The association between delayed amniotomy and adverse outcomes in labor induction

Journal Pre-proof The association between delayed amniotomy and adverse outcomes in labor induction Ashley N. Battarbee, Sharon Vaz, David M. Stamilio

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S0301-2115(20)30061-0

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https://doi.org/10.1016/j.ejogrb.2020.02.002

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EURO 11181

To appear in: Biology

European Journal of Obstetrics & Gynecology and Reproductive

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22 August 2019

Revised Date:

3 February 2020

Accepted Date:

4 February 2020

Please cite this article as: Battarbee AN, Vaz S, Stamilio DM, The association between delayed amniotomy and adverse outcomes in labor induction, European Journal of Obstetrics and amp; Gynecology and Reproductive Biology (2020), doi: https://doi.org/10.1016/j.ejogrb.2020.02.002

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The association between delayed amniotomy and adverse outcomes in labor induction

Ashley N. Battarbee MD MSCR,1 Sharon Vaz MD MPH,2 and David M. Stamilio MD MSCE1

Affiliations: 1

University of North Carolina at Chapel Hill, Department of Obstetrics and Gynecology, Division

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of Maternal-Fetal Medicine 2

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University of North Carolina at Chapel Hill, Department of Obstetrics and Gynecology

Corresponding Author:

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Ashley Battarbee, M.D., M.S.C.R.

Alabama at Birmingham

Birmingham, AL 35223

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Phone: 205-975-2361

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1700 6th Ave South, Suite 10270

E-mail: [email protected]

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Word count: Abstract – 219 Text – 2641

ABSTRACT

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Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of

Objective: To assess if delayed amniotomy during labor induction is associated with adverse delivery outcomes. Study Design: Retrospective cohort study of women with a viable, singleton gestation who underwent labor induction at a tertiary-care hospital (4/2014-3/2017). Women were excluded if oxytocin was not used or if spontaneous rupture of membranes (ROM) occurred 8 hours after oxytocin initiation. The primary outcome was cesarean delivery, and secondary outcomes

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included postpartum hemorrhage, maternal infectious morbidity, neonatal 5-minute Apgar score < 7, and neonatal intensive care unit admission. Women were compared by timing of

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amniotomy: delayed (ROM >8 hours after oxytocin initiation) versus not delayed. Multivariable

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logistic regression was used to estimate the association between delayed amniotomy and study outcomes.

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Results: Of 2,081 women who met inclusion criteria, 1,125 (54%) had delayed amniotomy. Women with delayed amniotomy had ROM 12.7 hours (IQR 10.0, 17.9) after oxytocin versus

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5.0 hours (IQR 3.7, 6.5) without delayed amniotomy. In multivariable regression, delayed amniotomy was associated with increasingly higher odds of cesarean as maternal obesity

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severity increased (aOR 1.58, 95%CI 1.24-2.03 at BMI 30kg/m2; aOR 2.15, 95%CI 1.45-3.21 at BMI 40kg/m2; aOR 2.93, 95%CI 1.54-5.57 at BMI 50kg/m2). Conclusion: Delayed amniotomy >8 hours after starting oxytocin for labor induction was associated with higher odds of cesarean delivery. Significant delay in ROM should be avoided

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during labor induction.

Key words: amniotomy, cesarean, induction, labor, nulliparous

INTRODUCTION

Over the last 30 years the rate of labor induction has more than doubled in the United States, making it one of the most common obstetrical procedures performed.1 Today close to 1 in 4 pregnant women undergo labor induction. Induction of labor involves the stimulation of uterine contractions and rupture of membranes prior to the onset of spontaneous labor and can be used to facilitate delivery either for maternal or fetal medical indications or purely for elective reasons. There are multiple methods used for labor induction beginning with mechanical agents

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and prostaglandins for cervical ripening followed by oxytocin and amniotomy.2 And, implementation of these methods varies widely across and within medical facilities. Given the

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large number of women undergoing labor induction, optimization of the methods used for labor induction has recently gained more attention.

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Amniotomy is a commonly used, inexpensive, low-resource method of labor induction.

