Uncertain prelabor rupture of membranes at term and associated delivery outcomes

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Uncertain prelabor rupture of membranes at term and associated delivery outcomes

https://doi.org/10.21203/rs.3.rs-3927382/v1

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published 14 Jun, 2024

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Background

Prelabor rupture of membranes (PROM) is a common obstetrical event, but its diagnosis is frequently challenging. The aim of the study was to determine whether equivocal PROM cases are associated with adverse outcomes.

Methods

A retrospective study was conducted in a tertiary medical center between July 2012 and March 2022. The cohort consisted of women diagnosed with term PROM (≥ 37 gestational weeks), divided into two groups: (1) certain PROM - suggestive history of a watery vaginal discharge confirmed by visualization of fluid leaking from the cervix or pooling in the vagina on speculum examination; (2) uncertain PROM - suggestive history of a watery vaginal discharge not supported by speculum examination. All patients were hospitalized and gave birth spontaneously or following either expectant management for up to 24 hours from PROM or induction. The primary outcome measure was cesarean delivery rate. Secondary outcome measures were adverse maternal and neonatal events.

Results

A total of 2012 women were included in the study, 1750 with certain PROM and 262 with uncertain PROM. The cesarean delivery rate was 5.8% in the certain PROM group and 8.8% in the uncertain PROM group; the difference was not statistically significant (p = .074). There was a significant between-group difference in the rate of cesarean delivery due to failed induction on univariate analysis (0.69% vs 2.67%, respectively, p = .007), but it was not maintained on multivariate logistic regression (OR 0.37, 95% CI 0.117–1.172). Other maternal and neonatal outcomes were similar in the two groups.

Conclusions

In our study, following the same management guidelines for equivocal cases of ruptured membranes as for confirmed cases of term PROM did not compromise maternal or fetal outcomes.

Prelabor rupture of membranes

Term pregnancy

Diagnosis

Induction of labor

Prelabor rupture of membranes (PROM) at term (≥ 37 gestational weeks) complicates approximately 8% of pregnancies and is generally followed by prompt onset of spontaneous labor and delivery [1]. The most significant maternal consequence of term PROM is intrauterine infection, including chorioamnionitis and postpartum febrile morbidity. Fetal consequences include ascending infection and in utero cord compression [2].

A meta-analysis of 23 randomized controlled trials (8615 women) found that induction of labor reduced the time from rupture of membranes to birth and the rates of chorioamnionitis, endometritis, or both, and was associated with a lower likelihood for neonatal intensive care unit (NICU) admission. There was no accompanying increase in rates of cesarean delivery (CD) or operative vaginal delivery [1]. For women with term PROM who have no contraindication for labor, induction is usually recommended. As long as maternal and fetal conditions are reassuring, expectant management for a short duration may also be a reasonable choice, given that half the women with term PROM who are managed expectantly give birth within 33 hours [3].

The diagnosis of PROM is usually made by clinical assessment, which includes visualization of amniotic fluid passing from the cervical canal and pooling in the posterior vaginal fornix on speculum evaluation, higher than normal value on pH test of the vaginal fluid, or arborization (ferning) of dried vaginal fluid on microscopic evaluation. Currently, various tests are available for detecting amniotic proteins, such as placental alpha microglobulin 1 (PAMG), which is known for high sensitivity in diagnosing PROM [2]. However, several factors can influence the diagnostic accuracy and feasibility of these tests, yielding false-positive results in about one-third of cases [4]. Reasons for a false-positive may be presence of blood or semen, alkaline antiseptics, certain lubricants, trichomonas, or bacterial vaginosis. False-negative test results may arise with prolonged membrane rupture and minimal residual fluid. In ambiguous cases, sonographic evaluation of amniotic fluid volume may be a useful adjunct, but it is not diagnostic. Thus, the optimal approach to clinical assessment and diagnosis of PROM is still controversial [2].

