Labor Pain, Pregnancy
Conditions
Keywords
labor pain, cesarean section, epidural analgesia, opioid analgesics, local anesthetics, labor induced
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.
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).
Interventions
PROCEDUREcombined 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.
PROCEDURElate 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.
Sponsors
International Anesthesia Research Society (IARS)
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Vomiting | Vomiting at second analgesia request | Vomiting during labor analgesia |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Early Analgesia:Combined-spinal Epidural 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. | 408 |
| Systemic 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 | 410 |
| Total | 818 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Allocation prior to analgesia request | 1 | 2 |
| Overall Study | Parous patient | 1 | 0 |
| Overall Study | Refused allocated intervention | 0 | 6 |
| Overall Study | Wrong study envelope | 0 | 2 |
Baseline characteristics
| Characteristic | Systemic Analgesia | Early Analgesia:Combined-spinal Epidural | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 410 Participants | 408 Participants | 818 Participants |
| Age, Continuous | 31 years STANDARD_DEVIATION 5 | 31 years STANDARD_DEVIATION 6 | 31 years STANDARD_DEVIATION 6 |
| Region of Enrollment United States | 410 participants | 408 participants | 818 participants |
| Sex: Female, Male Female | 410 Participants | 408 Participants | 818 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 406 | 134 / 400 |
| serious Total, serious adverse events | 0 / 406 | 0 / 400 |
Outcome results
Primary
Delivered by Cesarean Section
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)
Population: Analysis per protocol. 10 did not receive intervention in combined spinal epidural group and 2 in the systemic analgesia group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Delivered by Cesarean Section | 134 participants |
| Systemic Analgesia | Delivered by Cesarean Section | 126 participants |
Comparison: Group sample sizes of 800 in each group achieve 80% power to detect equivalence when the margin of equivalence extends from 0.1 to 0.25p-value: 0.6595% CI: [0.9, 1.2]Chi-squared, Corrected
Secondary
Analgesia Efficacy
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Analgesia Efficacy | 1 Scores on a scale |
| Systemic Analgesia | Analgesia Efficacy | 5 Scores on a scale |
p-value: <0.00595% CI: [-4, -3]Wilcoxon (Mann-Whitney)
Secondary
Duration of Labor
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
Population: Per protocol
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Duration of Labor | 528 minutes |
| Systemic Analgesia | Duration of Labor | 569 minutes |
p-value: 0.047Log Rank
Secondary
Indication for Cesarean Delivery
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
Population: Number of cesarean deliveries
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Indication for Cesarean Delivery | Arrested dilation | 85 participants |
| Early Analgesia:Combined-spinal Epidural | Indication for Cesarean Delivery | Arrested descent | 18 participants |
| Early Analgesia:Combined-spinal Epidural | Indication for Cesarean Delivery | Non-reassuring fetal status | 27 participants |
| Early Analgesia:Combined-spinal Epidural | Indication for Cesarean Delivery | Other | 4 participants |
| Systemic Analgesia | Indication for Cesarean Delivery | Other | 4 participants |
| Systemic Analgesia | Indication for Cesarean Delivery | Arrested dilation | 83 participants |
| Systemic Analgesia | Indication for Cesarean Delivery | Non-reassuring fetal status | 16 participants |
| Systemic Analgesia | Indication for Cesarean Delivery | Arrested descent | 23 participants |
p-value: 0.35Chi-squared
Secondary
Instrumented Vaginal Delivery
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
Population: Per protocol - subjects that delivered vaginally
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Instrumented Vaginal Delivery | 57 participants |
| Systemic Analgesia | Instrumented Vaginal Delivery | 59 participants |
Comparison: There rate of instrumented vaginal delivery will be equal in both groups.p-value: 0.6395% CI: [0.8, 1.2]Chi-squared
Secondary
Nausea
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Nausea | Moderate | 5 participants |
| Early Analgesia:Combined-spinal Epidural | Nausea | None | 372 participants |
| Early Analgesia:Combined-spinal Epidural | Nausea | Severe | 2 participants |
| Early Analgesia:Combined-spinal Epidural | Nausea | Mild | 25 participants |
| Systemic Analgesia | Nausea | Severe | 16 participants |
| Systemic Analgesia | Nausea | Mild | 69 participants |
| Systemic Analgesia | Nausea | Moderate | 49 participants |
| Systemic Analgesia | Nausea | None | 265 participants |
p-value: <0.005Chi-squared, Corrected
Secondary
Neonatal Outcome (APGAR Score < 7 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.
Time frame: APGAR score at 5 minutes
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Neonatal Outcome (APGAR Score < 7 at 5 Minutes) | 14 participants |
| Systemic Analgesia | Neonatal Outcome (APGAR Score < 7 at 5 Minutes) | 6 participants |
p-value: 0.11Fisher Exact
Secondary
Vomiting
Vomiting during labor analgesia
Time frame: Vomiting at second analgesia request
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Analgesia:Combined-spinal Epidural | Vomiting | 12 participants |
| Systemic Analgesia | Vomiting | 61 participants |
p-value: <0.005Chi-squared, Corrected