Epidural analgesia in labor: A narrative review

Lumbar epidural is the most effective form of pain relief in labor with around 30% of laboring women in the UK and 60% in the USA receiving epidural analgesia. Associations of epidural on maternal, obstetric, and neonatal outcomes have been the subject of intense study, though a number of uncertainties persist. The present narrative review explores important areas of research surrounding epidural analgesia in obstetric patients including methods of initiation and administration, choice of local anesthetic solution, and the addition of adjuvants. Key meta‐analyses exploring associations of epidural analgesia on maternal and neonatal outcomes are identified and summarized.

"obstetric analgesia," "labor analgesia," and "labor pain." Relevant articles were obtained, and the reference sections of these articles were reviewed to identify additional relevant literature.
The population of interest was women receiving epidural analgesia for labor. All obstetric, maternal, neonatal, and early childhood outcomes were considered. This article was prepared using the SARNA guidelines for quality assessment of narrative review articles. 4

| Epidural anatomy and insertion techniques
The epidural space is a potential space containing fat, blood vessels, and spinal nerve roots and lies between the ligamentum flavum and dura mater (Figure 1). 2 The spinal cord ends around L1/L2 and becomes a loose bundle of intradural nerves, the cauda equina. Labor epidurals are sited below the level of the spinal cord to minimize risk of nerve injury. Before insertion of the epidural, parturients should be counseled on the risks and benefits ( Table 1). As pain and analgesic agents may influence the ability to give informed consent during labor, this should be initially discussed during the antenatal period as part of a delivery plan. There are two well-established techniques for initiating labor epidural analgesia: conventional lumbar epidural and combined spinal epidural (CSE).

| Conventional lumbar epidural
Epidurals are most commonly inserted using a Tuohy needle and "loss of resistance technique." A low resistance syringe containing a column of saline or air is attached to the Tuohy needle after insertion into the inter-spinous ligaments. Continuous pressure is applied to the plunger of the syringe as the needle is slowly advanced. A sudden loss of resistance as the needle exits the ligamentum flavum identifies the epidural space. In conventional lumbar epidural, once the epidural space is identified, a thin catheter is threaded through the hollow Tuohy needle to lie 3-5 cm within the epidural space, and the needle removed. The epidural catheter lies near the T10-L1 nerve roots, providing excellent coverage for the first stage of labor. The sacral nerve roots lie further away from the epidural catheter and therefore second-stage analgesia may be less effective. 2 An initial "test dose" of local anesthetic is given, and the patient is closely observed to assess for inadvertent intrathecal placement (effects more in keeping with spinal anesthesia) or intravascular placement (signs of local anesthetic toxicity). Identification of the epidural space can be technically challenging and even when inserted without difficulty, unilateral block and missed segments can result in inadequate analgesia in up to one in eight women. 2 F I G U R E 1 (a) Conventional epidural catheter insertion and (b) combined spinal epidural. (a) The Tuohy needle within the epidural space before threading of epidural catheter through the hollow Tuohy needle to lie within the epidural space demonstrates (b) the Tuohy needle within the epidural space and the spinal needle puncturing the dura mater and the delivery of intrathecal medication into the subarachnoid space

| Combined spinal epidural
In the needle-through-needle technique of CSE, the dura mater is intentionally punctured with a spinal needle after the epidural space is identified. Intrathecal drugs are administered before threading the epidural catheter into the epidural space ( Figure 1). 2,5 CSE has potential advantages of rapid-onset analgesia, improved sacral analgesia, reduced failure rate, and high maternal satisfaction. Furthermore, CSE may be advantageous for anesthesia in the high-risk parturient (e.g. cardiac disease) where gradual and incremental onset of sympathetic block is desirable. CSE is more technically challenging than conventional lumbar epidural and is associated with a higher incidence of permanent neurological complications (9.6/100 000 vs 6.1/100 000 for conventional lumbar epidural). 6

