Neuraxial analgesia is the most effective way to provide labor pain relief. Epidural analgesia and combined spinal–epidural (CSE) analgesia are both recommended by the UK National Institute for Health and Clinical Excellence.1 Usually, local anesthetics are used in combination with lipid-soluble opioids for both the epidural and the intrathecal route.
Abrão et al2 reported a higher incidence of fetal heart rate (FHR) abnormalities after CSE analgesia compared with epidural analgesia, a finding that was not corroborated in a recent trial by Patel et al.3 A meta-analysis from 20024 reported that the incidence of fetal bradycardia was significantly increased in parturients receiving an intrathecal opioid compared with any nonintrathecal opioid neuraxial technique. The risk for cesarean delivery because of FHR abnormalities was not greater with intrathecal opioids.4 Moreover, intrathecal opioids had no effect on the instrumental vaginal or cesarean delivery rates or oxytocin use during labor.4
We therefore aimed to perform a systematic review and meta-analysis of randomized controlled trials that compared the incidence of nonreassuring FHR tracings in parturients who received labor analgesia initiated by a CSE versus epidural analgesia technique.
This analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.5 We searched the databases PubMed, Embase, CINAHL, LILACS, CENTRAL, Clinicaltrials.gov, and ISI WOS to identify randomized controlled trials that assessed the incidence of nonreassuring FHR tracings in laboring women undergoing CSE versus epidural analgesia. Filters for randomized or clinically controlled trials or language restrictions were not applied. Our search was done on August 25, 2015. A high-sensitivity, low-specificity search was performed because we expected that many trials did not list nonreassuring FHR tracings as a key word or report data on this outcome in the abstract. The search terms used were: ([“spinal” OR “intrathecal” OR “subarachnoid”] OR [“combined spinal epidural”]) AND (“analgesia” OR “anesthesia”) AND ([“epidural” OR “peridural”] AND [“anesthesia” OR “analgesia”]) AND ([“labor” OR “obstetric”] AND [“analgesia” OR “anesthesia”]). To identify additional studies, the bibliographies of retrieved articles were screened. Each study was independently evaluated by 2 investigators (J.H., M.H.) for methodological quality, based on guidance developed by the Cochrane collaboration to determine the various risks of bias.6 We a priori decided that in case of discrepancies a third author had to be involved (M.K.). However, discrepancies did not occur. Because of the rapid onset of CSE analgesia, blinding of patients and care providers is difficult to achieve in these types of trials. We therefore accepted randomized controlled trials regardless of the blinding of patients and care providers. Only trials scored “yes” in at least 6 of the 12 quality domains were included in the analysis. A sensitivity analysis for blinding of the FHR tracing outcome assessor was planned a priori; that is, one analysis included and another analysis excluded studies in which the FHR outcome assessor was not blinded to group allocation.
Trials were considered eligible if (1) in the CSE analgesia group a medication (local anesthetic and/or opioid) was given intrathecally and (2) in the epidural analgesia group a medication (local anesthetic and/or opioid) was given epidurally. A study was excluded when a spinal puncture was done in both groups.
The primary outcome variables of our study were nonreassuring FHR tracings and fetal bradycardia, according to its definition in each study. The secondary outcome was the incidence of cesarean delivery indicated by nonreassuring FHR tracing.
If 2 or more CSE analgesia groups were included in a single trial, we first combined the data for meta-analysis. The same was done if 2 or more epidural analgesia groups were studied.
Subgroup analyses were planned in our protocol, including studies that used low-dose epidural bupivacaine regimes (defined as a concentration ≤0.125% epidural bupivacaine7), as recommended in the practice guidelines for obstetric anesthesia of the American Society of Anesthesiologists (ASA).8
We used the Review Manager (RevMan, version 5.1) Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008, for meta-analysis. A random-effects model was applied because we expected clinical and methodological heterogeneity across studies. The risk ratio (RR) and 95% confidence interval (95% CI) were calculated for binary variables. The I2 statistic served to assess heterogeneity describing the percentage of variation across trials that is caused by heterogeneity rather than chance.9P values <.05 were considered statistically significant.
