Effectiveness and adverse effects of vaginal misoprostol as a single agent for second trimester pregnancy termination: The impact of fetal viability

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Methods Singleton pregnancies with live fetuses and dead fetuses, between 14 and 28 weeks, with unfavorable cervix were recruited to have pregnancy termination with intravaginal misoprostol 400 mcg every 6 hours. Results Misoprostol was highly effective for termination, with a low failure rate of 6.3%. The effectiveness was significantly higher in pregnancies with a dead fetus (log-rank test; p: 0.008), with median delivery time of 11.2 vs 16.7 hours. Fetal viability, fetal weight or gestational age and an initial Bishop score were significantly related with total amount of misoprostol dosage used for induction. Fetal viability and gestational age / fetal weight were still an independent factor after adjustment on multivariate analysis. Conclusion Vaginal misoprostol is highly effective for second trimester termination, with significantly higher effectiveness in pregnancies with a dead fetus. Also, the effectiveness is significantly associated with birth weight / gestational age, and initial Bishop score, suggesting that the regimen of misoprostol should be modified, depending on fetal viability and gestational age. Dead fetus in utero pregnancy termination second trimester misoprostol Figures Figure 1 Figure 2 Figure 3 Figure 4 Take Home Message Effectiveness of is vaginal misoprostol significantly associated with fetal viability, birth weight / gestational age, and initial Bishop score, suggesting that the regimen of misoprostol should be modified, depending on fetal viability and gestational age. Introduction Termination of pregnancy (TOP) both with dead fetus and live fetus in the second trimester is still challenging. Various techniques have been practiced, either by medical or surgical approach. Medical methods seem to be less complicated, easier in management and more widely accepted by most patients, whereas surgical methods (such as dilation and evacuation) are more invasive and need experienced physicians to perform the procedures. In the developed countries or in the perfect settings of medical facilities, safety and success rates of surgical methods (dilatation and evacuation) and medical methods (misoprostol plus mifepristone) in second trimester TOP are comparable [ 1 , 2 ]. Though in experienced hands, surgical methods seems to be safe in terms of less complications such as infection, blood transfusion and retained product of conception, when compared to misoprostol [ 3 ], serious morbidity like cardiopulmonary arrest complicated by dilatation and evacuation could be found. Of medical methods, misoprostol plus mifepristone are preferred for second trimester termination while misoprostol alone is also a reasonable alternative, especially, in the low resource settings. Accordingly, misoprostol is the most commonly used methods worldwide, especially where mifepristone is unavailable [ 4 ]. According to WHO guidelines, misoprostol as a single agent 400 mcg every 4–6 hours and every 3 hours are recommended for second trimester termination of dead fetuses (14–28 weeks) and induced abortion ( ≥ 12 weeks), respectively [ 5 ]. The regimens for pregnancies with dead or live fetuses are mostly based on expert opinion with limited data. Based on meta-analysis of medical abortion in the second trimester [ 6 ], while the optimal route for administering misoprostol is vaginally, several aspects of analysis are limited by the fetal viability, gestational age ranges and variable medical regimens. Though, the efficacy of misoprostol on second trimester termination seems theoretically to be higher in pregnancies with dead fetus in utero, the evidence supporting such a hypothesis is limited. The knowledge concerning of the effectiveness of misoprostol alone on the two groups is expected to be helpful in counseling and predicting the successful outcomes and, more importantly, serve as a base for development of the different regimens for the two entities. Therefore we conducted this study with the primary objective to compare the effectiveness of vaginal misoprostol (400 mcg every 6 hours) for second trimester termination between pregnancies with a dead fetus in utero and those with a live fetus. The secondary objectives are to identify potential factors associated with the success rate of termination and also to compare the adverse effects between the two groups. Patients And Methods This study is a retrospective comparative study based on our prospective database to compare the effectiveness and adverse effects of the same regimen of second trimester termination between the pregnancies with dead fetus in utero and those with live fetuses. The study was conducted at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai university, Thailand, with ethical approval by the Institution Review Boards, Faculty of Medicine, Chiang Mai University ( Research Study ID 8182). The prospective database was developed in 1997 to collect all consecutive cases of misoprostol use in our Department. On the database development, written informed consent was obtained from all participants. The baseline demographic data (such as maternal age, parity, obstetric history, gestational age, etc.) and clinical data (such as Bishop score details of drug administration, adverse effects associated with misoprostol, intravenous analgesia requirement, need of oxytocin, induction to fetal delivery time, induction-to-placenta delivery, estimated blood loss, total amount of misoprostol dosage used, etc.) were assessed and prospectively recorded in the research form. The success of termination was defined as fetal delivery within 48 hours after initiation of misoprostol administration. The pregnancies recruited to the study met the following criteria: 1) Singleton pregnancy; 2) Gestational age between 14 and 28 weeks of pregnancy; 3) Unfavorable cervix, defined as Bishop score of four or less; 4) the presence of medical indication for pregnancy termination; and 5) receiving the regimen of intravaginal misoprostol 400 mcg every 6 hours. The exclusion criteria are as follows: 1) The presence of spontaneous labor pain (regular uterine contraction with cervical progression) before misoprostol administration; 2) Rupture of membranes before misoprostol administration; 3) Previous cesarean section or major uterine surgery such as myomectomy. After the initiation of the first dose, misoprostol was repeated every 6 hours if the Bishop score was still of four or less and adequate uterine contractions could not be achieved. However, if the cervix was unfavorable but uterine contraction was adequate, the scheduled dose of misoprostol was skipped and reassessed again at the scheduled time interval. If adequate uterine contraction was not achieved and the cervix was still unfavorable, misoprostol was then repeated again. If the cervix became favorable (Bishop score > 4) but adequate uterine contractions were not achieved, misoprostol at the scheduled time interval was discontinued and intravenous oxytocin was infused by automatic infusion pump, starting with 2 mU/min and increased, if necessary, every 15 min to 4, 8, 12, 16, 20, 25, and maximum of 30 mU/min. Intravenous meperidine 50 mg for painful labor was prescribed, as requested by the women. Successful termination was defined as fetal delivery within 48 hours of induction. The main outcomes included the success rate of termination, induction-to-fetal delivery time, induction-to-placental delivery time and total amount of misoprostol dosage used. Statistical analysis was performed using the statistical package for the social sciences (SPSS) software version 26.0 (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp). The baseline data were presented as mean ± SD or median (IQR) for continuous data, as appropriate and percentage for categorical data. In comparisons, Chi-square test was used for the categorical variables, whereas Student T test or Mann-Whitney-U was used for continuous variables as appropriate. Regression analysis was performed to identify the correlation between clinical variables and total amount of misoprostol dosage. Kaplan-Meier survival curve as well as log rank test was used to compare the effectiveness of