| Ultrasound
Palpation of bony landmarks is traditionally used to identify a site for epidural insertion. Identifying a space can be challenging, especially in patients with obesity, scoliosis, or previous spinal surgery. A study in non-obstetric patients assessing the ability of anesthesiologists to identify a lumbar interspace found that the correct interspace was identified in just 29% of cases with 68% being one or more vertebral spaces higher than predicted, increasing the potential risk of neurological injury. 8 This may be even more challenging in obstetric patients due to the limitation of a gravid uterus on forward flexion. Ultrasound can be used as a pre-procedural tool to identify specific intervertebral spaces and depth of epidural and intrathecal spaces. Three meta-analyses have investigated the use of pre-procedural ultrasound for epidural. A meta-analysis of 14 RCTs (eight obstetric epidural, three orthopedic spinal, and three lumbar puncture, 1786 patients in total) found a 49% reduction in procedural failure and a significantly reduced number of needle passes (mean difference 0.75) with pre-procedural ultrasound compared to palpation alone, though data for the obstetric subgroup were not provided. They also found a non-significant trend towards a lower incidence of headache and backache but did not provide results for analgesic efficacy. 9

| Epidural agents
Once an epidural catheter has been inserted, local anesthesia, with or without adjuvant medications, are used to provide analgesia. In the UK, levobupivacaine with fentanyl is most commonly used, 13 but there is no universally accepted standard injectate to optimize analgesia and avoid adverse outcomes.

| Local anesthetics
Bupivacaine, levobupivacaine, and ropivacaine are most commonly used for labor epidural analgesia. 13 Levobupivacaine and bupivacaine are almost equipotent 14,15 and produce a dosedependent motor block. Ropivacaine has a relative potency of 0.6 when compared to bupivacaine, is less cardiotoxic/neurotoxic, and is associated with less motor block. 16 When ropivacaine and bupivacaine are used in equipotent doses, the incidence of adverse TA B L E 1 Counseling women before insertion of labor epidural a

Risk Frequency
Additional pain relief required on top of epidural 1 in 8 Epidural not functioning well enough for cesarean delivery-require a spinal or general anesthetic 1 in 20 Significant drop in blood pressure 1 in 50 Severe headache 1 in 100 Temporary nerve damage (e.g. patch of numbness on leg or weakness in leg)

Meningitis 1 in 100 000
Epidural hematoma (blood clot) 1 in 170 000 Severe injury (including paralysis) 1 in 250 000 a Before insertion of the epidural, women should be counseled on the risks and benefits of the procedure. Information leaflets can be downloaded from www.labou rpains.com-the public information website of the Obstetric Anesthetists' Association (OAA). These leaflets are currently available in up to 40 languages. In addition, the anesthetics performing the procedure should discuss the risks with the parturients and allow the opportunity for questions.
obstetric, neonatal, and maternal outcomes, including motor block, are similar. 16 Historically, labor epidurals were maintained with 0.25% bupivacaine. In 2001, the COMET trial enrolled 1054 nulliparous women and randomized them to "traditional" epidural management (0.25% bupivacaine), low dose epidural, or low dose CSE using 0.1% bupivacaine combined with 2 μg/ml fentanyl. 17 Techniques utilizing the lower concentration of local anesthesia were associated with a reduction in the rate of assisted vaginal delivery (AVD) with no compromise in analgesia. This difference was attributed to the preservation of motor tone, shorter second stage of labor, and reduced total dose of local anesthetic. 17 Since 2001, the use of lower concentrations of local anesthesia has increased, and a 2014 survey by the Obstetric Anesthetists' Association found that 0.1% bupivacaine was the standard concentration used in the UK. 13

| Opioids
Epidural opioids act synergistically with local anesthetics. The minimum local analgesic concentration (MLAC) is the median effective concentration to produce analgesia. MLAC studies are used to compare relative potencies of local anesthesia and the effect of adding adjuvant medications. Fentanyl is short-acting and reduces the MLAC of bupivacaine by 31%-72% depending on the dose used. 18 Sufentanil has a more rapid onset, shorter duration of action, and is 4.5 times more potent than fentanyl, reducing the MLAC of bupivacaine by up to 91%. 19 Diamorphine and morphine are long-acting opiates and are less suitable for epidural maintenance solutions. Epidural opioids can also be used in bolus doses for rescue analgesia. 20 Non-opioid adjuvants may be added to the epidural solution to prolong duration and limit overall dose of local anesthesia, thus reducing the incidence of dose-dependent side effects. These additional adjuncts may be beneficial in parturients who wish to avoid exposure to opioids.

