Clinical analysis of the regimens for terminating the second-trimester pregnancy in cesarean section women

Abstract Objective To explore the suitable regimens of induced termination of second-trimester pregnancy in women with prior cesareans. Methods A total of 204 s-trimester pregnant women with prior cesareans at the Third Affiliated Hospital of Zhengzhou University from January 2019 to December 2020 were included in this retrospective study. Group A included pregnant women who were administered mifepristone with misoprostol, Group B included those administering mifepristone with misoprostol as well as a transcervical Cook double-balloon catheter, Group C included those receiving mifepristone with an intra-amniotic injection of ethacridine lactate, and Group D included those receiving mifepristone, transcervical Cook double-balloon catheter, and intra-amniotic injection of ethacridine lactate. Their characteristics, clinical outcomes, and complications among the four groups were compared. Results All women had similar profiles in maternal age, gravidity, and previous cesarean delivery (p > .05). There was no significant difference in successful abortion among the four groups (p > .05). Group C had a significantly shorter induction-to-abortion interval than Group D (p < .01). The blood loss after abortion at 2 h in Group B was much less than Group A (p < .05). It made a significant difference between Group B and Group D regarding the blood loss after abortion at 2 h (p < .01). With regard to total incidences of adverse reactions, there were much fewer in the group B than the group A (p < .05). Conclusion The four regimens are all effective for the termination of second-trimester pregnancy in women with prior cesareans. The use of transcervical Cook double-balloon could reduce the risks caused by misoprostol, and the combination of these is feasible to induce second-trimester pregnancy termination in women with prior cesareans.


Introduction
Second-trimester is defined as the period between the 14th and 28th weeks of pregnancy.As more and more women have experienced cesarean section, they have induced labor to obstetricians for various obstetric indications.However, women with a prior cesarean history tend to have a higher risk of uterine rupture during the termination of pregnancy in the second or third -trimester than those without cesarean history [1,2].Second-trimester induced abortion can be performed by surgical or medical means [3].
In the process of termination, the method of induced abortion is a very important influencing factor.Prostaglandins have been widely used for medical termination in second-trimester pregnancy because of their effects on cervical ripening and uterine contraction [4].Misoprostol with or without mifepristone has been researched for second-trimester medical termination of pregnancy.Intra-amniotic injection of ethacridine lactate (EL; Rivanol), a dye with antiseptic properties, is the most common method for second-trimester termination in China since 1970 [5].Pressure in the cervix caused by a mechanical device, such as a single balloon or double balloon catheter, can lead to the release of endogenous prostaglandins [6].As the modern abortion methods, prostaglandin analogs, mifepristone, osmotic cervical dilators, Foley catheter, oxytocin, or a combination of these can be utilized in women with prior cesarean.However, the optimum one is yet to be chosend for effective termination with the least complications and side effects and the highest efficiency.Moreover, few studies have compared the effect of prostaglandins, the transcervical Cook double-balloon catheter and intra-amniotic injection of ethacridine lactate.Therefore, we aimed to explore the efficacy and safety of the four regimens of induced termination of second-trimester pregnancy in women with a prior cesarean, including mifepristone, misoprostol, transcervical Cook double-balloon catheter and the intra-amniotic injection of ethacridine lactate (Group C); mifepristone.