pregnancy termination between the two groups. A p-value of less than 0.05 was defined as statistical significance. Results During the study period, a total of 192 pregnancies met the inclusion criteria and are available for analysis. including 64 pregnancies with dead fetuses in utero (DFU) and 128 pregnancies with viable fetuses. Baseline characteristics of the participants were comparable, as presented in Table 1 . Note that initial Bishop scores were 1 and 2 in most cases. Among the group of live fetuses, indications for pregnancy termination were fetal severe thalassemia and fetal chromosomal / structural abnormalities in more than 90% of cases. Table 1 Baseline characteristics of participants DFU (n = 64) Live fetus (n = 128) p-value Age (years): mean ± SD 30.41 ± 6.81 30.69 ± 6.88 0.7834 Gestational age (weeks): median (q 1 – q 3 ) 20 (17.50–25) 21 (18–22) 0.2684 : mean ± SD 21.0 ± 3.9 20.2 ± 2.9 0.101 Birth weight 342.7 ± 214.2 381.7 ± 223.5 0.315 Initial Bishop score: median (q 1 – q 3 ) 1 (1–2) 1 (1–2) 0.3505 : mean ± SD 1.53 ± 1.11 1.32 ± 0.92 0.165 Nulliparous: n (%) 41 (64.06) 80 (62.50) 0.8330 Indication for pregnancy termination: n(%) • Intrauterine fetal death 64 (100.0) - • Fetal chromosomal/structural anomalies: n (%) - 69 (53.91) • Fetal severe thalassemia: n (%) - 49 (38.28) • Others - 10 (7.81) Common side effects of misoprostol between the two groups were not significantly different, as presented in Table 2 . No any case of uterine rupture was documented in this series and also no any case of blood loss of greater than 500 ml was observed in both groups. Interestingly, the rate of oxytocin requirement was significantly lower in the group of DFU (3.13% vs 12.50%; p-value : 0.036), whereas the rate of analgesia requirement and that of curettage requirement for incomplete abortion were comparable. Importantly, total amount of misoprostol dosage (mcg) as well as the number of drug administrations were significantly lower in the group of DFU. Table 2 Side effects and other variables DFU (n = 64) Live fetus (n = 128) p-value Fever (BT > 38.0 C): n (%) 25 (39.06) 60 (46.88) 0.3040 (b) Chill: n (%) 19 (29.69) 44 (34.88) 0.5140 (b) Diarrhea: n (%) 10 (15.63) 18 (14.06) 0.7720 (b) Nausea: n (%) 2 (3.13) 8 (6.25) 0.5000 (c) Vomiting: n (%) 2 (3.13) 5 (3.91) > 0.9999 (c) Intravenous analgesia requirement: n (%) 19 (29.69) 52 (40.63) 0.1390 (b) Curettage required for incomplete abortion: n (%) 12 (18.75) 15 (11.72) 0.1860 (b) Uterine rupture: n (%) 0 (0.00) 0 (0.00) Estimated blood loss (ml): median (q 1 – q 3 ) 100 (50–200) 100 (50–200) 0.3461 (a) : mean ± SD 127 ± 95 149 ± 124 0.211 Blood loss > 500 ml: n (%) 0 (0.00) 0 (0.00) In comparisons of the effectiveness of misoprostol for pregnancy termination in the second trimester, induction to fetal delivery interval in the DFU group was significantly shorter than that in the live fetus group (11.4 vs 16.7 hours, p-value < 0.001), as presented in Table 3 . Likewise, induction to placental delivery interval was also significantly shorter in the DFU group (12.0 vs 16.9 hours, p-value: 0.001). Considering the cases of successful termination within 48 hours, the effectiveness in the group of DFU was also significantly higher than that in the group of live fetuses, in terms of induction to fetal and placental delivery time interval, as presented in Table 3 . Of all, the success rate of fetal delivery within 12 hours of induction was significantly in the group of DFU (51.6% vs 32.0%; p-value: 0.009), whereas the success rates at the other time intervals after that were not significantly different. The overall failure rate (defined as fetal delivery time interval of greater than 48 hours) was 6.3% (12/192 cases) with a trend to be lower in the DFU group (3.1% vs 7.8%) but not significantly different, possibly due to the small number of cases). Based on Kaplan-Meier curves, median delivery time was 11.2 hours (95% CI: 7.5–14.7 hours) in the group of DFU and 16.7 hours (95% CI: 14.1–19.2 hours) in the group of live fetuses and the difference of the two delivery curves was statistically significant (Log rank test: p-value: 0.008, as presented in Fig. 1 . Table 3 Comparisons of various parameters associated with effectiveness of pregnancy termination DFU (n = 64) Live fetus (n = 128) p-value Induction fetal delivery interval (hour) for all: median (q 1 – q 3 ) 11.36 (5.9–20.64) 16.66 (10.95–24.83) 0.0009 (a) * Induction fetal delivery interval (hour) for success cases (fetal del within 48 hr) 10.75 (5.58– 19.92) 15.50 (10.62–22.58) 0.0023 (a) * Rate of fetal delivery for all at 12 hours: n (%) 33 (51.56) 41 (32.03) 0.0090 (b) * 24 hours: n (%) 53 (82.81) 94 (73.44) 0.1480 (b) 36 hours: n (%) 56 (87.50) 112 (87.50) > 0.9999 (b) 48 hours: n (%) 62 (96.88) 118 (92.19) 0.3430 (c) Rate of fetal delivery for success cases (fetal del within 48 hr) at 12 hours: n (%) 33 (53.23) 41 (34.75) 0.0170 (b) * 24 hours: n (%) 53 (85.48) 94 (79.66) 0.3370 (b) 36 hours: n (%) 56 (90.32) 112 (94.92) 0.3450 (c) 48 hours: n (%) 62 (100.00) 118 (100.00) Induction placental delivery interval (hour) for all: median (q 1 – q 3 ) 12 (6.49–22.17) 16.88 (11.15–26.43) 0.0010 (a) * Induction placental delivery interval (hour) for success cases (fetal del within 48 hr): median (q 1 – q 3 ) 11.2 (6.32– 20.67) 16 (11.03–23.33) 0.0012 (a) * Oxytocin requirement: n (%) 2 (3.13) 16 (12.50) 0.0360 (b) * Total doses of misoprostol (mcg): median (q 1 – q 3 ) 800 (400–1000) 800 (400–1200) 0.0180 (a) * The number of misoprostol administrations: median (q 1 – q 3 ) 2 (1-2.50) 2 (1–3) 0.0180 (a) * * Significant According to regression analysis between total amount of misoprostol dosage (mcg) in all fetuses as a dependent variable and birth weight as well as gestational age, as presented in Figs. 2 and 3 , The total dosage was significantly inversely associated with fetal weight, gestational age and Bishop score (R 2 : 0.050; p-value: 0.002; R 2 : 0.068; p-value < 0.001, and R 2 : 0.021; p-value < 0.046, respectively). On subgroup analysis, the correlations were still significant in both DFU and live fetuses groups. Multiple regression analysis to identify the significant factors on the total amount of misoprostol dosage demonstrated that status of fetal life and birth weight were independent factors, as presented in Table 4 . Based on standardized coefficient beta, birth weight seemed to have higher inverse impact on the amount of misoprostol dosage than fetal viability. Note that gestational age is not incorporated into the model since it has high collinearity with birth weight or dependence on each other. Table 4 Multiple regression analysis for total amount of misoprostol dosage (mcg) Unstan-dardized B Standardized Coef. Beta P-value 95% Confidence interval for B (Constant) 1271.069 0.000 620.769 1921.369 Viability (Live/dead) 241.165 0.153 0.033 19.705 462.625 Maternal age -11.203 -0.102 0.175 -27.432 5.027 Birth weight -0.680 -0.235 0.002 -1.106 -0.255 Parity (0/1) -23.403 -0.015 0.837 -247.579 200.772 Bishop scores (0–4) -48.605 -0.064 0.388 -159.379 62.169 Discussion The main insights gained from this study are as follows: 1) Misoprostol as a single agent for pregnancy termination in the second trimester is highly effective, with a low failure rate of 6.3%. 2) Misoprostol was significantly higher effective in pregnancies with a dead fetus in utero than that those with a live fetus. The higher success rate was more obvious in the first 12 hours of induction. 3) Side effects of misoprostol were comparable in the two groups but the group of pregnancies with a live fetus had higher rate of oxytocin requirement. 