Abstract
Objective
To compare the efficacy and safety of cervical ripening and induction of labor with prostaglandin E1 among primiparas, multiparas and grand multiparas.
Study design
This was a retrospective cohort study.
Results
Between January and December 2017, 1713 women underwent cervical ripening and induction of labor with prostaglandin E1: 523 were primiparas, 656 were multiparas, and 534 were grand multiparas. Four hundred and seventy-nine (91.6%) primiparas delivered vaginally as did 640 (97.6%) multiparas and 521 (97.6%) grand multiparas. Forty-four (8.4%) primiparas underwent cesarean delivery compared to 16 (2.4%) multiparas and 13(2.4%) grand multiparas. Induction to delivery interval was significantly longer in primiparas (29.7 ± 22.8 h). There were no cases of uterine rupture, and the rates of postpartum hemorrhage and endometritis were similar among the three groups. Neonatal outcomes including Apgar score < 7 and umbilical artery pH < 7.1 were not significantly different between the groups.
Conclusion
Using prostaglandin E1 for cervical ripening and labor induction is efficient and safe in primiparas, multiparas and grand multiparas.
Keywords: Grand multiparas, Cervical ripening, Induction of labor, Prostaglandin E1
Introduction
The USA has witnessed a significant increase in the induction of labor rate over recent years [1]. This surge in induction might be attributed to the findings of various studies and systematic reviews, which have indicated that term induction of labor is not linked to higher rates of cesarean births and could potentially lower the occurrences of perinatal mortality and morbidity [2]. In 2020, the rate of IOL in the USA was 31% [1].
Diverse pharmacological and mechanical techniques are employed for induction of labor (IOL). Among these methods is the use of a prostaglandin E1 (PGE1) analogue known as misoprostol. Initially developed for the prevention and treatment of peptic ulcers, this medication has been extensively studied and proven to be a secure and efficient option for inducing labor in full-term pregnancies [3, 4]. The distinctive pharmacological attributes of misoprostol, when contrasted with prostaglandins E2, combined with its affordability and convenient storage, have contributed to the widespread adoption of misoprostol in the field of obstetrics [5, 6].
IOL with oral misoprostol has several benefits over other methods of IOL including minimizing the frequency of vaginal examinations and enabling unrestricted mobility, which increase women’s satisfaction. The authors of the PROBAAT II trial, which examined the safety of IOL using misoprostol, reported that using oral misoprostol in women with unfavorable cervix at term had a safety profile similar to that of using Foley catheter for this purpose [7]. The use of oral misoprostol for IOL is strongly recommended by the World Health Organization (WHO) [4]. Moreover, the WHO entered misoprostol into the list of essential medications for obstetrical use, and medical organizations such as the International Federation of Gynecology and Obstetrics (FIGO) and the American College of Obstetrician and Gynecologists (ACOG) recommended its use in pregnant women [8].
As documented in the literature, employing prostaglandins for elective induction of labor (IOL) in nulliparous women with an unripe cervix at term is linked to a reduced likelihood of vaginal delivery, with rates ranging between 56.8 and 58.0%. In contrast, the vaginal delivery rate for elective IOL in multiparous women at term with an unripe cervix is notably higher, ranging from 83.7 to 87.7% [9]. For that reason, prior to non-emergent IOL, we perform cervical ripening in all women whose cervix is not ripe. Most women who received misoprostol for cervical ripening developed active labor and did not require additional interventions.
There is a paucity of information regarding the safety of using misoprostol for cervical ripening and IOL in grand multiparous women. The goal of this study was to compare the efficacy and safety of IOL with misoprostol among primiparas, multiparas and grand multiparas.
