Neonatal outcome and mode of delivery after epidural analgesia for labour with ropivacaine and bupivacaine: a prospective meta-analysis

British Journal of Anaesthesia 1998; 81: 713–717

Neonatal outcome and mode of delivery after epidural analgesia for labour with ropivacaine and bupivacaine: a prospective meta-analysis W. D. R. WRITER, R. STIENSTRA, J. M. EDDLESTON, S. P. GATT, R. GRIFFIN, B. B. GUTSCHE, T. H. JOYCE, C. HEDLUND, K. HEEROMA AND D. SELANDER Summary In this prospective meta-analysis, we have evaluated the effect of epidural analgesia with ropivacaine for pain in labour on neonatal outcome and mode of delivery compared with bupivacaine. In six randomized, double-blind studies, 403 labouring women, primigravidae and multiparae, received epidural analgesia with ropivacaine or bupivacaine 2.5 mg ml91. The drugs were administered as intermittent boluses in four studies and by continouous infusion in two. Apgar scores, neurological and adaptive capacity scores (NACS), degree of motor block and mode of delivery were recorded. The studies were designed prospectively to fit meta-analysis of the pooled results. Results showed similar pain relief and consumption of the two drugs. In the vaginally delivered neonates, NACS scores were approximately equal for both groups at 2 h, but at 24 h there were fewer infants with NACS less than 35 in the ropivacaine compared with the bupivacaine group (2.8% vs 7.6%; P:0.05). Spontaneous vaginal deliveries occurred more frequently overall with ropivacaine than with bupivacaine (58% vs 49%; P:0.05) and instrumental deliveries (forceps and vacuum extraction) less frequently (27% vs 40%; P:0.01), while the frequency of Caesarean section was similar between groups. The intensity of motor block was lower with ropivacaine. There were no significant differences in adverse events. (Br. J. Anaesth. 1998; 81: 713–717). Keywords: anaesthetics local, ropivacaine; anaesthetics local, bupivacaine; analgesic techniques, epidural; analgesia, obstetric

Epidural administration of local anaesthetics, with or without opioids, is commonly used for the relief of pain in labour. Although effective and safe for the mother and fetus,1 2 obstetric epidural analgesia may be associated with prolonged labour and increased incidence of instrumental deliveries and Caesarean section for dystocia.3–6 This has been attributed to the reduced muscle power and relaxed pelvic diaphragm, which result from concomitant motor block.2 5 Ropivacaine is a new long-acting local anaesthetic, chemically homologous to bupivacaine and mepivacaine, but manufactured as the pure S-enantiomer, whereas the others are racemic mixtures. Preclinical studies demonstrated less central nervous and cardiovascular toxicity than with bupivacaine,7 findings later confirmed in human volunteers.8 9 The analgesic

potency of ropivacaine is similar to that of bupivacaine, while motor block is less pronounced and of shorter duration.7 10 This separation between motor and sensory block suggests that ropivacaine would be well suited for obstetric pain relief. In this article we report a meta-analysis, based on the pooled results of six randomized, double-blind studies. The studies were designed prospectively to fit meta-analysis of neonatal outcome and mode of delivery, and to compare the efficacy and safety of epidural ropivacaine and bupivacaine 2.5 mg ml91 when used for pain relief in labour11–15 (note that Eddelston and colleagues12 includes two studies). Objectives, variables to be compared and the studies included in the meta-analysis were specified in a formal protocol written before patient recruitment in any of the studies was finalized. The main objective was to compare the effects of ropivacaine and bupivacaine on neonatal adaptation, evaluated by the neurological and adaptive capacity scores (NACS16) during the first 24 h of life. Secondary objectives included comparison of the effects of ropivacaine and bupivacaine on delivery outcome, measured by the frequency of spontaneous delivery, and incidence of instrumental deliveries and Caesarean section. Although current practice in most centres is to use low-dose bupivacaine with an opioid, this study compared the efficacy and profile of ropivacaine with that of bupivacaine, both without opioids. The underlying six double-blind studies all showed that both drugs provided effective pain relief in labour.11–15