4) Fetal viability, fetal weight or gestational age and an initial Bishop score were significantly related with total amount of misoprostol dosage used for induction. While fetal viability and fetal weight / gestational age were still an independent factor of total dosage use on multiple regression analysis, Bishop score was not significantly, possibly due to too low frequency of the cases with score of 4. The new insights gained from this study are probably helpful in counseling and predicting the successful outcomes. Also, we provide evidence-based insights to support a revisit on current practice in second trimester termination of pregnancy. Our finding of higher effectiveness in the group of dead fetuses was consistent with that in the preliminary study by Srisomboon et al [ 7 ] who compare the induction-to-delivery time between the groups receiving intracervical misoprostol 200 mcg every 12 hours, though different in route, dosage and drug administration interval. Likewise, side effects found in the two groups were not significant different, similar to the findings in the study comparing complications of second- trimester medical termination of pregnancy for fetal anomalies with pregnancy with intrauterine fetal demise [ 8 ]. In evaluation of independent impact factors on the effectiveness of misoprostol, we preferred to assess total amount of misoprostol dosage required for successful termination rather than induction to fetal delivery time. This is due to the fact that, induction-to-delivery time is associated with multiple factors, including higher misoprostol dosage itself which certainly shortens the active phase of labor, oxytocin use and variations of labor curve. Actually, the main purpose of misoprostol is to prime the cervix to become favorable rather than stimulate uterine contraction, though spontaneous contractions commonly occur after misoprostol use. Theoretically, the effectiveness of misoprostol is expected to be higher in pregnancies with fetal death than those with viable fetuses and also in pregnancies in late gestation than those in early gestation. However, the data supporting such a belief is very limited, leading to different recommendations among various guidelines. For examples, WHO guideline [ 5 ] recommends buccal, intravaginal or sublingual 400 mcg every 3 hours for pregnancy termination at 12–28 weeks of gestation, while FIGO guideline [ 9 ] recommends 400 mcg every 3 hours for 13–24 weeks and 200 mcg every 4 hours for 25–28 weeks. Additionally, several guidelines recommend the same regimens regardless of fetal viability. Nevertheless, our findings suggest that for misoprostol administration, fetal viability and gestational age should be taken into account. As noted above, even in our practice in the past, we used the same regimen for second trimester termination from 14–28 weeks of gestation, regardless of fetal viability and Bishop score (0–4). Note that, in our practice, vaginal misoprostol 400 mcg every 6 hours, different from 3-hour interval as recommended by WHO guideline, also is highly effective in both groups. Importantly, our findings support the FIGO guideline [ 9 ], which is based on both fetal viability and gestational age. For example, the FIGO guideline recommends a lower dosage to be 200 mcg for fetal dead during 13–26 weeks and 100 mcg during 27–28 weeks, and higher dosage for pregnancies with a live fetus. Actually, the recommended dosages by the FIGO have been decided on the basis of limited evidence and expert opinion, new evidence is regularly emerging and thus there is a need to review and revise the recommendations in the future [ 9 ]. In other words, pregnancy termination, based on our findings, the same regimen for both pregnancies with dead fetuses and live fetuses and for all gestational age (14–28 weeks), as recommended by several guidelines including that of our own practice, is no longer justified. Note that all pregnancies with viable fetuses were sacrificed, though gestational age of greater than 24 weeks of which we usually make attempts to resuscitate for the highest chance of survival, because they were associated with severe perinatal morbidity. Accordingly, in termination of pregnancy after 24 weeks with expectation of live birth, the misoprostol regimen should be considered differently, lower dosage or longer interval of administration, and intrapartum surveillance must be incorporated to avoid non-reassuring fetal heart rate associated with misoprostol. The limitations of this study include: 1) retrospective nature, though based on prospective database with high reliability; 2) Though the sample size was adequate to address the primary objective, it might be too low for multivariate analysis of some potentials confounders to show their significant effect, for example low frequency of cases with Bishop score of 4. 3) The results represent only the regimen of 400 mcg every 6 hour, which may not reproducible for other regimens. The strengths of this study are as follows: 1) high homogeneity of drug administration in both groups, the same regimen in terms of route, dosage, and interval; 2) comprehensive analysis to compare the effectiveness based on time-event analysis and multiple regression analysis; 3) The findings could represent the effectiveness in actual practice because of being conducted on service setting, not research setting. Future studies concerning termination of pregnancy should focus on incorporation of all of the potential predictors to develop models, probably derived from machine learning, in predicting the chance of successful termination, including misoprostol dosage, route, interval, fetal viability, initial Bishop score, gestational age / estimated fetal weight, etc., to guide the best regimen for an individual rather than one regimen for all. In conclusion, the regimen of vaginal misoprostol 400 mcg every 6 hours is highly effective for second trimester termination with the overall success rate of more than 90%. The regimen is significantly higher effective in pregnancies with a dead fetus. Also, the effectiveness is significantly associated with birth weight / gestational age, fetal viability and initial Bishop score. Our findings suggest that the regimen of misoprostol as a single agent for second trimester termination should be modified, depending on fetal viability and gestational age. Declarations Statement of Ethics: The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Research Ethics Committee, Faculty of Medicine, Chiang Mai University (The Research Ethics Committee 4; Faculty of Medicine, Chiang Mai University; (Research ID: ID 8182). All of the participants provided written informed consents. Funding: This work was supported by The Chiang Mai University Research Fund CMU-2566. The funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The funder had no role in the study design, data collection, data analysis, or the manuscript preparation for publication of the findings. Author contributions: SP: conceptualization, proposal development, acquisition of data, data validation, manuscript writing; NS.: data validation, acquisition of data, manuscript editing, final approval; TT.: data validation, formal analysis and manuscript writing / editing, final approval; All authors have read and agreed to the published version of the manuscript. Data Availability Statement: The datasets analyzed during the current study are available from the corresponding author upon reasonable request. Conflict of interest: None References Jacques L, Heinlein M, Ralph J, et al. Complication rates of dilation and evacuation and labor induction in second-trimester abortion for fetal indications: A retrospective cohort study. Contraception. 2020;102:83-6. McLaren H, Cancino D, McCulloch M, Wolff S, French V. Rates of complication for dilation and evacuation versus induction of labor in treatment of second trimester intrauterine fetal demise. Eur J Obstet Gynecol Reprod Biol. 2022;277:16-20. Sonalkar S, Ogden SN, Tran LK, Chen AY. Comparison of complications associated with induction by misoprostol versus dilation and evacuation for second-trimester abortion. Int J Gynaecol Obstet. 2017;138:272-5. Pongsatha S, Tongsong T. Outcomes of pregnancy termination by misoprostol at 14-32 weeks of gestation: a 10-year-experience. J Med Assoc Thai. 2011;94:897-901. Organization WH. Medical management of abortion. World Health Organization; ‎2018. Wildschut H, Both MI, Medema S, Thomee E, Wildhagen MF, Kapp N. Medical methods for mid-trimester termination of pregnancy. Cochrane Database Syst Rev. 2011;2011:Cd005216. Srisomboon J, Pongpisuttinun S. Efficacy of intracervicovaginal misoprostol in second-trimester pregnancy termination: a comparison between live and dead fetuses. J Obstet Gynaecol Res. 1998;24:1-5. Testani E, Latta K, Barker E, York SL, Laursen L. Complications of second-trimester medical termination of pregnancy for fetal anomalies compared with intrauterine fetal demise. Int J Gynaecol Obstet. 