Subjects and methods
A total of 204 s-trimester pregnant women with prior cesareans at the Third Affiliated Hospital of Zhengzhou University from January 2019 to December 2020 were included in this retrospective study.Inclusion criteria: (1) women aged more than 18 years old; (2) healthy women who were 14-27 weeks pregnant confirmed by Ultrasonic examination; (3) admitted for legal termination of pregnancy due to intrauterine fetal death or gross congenital abnormality; (4) with at least had one or more cesarean deliveries; (5) agreed to terminate the pregnancy after the failure of drug-induced labor.Exclusion criteria: (1) women with known placenta previa or unexplained vaginal bleeding and rupture of membranes; (2) allergy to mifepristone or misoprostol; (3) with contraindications of mifepristone or misoprostol (such as a malignant tumor, obvious abnormal liver and kidney function and serious internal and surgical complications such as blood system diseases); (4) abnormal pregnancy such as trophoblastic disease, threatened abortion, inevitable abortion, incomplete abortion, missed abortion, etc.; (5) with hemoglobin < 90 g/L, or abnormal coagulation function; (6) with the following special circumstances, such as taking anticoagulant or hemostatic drugs, long-term history of tobacco use and cervical surgery, lactation, pregnancy with devices, etc.The study protocol was approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University, China.All subjects in the study signed a written informed consent before labor induction.Patients were informed about the potential advantages and disadvantages of treatment methods and their side effects.
A total of 67 cases adopted mifepristone with misoprostol as Group A, 31 received mifepristone and the transcervical Cook double-balloon catheter combined with misoprostol as Group B, 68 adopted mifepristone with the intra-amniotic injection of ethacridine lactate as Group C, and 38 received mifepristone and the transcervical Cook double-balloon catheter combined with intra-amniotic injection of ethacridine lactate as Group D.
In Group A, women received 200 mg of oral mifepristone (Beijing ZiZhu Pharma Co., Ltd, China) followed by 600 mg of vaginal misoprostol (Hubei Gedian Humanwell Pharmaceutical Co., Ltd, China) 1 day later, and 400 mg of oral misoprostol every 3 h for a maximum of 3 doses within 24 h.In Group B, women received the Cook double-balloon catheter (Cook Cervical Ripener Balloon, Cook OB/GYN, USA).It was inserted through the cervix and balloons on either side of the cervix.80 ml of normal saline was inflated with the recommendations from the manufacturer.After cleaning the cervix with disinfectant, the doctor placed the catheter with the help of a speculum and confirmed the correct placement of the catheter by finger.At the same time, 200 mg of oral mifepristone was administrated.Following spontaneous expulsion or manual removal of the double-balloon after 12 h of placement, women received the same dosage of misoprostol as above.In Group C, women received 200 mg of oral mifepristone.One day later, they underwent an ultrasound-guided amniocentesis with an intra-amniotic injection of 100 mg ethacridine lactate.In Group D, women first received 200 mg of oral mifepristone and the Cook double-balloon catheter then took the ultrasound-guided amniocentesis with the intra-amniotic injection of 100 mg ethacridine lactate followed by spontaneous expulsion or manual removal of the double-balloon after 12 h of placement.
Diagnosis and management of abnormal labor processes were performed according to the recommendations of the American College of Obstetricians and Gynecologists [7].After the fetus was excreted, natural placental delivery was allowed unless the bleeding exceeded 100 ml or the placenta was not excreted naturally after 30 min.In all cases, the placenta was manually removed.Curettage of the uterus was performed if there was clinical evidence of retained placental tissue or suspicion of incomplete abortion.Successful abortion is defined as the expulsion of the fetus from the body, regardless of whether evacuation is required due to incomplete termination of pregnancy.Failed abortion is defined as failure to terminate the pregnancy not by the regimes mentioned above but by other interventions.
Primary outcomes were successful abortion, the induction-to-abortion interval in hours, blood loss after abortion at 2 h, and hospital stay.Secondary outcomes included the complications, such as postpartum hemorrhage, puerperal morbidity, laceration of the birth canal, rupture of the uterus, placental abruption, abdominal exploration, and total incidences.
All analysis was performed using the SPSS (Version 25.0).The data were expressed as mean ± standard deviation (SD) or percentage (%).Homogeneity and normality were examined.Differences in the continuous variables were compared by using Student's t-test and Mann-Whitney U test.Differences in the categorical variables were analyzed using the Chi-square test and the Fisher exact test.One-way ANOVA and Student-Newman-Keuls (SNK) test were used to test the differences among the four groups.Statistical significance was defined as p < 0.05.

Results
The However, the gestational age in Group D was significantly longer than the other three groups (p < 0.05).Moreover, the number of previous cesarean delivery among the four groups was also similar (p > .05,Table 1).
Table 2 showed the clinical outcomes in all the groups.There were no significant differences in successful abortion among the four groups (p > .05).As for the induction-to-abortion interval in hours, no differences were found in Group A compared with Group B as well as Group B compared with Group D. Nevertheless, Group C had a significantly shorter induction-to-abortion interval in hours than Group D (p < .01).The blood loss within 2 h after abortion in Group B was much less than that in Group A (p < .05).
There was no significant difference between Group C and Group D in terms of blood loss within 2 h after abortion (p > .05).There was also no significant difference in the hospital stay between Group A and Group B or between Group C and Group D (p > .05;p > .05;respectively).Group B had a significantly longer hospital stay compared to Group D (p < .05).
The complications were shown in Table 3. Complications mainly included postpartum hemorrhage, puerperal morbidity, laceration of the birth canal, rupture of the uterus, placental abruption, and abdominal exploration results.With regards to total incidences of adverse reactions, there was much less in Groups B, C, and D than Group A (p < 0.05).At the same time, there were no significant differences in the total incidence among Groups A, C and D (p > .05).One case in Group A and one case in Group D had a laceration of the birth canal.Besides, only in Group A, one woman had a rupture of the uterus, one woman had a placental abruption and two women had abdominal explorations.