Patients and methods After obtaining approval from the respective Research and Ethics Committees, we undertook six W. DESMOND R. WRITER, MB, Department of Anaesthesia, IWK Grace Health Centre, Halifax, Canada. RUDOLF STIENSTRA, MD, PHD, Department of Anesthesiology, University Hospital Leiden, Leiden, The Netherlands. JANE M. EDDLESTON, MB, CHB, FRCA, Department of Anaesthesia, Manchester Royal Infirmary, Manchester, UK. STEPHEN P. GATT, MD, FANZCA, Department of Anaesthesia, Royal Hospital for Women, Paddington, Australia. RUSSELL GRIFFIN, MD, Department of Anaesthesia, St Thomas’ Hospital, London, UK. BRETT B. GUTSCHE, MD, Department of Anesthesiology, University Hospital of Pennsylvania, Philadelphia, USA. THOMAS H. JOYCE, MD, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, USA. CECILIA HEDLUND, BSC, KARIN HEEROMA, PHD, DAG SELANDER, MD, PHD, Clinical Research and Development, Astra Pain Control AB, S-151 85 Södertälje, Sweden. Accepted for publication: June 1, 1998. Correspondence to D. S.

714 randomized, double-blind, multicentre studies of pain relief in labour with epidural ropivacaine or bupivacaine 2.5 mg ml91, administered in equal doses. Healthy, primigravid and multiparous ASA I or II women, aged 18–40 yr and in spontaneous active labour with a singleton fetus at term participated in the studies after giving written informed consent. Estimated fetal weight in all patients was at least 2500 g. The study drug was administered epidurally either as intermittent bolus doses (top-ups) or as a continuous infusion. Epidural catheters were inserted via an appropriate lumbar interspace at L1–L4. In four studies, after excluding intravascular–subarachnoid placement of the epidural catheter, patients received 10 ml of epidural ropivacaine or bupivacaine 2.5 mg ml91 in 5-ml aliquots. If necessary, an additional 5-ml dose was given to secure analgesia. Subsequent top-up doses of 10 ml were given on patient request at the investigator’s discretion until delivery, or to a maximum of 8 top-ups (i.e. a maximum total dose of 237.5 mg). In two studies, the study drug was given by continuous infusion, after an initial dose of 10–15 ml. The infusion rate was adjusted within the range 6–12 ml h91 to provide optimal pain relief, and supplementary boluses of up to 12 ml of study drug were given as needed at the investigator’s discretion. The maximum total dose permitted in these studies was 450 mg in 24 h. The study allowed subjects to receive pethidine (maximum 125 mg) for analgesia, at least 1 h before administration of the study drug. No concurrent analgesics, other than nitrous oxide, were allowed during the administration period, which lasted until delivery. Obstetric management was undertaken according to the clinical routines of each study centre, and participants received oxytocin for induction or augmentation of labour as indicated. The following clinical assessments were made: Apgar scores at 1 and 5 min after birth, NACS at 2<0.5 h and 24<2 h after delivery, degree of maternal motor block and mode of delivery. NACS is a screening test to detect central nervous system depression caused by drugs and to differentiate such effects from those seen after birth trauma or perinatal asphyxia, or both. NACS assesses 20 criteria in five basic areas: active tone, adaptive capacity, general assessment, passive tone and primary reflexes. Each criterion is scored 0–2, depending on whether or not the neonate’s response is absent or grossly abnormal (0), mediocre or slightly abnormal (1) or normal (2). A total NACS of 35–40 indicates a neonate not affected by drugs administered during labour.16 Neonates were excluded from NACS assessments if birth weight was less than 2500 g, if the mother had received other medications than those permitted in the protocol, and if they were delivered by Caesarean section or forceps delivery (other than outlet forceps or vacuum extraction). Mode of delivery was recorded as normal (spontaneous vertex), forceps, vacuum extraction or Caesarean section. Motor block was assessed every 30 min until return of normal motor function, according to a modified, four-grade Bromage scale: 0:no motor block, 1:inability to raise extended legs (able to move knees and feet), 2:inability to flex knees (able to move feet only) and 3:complete paresis of leg and

British Journal of Anaesthesia foot. The highest degree of motor block reached during the study was recorded for each patient. Adverse events were defined as any unfavourable, unintended event (e.g. signs, symptoms) associated in time with administration of the study drug (including during the following 14 days), whether or not they were considered to be related to the drug. Adverse events were recorded during labour, daily during hospitalization and at follow-up by telephone 2–3 weeks after delivery. Adverse events were recorded separately for mother, fetus and neonate. STATISTICAL ANALYSIS