2022. Morris JL, Winikoff B, Dabash R, et al. FIGO's updated recommendations for misoprostol used alone in gynecology and obstetrics. Int J Gynaecol Obstet. 2017;138:363-6. Cite Share Download PDF Status: Published Journal Publication published 06 May, 2023 Read the published version in Archives of Gynecology and Obstetrics → Version 1 posted Reviewers agreed at journal 27 Mar, 2023 Editor invited by journal 22 Mar, 2023 Editor assigned by journal 21 Mar, 2023 First submitted to journal 20 Mar, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2716372","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":186924863,"identity":"cd01e4e3-1350-42de-bc89-56c61f4a5224","order_by":0,"name":"Saipin Pongsatha","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Saipin","middleName":"","lastName":"Pongsatha","suffix":""},{"id":186924864,"identity":"cc3b5662-32ff-465c-986e-064eb5505f76","order_by":1,"name":"Nuchanart Suntornlimsiri","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nuchanart","middleName":"","lastName":"Suntornlimsiri","suffix":""},{"id":186924865,"identity":"4152b501-7f50-4faf-bb1e-2e0e8f499089","order_by":2,"name":"Theera Tongsong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxElEQVRIiWNgGAWjYDACCSjNjyGCC/BAFUhINqCJENZicIBYLfbSzQcfV9Qw1BkfP50mwVBjBxRpwK+FR+ZYsuGZYwwSZmdyt0kwHEsGihwgoEUix0yygQ2o5QYvUAvbAaBIAiEt+d9/NvxjkDCeAdLyjygtOWyMjW1A70sAtTC2EaPlRpqxZGOfhOSMM7mbLRL7knl4bhDQwj4j+eHHhm82/PztZzfe+PDNTo59BgEtUACNC6BiHqLUj4JRMApGwSjADwCvwzacmel9KAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-3389-6478","institution":"Faculty of Medicine, Chiang Mai University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Theera","middleName":"","lastName":"Tongsong","suffix":""}],"badges":[],"createdAt":"2023-03-21 03:04:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-2716372/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-2716372/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00404-023-07068-8","type":"published","date":"2023-05-06T20:42:30+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":34985976,"identity":"ef1d56ed-2adc-4fb6-bddd-64aa4b622e1e","added_by":"auto","created_at":"2023-03-29 14:29:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":157039,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for the rates of no delivery of the groups of DFU and live fetuses as a function of induction to fetal delivery time (Log rank test; p-value 0.008)\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-2716372/v1/a552f961f1eb04a45df8279a.png"},{"id":34985968,"identity":"6ccbff2b-5f02-4c56-8d5f-d27c3bf4cf9d","added_by":"auto","created_at":"2023-03-29 14:29:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":178390,"visible":true,"origin":"","legend":"\u003cp\u003eTotal misoprostol dosage as a function of birth weight (R\u003csup\u003e2\u003c/sup\u003e: 0.050; p-value: 0.002)\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-2716372/v1/5dcf6f4e251e304a7727d211.png"},{"id":34987035,"identity":"2e307e7c-2063-42e8-bc85-c7deaa383d7b","added_by":"auto","created_at":"2023-03-29 14:37:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":183804,"visible":true,"origin":"","legend":"\u003cp\u003eTotal misoprostol dosage as a function of gestational age (R\u003csup\u003e2\u003c/sup\u003e:0.068; p-value\u0026lt;0.001)\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-2716372/v1/212aa0ccf198f92f92fc2ab3.png"},{"id":34985973,"identity":"e565051b-d18c-4d80-bab2-0006aa5e259e","added_by":"auto","created_at":"2023-03-29 14:29:41","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":114487,"visible":true,"origin":"","legend":"\u003cp\u003eTotal misoprostol dosage as a function of Bishop score (R\u003csup\u003e2\u003c/sup\u003e: 0.021; p-value \u0026lt;0.046)\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-2716372/v1/ecf7647d7842e2750ce93d94.png"},{"id":44727946,"identity":"baf6e369-3149-4e50-84e6-6086df1d280c","added_by":"auto","created_at":"2023-10-16 20:56:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":835346,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2716372/v1/de0942c6-5922-458b-8198-63fca1914220.pdf"}],"financialInterests":"","formattedTitle":"Effectiveness and adverse effects of vaginal misoprostol as a single agent for second trimester pregnancy termination: The impact of fetal viability","fulltext":[{"header":"Take Home Message","content":"\u003cp\u003eEffectiveness of is vaginal misoprostol significantly associated with fetal viability, birth weight / gestational age, and initial Bishop score, suggesting that the regimen of misoprostol should be modified, depending on fetal viability and gestational age.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eTermination of pregnancy (TOP) both with dead fetus and live fetus in the second trimester is still challenging. Various techniques have been practiced, either by medical or surgical approach. Medical methods seem to be less complicated, easier in management and more widely accepted by most patients, whereas surgical methods (such as dilation and evacuation) are more invasive and need experienced physicians to perform the procedures. In the developed countries or in the perfect settings of medical facilities, safety and success rates of surgical methods (dilatation and evacuation) and medical methods (misoprostol plus mifepristone) in second trimester TOP are comparable [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Though in experienced hands, surgical methods seems to be safe in terms of less complications such as infection, blood transfusion and retained product of conception, when compared to misoprostol [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], serious morbidity like cardiopulmonary arrest complicated by dilatation and evacuation could be found. Of medical methods, misoprostol plus mifepristone are preferred for second trimester termination while misoprostol alone is also a reasonable alternative, especially, in the low resource settings. Accordingly, misoprostol is the most commonly used methods worldwide, especially where mifepristone is unavailable [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. According to WHO guidelines, misoprostol as a single agent 400 mcg every 4–6 hours and every 3 hours are recommended for second trimester termination of dead fetuses (14–28 weeks) and induced abortion (\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e≥\u003c/span\u003e 12 weeks), respectively [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The regimens for pregnancies with dead or live fetuses are mostly based on expert opinion with limited data. Based on meta-analysis of medical abortion in the second trimester [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], while the optimal route for administering misoprostol is vaginally, several aspects of analysis are limited by the fetal viability, gestational age ranges and variable medical regimens. Though, the efficacy of misoprostol on second trimester termination seems theoretically to be higher in pregnancies with dead fetus in utero, the evidence supporting such a hypothesis is limited. The knowledge concerning of the effectiveness of misoprostol alone on the two groups is expected to be helpful in counseling and predicting the successful outcomes and, more importantly, serve as a base for development of the different regimens for the two entities. Therefore we conducted this study with the primary objective to compare the effectiveness of vaginal misoprostol (400 mcg every 6 hours) for second trimester termination between pregnancies with a dead fetus in utero and those with a live fetus. The secondary objectives are to identify potential factors associated with the success rate of termination and also to compare the adverse effects between the two groups.