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Previous studies have evaluated the effect of performing amniotomy early in the course of labor induction, defined variably based on either cervical dilation, time since completion of cervical

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ripening, or time since initiation of oxytocin.3–6 While the vast majority of these studies have found early amniotomy to be associated with a decrease in the duration of labor induction,3–5

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some of the observational studies have suggested an increase in cesarean delivery with early amniotomy.7,8 Other potential concerns with early amniotomy have included umbilical cord prolapse, intraamniotic infection, fetal malpresentation and labor dystocia. However, to our knowledge, the risk of adverse outcomes associated with delaying amniotomy until later in the

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induction process has not been studied. Thus, the objective of this study was to evaluate the association between delayed amniotomy and adverse outcomes in labor induction such as cesarean delivery, postpartum hemorrhage, maternal infectious morbidity, neonatal 5-minute Apgar score < 7, and neonatal intensive care unit admission.

STUDY DESIGN

This was a retrospective cohort study of women undergoing labor induction at the University of North Carolina at Chapel Hill. Women were included if they had a viable, singleton gestation in vertex presentation and were induced from April 2014 to March 2017. Induction of labor was defined as stimulation of uterine contractions before the spontaneous onset of labor. Women were excluded if oxytocin was not used for labor induction or if the time and type of membrane rupture was not documented. Additionally, women who had spontaneous rupture of

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membranes less than or equal to 8 hours after oxytocin initiation were excluded as they were not at risk for the primary exposure - delayed amniotomy. Delayed amniotomy was defined as

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rupture of membranes more than 8 hours after oxytocin initiation in contrast to no delayed

amniotomy, which included women with amniotomy less than or equal to 8 hours after oxytocin

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initiation. At our institution, it is customary to start oxytocin at 2mU/min and increase by

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2mU/min every 15-30 minutes in order to achieve an adequate contraction pattern with contractions every 2-3 minutes with a maximum infusion rate of 36mU/min.

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The primary study outcome was cesarean delivery. Secondary outcomes included postpartum hemorrhage, maternal infectious morbidity, neonatal 5-minute Apgar score < 7, and

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neonatal intensive care unit admission. Postpartum hemorrhage was defined as estimated blood loss > 500mL at the time of vaginal delivery or estimated blood loss > 1000mL at the time of cesarean delivery. Maternal infectious morbidity was a composite of chorioamnionitis and postpartum endometritis. Chorioamnionitis was identified as a clinical diagnosis based on

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maternal fever and at least one other sign of intraamniotic infection such as maternal or fetal tachycardia, foul smelling amniotic fluid, or fundal tenderness. Postpartum endometritis was also defined as a clinical diagnosis, based on maternal fever and fundal tenderness requiring treatment with antibiotics. Maternal demographic, obstetric and neonatal characteristics were abstracted from the electronic medical record. These characteristics were compared by delayed amniotomy versus no delayed amniotomy using chi-square, student’s t-test and Wilcoxon rank sum tests, as

appropriate. Multivariable logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals for the primary and secondary outcomes with delayed amniotomy, compared to no delayed amniotomy. We tested for effect modification of the association between delayed amniotomy and outcome by the following variables: maternal BMI, nulliparity, gestational age at delivery, and cervical ripening with foley balloon catheter. We included candidate co-variates identified in the unadjusted analysis or with historical significance in the

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initial multivariable model, and then to achieve the final parsimonious multivariable model we removed variables in a stepwise fashion using a change-in-effect method to retain only those

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factors that significantly confounded the association between the exposure and outcome by more than 10%. Finally, a sensitivity analysis was performed including women who had

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spontaneous rupture of membranes less than or equal to 8 hours after oxytocin initiation in the

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no delayed amniotomy group to explore the robustness of our results.

All analyses were performed with Stata, Version 14.0 (StataCorp, College Station, TX).

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All tests were two-tailed and p<0.05 was used to define significance. Approval for this study was

RESULTS

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obtained from the University of North Carolina – Chapel Hill Institutional Review Board.