Ladfors et al. [5] showed that even at term, speculum examination to visualize the amniotic fluid carries a 12% false-negative rate [5]. Nonconfirmatory test results in a patient with a history suggesting membrane rupture, or vice versa, creates an obstetrical dilemma. Early and accurate diagnosis of PROM allows for further interventions to optimize maternal and perinatal outcomes and minimize complications, whereas overdiagnosis may result in complications of overtreatment or unnecessary labor induction. Although labor induction is known to be beneficial in cases of PROM, whether it is also beneficial in cases of inconclusive PROM has not yet been determined.

The aim of the present study was to answer the question: By offering the same treatment for uncertain PROM as for certain PROM, are we exposing patients with uncertain PROM to greater risk?

Study population

A retrospective study was conducted at a tertiary university medical center from July 2012 to March 2022. The cohort included women with a singleton gestation who were diagnosed with ruptured membranes at ≥ 37 gestational weeks. Patients were categorized into two groups: (1) certain PROM -- women presenting with unequivocal clinical rupture of the membranes based on a suggestive history of watery vaginal discharge confirmed by speculum examination demonstrating fluid leaking from the cervix or pooling in the vagina; (2) uncertain PROM -- women for whom the diagnosis of PROM was inferred from a suggestive history of membrane rupture, although speculum examination was not supportive. No additional diagnostic methods were used in the uncertain PROM group.

Exclusion criteria were non-vertex presentation, multiple gestation, fetal malformations, contraindication for vaginal delivery (such as placenta previa or > 1 previous CD), and non-reassuring fetal status at admission.

Data collection

Clinical data on maternal and obstetrical characteristics and maternal and early neonatal outcomes were extracted from the electronic medical records.

Patient management

All patients were hospitalized and managed either actively or expectantly according to our departmental protocol for PROM, taking clinical-obstetrical status and maternal preference into consideration. Expectant management entailed a period of in-hospital observation lasting up to 24 hours following membrane rupture. If spontaneous labor did not commence naturally within this timeframe, or for reasons of maternal request, suspected maternal infection, or non-reassuring fetal status, labor was induced with either oxytocin infusion or prostaglandin E2 (PGE2) slow-release vaginal insert (Propess 10mg, Ferring Pharmaceuticals AB, Kiel, Germany). Active management was defined as the initiation of labor immediately upon admission, either spontaneously or through induction using oxytocin or PGE2, or by augmentation with oxytocin.

Prophylactic treatment with intravenous ampicillin (Penibrin; Sandoz, Kundl, Austria) was administered for the following indications: group B Streptococcus (GBS) carrier, previous infant with invasive GBS disease and prolonged PROM (≥ 18 hours), or intrapartum fever (≥ 37.8⁰C) when GBS carrier status was unknown.

Outcome measures

The primary outcome measure was the CD rate. Secondary outcome measures were duration of labor and adverse maternal and neonatal events. The adverse maternal outcomes assessed were operative vaginal delivery, intrapartum fever, clinical chorioamnionitis, and obstetrical anal sphincter injuries (OASIS). Clinical chorioamnionitis was defined as fever (≥ 37.8⁰C) accompanied by one or more of the following: maternal tachycardia (> 100 bpm), fetal tachycardia (> 160 bpm), leukocytosis (> 15,000/mm³), uterine tenderness, and foul-smelling vaginal discharge. The composite adverse maternal outcome was defined as any of the following: cesarean delivery, assisted vaginal delivery, clinical chorioamnionitis, intrapartum fever, and OASIS. The adverse neonatal outcomes assessed were 5-minute Apgar score < 7, umbilical pH < 7.2, NICU admission, and/or neonatal death.

Ethics

The study adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Board (approval no. 0089-22-RMC) which waived the need for informed consent.

Statistical analysis

Statistical analysis was generated with SAS software, version 34.0 (SAS Corp., Cary, NC, USA). Continuous variables were summarized by mean and standard deviation or median and interquartile range. Categorical variables were summarized by number and percent. Normality of continuous variables was assessed using the Kolmogorov-Smirnov test. T-test was used to compare the value of normally distributed continuous variables between study groups, and Wilcoxon test was used for non-normal continuous variables. Fisher's exact test was used to compare categorical variables between groups. Logistic regression was used to calculate univariate and multivariate odds ratios (OR), presented with 95% confidence interval (CI). The Kaplan-Meier procedure was applied to graph latency time from PROM until delivery.