The literature search retrieved 17 randomized controlled studies2,3,10–24 comparing CSE with epidural analgesia and assessing nonreassuring FHR tracings (Figure 1); a total of 3947 parturients were included. Methodological quality of the studies is reported in Table 1. Table 2 contains the details of the included studies. Ten studies10–12,14,16,18–21,23 did not provide details on the definition of FHR abnormalities.
The period of FHR monitoring after initiation of neuraxial analgesia was 30 minutes in the studies by Dunn et al,12 Vernis et al,18 and Gambling et al,24 and 15 minutes in the study by Abrão et al,2 and Patel et al3 recorded the first 60 minutes. In the other studies,10,11,13–23 the monitoring period was not described.
Three studies reported no case of nonreassuring FHR tracings.14,17,20 Analysis of all studies that had cases of nonreassuring FHR tracings2,3,10–13,15,16,18–24 showed that CSE analgesia was associated with a significantly increased risk compared with epidural analgesia. The RR was 1.31, 95% CI 1.02–1.67, P = .03, I2 = 18% (Figure 2A). We performed a sensitivity analysis excluding the 6 studies10,11,15,16,19,22 without blinding of the outcome assessor. The RR was 1.59, 95% CI 1.12–2.25, P = .01, I2 = 2%.
Fetal bradycardia was reported in 4 studies2,10,15,24; this outcome was observed in 64 of 610 patients in the CSE analgesia group and in 32 of 606 in the epidural analgesia group. The corresponding RR was 1.93, 95% CI 1.28–2.92, P = .002, I2 = 0% (Figure 2B). When excluding 2 studies10,15 without blinding of the outcome assessor, the RR was 2.23, 95% CI 0.97–5.15, P = 0.06, I2 = 19%.
A subgroup analysis of the 10 studies3,11–13,15,16,18,21,22,24 using low-dose epidural bupivacaine found a RR of 1.12 for nonreassuring FHR (95% CI 0.93–1.34, P = .24, I2 = 0) (Figure 2C). Finally, we analyzed trials of low-dose epidural bupivacaine in which the outcome assessor was blinded.3,12,13,18,21,24 No difference between the 2 neuraxial groups was observed (RR 1.41, 95% CI 0.99–2.02, P = .06, I2 = 0%).
Two studies19,23 reported on nonreassuring FHR tracings as indications for cesarean delivery. The study by Pascual-Ramirez et al23 reported 6 of the 15 cesarean deliveries in the CSE analgesia group were due to nonreassuring FHR tracings compared with 2 of 10 in the epidural analgesia group. Côrtes et al19 reported 2 of 4 cesarean deliveries for fetal bradycardia indication in the CSE analgesia group, 1 cesarean delivery was performed in the epidural analgesia group, and this was not caused by nonreassuring FHR tracings. The studies reported that the differences between the 2 treatment arms were not significant.
A significantly increased risk for nonreassuring FHR tracings with CSE analgesia compared with epidural analgesia was observed in this meta-analysis. This result was found when studies not blinding the outcome assessor were included and also in a sensitivity analysis that excluded studies without blinding of the outcome assessor. Fetal bradycardia, a type of nonreassuring FHR tracing, was reported in only 4 studies, and the RR was significantly higher in parturients receiving CSE analgesia. There was a paucity of data on nonreassuring FHR tracings as indication for cesarean delivery; only 2 studies reported this outcome.
Nonreassuring FHR tracings were not analyzed in a 2012 Cochrane review comparing CSE with epidural analgesia.25 Our analysis thus provides additional data that may help the clinician to make an informed choice between the 2 neuraxial techniques. In 2002, Mardirosoff et al4 reported that intrathecal opioids were associated with an increased risk for fetal bradycardia compared with nonintrathecal opioid neuraxial techniques; no difference was observed when all nonreassuring FHR tracings were evaluated. This notion has likely spurred other investigators to study the effect of CSE analgesia on this outcome variable. A major difference between our meta-analysis and that by Mardirosoff et al4 is that those authors compared intrathecal opioids to any other medication, excluding intrathecal opioids. Their design also included studies that compared 2 CSE regimes as well as studies of high- and low-dose epidural bupivacaine. A systematic review7 and the practice guidelines of the ASA8 recommend the use of only low-dose epidural bupivacaine concentrations, that is, ≤0.125% bupivacaine. In our analysis including only studies of low-dose (≤0.125%) epidural bupivacaine in both treatment arms, the 95% CI contains a clinically significant difference between groups. A difference between CSE and low-dose epidural techniques cannot be excluded.
