstetrics and Gynecology, and Division of Maternal-Fetal Medicine (Dr Berghella), Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA. Received Nov. 10, 2015; revised Dec. 19, 2015; accepted Dec. 21, 2015. The authors report no conﬂict of interest. Corresponding author: Vincenzo Berghella, MD. [email protected] 0002-9378/$36.00 ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ajog.2015.12.044

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Materials and Methods clamp, or forceps). VA was defined as evacuation (for either I-TOP or SAB) Search strategy evacuation of the uterine contents using was defined as a nonsurgical uterine Electronic databases (ie, MEDLINE, an electric vacuum aspirator or manual evacuation in which pharmaceutical Scopus, ClinicalTrials.gov, EMBASE, vacuum aspirator. Medical uterine drugs are used to empty the uterus. Sciencedirect) were searched from their inception until January 2015 with no limit for language. Search terms used TABLE 1 were the following key words: low birth- Potential overall, sensitivity, and subgroup analyses planned weight, premature birth, preterm birth, small for gestational age, miscarriage, Intervention group Control group pregnancy, premature, newborn, uterine Overall analysis evacuation, abortion, induced abortion, Prior uterine evacuation (I-TOP and SAB) No prior uterine evacuation spontaneous abortion, termination of pregnancy, curettage, first trimester, sec- Planned sensitivity analyses in women with prior uterine evacuation for I-TOP ond trimester, mifepristone, misoprostol, laminaria, subsequent, and dilatation and Prior I-TOP No prior I-TOP evacuation; dilation and curettage; Prior surgical (either D&E or VA) I-TOP No prior I-TOP spontaneous preterm birth. Prior surgical I-TOP by D&E No prior I-TOP In addition, the reference lists of all Prior surgical I-TOP by VA No prior I-TOP identified articles were examined to a identify studies not captured by elec- Prior surgical I-TOP by D&E Prior surgical I-TOP by VA tronic searches. The electronic search Prior medical I-TOP No prior I-TOP and the eligibility of the studies were Planned sensitivity analyses in women independently assessed by the authors with prior uterine evacuation for SAB (G.S. and V.B.). Differences were Prior SAB No prior SAB resolved by discussion. Prior surgical (either D&E or VA) SAB No prior SAB Study selection Prior surgical SAB by VA No prior SAB We included all studies of women with Prior surgical SAB by D&E No prior SAB prior uterine evacuation for either I- a TOP or SAB, compared with a control Prior surgical SAB by D&E Prior surgical SAB by VA group without prior uterine evacuation, Prior medical SAB No prior SAB which reported data about the subse- Planned sensitivity analyses quent pregnancy. We excluded studies comparing I-TOP with SAB without a control group (eg, case series) Prior uterine evacuation for I-TOP Prior uterine evacuation for SABa as well as studies about stillbirth. I-TOP was defined as an intervention Planned subgroup analyses in study on to voluntarily terminate a pregnancy (ie, I-TOP and in study on SAB, separately induced abortion) by either surgical or Only 1 prior uterine evacuation No prior uterine evacuation medical means so it does not result in a More than 1 prior uterine evacuation No prior uterine evacuation fi live birth. SAB was de ned as sponta- More than 1 prior uterine evacuation Only 1 prior uterine evacuationa neous intrauterine pregnancy loss prior to 20 weeks. Surgical uterine evacuation Prior uterine evacuation in singletons No prior uterine evacuation in singletons (for either I-TOP or SAB) was defined as Prior uterine evacuation in multiple No prior uterine evacuation in multiple a procedure using surgical instruments, gestations gestations either D&E or vacuum aspiration (VA), Prior uterine evacuation in cohort studies No prior uterine evacuation in cohort studies to remove the fetus and placenta from Prior uterine evacuation in No prior uterine evacuation in the uterus. case-control studies case-control studies fi D&E was de ned as a procedure that According to gestational age at — includes mechanical cervical dilatation uterine evacuation (usually by using uterine dilators of increasing diameter to stretch the cervix) D&E, dilation and evacuation; I-TOP, induced termination of pregnancy; SAB, spontaneous abortion; VA, vacuum aspiration. a Because none of the included studies evaluated this outcome, we used an indirect comparison metaanalysis to assess this followed by the removal of uterine con- outcome. tents using a combination of suction and Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016. instruments (eg, sharp curette, ring

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Therefore, we had the potential for FIGURE 1 several sensitivity analyses according to Flow diagram of studies identiﬁed in the systematic review the type of abortion (Table 1). Primary and secondary outcomes were planned a priori. The primary outcome was the incidence of PTB (ie, preterm delivery < 37 weeks). Second- ary outcomes were neonatal outcomes including incidence of low birthweight (birthweight < 2500 g) and of small for gestational age (birthweight < 10th percentile for gestational age). We planned to assess the primary and the secondary outcomes in the overall population as well as in studies on I-TOP and SAB, separately. We also planned several subgroup analyses according to the number of prior uterine evacuation; the number of fetuses in the index pregnancy; the gestational age at abortion; or the type of the study (either cohort or case-control study) (Table 1). We assessed these subgroup analyses for only the primary outcome (ie, incidence of PTB) in both surgical and medical I-TOP and SAB, separately and not in the overall combined data (Table 1).

