Neuraxial Versus Systemic Analgesia for Latent Phase Labor Effect on Rate of Operative Delivery

• Sponsor: Northwestern University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00380978
• Collaborator: International Anesthesia Research Society (IARS) (Other)
• Enrollment: 1,026
• Location: 1
• Arms: 2
• Duration (Months): 83
• Patients Per Site Per Month: 12.4

Study Details

Study Description

Brief Summary

The purpose of this study in nulliparous women undergoing induction of labor is to determine whether initiation of neuraxial analgesia compared to systemic opioid analgesia early in labor (< 4 cm cervical dilation)affects the cesarean delivery rate.

Condition or Disease	Intervention/Treatment	Phase
Labor Pain; Pregnancy	Procedure: combined spinal epidural analgesia; Procedure: late analgesia (systemic)	N/A

Detailed Description

Women in early labor frequently request pain medication. Obstetricians may prescribe narcotics (administered as an intravenous (IV) or intramuscular (IM) injection). However, IV or IM narcotics provide incomplete pain relief and have maternal and fetal/neonatal side effects, e.g., maternal drowsiness, respiratory depression, nausea, vomiting, and neonatal respiratory depression. Other obstetricians allow their patients to request early neuraxial (spinal or epidural) analgesia. The results of several studies comparing patients who received epidural versus IV/IM narcotic labor analgesia (not specifically in early labor)suggest that initiation of early neuraxial analgesia may be associated with higher Cesarean delivery rates. It has been hypothesized that epidural/spinal local anesthetics may induce pelvic musculature relaxation leading to failure of fetal descent and rotation. However, early pain may be a marker for other factors that increase the risk of Cesarean delivery, e.g., large or malpositioned baby, or dysfunctional labor. Whether or not early neuraxial analgesia (particularly if narcotic based, which would not cause pelvic muscle paralysis) compared to IV/IM narcotics, adversely affects the outcome of labor has not been studied in a randomized, prospective fashion. The purpose of this study is to compare Cesarean and forcep delivery rates, and quality of pain relief, in first-time mothers undergoing induction of labor who receive neuraxial versus IV/IM analgesia for early labor (cervical dilation < 4 cm).

Study Design

• Study Type: Interventional
• Actual Enrollment: 1026 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Early Compared With Late Neuraxial Analgesia in Nulliparous Labor Induction
• Study Start Date: Oct 1, 2001
• Actual Primary Completion Date: Sep 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: early analgesia:combined-spinal epidural	Procedure: combined spinal epidural analgesia; Analgesia was initiated in the early group using a standard needle-through-needle technique with intrathecal fentanyl 25 mcg and an epidural test dose of lidocaine 15 mg/ml and epinephrine 5 mcg/ml in 3ml. At the second analgesia request, the cervix was examined. Epidural analgesia was initiated with a dilute bupivicaine/fentanyl solution if the cervix was less than 4 cm. If the cervix was 4 cm or more, epidural analgesia was initiated with bupivicaine 1.25 mg/ml. If no cervical exam was performed at the second request for analgesia, the cervix was assumed to be at least 4 cm dilated. Thereafter, analgesia was maintained in all participants in the early group with patient-controlled epidural analgesia.; Other Names: CSE
Active Comparator: late analgesia (systemic)	Procedure: late analgesia (systemic); Analgesia was initiated in the late group with hydromorphone 1mg intramuscularly (IM) and 1 mg intravenously (IV). If the cervix was less than 4 cm at the second analgesia request, hydromorphone analgesia was repeated. Epidural analgesia was initiated with bupivicaine 1.25 mg/ml if the cervix was 4 cm or more. At the third analgesia request, epidural analgesia was initiated regardless of cervical dilation. Thereafter, epidural analgesia was maintained with patient controlled analgesia until delivery.; Other Names: Dilaudid, narcotic

Outcome Measures

Primary Outcome Measures

1. Delivered by Cesarean Section [Time form initiation of labor analgesia to delivery (up to 24 hours)]

   The decision to proceed to operative delivery was made by the obstetric team for maternal or fetal indications.

Secondary Outcome Measures

1. Instrumented Vaginal Delivery [At time of decision for delivery]

   The decision to proceed to assisted/instrumental delivery was made by the obstetric team for maternal or fetal indications.

2. Duration of Labor [Initiation of induction of labor to time of delivery]

   Labor was induced by initiating an oxytocin infusion or by infusing extra-amniotic saline followed by oxytocin. All participants had continuous external electronic fetal heart rate (FHR) monitoring and tocodynamometry. Internal fetal scalp electrodes were placed when the external tracing was not interpretable, and intrauterine pressure catheters were used to measure the intensity of contractions when deemed necessary by the obstetricians. Artificial rupture of membranes was performed, and nurses titrated oxytocin infusions according to institutional protocol.