| Adrenaline
The effects of adrenaline are thought to be due to both alphareceptor activation and limiting the systemic absorption of local anesthesia by local vasoconstriction. 21 Adrenaline is associated with reduced MLAC, and increased duration of action/reduced cumulative dose of local anesthesia. It is not commonly used for labor analgesia.

| Clonidine
Clonidine is an alpha-2 receptor agonist which can be given via the epidural route, reducing requirements for local anesthesia by around 30%, and increasing duration of anesthesia with or without opioids. 22 Despite concerns about side effects of hypotension, bradycardia, and maternal sedation, a RCT of 98 parturients found no difference in analgesic efficacy between clonidine/bupivacaine and fentanyl/bupivacaine and no difference in adverse outcomes. 22

| Neostigmine
Neostigmine prevents the breakdown of acetylcholine, which stimulates production of nitric oxide in the spinal cord, providing analgesia. It can cause nausea but is not associated with respiratory depression or pruritis. A meta-analysis of 16 RCTs (1183 parturients) found that neostigmine reduced consumption of local anesthesia with no increased risk of adverse neonatal outcomes. 23 This evidence supports a potential role for neostigmine in patients wishing to avoid opioids.

| DRUG DELIVERY SYS TEMS
Epidural drug delivery systems affect the efficacy of analgesia.
Intermittent bolus, continuous infusion, patient-controlled epidural analgesia (PCEA), and computer integrated patient-controlled epidural analgesia (CIPCEA) have been described. 24 and high-concentration (>0.1% bupivacaine) epidurals found that lower concentration local anesthesia reduced the duration of the second stage of labor and incidence of AVD (odds ratio [OR] 0.70) but did not alter rates of cesarean delivery. 15 A third metaanalysis (10 RCTs, 1809 women) compared low-dose epidural with no epidural and found no statistically significant differences. 14 Collectively, these trials suggest that the concentration of local anesthesia has a significant effect on duration of labor and rate of AVD but not of cesarean delivery. These meta-analyses contain a large number of small studies of variable methodological quality.
Studies comparing low (~0.1%) with very low concentrations of bupivacaine/levobupivacaine (0.0568%-0.0625%) support the finding of reduced incidence of AVD with lower concentrations. 30 More research is needed to determine whether further reducing the concentration of local anesthesia will improve outcomes.

| Adverse effects
Epidurals reduce ambulation, which is known to shorten labor time, and reduce the need for analgesia. Furthermore, women may find excessive motor and sensory block uncomfortable. 5 Blockade of autonomic nerves may also cause hypotension and FHR abnormalities. 7 If epidural opioids are used, pruritus is a common side effect, affecting 60%-100% of parturients, which may require symptom control with antihistamines or, in severe cases, opioid receptor antagonists, e.g. naloxone. 31 Epidural opioids are also associated with nausea/vomiting and urinary retention, affecting 30% and 21%-53% of recipients, respectively, in a dosedependent manner. 31

| Maternal satisfaction
Uncontrolled labor pain significantly affects maternal satisfaction (independent of mode of delivery) but analgesia is only one component of maternal satisfaction. 32 A RCT comparing three different concentrations of local anesthetic found that the lowest concentration was associated with higher pain scores, but maternal satisfaction scores were unaffected. 30 This is consistent with a prospective study (294 women) that used 0.0625% bupivacaine with fentanyl and found that although almost one-quarter of women required a clinician-administered top-up, 92% were satisfied with their labor analgesia. Overweight women and those undergoing induced labor showed lower rates of maternal satisfaction. 32 Other factors influencing maternal satisfaction included quality of caregiver-patient relationship and involvement in decision making. 32

| Maternal hyperthermia
Maternal hyperthermia may be caused by intrapartum events such as infection and obstructed labor and is strongly associated with poorer neonatal neurological outcome. 33 It is unclear whether this is due to hyperthermia itself exacerbating an energy