Data extraction and risk of bias assessment Data abstraction was completed by 2 independent investigators (G.S. and V.B.). Each investigator independently abstracted data from each study separately. Data from each eligible study were extracted without modiﬁcation of original data onto custom-made data collection forms. Differences were resolved by consensus. Information of confounders adjusted and adjusted risk estimates were collected when available. When possible, all authors were con- tacted for missing data. Reviewers (G.S. and V.B.) independently assessed the risk of bias of the included studies via the Methodological Index for Non-Randomized Studies.12 Seven domains related to risk of bias were assessed in each study: (1) aim (ie, clearly stated aim), (2) rate (ie, inclusion of consecutive patients and response rate), (3) data (ie, prospective collection of data), (4) bias (ie, unbiased assess- I-TOP, induced termination of pregnancy; PTB, preterm birth; SAB, spontaneous abortion. ment of study endpoints), (5) time Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016. (ie, follow-up time appropriate), (6) loss

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(ie, loss to follow-up), and (7) size (ie, for Systematic Reviews and Meta- control studies16,20,28,31,34,36,38-41,43;7 calculation of the study size).4 Review Analyses statement.15 were large, high-quality population-based authors’ judgments were categorized as studies.30,32,35,42,45,47,51 The majority had low risk, high risk, or unclear risk of bias. Results a low risk of bias in the aim and the time. Discrepancies were resolved by Study selection and study discussion. characteristics Synthesis of results We included 36 studies in this meta- Uterine evacuation for induced termina- Data analysis analysis (1,047,683 women).16-51 The tion of pregnancy or spontaneous abortion: The data analysis was completed inde- flow of study identification is shown in combined data. In the overall population, pendently by two authors (G.S. and V.B.) Figure 1. Risk of publication bias was women with a history of uterine evacu- using Review Manager 5.3 (Copenhagen, assessed by visual inspection of funnel ation for either I-TOP or SAB had a Denmark: The Nordic Cochrane Centre, plot; the symmetric plot suggested no significantly higher risk of PTB (5.7% vs Cochrane Collaboration, 2014).13 Dis- publication bias (Figure 2). Publication 5.0%; OR, 1.44, 95% CI, 1.09e1.90; crepancies were resolved by discussion. bias, assessed using Begg’s and Egger’s Figure 4A; 34 studies, 1,031,320 Heterogeneity across studies was tests, showed no significant bias (P ¼.87 women), low birthweight (7.3% vs 5.9%; assessed using the Higgins I2 test.13 In and P ¼ .71, respectively). OR, 1.41, 95% CI, 1.22e1.62; Figure 4B; case of statistically significant heteroge- Thirty-one studies reported data 11 studies, 675,197 women), and small neity (I2 > 0%), the random-effects about prior uterine evacuation for I- for gestational age (10.2% vs 9.0%; OR, model of DerSimonian and Laird was TOP, whereas 5 studies reported data 1.19, 95% CI, 1.01e1.42; Figure 4C; used; otherwise, in case of no inconsis- regarding prior uterine evacuation for 3 studies, 43,411 women) compared tency in risk estimates (ie, I2 ¼ 0%), a SAB (Tables 2, 3, and 4).34,40,42,43,51 with controls (ie, women without a his- fixed-effect model was managed. The The quality of the studies included in tory of uterine evacuation). pooled results were reported as odds ratio our metaanalysis was assessed by (OR) with 95% confidence interval (CI). the Methodological Index for Non- Induced termination of pregnancy. Of the For the outcomes not directly assessed Randomized Studies’ tool for 31 studies reporting data regarding I- by any of the included studies, an indi- assessing the risk of bias (Figure 3).12 Nine TOP, 28 included 913,297 women with a rect comparison metaanalysis was per- of the included studies were history of surgical I-TOP,16-33,35-39,41,44-47 formed (Table 1).13 In the indirect retrospective cohorts,17-19,21,25,26,33,37,44 whereas 3 included 10,253 women comparison metaanalyses, data were whereas 9 were prospective co- with a prior medical I-TOP (Tables 2 combined in a 2-stage approach in which horts;22-24,27,29,46,48-50 11 were case- and 3).48-50 Women with a history of outcomes were analyzed in their original study and then summary statistics combined using standard summary data FIGURE 2 metaanalysis techniques to give an Funnel plot for assessing publication bias overall measure of effect (summary relative risk with 95% CI).13 For studies that reported both unad- justed and adjusted risk for confounders statistically proven, we performed metaanalyses using a generic inverse variance method to obtain the adjusted risk estimate (aOR) of the primary outcome (ie, incidence of PTB).13,14 We assessed the aOR only for the primary outcome (ie, incidence of PTB) in studies on both surgical and medical I-TOP and SAB, separately.14 Before data extraction, the review was registered with the PROSPERO Inter- national Prospective Register of Sys- tematic Reviews (registration number CRD42015026482). Therefore, all the analyses and the outcomes were planned a priori before the data extraction. OR, odds ratio. The metaanalysis was reported Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016. following the Preferred Reporting Item