3. Indication for Cesarean Delivery [At time of decision for delivery]

   The decision to proceed to operative delivery was made by the obstetric team for maternal or fetal indications.

4. Analgesia Efficacy [At first and second analgesia requests]

   Patients were asked to rate their average pain score using an 11-point verbal rating score (VRS)for pain (0 - 10: 0= no pain, 10= worst pain imaginable) between 1st and 2nd analgesia request.

5. Nausea [At second analgesia request]

   Participants were asked to rate their nausea (as none, mild, moderate, or severe) and report the presence or absence of vomiting.

6. Neonatal Outcome (APGAR Score < 7 at 5 Minutes) [APGAR score at 5 minutes]

   Infant's Apgar scores measured at 5 minutes of life and were assigned by nurses and pediatricians responsible for neonatal assessment. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing the five values. The categories are skin color, pulse, reflex to stimulation, muscle tome, and breathing. The test was done at one and five minutes after birth, and may be repeated later if the score is and remains low. Scores 3 and below are generally regarded as critically low, 4 to 6 fairly low, and 7 to 10 generally normal.

7. Vomiting [Vomiting at second analgesia request]

   Vomiting during labor analgesia

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• induction of labor

• nulliparity

• 36 weeks gestation

• singleton

• vertex position

• cervical dilation < 4 cm at first request for analgesia

• desires neuraxial analgesia

Exclusion Criteria:

• spontaneously laboring

• multiparity

• nonvertex presentation

• at or >4cm at analgesia request

• chronic opioid therapy

• acute opioid therapy within 4 hours of analgesia request

• allergy to study drugs (hydromorphone, fentanyl, bupivacaine, lidocaine)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern Memorial Hospital	Chicago	Illinois	United States	60611

Sponsors and Collaborators

• Northwestern University
• International Anesthesia Research Society (IARS)

Investigators

• Principal Investigator: Cynthia A Wong, MD, Northwestern University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Wong CA, Scavone BM, Peaceman AM, McCarthy RJ, Sullivan JT, Diaz NT, Yaghmour E, Marcus RJ, Sherwani SS, Sproviero MT, Yilmaz M, Patel R, Robles C, Grouper S. The risk of cesarean delivery with neuraxial analgesia given early versus late in labor. N Engl J Med. 2005 Feb 17;352(7):655-65.

• Responsible Party: Cynthia Wong, Professor of Anesthesiology, Northwestern University
• ClinicalTrials.gov Identifier: NCT00380978
• Other Study ID Numbers: 0524-009
• First Posted: Sep 27, 2006
• Last Update Posted: Apr 14, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Cynthia Wong, Professor of Anesthesiology, Northwestern University: labor pain; cesarean section; epidural analgesia; opioid analgesics; local anesthetics; labor induced
• Additional relevant MeSH terms: Labor Pain; Narcotics

Study Results

Participant Flow

Recruitment Details	Between October 2001 and December 2006, women presenting at Prentice Women's Hospital for induction of labor and who desired neuraxial analgesia were eligible to participate. Patients were asked to participate by study personnel after admission to the Labor and Delivery Unit and gave written informed consent before request for analgesia.
Pre-assignment Detail	A total of 1,026 women consented to participate. 208 women were excluded because cervical dilation was 4 cm or more at the first analgesia request. Twelve participants were excluded after randomization because they did not receive the allocated intervention and outcome data were not available. The remaining 806 women were included in the analysis.

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Period Title: Overall Study
STARTED	408	410
COMPLETED	406	400
NOT COMPLETED	2	10

Baseline Characteristics

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia	Total
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural	Total of all reporting groups
Overall Participants	408	410	818
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	408 100%	410 100%	818 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31 (6)	31 (5)	31 (6)
Sex: Female, Male (Count of Participants)
Female	408 100%	410 100%	818 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	408 100%	410 100%	818 100%

Outcome Measures

1. Primary Outcome

Title	Delivered by Cesarean Section
Description	The decision to proceed to operative delivery was made by the obstetric team for maternal or fetal indications.
Time Frame	Time form initiation of labor analgesia to delivery (up to 24 hours)

Outcome Measure Data

Analysis Population Description

Analysis per protocol. 10 did not receive intervention in combined spinal epidural group and 2 in the systemic analgesia group

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	406	400
Number [participants]	134 32.8%	126 30.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments	Group sample sizes of 800 in each group achieve 80% power to detect equivalence when the margin of equivalence extends from 0.1 to 0.25
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Equivalence
Statistical Test of Hypothesis	p-Value	0.65
	Comments
	Method	Chi-squared, Corrected
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Instrumented Vaginal Delivery
Description	The decision to proceed to assisted/instrumental delivery was made by the obstetric team for maternal or fetal indications.
Time Frame	At time of decision for delivery