At least 135 patients per treatment group were required to detect a difference of at least 2 points in total NACS between treatment groups (power of 90% and a significance level of 5%, assuming an SD of approximating 5 for both treatments). The variables analysed included: Apgar score at 1 and 5 min after delivery, NACS at 2 and 24 h, proportion of neonates with total NACS :35 at 2 and 24 h, proportion of patients (mothers, fetuses and neonates) with adverse events, and proportion of cases with a normal delivery, instrumental delivery (forceps and vacuum extraction) or Caesarean section. In addition, the proportion of patients with different maximum grades of motor block (0, 1, 2, 3) was analysed as a complement to the analysis of mode of delivery. The Wilcoxon rank sum test, stratified for study, centre and parity, was used to detect differences between groups for Apgar scores, total NACS and the sum of scores for individual tests within each group of tests. The Mantel–Haenszel test, similarly stratified, was used for analysis of differences in proportions between treatment groups. That the tests were stratified means that the comparison between treatment groups was performed within stratum and the strata were thereafter weighed together to obtain the pooled results.17 Each test of treatment differences was two-tailed, and P:0.05 was considered statistically significant.

Results We studied 403 patients; 206 in the ropivacaine group and 197 in the bupivacaine group. Because of technical failure, five and six subjects in the ropivacaine and bupivacaine groups, respectively, were excluded. An additional patient in the latter group was excluded because she did not receive the study drug. The number of mothers and fetuses/neonates valid for analysis of drug consumption, patient characteristics and adverse events was therefore 201 and 190 in the ropivacaine and bupivacaine groups, respectively. In agreement with the previously described exclusion criteria, NACS was analysed in 147 neonates after ropivacaine analgesia and in 144 after bupivacaine; 199 ropivacaine recipients and 188 bupivacaine patients proved valid for analysis of Apgar score, mode of delivery and motor block. Patient characteristics of the two groups were well matched, except for the number of patients who had undergone a previous Caesarean section (table 1). Nine women in the ropivacaine group and 15 in the bupivacaine group underwent a trial of vaginal birth after Caesarean section, however, this difference was

Epidural analgesia with ropivacaine and bupivacaine

715

Table 1 Patient characteristics (mean (SD) [range] or number). *Previous Caesarean section: nine patients in the ropivacaine group and 15 in the bupivacaine group

Age (yr) Height (cm) Weight (kg) Parity (n) Primiparae Multiparae ASA group (n) I II

Ropivacaine (n:201)

Bupivacaine (n:190)

28 [16–41] 165 (8) [145–184] 76 (11) [50–110]

27 [16–41] 164 (7) [150–179] 78 (12) [52–122]

125 76*

115 75*

180 21

168 22

Table 3 Duration of labour stages. *29 ropivacaine and 21 bupivacaine patients that underwent Caesarean section are excluded. Information regarding time to and duration of stage II is missing for two ropivacaine and two bupivacaine patients. **Information missing for one ropivacaine patient

Time from main dose to stage II (h) Median Range Duration of stage II (h) Median Range Time from main dose to delivery (h) Median Range

Ropivacaine (n:168)*

Bupivacaine (n:165)*

4.1 0.25–13.8

3.9 0.1–13.4

0.6 0.0–4.1 (n=169)** 5.4 0.1–14.8

0.9 0.0–5.8 (n=167)** 5.2 0.4–13.4

Table 4 Mode of delivery. *P:0.05, **P:0.01 Table 2 Study drug consumption

Top-up (ml) Mean (SD) Range No. of doses (SD) Continuous infusion (ml) Mean (SD) Range Total mean (SD) dose mg Mean (SD) (ml) Range (ml)

Ropivacaine 0.25% (n:201)

Bupivacaine 0.25% (n:190)

(n:124) 34.9 (19.4) 5.0–95.0 3.2 (2.0) (n:77) 51.2 (23.2) 11.5–111.1 103 (55.8) 41.2 (22.3) 5.0–111.1

(n = 115) 38.1 (18.8) 10.0–90.0 3.6 (1.9) (n=75) 53.2 (27.6) 12.0–135.0 110 (59.5) 44.1 (23.8) 10.0–135.0

Mode of delivery

Ropivacaine (n:199)

Bupivacaine (n:188)

Spontaneous vaginal Vacuum Forceps Caesarean section

116 26   28  29

92 33 42 21

58.3% 27.1% 14.6%

Table 5 Mode of delivery by parity, number of patients (%): 38% of ropivacaine patients and 39% of bupivacaine patients were multiparous Ropivacaine