MAY 2016 American Journal of Obstetrics & Gynecology 575 ytmtcReview Systematic 576 TABLE 2 mrcnJunlo Obstetrics of Journal American Characteristics of the included studies on surgically induced termination of pregnancy Number of Study included Method of Study location Type of study women abortion GA at abortion Confounders adjusted Primary outcome Pantelakis et al, 197316 Greece Case-control 4779 Surgical N/A None PTB Papaevangelou et al, Greece Retrospective cohort 3467 Surgical N/A None PTB 197317 Daling and Emmanuel, Taiwan Retrospective cohort 1516 Surgical N/A None PTB 18 & 1975 Gynecology Daling and Emmanuel, United States Retrospective cohort 553 D&E N/A None PTB 197719 Van der Slikke and The Netherlands Case-control 3432 Surgical N/A None GA at delivery 20 A 2016 MAY Treffers, 1978 World Health Europe Retrospective cohort 3352 Surgical N/A None GA at delivery Organization, 197921 Obel, 197922 Denmark Prospective cohort 497 Surgical N/A None Placental complications Mandelin and Finland Prospective cohort 696 Surgical N/A None Birthweight Karjalainen, 197923 Meirik et al, 198224 Sweden Prospective cohort 1442 Vacuum < 13 wks Marital status, smoking Birthweight Linn et al, 198325 United States Retrospective cohort 9823 Surgical N/A Age, ethnicity, smoking, economic Birthweight status, parity Meirik et al, 198326 Sweden Retrospective cohort 1292 Vacuum < 13 wks Marital status, smoking PTB Meirik et al, 198427 Sweden Prospective cohort 269 Prostaglandins < 13 wks Parity PTB followed by D&E Park et al, 198428 Korea Case-control 681 Surgical None N/A PTB Frank et al, 198529 United Kingdom Prospective cohort 1545 Surgical < 22 wks Age, marital status, gestational LBW age at entry Pickering and Forbes, United Kingdom Population-based 7000 Surgical N/A Maternal age, height, sex of infant, marital PTB 198530 cohort study status, social class Lekea-Karanika et al, Greece Case-control 4391 Surgical N/A Race, smoking PTB 199031 Martius et al, 199832 Germany Population-based 106,124 Surgical N/A Gravidity, uterine surgery, PTB case-control study type of work, urinary tract infection Zhou et al, 199933 Denmark Retrospective cohort 64,125 Surgical <14 wks Maternal age PTB

Henriet and Kaminski, French Population-based 12,336 Surgical < 22 wks Maternal age, parity, SGA ajog.org 200135 cohort study education, smoking

Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016. (continued) ajog.org Systematic Review

uterine evacuation for I-TOP had a signiﬁcantly higher risk of PTB (5.5% vs 4.4%; OR, 1.52, 95% CI, 1.09e2.13; Figure 5A, 29 studies, 907,187 women), low birthweight (7.3% vs 5.9%; OR, 1.41, 95% CI, 1.22e1.62; Figure 5B; 11 studies, 675,197 women), and small for gesta-

PTB PTB N/A tional age (10.2% vs 9.0%; OR, 1.19, 95% CI, 1.01e1.42; Figure 5C; 3 studies, 43,411 women) compared with controls (ie, women without history of uterine evacuation for I-TOP).

Surgically induced termination of pregnancy

, both dilatation and evacuation and vacuum. Table 2 shows the characteristics of the included studies on surgical I- TOP. 16-33,35-39,41,44-47 A total of 913,297 women from 28 studies with at least 1 Surgical abortion prior surgical I-TOP were included.

education, maternal BMI social class, smoking, parity education, smoking, alcohol consumption, parity, uterine surgery Seventeen studies reported information on confounders and adjusted risk estimates.24-33,35,37-39,45-47 Ten (continued) studies included only singleton gesta- 17-21,23,32,35,44,46 , small for gestational age; tions. The vast majority 14 wks Maternal age, weight, marital status, SGA < (27 of the 28) stratiﬁed data for number of prior I-TOP, whereas 1 did not report informative data about it.36

, preterm birth; Most of the studies had incidence of

PTB PTB as the primary outcome. Regarding the method of abortion, 5 studies Method of abortion GA at abortion Confounders adjusted Primary outcome deﬁned the procedure as only VA, 24,26,37,44,45 5 studies deﬁned the procedure as only D&E,19,27,36,46,47

45,631 D&E N/Awhereas the Smoking, social class others used both methods. PTB Number of included women 577,510 Vacuum N/A Maternal age, weight, smokingOne study reported PTB the use of prostaglandins followed by D&E.27 Women with a prior surgical I-TOP , data not reported in the original study; had a signiﬁcantly higher risk of PTB N/A (5.4% vs 4.4%; OR, 1.52, 95% CI, 1.08e2.16; Figures 6A; 27 studies,

cohort study cohort study 906,297 women), low birthweight (7.3% e

, low birth weight; vs 5.9%; OR, 1.41, 95% CI, 1.22 1.62;

LBW Figure 6B; 11 studies, 675,197 women), and small for gestational age (10.2% vs 9.0%; OR, 1.19, 95% CI, 1.01e1.42; Figure 6C; 3 studies, 43,411 women) Study location Type of study FrenchChina Case-controlUnited States Retrospective Case-control cohortEurope 17,411 2707French D&E VacuumFinland Case-control 654 Case-control SurgicalScotland N/A N/A Retrospective cohort 7721 26,967Multicenter N/A Surgical Population-based 2561Scotland Vacuum Parental None Prospective age, cohort occupation, Surgical N/A Population-based Maternal 4812 age, race, smoking, parity N/A D&E Maternal age, PTB marital status, None N/A PTB Maternal age, weight, smoking PTB PTB