It was previously speculated that CSE analgesia induces uterine tachysystole by the rapid onset of analgesia attributable to the spinal component of technique. Consequently, the plasma concentration of epinephrine, a hormone with tocolytic effects, is rapidly decreased, and this may result in an increase in uterine tone.26,27 Uterine tachysystole increases uterine vascular resistance and subsequently reduces fetal oxygenation, leading to nonreassuring FHR tracings.
In a multivariable analysis, Patel et al3 found that hypotension, parity, and efficacy of analgesia were not associated with nonreassuring FHR tracings, but exogenous oxytocin administration was. Hypotension is also an unlikely etiology of the difference between the 2 techniques because there is no difference in the risk of hypotension between CSE and epidural analgesia.25
There are several limitations to our analysis. Only 2 studies19,23 reported on nonreassuring FHR tracings as an indication for cesarean delivery. The impact of postneuraxial analgesia nonreassuring FHR tracings on labor outcome is therefore unclear. A Cochrane review25 investigated the association between CSE versus epidural analgesia and labor outcome but did not find a higher rate of cesarean delivery; however, no data were provided on the underlying indications for cesarean delivery. The period of FHR monitoring varied markedly among the studies included in our analysis (between 15 minutes and 60 minutes after induction of analgesia). The monitoring period may affect the number of captured nonreassuring FHR tracings; FHR tracing abnormalities associated with epidural analgesia occur later than for CSE analgesia, and therefore, a short monitoring interval will favor better outcome in the epidural group. It is also possible that longer monitoring periods capture nonreassuring FHR tracings caused by reasons other than neuraxial analgesia. The definition of nonreassuring FHR tracings may also have differed between the studies, and this may account for the differences observed. Most studies did not detail how nonreassuring FHR tracings were defined. A further limitation of our study is the clinical heterogeneity in drug and dose of intrathecal opioid, combined or not with intrathecal bupivacaine, and the drugs and doses used for epidural analgesia. Because of the small number of studies, a dose response or a drug combination response could not be determined.
In summary, CSE analgesia was associated with a higher risk of nonreassuring FHR tracings compared with epidural analgesia. Our analysis does not rule out that CSE compared with low-dose epidural bupivacaine analgesia is associated with a higher rate of nonreassuring FHR abnormalities. It is not clear whether this potentially higher incidence is associated with a greater risk of cesarean delivery for the indication of nonreassuring FHR. Further study is required.
Name: Judith Hattler, MD.
Contribution: This author helped design the study, conduct the review, analyze the data, and write the manuscript.
Name: Markus Klimek, MD, PhD, DEAA, EDIC.
Contribution: This author helped conduct the review, analyze the data, and write the manuscript.
Name: Rolf Rossaint, MD, PhD.
Contribution: This author helped design the review, analyze the data, and write the manuscript.
Name: Michael Heesen, MD, PhD.
Contribution: This author helped design the review, conduct the review, analyze the data, and write the manuscript.
This manuscript was handled by: Cynthia A. Wong, MD.
2. Abrão KC, Francisco RP, Miyadahira S, Cicarelli DD, Zugaib M. Elevation of uterine basal tone and fetal heart rate abnormalities after labor analgesia: a randomized controlled trial. Obstet Gynecol
3. Patel NP, El-Wahab N, Fernando R, et al. Fetal effects of combined spinal-epidural vs epidural labour analgesia: a prospective, randomised double-blind study. Anaesthesia.
4. Mardirosoff C, Dumont L, Boulvain M, Tramèr MR. Fetal bradycardia due to intrathecal opioids for labour analgesia: a systematic review. BJOG
5. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med
6. Higgins JPT, Green S.Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]
. New York, NY: John Wiley & Sons Ltd.