Material and Methods
We conducted a retrospective cohort study comparing the efficacy and safety of cervical ripening and IOL with misoprostol among primiparas, multiparas and grand multiparas delivered at our hospital. Included in this study were all women with unfavorable cervical exam (Bishop’s score < 5) [10], who underwent cervical ripening and IOL > 37 weeks’ gestation using misoprostol. Exclusion criteria included active labor, multiple gestations, history of cesarean section (CS), and fetuses with intrauterine growth restriction or known anomalies. Eligible women underwent at least 30 min of cardiotocographic assessment of fetal status and uterine activity prior to administration of misoprostol. Cervical ripening was administered only if the fetal tracing was reactive and there was no regular uterine activity. Women received 50 µg oral misoprostol (Cytotec ®, Pfizer pharmaceuticals, Israel Ltd). This dose was repeated every four hours if the cervical Bishop score was < 8 and there was no regular uterine activity, up to a maximal dose of 300 µg. Women whose cervix did not become favorable were then started on a different method of IOL (vaginal PGE2, extra-amniotic balloon or IV Oxytocin). Women who were excluded from this study underwent other methods of cervical ripening (e.g., vaginal administration of 0.75–3.0 mg PGE2 or insertion of extra-amniotic Foley catheter inflated with 60–80 ml saline).
We divided the participants into three groups: primiparas, multiparas (parity of 1–4), and grand multiparas (5 and above). Demographic data and women’s characteristics were collected including maternal age, gestational age at delivery and newborn birth weight. Primary outcome was the rate of vaginal delivery in each group. Secondary outcomes were the induction to delivery interval (IDI) (also defined as efficacy), maternal complications including postpartum hemorrhage, blood transfusion and endometritis, and neonatal outcome including 5-min Apgar score < 7, umbilical artery pH < 7.1, and admission to the neonatal intensive care unit.
The groups were compared with analysis of variance using Tukey’s multiple comparisons and Chi-Square or Fisher’s exact test for categorical data. A probability value of < 0.05 was considered significant. IBM SPSS Statistics for Windows [software], Version 25.0. Armonk, NY: IBM Corp; Released 2017, was used for all statistical analysis.
Results
Between January and December 2017, 11,967 women delivered at our hospital. Two thousand, eight hundred and twenty-eight (23.6%) underwent induction of labor, 1713 of them underwent cervical ripening and IOL using misoprostol. Indications for IOL included prolonged pregnancy, hypertensive disorders, maternal medical conditions, premature rupture of membranes and non-reassuring fetal status. Five hundred and twenty-three were primiparas, 656 were multiparas and 534 were grand multiparas (Table 1). Four hundred and seventy-nine (91.6%) primiparas delivered vaginally as did 640 (97.6%) multiparas and 521 (97.6%) grand multiparas (Table 2).
Table 1.
Demographic and obstetric characteristics for the study groups
| Overall (n = 1713) | Group 1: primiparas (n = 523) | Group 2: multiparas (n = 656) | Group 3: grand multiparas (n = 534) | p value | |
|---|---|---|---|---|---|
| Maternal age, Ya | 28.7 ± 6.0 | 23.8 ± 4.0 | 27.7 ± 4.0 | 34.7 ± 4.2 | < 0.001 |
| Gestational week at labora | 39.9 ± 1.2 | 40.0 ± 1.2 | 39.8 ± 1.2 | 39.7 ± 1.2 | 0.005 |
| Newborn birth weight (grams)a | 3399 ± 447 | 3290 ± 432 | 3416 ± 452 | 3483 ± 432 | < 0.001 |
a = Data are presented as mean ± SD
Table 2.