, gestational age; compared with controls (ie, women GA 44 without a history of uterine evacuation 46 47 41 for I-TOP). 39

37 The risk of PTB was still signiﬁcantly 36 higher after adjusting for confounders statistically proven, including marital

38 45 status, smoking, age, ethnicity, economic , dilatation and evacuation; Fox-Helias and Blondel, 2000 TABLE 2 Characteristics of the included studies on surgically induced termination of pregnancy Study D&E Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016. Che et al, 2001 Ancel et al, 2004 Raatikainen et al, 2006 Woolner et al, 2014 McCarthy et al, 2013 El-Bastawissi et al, 2003 Moreau et al, 2005 Bhattacharya et al, 2012 status, parity, maternal height, race, social class, gestational age at entry,

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TABLE 3 Characteristics of the included studies on medically induced termination of pregnancy Number of Study Type of included GA at Confounders Primary Study location study women Method of abortion abortion adjusted outcome Zhu et al, China Prospective 9363 200 mg mifepristone < 14 wks None Placental 200948 cohort complications Mirmilstein Australia Prospective 154 400 mg misoprostol 14-24 wks None PTB et al, 200949 cohort Winer et al, France Prospective 736 200 mg mifepristone < 22 wks None PTB 200950 cohort followed by 400 mg misoprostol GA, gestational age; PTB, preterm birth. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

gravidity, parity, parental age, education, significantly higher risk of PTB comparison metaanalysis, we found body mass index, uterine surgery, type of compared with those who received VA that women with more than 1 prior work, alcohol consumption, urinary (5.5% vs 3.6%; OR, 1.54, 95% CI, surgical I-TOP had a significantly tract infection, and sex of the infant 1.38e1.73). higher risk of PTB compared with (aOR, 1.25, 95% CI, 1.13e1.38; Figure 7; those who had only 1 prior surgical I- 16 studies, 874,080 women). Subgroup analysis: number of prior I- TOP (23.4% vs 5.1%; OR, 5.65, 95% TOP. Women with only 1 prior surgical CI, 5.10e6.25). Subgroup analysis: method of abortion. I-TOP had a significantly higher risk Comparing the women with a prior of PTB compared with those who did Subgroup analysis: number of fetuses. In a surgical I-TOP with those who did not, not have any prior I-TOP (5.1% subgroup analysis of studies in which both VA (3.6% vs 3.1%; OR, 1.20, 95% vs 4.4%; OR, 1.53, 95% CI, 1.02e2.31; only singleton gestations in the index CI, 1.16e1.24; Figure 8;5studies, Figure 10A; 23 studies, 875,356 pregnancy were enrolled, women with 609,912 women) and D&E (5.5% vs women). Women with more than 1 a history of surgical I-TOP had a signif- 4.3%; OR, 1.39, 95% CI, 1.08e1.80; prior surgical I-TOP had a significantly icantly higher risk of PTB compared Figure 9; 5 studies, 68,679 women) were higher risk of PTB compared with with controls (9.6% vs 6.6%; OR, 1.45, associated with an increased risk of those without any prior I-TOP (23.4% 95% CI, 1.27e1.65; Figure 11;10 PTB. Moreover, by using an indirect vs 8.6%; OR, 1.98, 95% CI, 1.46e2.68; studies, 152,668 women). No separate comparison metaanalysis, we found Figure 10B; 9 studies, 165,085 women). data about multiple gestations were that women who received D&E had a Moreover, by using an indirect reported in any studies.

TABLE 4 Characteristics of the included studies on spontaneous abortion Number of included Method of GA at Confounders Primary Study Study location Type of study women abortion abortion adjusted outcome Doyle 200034 Taiwan Case-control 12,273 Surgical N/A None PTB Nguyen Vietnam Case-control 1709 Surgical N/A None PTB et al, 200440 Smith et al, Scotland Population-based 84,391 Surgical N/A None PTB 200642 case-control Selo-Ojeme and United Kingdom Case-control 206 Surgical N/A None PTB Tewari, 200643 Freak-Poli et al, Australia Population-based 25,554 Surgical < 20 wks None N/A 200951 case-control study D&E, dilatation and evacuation; GA, gestational age; LBW, low birth weight; N/A, data not reported in the original study; PTB, preterm birth; SGA, small for gestational age; Surgical abortion, either dilatation and evacuation or vacuum. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

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FIGURE 3 Assessment of risk of bias

A, Summary of the risk of bias for each study. Plus sign indicates a low risk of bias; minus sign indicates a high risk of bias; question mark indicates an unclear risk of bias. B, Risk of bias graph about each risk of the bias item presented as percentages across all included studies. Aim, clearly stated aim; Bias, unbiased assessment of study endpoints; Data, prospective collection of data; Loss, loss to follow-up; Rate, inclusion of consecutive patients and response rate; Size, calculation of the study size; Time, follow-up time appropriate. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

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FIGURE 4 Primary and secondary outcomes in women with uterine evacuation for induced termination of pregnancy or spontaneous abortion

Forest plot for primary outcome (ie, risk of preterm birth) and for secondary outcomes (ie, low birthweight, small for gestational age) in overall women with a history of uterine evacuation for either induced termination of pregnancy or spontaneous abortion. A, Risk for PTB. B, Risk for LBW. C, Risk for SGA. CI, conﬁdence interval; LBW, low birthweight; M-H, Mantel-Haenszel test; PTB, preterm birth; SGA, small for gestational age. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