7. Liu EH, Sia AT. Rates of caesarean section and instrumental vaginal delivery in nulliparous women after low concentration epidural infusions or opioid analgesia: systematic review. BMJ.
8. Practice Guidelines for Obstetric Anesthesia: An Updated Report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia and the Society for Obstetric Anesthesia and Perinatology. Anesthesiology.
9. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med
10. Collis RE, Davies DW, Aveling W. Randomised comparison of combined spinal-epidural and standard epidural analgesia in labour. Lancet.
11. Nageotte MP, Larson D, Rumney PJ, Sidhu M, Hollenbach K. Epidural analgesia compared with combined spinal-epidural analgesia during labor in nulliparous women. N Engl J Med.
12. Dunn SM, Connelly NR, Steinberg RB, et al. Intrathecal sufentanil versus epidural lidocaine with epinephrine and sufentanil for early labor analgesia. Anesth Analg
13. Van de Velde M, Mignolet E, Vandermeersch E, Van Asche A. Prospective randomized comparison of epidural and combined spinal epidural analgesia during labor. Acta Anaesth Belg
14. Hepner DL, Gaiser RR, Cheek TG, Gutsche BB. Comparison of combined spinal-epidural and low dose epidural for labour analgesia. Can J Anaesth
15. Nickells JS, Vaughan DJ, Lillywhite NK, Loughnan B, Hasan M, Robinson PN. Speed of onset of regional analgesia in labour: a comparison of the epidural and spinal routes. Anaesthesia.
16. Comparative Obstetric Mobile Epidural Trial (COMET) Study Group UK. Effect of low-dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial. Lancet
17. Gomez P, Echevarriá M, Calderón J, Caba F, Martínez A, Rodríguez R. [The efficacy and safety of continuous epidural analgesia versus intradural-epidural analgesia during labor]. Rev Esp Anestesiol Reanim
18. Vernis L, Dualé C, Storme B, Mission JP, Rol B, Schoeffler P. Perispinal analgesia for labour followed by patient-controlled infusion with bupivacaine and sufentanil: combined spinal-epidural vs. epidural analgesia alone. Eur J Anaesthesiol
19. Côrtes CA, Sanchez CA, Oliveira AS, Sanchez FM. Labor analgesia: a comparative study between combined spinal-epidural anesthesia versus continuous epidural anesthesia. Rev Bras Anestesiol.
20. Ngamprasertwong P, Kumwilaisakmd K, Indrambarya T, Supbornsug K, Ngarmukos S. Combined spinal-epidural analgesia and epidural analgesia in labor: effect of intrathecal fentanyl vs. epidural bupivacaine as a bolus. J Med Assoc Thai
21. Bhagwat AG, Dua CK, Saxena KN, Srinivasan S, Dua K. Comparison of combined spinal epidural technique and low dose epidural technique in progress of labour. Indian J Anaesth.
22. Skupski DW, Abramovitz S, Samuels J, Pressimone V, Kjaer K. Adverse effects of combined spinal-epidural versus traditional epidural analgesia during labor. Int J Gynaecol Obstet.
23. Pascual-Ramirez J, Haya J, Pérez-López FR, Gil-Trujillo S, Garrido-Esteban RA, Bernal G. Effect of combined spinal-epidural analgesia versus epidural analgesia on labor and delivery duration. Int J Gynaecol Obstet.
24. Gambling D, Berkowitz J, Farrell TR, Pue A, Shay D. A randomized controlled comparison of epidural analgesia and combined spinal-epidural analgesia in a private practice setting: pain scores during first and second stages of labor and at delivery. Anesth Analg.
25. Simmons SW, Taghizadeh N, Dennis AT, Hughes D, Cyna AM. Combined spinal-epidural versus epidural analgesia in labour. Cochrane Database Syst Rev.
26. Clarke VT, Smiley RM, Finster M. Uterine hyperactivity after intrathecal injection of fentanyl for analgesia during labor: a cause of fetal bradycardia? Anesthesiology
27. Segal S, Csavoy AN, Datta S. The tocolytic effect of catecholamines in the gravid rat uterus. Anesth Analg.