Two-sided p-values less than .05 were considered statistically significant.

A total of 2012 women met the inclusion criteria: 1750 (87%) with certain PROM and 262 (13%) with uncertain PROM.

Their demographic characteristics are presented in Table 1. There was a marginal difference in median gestational age between the groups: 39.57 years (IQR 39-40.29) in the uncertain PROM group and 39.29 years (IQR 38.43-40) in the certain PROM group (p < .0001). No significant between-group differences were found in maternal age, gravidity, parity, proportion of previous cesarean deliveries, neonatal gender, and birthweight.

The prevalence of oligohydramnios was notably higher in the uncertain PROM group (10.31% vs. 1.49%; p < .001), with no significant differences between the groups in rates of hypertensive disorders, diabetes mellitus, polyhydramnios, and positive GBS carrier status.

Labor management strategies differed between the groups. The uncertain PROM group had a higher incidence of active management (68.70% vs. 55.43%; p < .001) and more frequent use of PGE2 for labor induction (9.92% vs. 2.0%; p < .001). Need for Induction following expectant management did not differ significantly between the groups.

Table 1

Maternal and obstetrical characteristics of cases of clinically certain and uncertain PROM
Parameters	Uncertain PROM N = 262	Certain PROM N = 1750	p-Value
Gestational age at delivery, weeks	39.57 (39-40.29)	39.29 (38.43-40)	< .0001
Gravidity	3 (1–4)	2 (1–4)	0.283
Parity	1 (0–2)	1 (0–2)	0.071
Neonatal gender, male	140 (53.44)	913 (52.17)	0.740
Neonatal birthweight, grams	3228 (2969–3494)	3198 (2934–3450)	0.078
Maternal age (years)	32.43 ± 4.64	32.04 ± 4.71	0.206
Previous cesarean delivery	24 (9.16)	162 (9.26)	> .999
Hypertensive disorders^a	9 (3.44)	34 (1.94)	0.163
Diabetes in pregnancy^b	14 (5.34)	87 (4.97)	0.762
Polyhydramnios	6 (2.29)	25 (1.43)	0.281
Oligohydramnios	27 (10.31)	26 (1.49)	< .001
Other maternal comorbidities^c	32 (12.21)	212 (12.11)	0.920
GBS carrier status, positive	16 (22.22)	132 (23.36)	0.883
Meconium	26 (9.92)	215 (12.29)	0.308
Cervical dilation at admission, cm	2 (1-2.5)	1.5 (1-2.5)	0.241
Cervical effacement at admission, %	70 (60–80)	70 (60–80)	0.094
Active management	180 (68.70)	970 (55.43)	< .001
Spontaneous initiation of labor	50 (19.08)	255 (14.57	0.064
Induction with oxytocin	104 (39.69)	680 (38.86)	0.839
Induction with PGE2	26 (9.92)	35 (2.0)	< .001
Expectant management	82 (31.2)	780 (44.6)	< .001
Need for induction after expectant management	39 (14.89)	276 (15.77)	0.785
With oxytocin	18 (6.8)	144 (8.2)	0.802
With PGE2	21 (8)	132 (7.5)	0.542

*Data are presented as mean ± standard deviation, median (interquartile range), or number (percentage).

^aChronic hypertension, gestational hypertension, preeclampsia with or without severe features, superimposed preeclampsia and eclampsia.

^bGestational and pregestational diabetes.

^cThyroid disorders, asthma, epilepsy, smoking, alcohol or drug abuse.

PROM, premature rupture of membranes; GBS, group B Streptococcus; PGE2, prostaglandin E2.

Table 2 summarizes the maternal and neonatal outcomes. No significant between-group differences were found in overall rates of CD, assisted vaginal delivery, or maternal complications such as clinical chorioamnionitis, intrapartum fever, OASIS and composite maternal outcome. Similarly, neonatal outcomes including Apgar score, umbilical cord pH, NICU admission, and death were consistent across both groups. A higher rate of CD due to failed induction was observed in the uncertain PROM group (2.67% vs. 0.69%, respectively; p = .007).