\u003c/p\u003e "},{"header":"Patients And Methods","content":"\u003cp\u003eThis study is a retrospective comparative study based on our prospective database to compare the effectiveness and adverse effects of the same regimen of second trimester termination between the pregnancies with dead fetus in utero and those with live fetuses. The study was conducted at the Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai university, Thailand, with ethical approval by the Institution Review Boards, Faculty of Medicine, Chiang Mai University ( Research Study ID 8182). The prospective database was developed in 1997 to collect all consecutive cases of misoprostol use in our Department. On the database development, written informed consent was obtained from all participants. The baseline demographic data (such as maternal age, parity, obstetric history, gestational age, etc.) and clinical data (such as Bishop score details of drug administration, adverse effects associated with misoprostol, intravenous analgesia requirement, need of oxytocin, induction to fetal delivery time, induction-to-placenta delivery, estimated blood loss, total amount of misoprostol dosage used, etc.) were assessed and prospectively recorded in the research form. The success of termination was defined as fetal delivery within 48 hours after initiation of misoprostol administration.\u003c/p\u003e\u003cp\u003eThe pregnancies recruited to the study met the following criteria: 1) Singleton pregnancy; 2) Gestational age between 14 and 28 weeks of pregnancy; 3) Unfavorable cervix, defined as Bishop score of four or less; 4) the presence of medical indication for pregnancy termination; and 5) receiving the regimen of intravaginal misoprostol 400 mcg every 6 hours. The exclusion criteria are as follows: 1) The presence of spontaneous labor pain (regular uterine contraction with cervical progression) before misoprostol administration; 2) Rupture of membranes before misoprostol administration; 3) Previous cesarean section or major uterine surgery such as myomectomy.\u003c/p\u003e\u003cp\u003eAfter the initiation of the first dose, misoprostol was repeated every 6 hours if the Bishop score was still of four or less and adequate uterine contractions could not be achieved. However, if the cervix was unfavorable but uterine contraction was adequate, the scheduled dose of misoprostol was skipped and reassessed again at the scheduled time interval. If adequate uterine contraction was not achieved and the cervix was still unfavorable, misoprostol was then repeated again. If the cervix became favorable (Bishop score \u0026gt; 4) but adequate uterine contractions were not achieved, misoprostol at the scheduled time interval was discontinued and intravenous oxytocin was infused by automatic infusion pump, starting with 2 mU/min and increased, if necessary, every 15 min to 4, 8, 12, 16, 20, 25, and maximum of 30 mU/min. Intravenous meperidine 50 mg for painful labor was prescribed, as requested by the women. Successful termination was defined as fetal delivery within 48 hours of induction. The main outcomes included the success rate of termination, induction-to-fetal delivery time, induction-to-placental delivery time and total amount of misoprostol dosage used.\u003c/p\u003e\u003cp\u003eStatistical analysis was performed using the statistical package for the social sciences (SPSS) software version 26.0 (IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Armonk, NY: IBM Corp). The baseline data were presented as mean \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e±\u003c/span\u003e SD or median (IQR) for continuous data, as appropriate and percentage for categorical data. In comparisons, Chi-square test was used for the categorical variables, whereas Student T test or Mann-Whitney-U was used for continuous variables as appropriate. Regression analysis was performed to identify the correlation between clinical variables and total amount of misoprostol dosage. Kaplan-Meier survival curve as well as log rank test was used to compare the effectiveness of pregnancy termination between the two groups. A p-value of less than 0.05 was defined as statistical significance.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period, a total of 192 pregnancies met the inclusion criteria and are available for analysis. including 64 pregnancies with dead fetuses in utero (DFU) and 128 pregnancies with viable fetuses. Baseline characteristics of the participants were comparable, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Note that initial Bishop scores were 1 and 2 in most cases. Among the group of live fetuses, indications for pregnancy termination were fetal severe thalassemia and fetal chromosomal / structural abnormalities in more than 90% of cases.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDFU\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLive fetus\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years): mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.41\u0026thinsp;\u0026plusmn;\u0026thinsp;6.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.69\u0026thinsp;\u0026plusmn;\u0026thinsp;6.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7834\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks): median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (17.50\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 (18\u0026ndash;22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.2684\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e: mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.0\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.2\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;2.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.101\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e342.7\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;214.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e381.7\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;223.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.315\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInitial Bishop score: median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (1\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.3505\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e: mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.53\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.32\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.165\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNulliparous: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (64.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80 (62.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.8330\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndication for pregnancy termination: n(%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Intrauterine fetal death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Fetal chromosomal/structural anomalies: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (53.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Fetal severe thalassemia: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49 (38.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026bull; Others\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (7.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCommon side effects of misoprostol between the two groups were not significantly different, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. No any case of uterine rupture was documented in this series and also no any case of blood loss of greater than 500 ml was observed in both groups. Interestingly, the rate of oxytocin requirement was significantly lower in the group of DFU (3.13% vs 12.50%; p-value : 0.036), whereas the rate of analgesia requirement and that of curettage requirement for incomplete abortion were comparable. Importantly, total amount of misoprostol dosage (mcg) as well as the number of drug administrations were significantly lower in the group of DFU.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSide effects and other variables\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDFU\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLive fetus\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFever (BT\u0026thinsp;\u0026gt;\u0026thinsp;38.0 C): n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (39.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60 (46.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3040 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChill: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (29.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44 (34.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5140 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhea: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (15.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (14.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.7720 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (6.