Of 2,892 women who underwent induction of labor during the study period, 2,081 met inclusion criteria (Figure 1). Among women who were expectantly managed without artificial

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rupture of membranes, 50% of women still had intact membranes at 9.1 hours after oxytocin initiation and 25% of women still had intact membranes at 15.5 hours after oxytocin initiation. A total of 1125 (54%) women had delayed amniotomy based on our study exposure definition and 996 (46%) did not have delayed amniotomy. Women with delayed amniotomy had rupture of membranes at a median of 12.7 hours (IQR 10.0, 17.9) after oxytocin initiation versus a median of 5.0 hours (IQR 3.7, 6.5) after oxytocin initiation among women without delayed amniotomy. Women who had delayed amniotomy were less likely to be Hispanic and more likely to be

nulliparous, have gestational hypertension or preeclampsia, and have an unfavorable cervical exam on admission (Table 1). There were no statistically significant differences in maternal BMI, history of prior cesarean delivery, or neonatal birthweight (Table 1). In unadjusted analyses, women with delayed amniotomy were more likely to be delivered by cesarean, compared to those without delayed amniotomy (27.4% versus 15.9%, p<0.001; OR 1.99, 95% CI 1.60-2.48). There were no statistically significant differences in

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postpartum hemorrhage or infectious morbidity among women with delayed amniotomy compared to those without (Table 2). Women with delayed amniotomy were more likely to

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deliver a neonate with 5-minute Apgar score < 7, compared to those without delayed amniotomy (4.4% versus 1.9%, p=0.001). Neonatal intensive care unit admission was also more frequent

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among women with delayed amniotomy, compared to those without (16.2% versus 12.3%,

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p=0.01).

In the multivariable logistic regression analysis delayed amniotomy was associated with

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higher odds of cesarean delivery (Table 3). Maternal BMI was found to be an effect modifier of the association between delayed amniotomy and cesarean delivery whereby delayed

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amniotomy was associated with increasingly higher odds of cesarean delivery with increasing severity of maternal obesity based on BMI (Figure 2). The final logistic regression model, which included the BMI-amniotomy interaction term and maternal BMI as a continuous variable, was used to estimate adjusted odds ratios for cesarean delivery across the continuous range of maternal BMI values. For example, the adjusted odds ratio of cesarean delivery with delayed

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amniotomy, compared to no delayed amniotomy, for a woman with BMI of 30 kg/m2 was 1.58 (95% CI 1.24-2.03) whereas for a woman with BMI of 40 kg/m2 it was 2.15 (95% CI 1.45-3.21) and for a woman with BMI of 50 kg/m2 it was 2.93 (95% CI 1.54-5.57). There was no evidence of effect modification by parity, gestational age, or cervical ripening with foley balloon, and thus we did not stratify our results by these characteristics. There was no significant association between delayed amniotomy and the secondary maternal outcomes, postpartum hemorrhage

and infectious morbidity. There was an association between delayed amniotomy and increased odds of 5-minute neonatal Apgar score < 7 (aOR 2.16, 95% CI 1.20-3.88). The association between delayed amniotomy and neonatal intensive care unit admission was not statistically significant after adjusting for confounding factors (Table 3). In a sensitivity analysis including women with spontaneous rupture of membranes < 8 hours after oxytocin initiation, cesarean delivery was still more common among women with

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delayed amniotomy compared to no delayed amniotomy (27.4% versus 16.2%, p<0.001). Using multivariable logistic regression within the less selective (or exclusive) sensitivity analysis

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cohort, there remained an association between delayed amniotomy and cesarean delivery

(Table 4) with evidence of effect modification by maternal BMI. The odds of cesarean delivery

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increased with increasing maternal BMI. While there was still no significant association between

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delayed amniotomy and infectious morbidity, delayed amniotomy was associated with higher odds of postpartum hemorrhage (aOR 1.41, 95% CI 1.08-1.84). Delayed amniotomy remained

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associated with higher odds of 5-minute neonatal Apgar score < 7 (aOR 2.01, 95% CI 1.223.31) and was also associated with higher odds of neonatal intensive care unit admission (aOR

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1.87, 95% CI 1.40-2.50).