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FIGURE 5 Primary and secondary outcomes in induced termination of pregnancy

Forest plot for primary outcome (ie, risk of preterm birth) and for secondary outcomes (ie, low birthweight, small for gestational age) in women with a history of uterine evacuation for induced termination of pregnancy. A, Risk for PTB. B, Risk for LBW. C, Risk for SGA. CI, conﬁdence interval; I-TOP, induced termination of pregnancy; LBW, low birthweight; M-H, Mantel-Haenszel test; PTB, preterm birth; SGA, small for gestational age. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

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FIGURE 6 Primary and secondary outcomes in uterine evacuation for surgically induced termination of pregnancy

Forest plot for primary outcome (ie, risk of preterm birth) and for secondary outcomes (ie, low birthweight, small for gestational age) in women with a history of uterine evacuation for surgically induced termination of pregnancy. A, Risk for PTB. B, Risk for LBW. C, Risk for SGA. CI, conﬁdence interval; I-TOP, induced termination of pregnancy; LBW, low birthweight; M-H, Mantel-Haenszel test; PTB, preterm birth; SGA, small for gestational age. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

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FIGURE 7 Adjusted estimates for primary outcome in surgically induced termination of pregnancy

Adjusted estimates forest plot for primary outcome (ie, risk of preterm birth) in women with a history of surgically induced termination of pregnancy. CI, conﬁdence interval; IV, independent variable. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

Subgroup analysis: type of study. Of 28 analysis of only case-control studies Subgroup analysis: gestational age at included studies (Table 2),16-33,35-39,41,44-47 (15.7% vs 8.2%; OR, 1.52, 95% CI, abortion. Only 7 studies reported data 9 were case-control,16,20,28,31,32,36,38,39,41 1.31e1.75; 9 studies, 145,193 women), regarding gestational age at abor- whereas 19 were cohort studies.17-19,21- whereas the risk was similar in the tion.24,26,27,29,33,35,44 In subgroup anal- 27,29,30,33,35,37,44-47 Comparing I-TOP subgroup analysis of only cohort ysis of studies that included only women group with controls, women with a studies (4.7% vs 3.7%; OR, 1.55, 95% with a prior first-trimester (< 14 weeks) prior surgical I-TOP had a significant CI, 0.90e2.68; 18 studies, 761,104 surgical I-TOP,24,26,27,33,44 there was no higher risk of PTB in the subgroup women). statistically significant difference in the

FIGURE 8 Primary outcome in surgically induced termination of pregnancy with vacuum aspiration

Forest plot for primary outcome (ie, risk of preterm birth) in women with a history of surgically induced termination of pregnancy with vacuum aspiration. CI, conﬁdence interval; I-TOP, induced termination of pregnancy; M-H, Mantel-Haenszel test; PTB, preterm birth; VA, vacuum aspiration. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

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FIGURE 9 Primary in surgically induced termination of pregnancy with dilatation and evacuation

Forest plot for primary outcome (ie, risk of preterm birth) in women with a history of surgically induced termination of pregnancy with dilatation and evacuation. CI, conﬁdence interval; D&C, dilatation and evacuation; I-TOP, induced termination of pregnancy; M-H, Mantel-Haenszel test; PTB, preterm birth. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

risk of PTB comparing I-TOP group None of the included studies adjusted compared with those who had a history with controls (17.5% vs 4.5%; OR, 2.36, the incidence of PTB for confounders of uterine evacuation for I-TOP (9.4% vs 95% CI, 0.39e14.11; Figure 12; 5 studies statistically proven, so assessed the aOR 5.5%; OR, 1.80, 95% CI, 1.68e1.92). 94,096 women). by using generic inverse variance method was not feasible. Comment Medically induced termination of Main findings pregnancy Spontaneous termination of pregnancy. This metaanalysis evaluated the effect of Only 3 studies, including 10,253 women, Five studies, including 124,133 women, prior uterine evacuation on future PTB reported data about subsequent preg- reported data about subsequent preg- risk. We found that prior surgical uterine nancy in women with a prior medical I- nancy in women with a prior evacuation, for either I-TOP or SAB, was TOP (Table 3).48-50 SAB.42,43,51 In all of the included an independent risk factor for PTB. A One study enrolled women with a studies, the SAB was surgically summary of our findings is reported in prior first-trimester mifepristone I- managed. Two of them were large Table 5. Women with at least 1 prior TOP,48 1 study enrolled women with a population-based studies,42,51 whereas surgical I-TOP had a significantly higher prior midtrimester misoprostol I-TOP,49 the others were case-control studies risk of PTB, low birthweight, and small whereas the other study enrolled women (Table 4). Women with prior surgical for gestational age compared with those with prior misoprostol and mifepristone management of SAB had a higher risk of who did not have any prior surgical I-TOP in either the first or mid- PTB compared with those who did not I-TOP. Women with more than 1 prior trimester.50 All 3 of the studies were a have a history of SAB (9.4% vs 8.6%; surgical I-TOP had a significantly higher prospective cohort and enrolled only OR, 1.19, 95% CI, 1.03e1.37; Figure 14; risk of PTB compared with those who women with just 1 prior medical I-TOP. 5 studies, 124,133 women). Because of had only 1 prior surgical I-TOP. One study reported only data about the limited data, assessing subgroup and Subgroup analyses revealed a higher placental complications as outcomes,48 sensitivity analyses were not feasible. risk of PTB for both VA and D&E. The and so only 2 studies with 890 women None of the included studies adjusted risk of PTB was significantly higher in were included in the pooled results for the incidence of PTB for confounders theD&EgroupcomparedwiththeVA the primary outcome. statistically proven, so assessing the group. Data about medical I-TOP and Women with a prior medical I-TOP aOR by using generic inverse variance about SAB were limited. However, we had a similar risk of PTB compared with method was not feasible. did not find an increased risk of PTB those who did not have a prior medical I- in women with a history of medical I- TOP (28.2% vs 29.5%; OR, 1.50, 95% Spontaneous abortion vs induced TOP. The clinical significance of a CI, 1.00e2.25; Figure 13; 2 studies, 890 termination of pregnancy higher rate of PTB associated with women). No data were available By using an indirect comparison meta- uterine evacuation for SAB vs uterine regarding secondary outcomes. Because analysis, we found that women who had evacuation for I-TOP is of unclear of the limited data, assessing subgroup a history of uterine evacuation for SAB clinical significance and requires and sensitivity analyses were not feasible. had a significantly higher risk of PTB further study (Table 5).