Outcomes measured for safety and efficacy
| Overall (n = 1713) | Group 1: primiparas (n = 523) | Group 2: multiparas (n = 656) | Group 3: grand multiparas (n = 534) | p value | |
|---|---|---|---|---|---|
| Normal vaginal delivery | 1452 (84.8%) | 360 (68.8%) | 592 (90.2%) | 500 (93.6%) |
< 0.001 1 ≠ 2,3 |
| Instrumental Delivery | 188 (11%) | 119 (22.8%) | 48 (7.3%) | 21 (3.9%) |
0.017 1 ≠ 2 ≠ 3 |
| Cesarean delivery | 73 (4.3%) | 44 (8.4%) | 16 (2.4%) | 13 (2.4%) |
< 0.001 1 ≠ 2,3 |
| Blood transfusion rate, n (%) | 18 (1) | 10 (1.8) | 3 (0.5) | 5 (0.9) | 0.057 |
| Rate of APGAR 5’ minutes < 7, n (%) | 9 (0.5) | 2 (0.4) | 4 (0.6) | 3 (0.6) | 0.840 |
| Rate of UA pH < 7.1, n (%)a | 11 (7.7) | 9 (10.1) | 1 (3.0) | 1 (5.0) | 0.380 |
| Time to delivery, hrb | 22.0 (21.0–22.9) | 29.7 (27.8–31.7) | 18.6 (17.3–20.0) | 18.5 (17.0–20.1) |
< 0.001 1 ≠ 2,3 |
| Deliveries within 24 h, n (%) | 1181 (67.5) | 294 (53.9) | 486 (73.0) | 401 (74.5) |
< 0.001 1 ≠ 2,3 |
| Deliveries in 24–48 h, n (%) | 384 (22) | 162 (29.7) | 129 (19.4) | 93 (17.3) |
< 0.001 1 ≠ 2,3 |
| Deliveries after more than 48 h, n (%) | 184 (10.5) | 89 (16.3) | 51 (7.7) | 44 (8.2) |
< 0.001 1 ≠ 2,3 |
a = UA pH was taken only in deliveries with suspected fetal distress, instrumental deliveries and cesarean deliveries. Percentages are related to total number of pH taken
b = Data are given with 95% confidence interval for mean in the parenthesis
Twenty-eight of the primiparas (62%) required cesarean section (CS) due to non-reassuring fetal status (NRFS), and 12 (25%) due to arrested dilation or descent. Induction of labor (IOL) was unsuccessful in one case, and another woman underwent cesarean delivery due to a failed vacuum extraction (Table 3). Among multiparas, sixteen (2.4%) required CS. Nine of these cases were attributed to NRFS, two cases had arrested dilation or descent, and two cases had fetuses in brow presentation during the second stage of labor. IOL was discontinued for three women: two due to suspected macrosomia after IOL initiation, and one due to a fetus transitioning into a breech position from an unstable lie observed at the start of IOL (Table 3).
Table 3.
Indications for cesarean sections among the groups
| Indication for cesarean section | Group 1: primiparas (n = 44) | Group 2: multiparas (n = 16) | Group 3: grand multiparas (n = 13) |
|---|---|---|---|
| Non-reassuring fetal status n (%) | 28 (63%) | 9 (57%) | 8 (62%) |
| Arrest of dilation or descent n (%) | 12 (27%) | 2 (12%) | 1 (8%) |
| Brow presentation/prolapse of cord n (%) | – | 2 (12%) | 2 (15%) |
| Failed induction/IOL was discontinued n (%) | 1 (2%) | 3 (19%) | 2 (15%) |
| Failed vacuum extraction n (%) | 1 (2%) | – | – |
Thirteen (2.4%) women in the grand multiparas group underwent CS. Among them, eight CS were performed due to NRFS, one due to arrested dilation or descent, one due to a fetus in brow presentation during the second stage of labor, and one due to cord prolapse. IOL was discontinued for two women due to suspected macrosomia (Table 3).
As expected, primiparas required a significantly longer period of time from misoprostol administration until delivery compared to multiparas and grand multiparas (Table 2): mean induction to delivery interval (IDI) in primiparas was 29.7 h (95% CI: 27.8–31.7 h), compared with 18.6 h in multiparas (95% CI: 17.3–20.0 h) and 18.5 h in grand multiparas (95% CI:17.0–20.1 h, P < 0.001). There were no significant differences between multiparas and grand multiparas in the percentage of women who delivered within 24 h, 24–48 h, and more than 48 h (73% vs. 74.5%, 19.4% vs. 17.3% and 7.7% vs. 8.2%, respectively, p > 0.05). There was a significant difference in the rate of instrumental deliveries among the three groups with decreasing rate along with increasing parity: 119 (22.8%) primiparas delivered by instrumental delivery, as did 48 (7.3%) multiparas and 21 (3.9%) grand multiparas (p = 0.017, Table 2). There were no cases of uterine rupture, and the rates of postpartum hemorrhage requiring a blood transfusion were similar among the three groups. Two women were diagnosed with endometritis, one from the primipara group and one from the multipara group. The rate of 5 min Apgar score below 7 and UA pH < 7.1 were not significantly different between the groups (Table 2). There were no significant difference in the rate neonatal intensive care unit (NICU) admission among the groups.