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.5000 (c)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (3.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9999 (c)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIntravenous analgesia requirement: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (29.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52 (40.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.1390 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCurettage required for incomplete abortion: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (18.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15 (11.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.1860 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUterine rupture: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEstimated blood loss (ml): median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100 (50\u0026ndash;200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 (50\u0026ndash;200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3461 (a)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e: mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e149\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.211\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood loss\u0026thinsp;\u0026gt;\u0026thinsp;500 ml: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0 (0.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn comparisons of the effectiveness of misoprostol for pregnancy termination in the second trimester, induction to fetal delivery interval in the DFU group was significantly shorter than that in the live fetus group (11.4 vs 16.7 hours, p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001), as presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Likewise, induction to placental delivery interval was also significantly shorter in the DFU group (12.0 vs 16.9 hours, p-value: 0.001). Considering the cases of successful termination within 48 hours, the effectiveness in the group of DFU was also significantly higher than that in the group of live fetuses, in terms of induction to fetal and placental delivery time interval, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Of all, the success rate of fetal delivery within 12 hours of induction was significantly in the group of DFU (51.6% vs 32.0%; p-value: 0.009), whereas the success rates at the other time intervals after that were not significantly different. The overall failure rate (defined as fetal delivery time interval of greater than 48 hours) was 6.3% (12/192 cases) with a trend to be lower in the DFU group (3.1% vs 7.8%) but not significantly different, possibly due to the small number of cases). Based on Kaplan-Meier curves, median delivery time was 11.2 hours (95% CI: 7.5\u0026ndash;14.7 hours) in the group of DFU and 16.7 hours (95% CI: 14.1\u0026ndash;19.2 hours) in the group of live fetuses and the difference of the two delivery curves was statistically significant (Log rank test: p-value: 0.008, as presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparisons of various parameters associated with effectiveness of pregnancy termination\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDFU\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;64)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLive fetus\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction fetal delivery interval (hour) for all: median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.36 (5.9\u0026ndash;20.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.66 (10.95\u0026ndash;24.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0009 (a) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction fetal delivery interval (hour) for success cases (fetal del within 48 hr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.75 (5.58\u0026ndash; 19.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.50 (10.62\u0026ndash;22.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0023 (a) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRate of fetal delivery for all at\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (51.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (32.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0090 (b) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (82.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (73.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.1480 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (87.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112 (87.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;0.9999 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e48 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (96.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118 (92.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3430 (c)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRate of fetal delivery for success cases (fetal del within 48 hr) at\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (53.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (34.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0170 (b) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53 (85.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94 (79.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3370 (b)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e36 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e56 (90.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e112 (94.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.3450 (c)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e48 hours: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62 (100.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e118 (100.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction placental delivery interval (hour) for all: median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (6.49\u0026ndash;22.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.88 (11.15\u0026ndash;26.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0010 (a) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInduction placental delivery interval (hour) for success cases (fetal del within 48 hr): median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.2 (6.32\u0026ndash; 20.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (11.03\u0026ndash;23.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0012 (a) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxytocin requirement: n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (3.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (12.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0360 (b) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal doses of misoprostol (mcg): median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e800 (400\u0026ndash;1000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e800 (400\u0026ndash;1200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0180 (a) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThe number of misoprostol administrations: median (q\u003csub\u003e1\u003c/sub\u003e \u0026ndash; q\u003csub\u003e3\u003c/sub\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (1-2.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (1\u0026ndash;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.0180 (a) *\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* Significant\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAccording to regression analysis between total amount of misoprostol dosage (mcg) in all fetuses as a dependent variable and birth weight as well as gestational age, as presented in Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e3\u003c/span\u003e, The total dosage was significantly inversely associated with fetal weight, gestational age and Bishop score (R\u003csup\u003e2\u003c/sup\u003e: 0.050; p-value: 0.002; R\u003csup\u003e2\u003c/sup\u003e: 0.068; p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001, and R\u003csup\u003e2\u003c/sup\u003e: 0.021; p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.046, respectively). On subgroup analysis, the correlations were still significant in both DFU and live fetuses groups.