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FIGURE 10 Primary outcome of prior terminations of pregnancy in surgically induced termination of pregnancy

Forest plot for primary outcome (ie, risk of preterm birth) according to number of prior termination of pregnancy in women with history of surgically induced termination of pregnancy. A, Women with only 1 prior surgical I-TOP. B, Women with more than 1 prior surgical I-TOP. CI, conﬁdence interval; I-TOP, induced termination of pregnancy; M-H, Mantel-Haenszel test; PTB, preterm birth. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

Comparison with existing literature include all currently available studies, Strengths and limitations One other metaanalysis has evaluated outcomes considered were different, Our study has several strengths. To our the risk of PTB in women with prior subgroup and sensitivity analyses were knowledge, no prior metaanalysis on this surgical I-TOP.10 Shah and Zao10 not performed, the number of issue is as large, up to date, or compre- showed that a previous surgical I- included women was lower, and hensive. The number of the included TOP was associated with an increased medical I-TOP and SAB were not women is large. Most of the included risk of PTB. However, it did not analyzed.10 studies had incidence of PTB as the

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FIGURE 11 Primary outcome in singleton gestations with surgically induced termination of pregnancy

Forest plot for primary outcome (ie, risk of preterm birth) in singleton gestations with a history of surgically induced termination of pregnancy. CI, conﬁdence interval; I-TOP, induced termination of pregnancy; M-H, Mantel-Haenszel test; PTB, preterm birth. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016. primary outcome. We planned several of preterm delivery, as a potential dilators used for surgical I-TOP to subgroup and sensitivity analyses to confounder.25,27,32,35,38,44 Women who analyze the effect of cervical trauma reduce the heterogeneity between the have induced abortions typically have a related to the size of dilators. Most of studies and to have higher-quality data. lower socioeconomic status, are more the included studies did not report Limitations of our study are inherent likely to smoke, and generally have other gestational age of prior surgical TOP to to the limitations of the included risk factors for PTB.1-4 analyze whether late surgical TOP has studies. Most of the studies did not In all of the included studies, cervical different effect than early surgical TOP. report a mechanism of surgical abortion dilatation was performed mechanically Some studies compared women with and did not control appropriately for using uterine dilators; none of them prior surgical TOP to nulliparous confounders. Only 6 studies included used balloon catheter or laminaria. No women whereas others to multiparous parity, an important determinant studies reported the size or type of women.

FIGURE 12 Primary outcome in ﬁrst-trimester surgically induced termination of pregnancy

Forest plot for primary outcome (ie, risk of preterm birth) in women with a history of ﬁrst-trimester (< 14 weeks) surgically induced termination of pregnancy. CI, conﬁdence interval; I-TOP, induced termination of pregnancy; M-H, Mantel-Haenszel test; PTB, preterm birth. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

586 American Journal of Obstetrics & Gynecology MAY 2016 ajog.org Systematic Review

FIGURE 13 Primary outcome in medically induced termination of pregnancy

Forest plot for primary outcome (ie, risk of preterm birth) in women with a history of medically induced termination of pregnancy. CI, conﬁdence interval; I-TOP, induced termination of pregnancy; M-H, Mantel-Haenszel test; PTB, preterm birth. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