Name, authors, and year of publication Trials and participants Key findings
The effect of low concentrations versus high concentrations of local anesthetics for labour analgesia on obstetric and anesthetic outcomes: a meta-analysis. Sultan et al. (2013) 15 11 RCTs 1997 parturients Compared to high concentration, low concentration local anesthetics are associated with: 1. Reduced incidence of AVD 2. Shorter second stage of labor 3. Fewer motor blocks 4. Less urinary retention 5. More pruritis 6. Greater incidence of 1-min Apgar score <7 No significant differences for incidence of cesarean delivery, pain scores, maternal nausea and vomiting, hypotension, FHR abnormalities, 5-min Apgar scores, or need for neonatal resuscitation The effects of epidural/spinal opioids in labor analgesia on neonatal outcomes: a meta-analysis of randomized controlled trials. Wang et al. (2014) 30 21 RCTs 2859 parturients Neonates whose mother received neuraxial opiates in labor compared to those not receiving neuraxial opioids: 1. No difference in Apgar score <7 at 1 min 2. No difference in Apgar score <7 at 5 min 3. No significant differences were found in umbilical cord arterial or venous pH Abbreviations: AVD, assisted vaginal delivery; CSE, combined spinal epidural; FHR, fetal heart rate; PCEA, patient-controlled epidural analgesia; RCT, randomized controlled trial.

TA B L E 2 (Continued)
deficit in the fetus, or maternal proinflammatory mediators triggering an inflammatory response in the fetus. Epidural hyperthermia affects one in five women receiving epidural analgesia, with risk increasing as duration of infusion increases. 34 The etiology is not understood though there are two main theories: sympathetic blockade and immunomodulation. Blockade of sympathetic nerves may prevent vasodilatation and sweating, thus reducing heat loss. 34 The immunomodulation theory suggests that temperature increase is centrally mediated and driven by proinflammatory mediators triggered by epidural medications. 34  women who received epidural and were pyrexial found that increasing maximum maternal intrapartum temperature was associated with adverse neonatal outcomes, including a significantly increased risk of neonatal seizures (>101°F vs <99.5°F; OR 6.5, no confidence interval provided). However, the actual number of events was very small (n = 8) and the group not receiving epidural was excluded due to inadequate patient numbers. 36 This is a key knowledge gap that needs addressing. 33

| Postpartum depression
Labor is one of the most painful human experiences, with the effectiveness of labor analgesia potentially contributing to the longerterm emotional and psychological state of the mother and their initial interaction with their newborn. 37 Uncontrolled pain during childbirth is a well-established risk factor for the development of postpartum depression but there is limited information on whether epidural positively or negatively impacts on its development. 37

| OFFS PRING OUTCOME S
Both local anesthetics and opioids can cross the placenta and can be detected in the umbilical vein and neonatal urine after delivery. 38 These drugs may accumulate and lead to neonatal depression due to ion-trapping in the more acidic fetal circulation and impaired clearance due to immature liver enzymes. 38 Epidural is associated with a reduction in uterine artery blood flow during contractions, even when using low concentrations of local anesthetic. This does not appear to be associated with any significant difference in Apgar score or degree of neonatal acidosis 39

| Breastfeeding
Breastfeeding has significant well-established benefits for both the neonate and the mother. 40

CO N FLI C T S O F I NTE R E S T
All authors completed the ICMJE uniform disclosure form at www. There are no other relationships or activities that could appear to have influenced the submitted work.

AUTH O R CO NTR I B UTI O N S
RK, LH, and SMN designed the study. LH, RK, and SMN drafted the initial manuscript. All authors contributed to critical revision and final approval of the submitted manuscript.

DATA AVA I LBA I LIT Y S TATEM ENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.