Cervical ripening with multiple medical or combined induction methods: Risks of subsequent preterm birth in nulliparous women

To determine the impact of combined medical and medical/mechanical methods for cervical ripening on the risk of preterm birth in subsequent pregnancy, in nulliparous women.

depending on the Bishop score. Unfavorable cervix is usually induced medically or by mechanical devices. Prostaglandin drugs, dinoprostone and misoprostol, are the most common preparations used for cervical ripening. In the mechanical method, single-or double-balloon devices are widely used. The proposed mechanism of the double balloon is to apply internal and external pressure on the internal and external cervical os simultaneously, 5,6 whereas in single balloon the cervical ripening is achieved by direct expansion of the balloon on the cervix and lower uterine segment. In addition, the balloon catheter enhances prostaglandin secretions, which are probably also engaged in cervical ripening. 7 Preterm birth (PTB) is a serious obstetrics burden responsible for a diversity of obstetrics complications, including almost half of congenital neurologic adverse sequelae and the majority of fetal deaths. 8,9 Cervical weakness, either congenital or following cervical trauma, is a risk factor for cervical insufficiency, which increases the risk of PTB. Numerous studies have addressed the impact of mechanical or medical induction on risk of PTB in the subsequent pregnancy, [10][11][12][13] but the impacts of combined or repeated doses on subsequent pregnancy have not yet been studied. There is a hypothetical risk that the mechanical stretching of the cervix by multiple medical doses or combined induction methods can lead to cervical tissue damage and potentially increase the risk of PTB in a subsequent pregnancy. In this study we aimed to test whether combined induction methods or multiple doses of prostaglandins could lead to cervical insufficiency, and increase the risk of PTB in the subsequent pregnancy.

| MATERIAL S AND ME THODS
This is a retrospective case-control study of nulliparous pregnant women who delivered in our tertiary care center during 2009-2019. The local ethics committee approved this study (RMB-0310-19). Our study included three groups of women who underwent the following: (1) single round of pharmacologic induction, (2) multiple inductions (i.e. two or more rounds of pharmacologic induction or both pharmacologic and mechanical induction), and (3) mechanical induction; as well as a control group (4) no intervention.
Data were extracted from the hospital's computerized database and included maternal age, diseases, and both postpartum and neonatal parameters. Data were validated by the authors, all registered MDs, by randomly reviewing the accuracy of data extracted from the written charts. The study groups included nulliparous women who underwent induction of labor by mechanical or medical cervical ripening methods, and delivered their subsequent labor in our medical center. The groups were computer matched to a control group that included nulliparous women who did not undergo induction of labor by any type of cervical ripening method and subsequently delivered in our hospital. Matching ratio was 1:3 in favor of the control group. To minimize the effect of previous pregnancy events on the rate of PTB in a future pregnancy, we only included nulliparous women in our study.  The primary outcome of the study was the rate of PTB in the subsequent labor after cervical ripening by combined methods or multiple doses of prostaglandins.
Secondary outcomes were mode of delivery and additional maternal and neonatal adverse events.
Descriptive statistics in terms of mean, standard deviation, median, interquartile range, and percentages were calculated for all parameters in the study. Normal distribution of the continuous parameters was tested by Kolmogorov-Smirnov test. The results of this test were used in subsequently conducting analysis of variance or Kruskal-Wallis test with multiple comparisons made among groups. Differences between categorical parameters were tested by χ 2 analysis. Variables statistically significant at the initial analyses,

What are the novel findings of this work?
The present study addresses the impact of combined medical and combined medical plus mechanical induction of labor on the risk of preterm birth in a subsequent pregnancy in nulliparous women scheduled for labor induction.

What are the clinical implications of this work?
Our findings highlight that induction of labor by either combined medical or combined medical plus mechanical methods, did not increase the risk of preterm birth in a subsequent delivery by the suspected mechanism of cervical trauma. Physicians should be informed that this approach is safe with no anticipated increase in maternal or neonatal risk.

| RE SULTS
The 1277 women included in the study group were matched with 3903 women in the control group. The study group included 942 women in the single round of pharmacologic induction group, 248 in the multiple attempts at induction group (two or more rounds of pharmacologic induction and either pharmacologic or mechanical induction methods), and 87 in the mechanical induction group.
Comparisons of demographic data and clinical characteristics among the groups are presented in Table 1.
There were no significant differences in rates of spontaneous PTB in the study groups compared with the control group in the index pregnancy (4.9% in the single dose group, 2% in the multiple induction group, 6.9% in the mechanical induced group, and 4.3% in the control group). Moreover, the rates of early PTB (<34 weeks) did not differ among the groups (Table 2). After adjusting for confounding variables, using multivariate logistic regression, the rates of subsequent PTB remained non-significant.  cesarean deliveries in the first pregnancy in the multiple induction group was significantly higher compared with the control group (37% vs 21%, P < 0.0001). We did not observe any significant maternal or neonatal differences in secondary outcomes.

| DISCUSS ION
In the current study we tested the impact of repeated medical or combined methods of labor induction on the risk of PTB in a subsequent pregnancy among nulliparous women. Our data indicated that repeated attempts, either medical or combined methods, did not increase the rates of PTB in a subsequent pregnancy. we observed a slightly increased rate of PTB during 34-36+6 weeks gestation or pregnancy compared with the other groups. We assume that this difference could be attributed, in part, to the shorter pregnancy interval observed in these two groups. Previous studies have found that short intervals between the birth of one child and subsequent pregnancy are associated with an increased risk of PTB 7,16,17 ; nevertheless, this slight increase was not statistically significant.
Moreover, the neonatal secondary outcomes in term of admission to neonatal intensive care unit or Apgar scores were similar in all groups.
In this study, the mechanical group was induced only by doubleballoon catheter. In spite of the large volume of fluid placed in the catheter and the use of traction, comparable with other studies, we did not observe a significantly increased rate of PTB. The similarity in PTB in all groups, regardless of the induction method, favors the hypothesis that the main mechanism of cervical ripening by the double balloon could be related to prostaglandin release from decidual separation as in single-balloon catheters, 7 rather than by its mechanical effects.
We observed that cesarean delivery was significantly higher in the multiple induction group compared with the control (Table 1).

TA B L E 2
The relation between type of induction to gestational age at second delivery Note. Values are presented as n (%). a P < 0.05 is considered significant.