Half of more than 1 million women I-TOP did not report data regarding Data regarding PTB referred to both included in this metaanalysis were previous cervical preparation with cer- spontaneous and indicated as the etiology drawn from a single national register- vical ripening, which could lead to less of PTB. Most outcomes had a very high based cohort study.45 In this study, cervical injury; only 1 study reported the statistically heterogeneity, and this was a Bhattacharya et al45 reported that data use of prostaglandins before D&E.27 major shortcoming of the metaanalysis. regarding smoking were frequently None of the included studies re- Notably, the PTB rate in the control group missing and that the interpregnancy ported data about the type of VA, ranged widely from approximately 4% to interval was much shorter in the I-TOP whether electric vacuum aspirator or approximately 29%. Whereas most of the group compared with the controls. manual vacuum aspirator. Because comparisons are statistically significant Moreover, the specific methods of abor- women face a stigma when reporting on (Table 5), their clinical significance may tion were not well described.45 Bhatta- an induced abortion, women in the case be valued by some clinicians and patients charya et al also found no increased risk or control group could have omitted I- as less compelling; for example, the dif- of PTB after the first I-TOP. TOP from their medical history, which ference in the incidence of PTB in women There were no randomized controlled wouldleadtounderreportingofabor- with a prior uterine evacuation is just trials included in the metaanalysis and tion in the control group and under- 0.7% higher in absolute numbers (5.7%) no studies comparing prior medical with reporting of the number of abortions in than in women without prior uterine prior surgical uterine evacuation. Data the case group. This recall bias has the evacuation (5.0%). about medical I-TOP and about SAB potential to have a dramatic impact on were limited. Search strategies for the risk of PTB associated with uterine Implications retrieving studies in electronic databases evacuation procedures, particularly if The are many methods of abortion.52-61 are limited, and this could have influ- abortion were underreported in the The procedure used depends largely on enced our findings. Study on surgical control group. the stage of pregnancy and the size of the

FIGURE 14 Primary outcome in spontaneous abortion

Forest plot for primary outcome (ie, risk of preterm birth) in women with a history of spontaneous abortion. M-H, Mantel-Haenszel test; CI, conﬁdence interval; PTB, preterm birth; SAB, spontaneous abortion. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

MAY 2016 American Journal of Obstetrics & Gynecology 587 Systematic Review ajog.org

TABLE 5 Summary of the pooled results for the risk of preterm birth Intervention group Control group Results, n, %a OR, 95% CI Overall analysis — Women with prior uterine evacuation Women with no prior uterine evacuation 9170/160,143 (5.7%) vs OR, 1.44, 95% CI, (both I-TOP and SAB) 43,750/871,177 (5.0%) 1.09e1.90b Planned sensitivity analyses in women with — prior uterine evacuation for I-TOP Women with prior I-TOP (either surgical Women with no prior I-TOP 8159/149,395 (5.5%) vs OR, 1.52, 95% CI, or medical) 34,034/757,792 (4.4%) 1.09e2.13b Women with prior surgical (either D&E or Women with no prior I-TOP 8110/149,221 (5.4%) vs OR, 1.52, 95% CI, VA) I-TOP 33,823/757,076 (4.4%) 1.08e2.16b Women with prior surgical I-TOP by VA Women with no prior I-TOP 4553/125,554 (3.6%) vs OR, 1.20, 95% CI, 15,063/484,358 (3.1%) 1.16e1.24b Women with prior surgical I-TOP by D&E Women with no prior I-TOP 342/6232 (5.5%) vs 2657/ OR, 1.39, 95% CI, 62,447 (4.3%) 1.08e1.80b Women with prior surgical I-TOP by D&E Women with prior surgical I-TOP by VA 342/6232 (5.5%) vs 4553/ OR, 1.54, 95% CI, 125,554 (3.6%) 1.38e1.73b Women with prior medical I-TOP Women with no prior I-TOP 49/174 (28.2%) vs 211/716 OR, 1.50, 95% CI, (29.5%) 1.e2.25 Planned subgroup analyses in women with prior uterine evacuation for I-TOP Women with only one prior surgical Women with no prior I-TOP 7,336/142,543 (5.1%) vs OR, 1.53, 95% CI, (either D&E or VA) I-TOP 32,578/732,813 (4.4%) 1.02e2.31b Women with more than one prior surgical Women with no prior I-TOP 518/2,209 (23.4%) vs OR, 1.98, 95% CI, (either D&E or VA) I-TOP 14,022/162,876 (5.1%) 1.46e2.68b Women with more than one prior surgical Women with only one prior surgical (either 518/2209 (23.4%) vs 7336/ OR, 5.65, 95% CI, (either D&E or VA) I-TOP D&E or VA) I-TOP 142,543 (5.1%) 5.10 to 6.25 Women with prior surgical (either D&E or Women with no prior surgical (either D&E or 1129/11,766 (9.6%) vs OR, 1.45, 95% CI, VA) I-TOP with singleton gestation in the VA) I-TOP with singleton gestation in the 10,058/151,492 (6.6%) 1.27 to 1.65b index pregnancy index pregnancy Women with prior surgical (either D&E or Women with no prior surgical (either D&E or — Not feasible VA) I-TOP with multiple gestation in the VA) I-TOP with multiple gestation in the index pregnancy index pregnancy Women with prior surgical (either D&E or Women with no prior surgical (either D&E or 6568/139,372 (4.7%) vs OR, 1.55, 95% CI, VA) I-TOP in only cohort studies VA) I-TOP in only cohort studies 22,714/621,732 (3.7%) 0.90e2.68 Women with prior surgical (either D&E or Women with no prior surgical (either D&E or 1542/9849 (15.7%) vs OR, 1.52, 95% CI, VA) I-TOP in only case-control studies VA) I-TOP in only case-control studies 11,109/135,344 (8.2%) 1.31e1.75b Women with prior surgical (either D&E or Women with no prior surgical (either D&E or 1063/6083 (17.5%) vs 3947/ OR, 2.36, 95% CI, VA) I-TOP in the ﬁrst trimester (< 14 wks) VA) I-TOP in the ﬁrst trimester (< 14 wks) 88,013 (4.5%) 0.39e14.11 Planned sensitivity analyses in women with — prior uterine evacuation for SAB Women with prior surgical Women with no prior SAB 1,011/10,748 (9.4%) vs OR, 1.19, 95% CI, (either D&E or VA) SAB 9,716/113,385 (8.6%) 1.03e1.37b Women with prior surgical SAB by VA Women with no prior SAB — Not feasible Women with prior surgical SAB by D&E Women with no prior SAB — Not feasible Women with prior surgical SAB by D&E Women with prior surgical SAB by VA — Not feasible Women with prior medical SAB Women with no prior SAB — Not feasible

Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016. (continued)

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TABLE 5 Summary of the pooled results for the risk of preterm birth (continued) Intervention group Control group Results, n, %a OR, 95% CI Planned subgroup analyses in women with prior uterine evacuation for SAB Women with only 1 prior SAB Women with no prior SAB — Not feasible Women with more than 1 prior SAB Women with no prior SAB — Not feasible Women with more than 1 prior SAB Women with only 1 prior SAB — Not feasible Women with prior SAB with singleton Women with no prior SAB with singleton — Not feasible gestation in the index pregnancy gestation in the index pregnancy Women with prior SAB with multiple Women with no prior SAB with multiple — Not feasible gestation in the index pregnancy gestation in the index pregnancy Women with prior SAB in only case- Women with no prior SAB in only case- — Not feasible control studies control studies Women with prior SAB in only cohort Women with no prior SAB in only cohort — Not feasible studies studies Subgroup analysis according to — Not feasible gestational age at prior uterine evacuation for SAB Planned analysis in women with prior uterine evacuation for SAB vs women with prior uterine evacuation for I-TOP Women with prior SAB Women with prior I-TOP 1011/10,748 (9.4%) vs OR, 1.80, 95% CI, 8159/149,395 (5.5%) 1.68e1.92b CI, conﬁdence interval; D&E, dilation and evacuation; I-TOP, induced termination of pregnancy; OR, odds ratio; SAB, spontaneous abortion; VA, vacuum aspiration. a Data are presented as number in the intervention group vs number in the control group (with percentages); b Statistically signiﬁcant. Saccone. Abortion and risk of preterm birth. Am J Obstet Gynecol 2016.

fetus.52 Dilatation of the cervix is anesthesia is given to the pregnant is the most effective and fastest required during surgical methods of woman and her cervix is quickly dilated. regimen.60 Typically, mifepristone 200 abortion.52 In contrast to normal birth, Surgical evacuation with the added mg is followed by the use of misoprostol during which the dilation occurs slowly insertion of a spoon-shaped scraper 24-48 hours later.61 over a period of many hours, during a (curette) is not the preferred method to The biological plausibility to explain surgical abortion, the cervix is usually evacuate the uterus because it is associ- the higher risk of PTB in women with mechanically stretched.53 This stretching ated with more complications.52 a history of uterine evacuation is not of the cervix may result in permanent Compared with labor-induction abor- completely clear. However, 3 main physical injury to the cervix.53 Osmotic tion, surgical uterine evacuation offers a hypotheses can be made. Previous dilators are often used to reduce the need more predictable timing of evacuation studies have suggested that infectious for mechanical dilation. Osmotic di- and greater cost savings.52 Moreover, this diseases following surgical uterine evac- lators are inserted into the cervix prior to surgical procedure also allows women to uation account for the increased risk the procedure, and they absorb water avoid the labor-like process of a medical of PTB.62,63 The increased risk of and swell, gradually stretching the cervix induction. Medical abortion is effective PTB could result from the overt or open.54 throughout the ﬁrst and the second covert infection following surgically VA or suction dilation and curettage trimester; however, in randomized trials uterine evacuation62 as well as from may be used to evacuate the uterus up to it has been shown to have greater com- mechanical trauma to the cervix, 16 weeks’ gestation. This is the most plications when compared with surgical leading to increased risk of cervical common way to evacuate the uterus in uterine evacuation.58 It is the termina- insufﬁciency.5,6,8 the developed world.55,56 In gestations tion of pregnancy by stimulation of The greater mechanical dilation of the above 8-12 weeks, misoprostol is often labor-like contractions that cause even- cervix obtained during the D&E used in combination with mechanical tual expulsion of the fetus and placenta compared to VA58-59 could explain the dilation to prepare the cervix prior from the uterine cavity.59 The combi- higher risk of PTB in women with a prior to evacuation.57 General and/or local nation of mifepristone and misoprostol D&E compared with those with a history

MAY 2016 American Journal of Obstetrics & Gynecology 589 Systematic Review ajog.org of VA. Moreover, surgical procedures abortion, more research is needed. In Development and validation of a new instrument. including curettage during D&E may particular, there is a need for random- ANZ J Surg 2003;73:712-6. 13. Higgins JPT, Green S, eds. Cochrane result in scar tissue that may increase the ized controlled trials that investigate handbook for systematic reviews of in- probability of faulty placental implanta- whether technical interventions (eg, terventions, version 5.1.0 (update March 2011). tion. Indeed, same studies reported an cervical preparation before uterine The Cochrane Collaboration; 2011. Available at: association between prior D&E and evacuation) diminish the risk of PTB www.cochrane-handbook.org. Accessed Jan. subsequent complications such as pre- associated with surgical uterine evacu- 15, 2014. 14. Peters J, Mengersen K. 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