\u003c/p\u003e \u003cp\u003eMultiple regression analysis to identify the significant factors on the total amount of misoprostol dosage demonstrated that status of fetal life and birth weight were independent factors, as presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. Based on standardized coefficient beta, birth weight seemed to have higher inverse impact on the amount of misoprostol dosage than fetal viability. Note that gestational age is not incorporated into the model since it has high collinearity with birth weight or dependence on each other.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultiple regression analysis for total amount of misoprostol dosage (mcg)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnstan-dardized B\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStandardized Coef. Beta\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003e95% Confidence \u003c/p\u003e \u003cp\u003einterval for B\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e(Constant)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1271.069\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e620.769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1921.369\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eViability (Live/dead)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e241.165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19.705\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e462.625\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMaternal age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-11.203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.175\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-27.432\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.680\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.235\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.255\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eParity (0/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-23.403\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.837\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-247.579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e200.772\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBishop scores (0\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-48.605\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-0.064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.388\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-159.379\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e62.169\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main insights gained from this study are as follows: 1) Misoprostol as a single agent for pregnancy termination in the second trimester is highly effective, with a low failure rate of 6.3%. 2) Misoprostol was significantly higher effective in pregnancies with a dead fetus in utero than that those with a live fetus. The higher success rate was more obvious in the first 12 hours of induction. 3) Side effects of misoprostol were comparable in the two groups but the group of pregnancies with a live fetus had higher rate of oxytocin requirement. 4) Fetal viability, fetal weight or gestational age and an initial Bishop score were significantly related with total amount of misoprostol dosage used for induction. While fetal viability and fetal weight / gestational age were still an independent factor of total dosage use on multiple regression analysis, Bishop score was not significantly, possibly due to too low frequency of the cases with score of 4. The new insights gained from this study are probably helpful in counseling and predicting the successful outcomes. Also, we provide evidence-based insights to support a revisit on current practice in second trimester termination of pregnancy.\u003c/p\u003e \u003cp\u003eOur finding of higher effectiveness in the group of dead fetuses was consistent with that in the preliminary study by Srisomboon et al [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] who compare the induction-to-delivery time between the groups receiving intracervical misoprostol 200 mcg every 12 hours, though different in route, dosage and drug administration interval. Likewise, side effects found in the two groups were not significant different, similar to the findings in the study comparing complications of second- trimester medical termination of pregnancy for fetal anomalies with pregnancy with intrauterine fetal demise [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn evaluation of independent impact factors on the effectiveness of misoprostol, we preferred to assess total amount of misoprostol dosage required for successful termination rather than induction to fetal delivery time. This is due to the fact that, induction-to-delivery time is associated with multiple factors, including higher misoprostol dosage itself which certainly shortens the active phase of labor, oxytocin use and variations of labor curve. Actually, the main purpose of misoprostol is to prime the cervix to become favorable rather than stimulate uterine contraction, though spontaneous contractions commonly occur after misoprostol use.\u003c/p\u003e \u003cp\u003eTheoretically, the effectiveness of misoprostol is expected to be higher in pregnancies with fetal death than those with viable fetuses and also in pregnancies in late gestation than those in early gestation. However, the data supporting such a belief is very limited, leading to different recommendations among various guidelines. For examples, WHO guideline [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] recommends buccal, intravaginal or sublingual 400 mcg every 3 hours for pregnancy termination at 12\u0026ndash;28 weeks of gestation, while FIGO guideline [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] recommends 400 mcg every 3 hours for 13\u0026ndash;24 weeks and 200 mcg every 4 hours for 25\u0026ndash;28 weeks. Additionally, several guidelines recommend the same regimens regardless of fetal viability. Nevertheless, our findings suggest that for misoprostol administration, fetal viability and gestational age should be taken into account. As noted above, even in our practice in the past, we used the same regimen for second trimester termination from 14\u0026ndash;28 weeks of gestation, regardless of fetal viability and Bishop score (0\u0026ndash;4). Note that, in our practice, vaginal misoprostol 400 mcg every 6 hours, different from 3-hour interval as recommended by WHO guideline, also is highly effective in both groups. Importantly, our findings support the FIGO guideline [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], which is based on both fetal viability and gestational age. For example, the FIGO guideline recommends a lower dosage to be 200 mcg for fetal dead during 13\u0026ndash;26 weeks and 100 mcg during 27\u0026ndash;28 weeks, and higher dosage for pregnancies with a live fetus. Actually, the recommended dosages by the FIGO have been decided on the basis of limited evidence and expert opinion, new evidence is regularly emerging and thus there is a need to review and revise the recommendations in the future [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In other words, pregnancy termination, based on our findings, the same regimen for both pregnancies with dead fetuses and live fetuses and for all gestational age (14\u0026ndash;28 weeks), as recommended by several guidelines including that of our own practice, is no longer justified.\u003c/p\u003e \u003cp\u003eNote that all pregnancies with viable fetuses were sacrificed, though gestational age of greater than 24 weeks of which we usually make attempts to resuscitate for the highest chance of survival, because they were associated with severe perinatal morbidity. Accordingly, in termination of pregnancy after 24 weeks with expectation of live birth, the misoprostol regimen should be considered differently, lower dosage or longer interval of administration, and intrapartum surveillance must be incorporated to avoid non-reassuring fetal heart rate associated with misoprostol.\u003c/p\u003e \u003cp\u003eThe limitations of this study include: 1) retrospective nature, though based on prospective database with high reliability; 2) Though the sample size was adequate to address the primary objective, it might be too low for multivariate analysis of some potentials confounders to show their significant effect, for example low frequency of cases with Bishop score of 4. 