Discussion
The increasing trend in the induction of labor over recent years, coupled with the findings from the ARRIVE study indicating a reduction in cesarean birth rates among nulliparous women who underwent elective induction at 39 weeks gestation [11], have made induction of labor a common practice. The ease of administration of misoprostol, the pharmacological characteristics, convenience of storage and its low price make this medication an ideal agent for IOL globally, in both developed and developing countries. The safety of IOL with misoprostol among nulliparous has been studied extensively [12]. However, due to low rate of multiparas in developed countries [13], there is limited information regarding the safety of using misoprostol for IOL in multiparas and grand multiparas.
Our hospital serves a highly parous population composed mainly of orthodox religious families, with an average of six deliveries per woman. The rate of vaginal delivery at our hospital is much higher than in neighboring hospitals (89% for nulliparas and 95% for multiparas, data not published), and annual total cesarean section rate at our hospital, both elective and planned, is 9%, significantly lower than the national average. Our results suggest that IOL using misoprostol is a safe method for IOL in primiparas, multiparas, and grand multiparas. Our results differ from those of a multivariate analysis of parity and pregnancy outcome that reported a significantly increased risk of “any obstetric complication” among women of parity 4, 5, 6, and 7–8 when compared with women with lower parity (parity 1–3) [14]. We found a similar rate of adverse maternal and neonatal outcomes among multiparous and grand multiparous women. Over 70% of the multiparas and grand multiparas delivered within 24 h as compared to only 53% of the primiparas.
A cross-section, multivariate analysis of births in Australian women with parity between 0 and 8 suggested that the risk of obstetric complications was highest in nulliparas, lowest in multiparas who had one to three deliveries, and was intermediate in multiparas who had four or more deliveries [14]. Similarly, three other groups did not find an association between grand multiparity and an increased rate of obstetrical complications: they were not at an increased risk of gestational diabetes, gestational hypertension, cesarean deliveries, admission to NICU, and maternal or perinatal mortality [1, 15–17]. These findings suggest that the risk of obstetric complications associated with parity is bimodal. In our population, we found a similar rate of adverse outcomes among multiparous and grand multiparous women.
Many complications that have been associated with grand multiparity have also been associated with advanced maternal age [18]. Increasing maternal age is associated with an increased prevalence of comorbidities such as type 2 diabetes, hypertension and obesity, which also increase the risk of adverse pregnancy outcome. Thus, maternal age is an important confounder that must be accounted for in order to minimize bias in interpreting the results. The importance of maternal age was illustrated in a retrospective cohort study done in Utah that suggested that young grand multiparas were at a significantly lower risk of intrapartum complication (e.g., placental abruption, placenta previa, intrapartum vaginal bleeding, umbilical cord prolapse, fetal distress, malpresentation, surgical and instrumental delivery) compared with young primiparas [19]. In addition, young grand multiparas were at significantly lower risk for intrapartum complication when compared with older grand multiparas. In our population, maternal age and grand multiparity might have been the reasons for IOL but did not change the primary outcome.
The strength of our study is the large number of women in each group and the diverse reasons for IOL. Weaknesses include the retrospective nature and the unique population served by our hospital, which consists of relatively healthy women with very low percentage of infertility cases, alcohol and tobacco use and obesity.
Conclusion
We found that the use of misoprostol is an efficient and safe method of IOL in primiparas, multiparas, and grand multiparas. These findings may reassure medical caregivers that misoprostol is a safe agent for IOL in these populations.
Acknowledgements
This work has been presented in the POSTER SESSION of the SMFM 40th Annual Meeting at Las Vegas 2019.
Author Contributions
LKL and AB were involved in contemplation and study design and were responsible for data gathering and statistical analysis. LKL, AB and RN contributed substantially to data interpretation and wrote the manuscript with revisions by JBL and RN. All authors read and approved the final manuscript.
Funding
There was no funding for this study.
Declarations
Conflict of interest
The authors declare that they have no competing interests.
Ethical approval
The local institutional review board approved the study on 13th December 2018 (0037–18-MHMC).
Consent to participate
Since the study was retrospective, there was a waiver from informed consent by the local ethical committee.
Footnotes
Lior Kashani Ligumsky: Clinical instructor, Senior physician, Department of Obstetrics and Gynecology; Asaf Bilgory: Clinical instructor, Senior physician, Department of Obstetrics and Gynecology; Ran Neiger: Professor, consultant, Department of Obstetrics and Gynecology.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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