Table 2

Maternal and neonatal outcome in cases of clinically certain and uncertain PROM
Parameter	Uncertain PROM N = 262	Certain PROM N = 1750	p-Value
Maternal outcome
Cesarean delivery	23 (8.80)	102 (5.80)	0.074
Due to failed induction	7 (2.67)	12 (0.69)	0.007
Due to labor dystocia	1 (0.38)	22 (1.26)	0.348
Assisted vaginal delivery	19 (7.25)	168 (9.60)	0.254
Clinical chorioamnionitis	0	7 (0.40)	0.605
Intrapartum fever	0	12 (0.69)	0.385
Obstetrical anal sphincter injuries	1 (0.38)	9 (0.51)	> 0.999
PROM to delivery time, hours	13.57 (7-31.08)	15.35 (9.48–26.93)	0.136
Composite maternal outcome^a	43 (16.41)	280 (16.0)	0.857
Neonatal outcome
5-minute Apgar score < 7	0	8 (0.46)	0.607
Umbilical cord pH < 7.2	7 (3.50)	37 (2.81)	0.505
NICU admission	1 (0.38)	29 (1.66)	0.167
Death	0	0	-

*Data are presented as mean ± standard deviation, median (interquartile range), or number (percentage).

^aCesarean delivery, assisted vaginal delivery, maternal infection, intrapartum fever, Obstetrical anal sphincter injuries.

PROM, premature rupture of membranes, NICU, neonatal intensive care unit.

The time from PROM to delivery across all cases of certain and uncertain PROM was plotted in a Kaplan-Meier survival curve (Fig. 1). No statistically significant difference was noted between the groups (p = 0.381, log-rank test). As shown in Fig. 2, there was also no between-group difference in time to delivery within the subset of 862 women who were managed expectantly (p = 0.128, log-rank test).

Univariate and multivariate logistic regression analyses were performed to evaluate the factors associated with cesarean delivery (CD) due to failed induction. This analysis was conducted within a subset of 1,160 women who underwent labor induction. This group comprised patients following either active or expectant management strategies, including 991 women with confirmed certain PROM and 169 women with uncertain PROM.

The results are shown in Table 3. Certain PROM was associated with lower odds of CD due to failed induction in the univariate model (OR 0.321, 95% CI 0.122–0.842), but this association did not reach statistical significance in the multivariate model (OR 0.382, 95% CI 0.12–1.215). Parity (OR 0.294, 95% CI 0.088–0.983) and cervical dilation at admission (OR 0.131, 95% CI 0.049–0.35) were found to be protective. Previous CD emerged as a significant predictor for CD due to failed induction in the multivariate model (OR 7.765, 95% CI 1.313–45.912). Maternal age and gestational age at delivery were not associated with failed induction-indicated CD.

Table 3

Univariate and multivariate analysis of factors associated with cesarean delivery due to failed induction
Parameter	Univariate OR with 95% CI	Multivariate OR with 95% CI
Certain PROM	0.321 [0.122–0.842, p = .021]	0.382 [0.12–1.215, p = .103]
Maternal age	0.975 [0.886–1.073, p = .610]	1.064 [0.95–1.191, p = .284]
Parity	0.342 [0.165–0.708, p = .004]	0.294 [0.088–0.983, p = .047]
Gestational age at delivery	1.024 [0.677–1.549, p = .91]	1.009 [0.622–1.635, p = .972]
Previous cesarean delivery	4.51 [1.358–14.974, p = .014]	7.765 [1.313–45.912, p = .024]
Cervical dilatation at admission	0.092 [0.037–0.23, p < .0001]	0.131 [0.049–0.35, p < .0001]

PROM, premature rupture of membranes; OR, Odds ratio; CI, confidence interval

The present study demonstrates that women with suspected membrane rupture who were managed like women with certain (unequivocal) PROM and underwent induction or expectant management were not compromised compared to women with certain PROM. Our findings show no significant difference between the groups in maternal outcomes, including CD rates, and in short-term neonatal outcomes.

In most women, the diagnosis of ruptured fetal membranes can be confirmed on the basis of a suspicious history and findings of leaking or pooling of amniotic fluid during speculum examination. However, in approximately 10% of cases, the diagnosis is difficult to establish [6].