Discussion
With the development of prenatal diagnosis, the improvement of operation skills, and the expansion of indications for cesarean section, the cesarean section rate in China has increased significantly to 46.2% in the past decade [8].Therefore, the number of cesarean-section women who have experienced termination of pregnancy has also increased.Terminations in the second -trimester account for 10-15% of all abortions worldwide [9].Termination of pregnancy is a common medical procedure, which is induced by surgery or drugs.A variety of techniques can be used to terminate the second trimester of pregnancy, but there is no consensus on which one is the best [10].At present, the best induction regimen of cesarean section is being searched to increase the chance of vaginal delivery and minimize or eliminate the possibility of scar dehiscence and uterine rupture.
Our study demonstrated that the four regimens were all effective for the termination of second-trimester pregnancy in women with prior cesareans.There was no significant difference in successful abortion among the four groups.Few studies explored these methods to compare which one was effective in the past literature.As for induction-to-abortion interval in hours, no differences were found between Group A and Group B as well as Group B and Group D. Nevertheless, Group C had a significantly shorter induction-to-abortion interval in hours compared to Group D. Those results suggested that compared with the regimen of the intra-amniotic injection of ethacridine lactate, it might need much time on inductionto-abortion intervals with the usage of transcervical Cook double-balloon.From a clinical point of view, long intervals of induction of labor may increase the need for overnight waiting, as well as the risks and costs of management, and bring inconvenience to women.Hence, the regimen of transcervical Cook double-balloon catheter combined with intra-amniotic injection of ethacridine lactate could be one of the alternative medical methods if other procedures failed to induce labor.
The blood loss within 2 h after abortion in Group B was much less than in Group A. Meanwhile, it made a significant difference between group B and group D. There were 13 cases of shad complications, including postpartum hemorrhage (7 cases), puerperal morbidity (1 case), laceration of the birth canal (1 case), rupture of the uterus (1 case), placental abruption (1 case), abdominal exploration (2 cases) in Group A (mifepristone with misoprostol).With regards to total incidences of adverse reactions, there were much fewer in Group B (mifepristone and the transcervical Cook double-balloon catheter combined with misoprostol) than Group A.
Uterine rupture is a rare complication of second-trimester termination in women with a history of cesarean section.Uterine rupture can occur in 0.28% of women with a cesarean scar and 0.04% without a history of hysterotomy [11].Uterine rupture may present as abdominal pain, loss of fetal station, severe vaginal bleeding, or hemorrhagic shock, which is a potentially life-threatening complication.Misoprostol is considered to increase the risk of the uterine rupture as compared to other induction methods [12,13].The use of transcervical Cook double-balloon could reduce the related risks caused by misoprostol and the combination was feasible to induce second-trimester pregnancy termination in women with prior cesarean.The results of this study tended to favor the transcervical Cook doubleballoon catheter combined with misoprostol over the prostaglandin alone for women with prior cesareans.This process is closer to the physiology of the beginning of childbirth, thus reducing the possibility of overstimulation and postpartum hemorrhage.
It has been reported that Misoprostol alone is a safe and effective option for terminating second-trimester pregnancies with one or more previous cesarean sections in settings where mifepristone is unavailable [14].The two most common regimens for Misoprostol to perform cesarean sections were 400 mcg injected intravaginally every 6 h and 400 mcg taken orally every 4 h [15].Moreover, a high-dose regimen (400 mg every 6 h) for misoprostol terminations of pregnancy aeffects delivery more rapidly without an appreciable increase in side effects or complications [16].
The strength of this study is that it compares the four regimens of second-trimester abortion with scarred uterus reported by few studies in the literature.It showed that we could choose these different regimens to induce termination of second-trimester pregnancy in women with prior cesarean.At the same time, the usage of transcervical Cook double-balloon catheter could reduce the related complication and did not increase the women's hospital stay.However, the investigation is likely to have some limitations.First, there is the demographic difference in gestational age.Second, retrospective data collection has affected the results.Third, women with cesarean scar pregnancy (CSP) or placenta previa spectrum (PP) are excluded in the exclusion criteria.Hence, we did not include the cases of PP or CSP.However, we could evaluate this management in the scientific literature in the future.In addition, we did not address patient satisfaction with the cervical ripening process.A comparison of patient satisfaction with four labor induction methods would be interesting since all methods do not imply repeated vaginal examinations.Finally, a much larger study, such as a multicenter randomized investigation of a large number of women, would be necessary.In a further study, these parameters would be considered to modify the clinical investigation design.

Conclusion
In conclusion, we show that four regimes are all effective for the termination of second-trimester pregnancy in women with prior cesarean.Furthermore, the use of transcervical Cook double-balloon could reduce the related risks caused by misoprostol and the combination of these is feasible to induce the termination of second-trimester pregnancy in women with prior cesarean.

Table 1 .
Baseline characteristics of study subjects.

Table 2 .
Clinical outcomes of pregnancy termination among the four groups.< .05:As for blood loss after abortion at 2 h Group B compared with Group A; ÃÃ p < .01:As for Induction-to-abortion interval in hours Group D compared with Group C.

Table 3 .
Comparison of complications among the four groups.