Outcome Measure Data

Analysis Population Description

Per protocol - subjects that delivered vaginally

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	272	274
Number [participants]	57 14%	59 14.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments	There rate of instrumented vaginal delivery will be equal in both groups.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Duration of Labor
Description	Labor was induced by initiating an oxytocin infusion or by infusing extra-amniotic saline followed by oxytocin. All participants had continuous external electronic fetal heart rate (FHR) monitoring and tocodynamometry. Internal fetal scalp electrodes were placed when the external tracing was not interpretable, and intrauterine pressure catheters were used to measure the intensity of contractions when deemed necessary by the obstetricians. Artificial rupture of membranes was performed, and nurses titrated oxytocin infusions according to institutional protocol.
Time Frame	Initiation of induction of labor to time of delivery

Outcome Measure Data

Analysis Population Description

Per protocol

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	406	400
Median (Inter-Quartile Range) [minutes]	528	569

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Indication for Cesarean Delivery
Description	The decision to proceed to operative delivery was made by the obstetric team for maternal or fetal indications.
Time Frame	At time of decision for delivery

Outcome Measure Data

Analysis Population Description

Number of cesarean deliveries

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	134	126
Arrested dilation	85 20.8%	83 20.2%
Arrested descent	18 4.4%	23 5.6%
Non-reassuring fetal status	27 6.6%	16 3.9%
Other	4 1%	4 1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.35
	Comments
	Method	Chi-squared
	Comments

5. Secondary Outcome

Title	Analgesia Efficacy
Description	Patients were asked to rate their average pain score using an 11-point verbal rating score (VRS)for pain (0 - 10: 0= no pain, 10= worst pain imaginable) between 1st and 2nd analgesia request.
Time Frame	At first and second analgesia requests

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	406	400
Median (Inter-Quartile Range) [Scores on a scale]	1	5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.005
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	-4
	Confidence Interval	(2-Sided) 95%; -4 to -3
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Nausea
Description	Participants were asked to rate their nausea (as none, mild, moderate, or severe) and report the presence or absence of vomiting.
Time Frame	At second analgesia request

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	406	400
None	372 91.2%	265 64.6%
Mild	25 6.1%	69 16.8%
Moderate	5 1.2%	49 12%
Severe	2 0.5%	16 3.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.005
	Comments
	Method	Chi-squared, Corrected
	Comments

7. Secondary Outcome

Title	Neonatal Outcome (APGAR Score < 7 at 5 Minutes)
Description	Infant's Apgar scores measured at 5 minutes of life and were assigned by nurses and pediatricians responsible for neonatal assessment. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from zero to two, then summing the five values. The categories are skin color, pulse, reflex to stimulation, muscle tome, and breathing. The test was done at one and five minutes after birth, and may be repeated later if the score is and remains low. Scores 3 and below are generally regarded as critically low, 4 to 6 fairly low, and 7 to 10 generally normal.
Time Frame	APGAR score at 5 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	406	400
Number [participants]	14 3.4%	6 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	Vomiting
Description	Vomiting during labor analgesia
Time Frame	Vomiting at second analgesia request

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Early Analgesia:Combined-spinal Epidural	Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
Measure Participants	406	400
Number [participants]	12 2.9%	61 14.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Early Analgesia:Combined-spinal Epidural, Systemic Analgesia
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.005
	Comments
	Method	Chi-squared, Corrected
	Comments

Adverse Events

Arm/Group Title	Early Analgesia:Combined-spinal Epidural		Systemic Analgesia
Arm/Group Description	Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive spinal fentanyl 25 micrograms and epidural bupivacaine 6.25 mg/ml and fentanyl 1.96 micrograms/ml for labor analgesia.		Laboring women with induction of labor requesting analgesia at cervical dilation less than 4 cm randomized to receive hydromorphone 1mg IM and 1mg IV until cervical dilation greater than 4 cm or third request for analgesia. Epidural
All Cause Mortality
	Early Analgesia:Combined-spinal Epidural		Systemic Analgesia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Early Analgesia:Combined-spinal Epidural		Systemic Analgesia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/406 (0%)		0/400 (0%)
Other (Not Including Serious) Adverse Events
	Early Analgesia:Combined-spinal Epidural		Systemic Analgesia
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	32/406 (7.9%)		134/400 (33.5%)
Gastrointestinal disorders
Nausea and/or vomiting	32/406 (7.9%)	32	134/400 (33.5%)	134

Limitations/Caveats

The study was not powered to detect a small difference between groups in the cesarean delivery rate. It was not blinded. Different obstetric providers have different management styles, and different triggers for performing cesarean delivery.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.