Previous studies of diagnostic tests to confirm PROM in patients with a questionable state of the membranes reported varying efficacy. The tests investigated included the fern test [7], nitrazine test [8], fibronectin immunoassay [9], insulin-like growth factor binding protein-1 (IGFBP-1) test [10], alpha-fetoprotein (AFP) kit [11], placental α microglobulin-1 (PAMG) immunoassay [12, 13], and dye injection [14]. A meta-analysis of studies that focused on the clinical use of biochemical marker tests in patients with suspected membrane rupture found that PAMG-1 and IGFBP-1 had high positive (98.4% and 87.9%, respectively) and negative (96.7% and 93.9%, respectively) predictive values, making them useful diagnostic aids [15]. As rupture of the membranes in the preterm period (> 37 gestational weeks) is associated with prematurity, neonatal morbidity, and mortality, alongside an increased risk of maternal infection, a concise diagnosis is needed.

In 2018, Grobman et al. [16] published the results of the ARRIVE trial which evaluated the perinatal and maternal consequences of inducing labor at 39 weeks in nulliparous women at low risk. The results showed that this approach did not lead to adverse outcomes, and indeed, even led to a reduction in CDs. Our results align with these findings, as the gestational age of most of our cohort (62.6% of the certain PROM group, 75.2% of the uncertain PROM group) was 39 weeks or more. This suggests that induction of labor following suspected and unconfirmed PROM at term would not be expected to have adverse maternal or neonatal consequences. Furthermore, the time to delivery in the two groups remained similar, even when including women who were managed expectantly. Thus, a notable portion of women with uncertain PROM may have actually experienced membrane rupture despite the absence of clear evidence of amniotic fluid loss by speculum examination.

In a Cochrane review comparing planned early birth versus expectant management for term PROM, the rates of overall chorioamnionitis (either suspected or proven) and/or intrapartum fever, as reported by 14 studies, varied between 1.0% and 26.9% [6]. In the present study, rates of clinical chorioamnionitis and intrapartum fever were closer to the lower end of this range for both groups. The difference between the studies could be due to the active management approach we used for most of our patients, likely reducing the risk of these conditions.

The present study has several limitations that need to be considered when interpreting the data. The retrospective design could have created a selection as well as an information bias. In addition, gestational age was more than 39 weeks in most of the women in our cohort, and it is unknown whether the results are applicable to cohorts with a lower gestational age. Our data did not include postpartum maternal and neonatal infections which are associated with PROM. Nevertheless, to our knowledge, this is the first study to examine the outcomes of equivocal cases of membrane rupture at term that were managed as PROM. This information may guide physicians facing controversial findings between anamnesis and physical examination when confirmatory tests are unavailable.

In conclusion, the diagnosis of rupture of membranes should be pursued due to the associated risks. The present study suggests that the management of questionable rupture of membrane at term as PROM does not result in adverse maternal or neonatal outcomes.

CD, cesarean delivery

GBS, group B Streptococcus

NICU, neonatal intensive care unit

OASIS, obstetrical anal sphincter injuries

PGE2, prostaglandin 2

PROM, premature rupture of membranes

Ethics approval and consent to participate

The study adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Board (approval no. 0089-22-RMC) which waived the need for informed consent.

Consent for publication

Not applicable.

Availability of data and materials

Data is available from the corresponding author upon reasonable request, with appropriate regulatory approvals. All data relevant to the study was included in the article.

Competing Interest

None declared.

Authors' contributions

Y.G. and E.H. conceptualized and designed the study. Material preparation and data collection were performed by N.R.N., R.M. and S.D.G. Data analysis and interpretation were performed by R.M. and N.H. The manuscript was written by Y.G, N.R.N., A.S. and E.H. All authors approved the final article as submitted.

Funding

This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

Not applicable.

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No competing interests reported.

Download PDF

Journal Publication

published 14 Jun, 2024

Read the published version in International Journal of Gynecology & Obstetrics →

Version 1

posted

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Uncertain prelabor rupture of membranes at term and associated delivery outcomes

Status:

Journal Publication

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

Background

Methods

Study population

Data collection

Patient management

Outcome measures

Ethics

Statistical analysis

Results

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1