DISCUSSION

In this retrospective cohort study, we found that delayed amniotomy was associated with

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increased odds of cesarean delivery, compared to no delayed amniotomy. This association between delayed amniotomy and increased cesarean delivery risk was modified by maternal BMI such that there was an increasing chance of cesarean with increasing obesity severity based on BMI, which ranged from a 50% increase to a 300% increase depending on maternal BMI. Delayed amniotomy was not associated with other adverse maternal outcomes such as postpartum hemorrhage or infectious morbidity, but it was associated with a 2-fold higher odds of 5-minute neonatal Apgar score < 7, compared to those without delayed amniotomy. In

unadjusted and sensitivity analyses, delayed amniotomy was also associated with almost 2-fold higher odds of neonatal intensive care unit admission. These findings support prior research that indicates timing of amniotomy has an effect on labor induction outcomes and further characterize the effect of amniotomy timing by estimating the impact of postponed amniotomy. In the 1960s, observational studies demonstrated that up to one-third of women who were undergoing induction of labor with

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oxytocin alone would remain undelivered after 2-3 days.9 Following that observation, amniotomy became a more commonly used method of facilitating labor induction, and more recently early

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amniotomy has been investigated as a potential method to shorten the duration of labor

induction. However, there is no consensus on a definition of early amniotomy. Some studies

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have defined early amniotomy with respect to cervical dilation3,7,8,10 while others have defined

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early amniotomy by the number of hours since completion of cervical ripening or initiation of oxytocin.4–6,11 Unfortunately not all of these studies describe the timing of amniotomy with

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regards to both cervical dilation and time in hours, and some have even found that women with early amniotomy defined as less than 4cm cervical dilation actually had a longer duration of time

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from oxytocin initiation to amniotomy.7,8 Thus, it is difficult to tease out whether the performance of amniotomy at less cervical dilation increased the chance of cesarean or whether the delay for a greater number of hours after oxytocin initiation increased the risk of cesarean. Additionally, it is possible that neither of these exposures caused the increase in cesarean, but rather it was

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the indication for amniotomy that was driving the association. It is also difficult to extrapolate the results of these early amniotomy trials to assess the effects of a strategy of delaying amniotomy, as we evaluated in this cohort study. In the previously published studies the later amniotomy groups still had rupture of membranes at 4 to 6 hours after oxytocin, whereas our delayed amniotomy group did not have membrane rupture until a median of 12.7 hours after oxytocin. This is likely due to the fact that historically a less aggressive intervention approach to labor

induction, especially with regard to rupture of membranes, has been prevalent at our medical center. It is biologically plausible that delayed amniotomy after oxytocin initiation may increase the risk of cesarean delivery and other adverse outcomes. In vitro studies of myometrial oxytocin receptors have demonstrated desensitization of the receptors after prolonged or repeated stimulation.12,13 While this theory has never been proven in clinical studies, it is

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possible that prolonged exposure to oxytocin prior to amniotomy may decrease the uterotonic effectiveness of oxytocin and increase the risk of labor dystocia and cesarean delivery. Higher

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doses of oxytocin have been required among obese women undergoing labor induction,

compared to non-obese women,14,15 which may provide some explanation for our observed

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interaction between maternal BMI and delayed amniotomy. If obesity is associated with

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increased baseline tolerance to oxytocin, then it is plausible that delayed amniotomy with prolonged exposure to oxytocin may result in even greater desensitization, thus increasing the

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chance of dysfunctional labor and cesarean delivery. Prospective clinical studies including pharmacokinetic estimates are warranted to further explore these hypotheses.

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This study has several strengths. We examined a large cohort of over 2,000 women undergoing labor induction at a hospital where there is marked variability in the timing of amniotomy based on individual provider preferences. In addition, we evaluated for potential effect modification by factors known to be associated with induction outcomes including

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maternal BMI, parity, cervical ripening and gestational age at delivery. The results of our study, however, should be interpreted within the context of the study design. This study was conducted at a single, tertiary-care center and thus our findings may not be generalizable to all populations. Additionally, although the cutoff of 8 hours chosen to represent a delayed amniotomy was somewhat arbitrary, we established this exposure definition prior to performing our study, without assessing other multiple time cutoffs and based on previous study definitions of typical amniotomy timing at ≤ 4 hours. Our method for defining delayed amniotomy limits the

potential for false positive study findings due to type 1 error in multiple comparisons, reduces the chance of false negative study findings due to overlapping study groups and aligns the study definition with prior research and common clinical practice. While we adjusted for confounding factors and effect modifiers, we were not able to characterize the cervical exam immediately after cervical ripening, the frequency of contractions at the time of membrane rupture or identify the specific indication for amniotomy. Thus, we are limited by the possibility of confounding by

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indication. For example, if amniotomy were performed more commonly at < 8 hours of oxytocin initiation due to fetal heart rate abnormalities and need for internal monitors, the indication for

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amniotomy may bias our results favoring amniotomy > 8 hours. In contrast, if amniotomy were performed more commonly at > 8 hours after oxytocin initiation due to inadequate labor

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progression, the indication for amniotomy may bias our results favoring amniotomy < 8 hours

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after oxytocin. We also did not have information about the indication for labor induction or neonatal intensive care unit admission. Lastly, our sample size limited our ability to detect small

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differences in less frequent adverse outcomes such as postpartum hemorrhage and infectious morbidity.