Bupivacaine

Primigravidae

Multiparae

Primigravidae

Multiparae

(n:124) %

(n:75) %

(n:114) %

(n:74) %

56 45 23

60 9 6

45 54 15

47 21 6

45 36 19

40.0%** 11.2%

Twenty-four hours after delivery, median NACS were 38 and 37 in the ropivacaine and bupivacaine groups, respectively. Total NACS, active tone and capacity scores were all significantly higher in the ropivacaine group than in the bupivacaine group (P:0.05 for each comparison). Four neonates in the ropivacaine group (2.8%) and 11 in the bupivacaine group (7.6%) had NACS :35 at 24 h (P:0.05). A higher proportion of spontaneous vaginal deliveries occurred in the ropivacaine group compared with the bupivacaine group (58 vs 49%; P : 0.05) (table 4). The proportion of instrumental deliveries, calculated as the sum of forceps deliveries and vacuum extractions, was smaller after ropivacaine than after bupivacaine (27 vs 40%; P:0.01). The overall percentage of patients who proceeded to Caesarean section did not differ between groups. The proportion of multiparae was comparable in the ropivacaine and bupivacaine groups (38 vs 39%) (table 5). Significantly more patients among the multiparae in the bupivacaine group required instrumental delivery (28 vs 12%; P:0.05) and the frequency of spontaneous vaginal delivery was significantly higher in the ropivacaine group (80 vs 64%; P:0.05) (table 5). Because of the skewed distribution between treatment groups with respect to the number of previous Caesarean sections, we undertook statistical

not statistically significant. Pethidine was administered to 16 ropivacaine and 21 bupivacaine patients, before administration of the study drug, as permitted by the protocol. The amount of administered drug was similar between groups, with mean total doses of 103 mg for ropivacaine and 110 mg for bupivacaine, corresponding to 41.2 and 44.1 ml, respectively (table 2). Time from anaesthetic dose to delivery, and duration of labour were also similar between groups (table 3). There was no significant difference in oxytocin administration before delivery between the ropivacaine and bupivacaine groups (62 vs 59%, respectively). At 1 min, median Apgar scores were 9 and 8 in the ropivacaine and bupivacaine groups, respectively; at 5 min, median scores were 9 in both groups. Two hours after delivery median NACS was 36 in both groups. There were 32 (21.8%) and 37 (25.7%) neonates with NACS :35 in the ropivacaine and bupivacaine groups, respectively (ns).

Spontaneous Instrumental Caesarean section

48.9%*      

80 12 8

39 47 13

64 28 8

716

Figure 1 Maximum level of motor block (Bromage score) expressed as percentage of patients within groups. The overall degree of motor block was lower with ropivacaine (P:0.05).

analyses of delivery mode by stratifying subjects into those who had and had not undergone a previous Caesarean section. Among women who had had a previous Caesarean section, the frequency of spontaneous vaginal delivery was significantly higher in the ropivacaine group (78 vs 33%; P:0.05). Among those multiparae with no previous Caesarean section, 53 (80%) of the ropivacaine subjects and 42 (71%) of the bupivacaine recipients delivered spontaneously (ns). The maximum degree of motor block was significantly less among the ropivacaine treated mothers than in the bupivacaine group (P:0.05). In the ropivacaine group, 51% of mothers had no measurable motor block (Bromage score:0) during the entire study compared with 42% in the bupivacaine group (fig. 1). There were no significant differences in adverse events between groups. Among mothers in the ropivacaine group, hypotension was the most common adverse event, reported in 15% of cases, compared with 9.5% in the bupivacaine mothers (ns). Poor progression of labour was similar between groups (11% in the ropivacaine group vs 12% in the bupivacaine group; ns). Fetal bradycardia, classified as moderate or severe, occurred in 18% of ropivacaine cases and 19% of bupivacaine recipients. The incidence of jaundice, the commonest neonatal adverse event, did not differ between groups (9.5% and 10% for ropivacaine and bupivacaine, respectively).

Discussion This meta-analysis focused primarily on the effects of epidural analgesia on neonatal outcome using the NACS assessment and mode of delivery. One implication of the stratified statistical analysis is that differences between individual studies and centres regarding drug administration, obstetric policy and hospital routines, for example, are eliminated, as treatment comparisons were performed within strata before the pooled results were obtained. Our results showed a small advantage of ropiva-