3) The results represent only the regimen of 400 mcg every 6 hour, which may not reproducible for other regimens. The strengths of this study are as follows: 1) high homogeneity of drug administration in both groups, the same regimen in terms of route, dosage, and interval; 2) comprehensive analysis to compare the effectiveness based on time-event analysis and multiple regression analysis; 3) The findings could represent the effectiveness in actual practice because of being conducted on service setting, not research setting.\u003c/p\u003e \u003cp\u003eFuture studies concerning termination of pregnancy should focus on incorporation of all of the potential predictors to develop models, probably derived from machine learning, in predicting the chance of successful termination, including misoprostol dosage, route, interval, fetal viability, initial Bishop score, gestational age / estimated fetal weight, etc., to guide the best regimen for an individual rather than one regimen for all.\u003c/p\u003e \u003cp\u003eIn conclusion, the regimen of vaginal misoprostol 400 mcg every 6 hours is highly effective for second trimester termination with the overall success rate of more than 90%. The regimen is significantly higher effective in pregnancies with a dead fetus. Also, the effectiveness is significantly associated with birth weight / gestational age, fetal viability and initial Bishop score. Our findings suggest that the regimen of misoprostol as a single agent for second trimester termination should be modified, depending on fetal viability and gestational age.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eStatement of Ethics:\u003c/strong\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by Research Ethics Committee, Faculty of Medicine, Chiang Mai University (The Research Ethics Committee 4; Faculty of Medicine, Chiang Mai University;\u0026nbsp;(Research ID:\u0026nbsp;ID 8182). All of the participants provided written informed consents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by The Chiang Mai University Research Fund CMU-2566. The funder had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. The funder had no role in the study design, data collection, data analysis, or the manuscript preparation for publication of the findings.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e SP: conceptualization, proposal development, acquisition of data, data validation, manuscript writing; NS.: data validation, acquisition of data, manuscript editing, final approval; TT.: data validation, formal analysis and manuscript writing / editing, final approval; All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe datasets analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJacques L, Heinlein M, Ralph J, et al. Complication rates of dilation and evacuation and labor induction in second-trimester abortion for fetal indications: A retrospective cohort study. Contraception. 2020;102:83-6.\u003c/li\u003e\n\u003cli\u003eMcLaren H, Cancino D, McCulloch M, Wolff S, French V. Rates of complication for dilation and evacuation versus induction of labor in treatment of second trimester intrauterine fetal demise. Eur J Obstet Gynecol Reprod Biol. 2022;277:16-20.\u003c/li\u003e\n\u003cli\u003eSonalkar S, Ogden SN, Tran LK, Chen AY. Comparison of complications associated with induction by misoprostol versus dilation and evacuation for second-trimester abortion. Int J Gynaecol Obstet. 2017;138:272-5.\u003c/li\u003e\n\u003cli\u003ePongsatha S, Tongsong T. Outcomes of pregnancy termination by misoprostol at 14-32 weeks of gestation: a 10-year-experience. J Med Assoc Thai. 2011;94:897-901.\u003c/li\u003e\n\u003cli\u003eOrganization WH. Medical management of abortion. World Health Organization; \u0026lrm;2018.\u003c/li\u003e\n\u003cli\u003eWildschut H, Both MI, Medema S, Thomee E, Wildhagen MF, Kapp N. Medical methods for mid-trimester termination of pregnancy. Cochrane Database Syst Rev. 2011;2011:Cd005216.\u003c/li\u003e\n\u003cli\u003eSrisomboon J, Pongpisuttinun S. Efficacy of intracervicovaginal misoprostol in second-trimester pregnancy termination: a comparison between live and dead fetuses. J Obstet Gynaecol Res. 1998;24:1-5.\u003c/li\u003e\n\u003cli\u003eTestani E, Latta K, Barker E, York SL, Laursen L. Complications of second-trimester medical termination of pregnancy for fetal anomalies compared with intrauterine fetal demise. Int J Gynaecol Obstet. 2022.\u003c/li\u003e\n\u003cli\u003eMorris JL, Winikoff B, Dabash R, et al. FIGO\u0026apos;s updated recommendations for misoprostol used alone in gynecology and obstetrics. Int J Gynaecol Obstet. 2017;138:363-6.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Dead fetus in utero, pregnancy termination, second trimester, misoprostol","lastPublishedDoi":"10.21203/rs.3.rs-2716372/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-2716372/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo compare the effectiveness of vaginal misoprostol for second trimester termination between pregnancies with a dead fetus in utero and those with a live fetus and to identify factors associated with the success rate.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eSingleton pregnancies with live fetuses and dead fetuses, between 14 and 28 weeks, with unfavorable cervix were recruited to have pregnancy termination with intravaginal misoprostol 400 mcg every 6 hours.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMisoprostol was highly effective for termination, with a low failure rate of 6.3%. The effectiveness was significantly higher in pregnancies with a dead fetus (log-rank test; p: 0.008), with median delivery time of 11.2 vs 16.7 hours. Fetal viability, fetal weight or gestational age and an initial Bishop score were significantly related with total amount of misoprostol dosage used for induction. Fetal viability and gestational age / fetal weight were still an independent factor after adjustment on multivariate analysis.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eVaginal misoprostol is highly effective for second trimester termination, with significantly higher effectiveness in pregnancies with a dead fetus. Also, the effectiveness is significantly associated with birth weight / gestational age, and initial Bishop score, suggesting that the regimen of misoprostol should be modified, depending on fetal viability and gestational age.\u003c/p\u003e","manuscriptTitle":"Effectiveness and adverse effects of vaginal misoprostol as a single agent for second trimester pregnancy termination: The impact of fetal viability","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-03-29 14:29:28","doi":"10.21203/rs.3.rs-2716372/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2023-03-27T17:38:20+00:00","index":0,"fulltext":""},{"type":"editorInvited","content":"Archives of Gynecology and Obstetrics","date":"2023-03-22T07:00:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-03-21T14:15:37+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Gynecology and Obstetrics","date":"2023-03-20T23:04:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-gynecology-and-obstetrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"arch","sideBox":"Learn more about [Archives of Gynecology and Obstetrics](https://www.springer.com/journal/404)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/arch/default.aspx","title":"Archives of Gynecology and Obstetrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"953e0633-7dda-49df-a3f6-9d78641695d6","owner":[],"postedDate":"March 29th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T20:48:05+00:00","versionOfRecord":{"articleIdentity":"rs-2716372","link":"https://doi.org/10.1007/s00404-023-07068-8","journal":{"identity":"archives-of-gynecology-and-obstetrics","isVorOnly":false,"title":"Archives of Gynecology and Obstetrics"},"publishedOn":"2023-05-06 20:42:30","publishedOnDateReadable":"May 6th, 2023"},"versionCreatedAt":"2023-03-29 14:29:28","video":"","vorDoi":"10.1007/s00404-023-07068-8","vorDoiUrl":"https://doi.org/10.1007/s00404-023-07068-8","workflowStages":[]},"version":"v1","identity":"rs-2716372","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2716372","identity":"rs-2716372","version":["v1"]},"buildId":"zQwnuV7TCBrMSSSToR1PI","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}