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The recent randomized controlled trial of labor induction versus expectant management at 39 weeks in low-risk nulliparous women demonstrated that induction of labor decreased the rate of cesarean delivery and hypertensive disorders of pregnancy.16 Although induction of labor did not decrease the rate of perinatal death or severe neonatal complications, it also did not

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cause neonatal harm. As a result of this recent publication, it is possible, if not probable, that more women will elect to undergo labor induction, and it may become even more important to optimize the methods used for labor induction. While some providers may not find the apparently small decrease in the duration of labor induction associated with early amniotomy seen in prior studies clinically significant, there may be downstream benefits including reduced risk for neonatal acidemia or other adverse neonatal outcomes that have been shown to increase with increasing labor duration, as well as faster patient throughput for labor and

delivery floors that are overloaded by increased induction rates. Our study further characterizes the benefit of amniotomy during labor induction. Based on the results of this retrospective cohort study, providers should consider avoiding delayed amniotomy given the association with increased cesarean delivery. This recommendation can be made more definitively if our findings are validated in future studies.

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Disclosure statement: The authors report no conflict of interest.

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Declaration of interests

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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ACKNOWLEDGEMENTS

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There were no sources of funding for this study.

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TABLES Table 1. Maternal and obstetric characteristics by delayed amniotomy

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Delayed No delayed p-value amniotomy amniotomy (n = 1125) (n = 956) Demographic and antepartum obstetric characteristics Maternal age (years) 29.4 +/- 6.1 29.4 +/- 6.2 0.97 2 BMI (kg/m ) 28.6 +/- 8.4 28.2 +/- 8.3 0.34 Race/ethnicity <0.001 Non-Hispanic black 243 (22.2) 188 (20.1) Non-Hispanic white 564 (51.5) 368 (39.4) Hispanic 219 (20.0) 298 (31.9) Other 70 (6.4) 81 (8.7) Nulliparous 658 (58.5) 454 (50.7) <0.001 History of prior cesarean delivery 70 (6.2) 77 (8.1) 0.10 Pregestational diabetes 48 (4.3) 35 (3.7) 0.48 Gestational diabetes 125 (11.1) 117 (12.2) 0.42 Chronic HTN 134 (11.9) 92 (9.6) 0.10 Gestational HTN or preeclampsia 377 (33.5) 241 (25.2) <0.001 Intrauterine growth restriction 85 (7.6) 71 (7.4) 0.91 Intrapartum obstetric characteristics Gestational age at delivery (weeks) 39.4 (37.9, 40.9) 39.4 (38.6, 40.7) 0.77 Cervical dilation on admission (cm) 2 (1, 3) 3 (1, 4) <0.001 Cervical ripening with Foley balloon 623 (55.4) 388 (40.6) <0.001 Cervical ripening with misoprostol 98 (8.7) 58 (6.1) 0.02 Epidural analgesia 992 (88.2) 761 (79.6) <0.001 Intrapartum magnesium use 108 (9.6) 59 (6.2) <0.01 Neonatal characteristics Male sex 571 (50.8) 493 (51.6) 0.71 Neonatal birthweight 3288 +/- 619 3294 +/- 623 0.83 Data presented as n (%), mean +/- standard deviation, or median (interquartile range) Abbreviations: HTN, hypertension

Table 2. Maternal and neonatal outcomes by delayed amniotomy p-value

308 (27.4) 141 (12.5) 54 (4.8) 49 (4.4) 182 (16.2) 3.7 (1.4, 8.3)

152 (15.9) 96 (10.0) 43 (4.5) 18 (1.9) 118 (12.3) 4.1 (1.6, 10.8)