British Journal of Anaesthesia caine, with fewer babies demonstrating NACS :35 at 24 h after birth compared with bupivacaine. Although this difference was significant, the clinical relevance of this observation is probably small. Amiel-Tison and colleagues16 first described the NACS system for evaluating the effects of obstetric medication in full-term newborns in 1982. Whereas the early neonatal behavioural scale (ENNS), which preceded the NACS assessment and also evaluated the effects of maternal medication on neonates, concentrated on the newborn’s habituation ability, in contrast, NACS places emphasis on motor tone as a key indicator of drug-induced abnormal neurobehaviour.18 No pharmacokinetic analysis was performed in our studies, but Datta and colleagues19 undertook maternal pharmacokinetic analyses in women randomized to receive either ropivacaine or bupivacaine 150 mg (both as 30 ml of a 0.5% solution) for epidural anaesthesia for Caesarean section. They found that maternal Cpmax was similar for ropivacaine and bupivacaine (1.3 and 1.1 mg litre91, respectively). However, the terminal half-life of ropivacaine in plasma was shorter than that for bupivacaine (5.2 vs 10.9 h). At delivery, mean unbound plasma concentrations of ropivacaine were approximately twice those of bupivacaine in both maternal and neonatal blood, but well below the concentration at which symptoms of maternal CNS toxicity might be expected.9 All neonates in Datta’s study had normal Apgar scores, acid–base values and NACS. The significantly greater number of neonates with NACS 935 at 24 h after ropivacaine in our study may reflect a difference in the persistence of drug within the tissues of the neonate. Ropivacaine has lower lipid solubility and a shorter terminal half-life than bupivacaine.7 19 Thus one can hypothesize that bupivacaine persists in the neonatal neural tissues longer than ropivacaine, such that its subtle changes on neurological function become evident at a time when the effects of ropivacaine have declined. This is supported by the lack of neurobehavioural differences at 2 h, which may suggest that both drugs exist within the neonatal nervous system to the extent that their effects are indistinguishable during the first hours after birth. Experimental support for this hypothesis was presented by Rosenberg, Kyttä and Alila who found considerably higher uptake of bupivacaine than ropivacaine in human epidural fat and rat sciatic nerves.20 The differences in our study may therefore reflect the different physicochemical properties of the two local anaesthetics, and are not necessarily indicative of persistent adverse changes. The difference in NACS did not predict a less favourable outcome for the neonates in either group. The use of ropivacaine was associated with a greater overall frequency of spontaneous deliveries and a lower percentage of instrumental deliveries (forceps and vacuum extractions) compared with bupivacaine. While it might be argued that the preponderance of bupivacaine multiparae who underwent instrumental delivery or Caesarean section skewed the results in favour of ropivacaine, we believe the observed differences between groups, and the consistent trend towards more spontaneous deliveries in all ropivacaine subjects, merit further study, with more standardized obstetric management.

Epidural analgesia with ropivacaine and bupivacaine As the infusion rates and top-up doses of the drugs in both groups were individually titrated to provide optimal pain relief, and total consumption of local anaesthetic was similar between groups, ropivacaine, on a dose-for-dose basis, was equieffective with bupivacaine in its analgesic properties. However, ropivacaine may be more suitable for analgesia in labour than bupivacaine because of its less pronounced motor block. The less pronounced motor block in the ropivacaine group may have enabled more active participation and more effective bearing down, resulting in the increased incidence of spontaneous vaginal delivery. At the same time, a lesser reduction in the tone of the pelvic diaphragm might have enabled normal rotation of the fetal head during the second stage.7 21 However, Russell and Reynolds, when comparing epidural labour pain relief with plain bupivacaine 1.25 mg ml91 or bupivacaine 0.625 mg ml91 with lowdose fentanyl or sufentanil could not demonstrate a difference in spontaneous deliveries between these groups, although motor block was significantly lower in the latter group.22 In this study, pain relief with epidural plain ropivacaine 2.5 mg ml91 was found to be similar to that of plain bupivacaine 2.5 mg ml91. Recent studies with epidural infusions of ropivacaine 2 mg ml91 alone, in doses of 4–10 ml h91, demonstrated that this solution also provides effective analgesia in labour at infusion rates of 6–8 ml h91.23 Ropivacaine is characterised by lower CNS and cardiovascular toxicity than bupivacaine at equal doses.8 9 These qualities, and the results described above, suggest that ropivacaine is more suitable than bupivacaine for epidural analgesia in labour, and that further outcome studies, using more dilute solutions, should be undertaken.

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Acknowledgements We thank M. Joanne Douglas, MD, FRCPC, Sally K. Weeks, MD, Jan-Robert Jansson, MD and Marianne Hedström, RPh. Financial support was provided by Astra Pain Control AB.

17. 18.

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