<0.001 0.08 0.75 0.001 0.01 0.33

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No delayed amniotomy (n = 956)

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Cesarean delivery Postpartum hemorrhage Infectious morbidity Neonatal 5-minute Apgar < 7 Neonatal intensive care unit admission Neonatal intensive care unit length of stay (days) Data presented as n (%) or median (IQR)

Delayed amniotomy (n = 1125)

Table 3. Multivariable logistic regression of maternal and neonatal outcomes with delayed amniotomy, compared to no delayed amniotomy Delayed amniotomy Odds ratio (95% CI)

Delayed amniotomy Adjusted odds ratio* (95% CI)

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Cesarean delivery† Representative BMI values for continuous BMI effect modification BMI 20kg/m2 1.47 (1.06-2.04) 1.17 (0.82-1.66) BMI 30kg/m2 2.06 (1.65-2.59) 1.58 (1.24-2.03) 2 BMI 40kg/m 2.89 (2.01-4.18) 2.15 (1.45-3.21) 2 BMI 50kg/m 4.06 (2.23-7.37) 2.93 (1.54-5.57) Postpartum hemorrhage 1.29 (0.98-1.69) 1.26 (0.93-1.70) ‡ Infectious morbidity 1.07 (0.71-1.61) 0.92 (0.59-1.44) Neonatal 5-minute Apgar < 7 2.37 (1.37-4.10) 2.16 (1.20-3.88) Neonatal intensive care unit admission 1.37 (1.07-1.76) 1.12 (0.83-1.51) Abbreviations: CI, confidence interval; BMI, body mass index Referent = No delayed amniotomy *Adjusted for maternal age, BMI, race/ethnicity, nulliparity, cervical ripening with foley balloon, and gestational age at delivery † Significant effect modification between delayed amniotomy and maternal BMI (p=0.01), thus odds ratios for delayed amniotomy, compared to no delayed amniotomy, were calculated for multiple maternal BMI values ‡ Infectious morbidity included chorioamnionitis and postpartum endometritis

Table 4. Sensitivity analysis of maternal and neonatal outcomes with delayed amniotomy including women with spontaneous rupture of membranes < 8 hours after oxytocin Delayed amniotomy Odds ratio (95% CI)

Delayed amniotomy Adjusted odds ratio* (95% CI)

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Cesarean delivery† Representative BMI values for continuous BMI effect modification BMI 20kg/m2 1.45 (1.09-1.93) 1.21 (0.89-1.65) BMI 30kg/m2 2.02 (1.65-2.46) 1.66 (1.34-2.06) 2 BMI 40kg/m 2.80 (2.03-3.87) 2.29 (1.61-3.25) 2 BMI 50kg/m 3.89 (2.29-6.61) 3.14 (1.78-5.55) Postpartum hemorrhage 1.43 (1.11-1.84) 1.41 (1.08-1.84) ‡ Infectious morbidity 1.00 (0.68-1.49) 1.05 (0.73-1.51) Neonatal 5-minute Apgar < 7 2.33 (1.45-3.73) 2.01 (1.22-3.31) Neonatal intensive care unit admission 2.19 (1.72-2.81) 1.87 (1.40-2.50) Abbreviations: CI, confidence interval; BMI, body mass index Referent = No delayed amniotomy *Adjusted for maternal age, BMI, race/ethnicity, nulliparity, cervical ripening with foley balloon, and gestational age at delivery † Significant effect modification between delayed amniotomy and maternal BMI (p<0.01), thus odds ratios for delayed amniotomy, compared to no delayed amniotomy, were calculated for multiple maternal BMI values ‡ Infectious morbidity included chorioamnionitis and postpartum endometritis

FIGURE LEGENDS Figure 1. Flow diagram of study cohort Footnote: UNC-CH, University of North Carolina at Chapel Hill; PPROM, preterm premature rupture of membranes; ROM, rupture of membranes; SROM, spontaneous rupture of

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Figure 2. Estimated probability and adjusted odds of cesarean delivery by delayed amniotomy across a range of maternal body mass index Footnote: Probability of cesarean delivery and adjusted odds ratios estimated from the final

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logistic regression model adjusted for maternal race, parity, body mass index (BMI) and the BMI-delayed amniotomy interaction term.

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