British Journal of Anaesthesia 108 (3): 37483 (2012) Advance Access publication 3 February 2012 . doi:10.

1093/bja/aer509

REVIEW ARTICLES

Metoclopramide for nausea and vomiting prophylaxis during and after Caesarean delivery: a systematic review and meta-analysis
B. M. Mishriky and A. S. Habib*
Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710, USA * Corresponding author. E-mail: habib001@dm.duke.edu

Editors key points

The use of metoclopramide has declined in many surgical settings. The use of metoclopramide 10 mg for prophylaxis against intra- and postoperative nausea and vomiting associated with Caesarean section is analysed. Metoclopramide was effective in this group of patients. The role of this inexpensive drug may be worthy of re-evaluation.

Summary. Nausea and vomiting occur commonly during and after Caesarean delivery (CD) performed under neuraxial anaesthesia. Metoclopramide is a prokinetic agent reported to be safe in parturients. This meta-analysis assesses the efcacy of metoclopramide for prophylaxis against intra- and postoperative nausea and vomiting (IONV and PONV) in parturients undergoing CD under neuraxial anaesthesia. We performed a literature search of MEDLINE (1966 2011), Cochrane Central Register of Controlled Trials, EMBASE (1947 2011), Google scholar, and CINAHL for randomized controlled trials which compared metoclopramide with placebo in women having CD under neuraxial anaesthesia. Eleven studies with 702 patients were included in the analysis. Administration of metoclopramide (10 mg) resulted in a signicant reduction in the incidence of ION and IOV when given before block placement [relative risk (RR) (95% condence interval, 95% CI)0.27 (0.16, 0.45) and 0.14 (0.03, 0.56), respectively] or after delivery [RR (95% CI)0.38 (0.20, 0.75) and 0.34 (0.18, 0.66), respectively]. The incidence of early (0 3 or 04 h) PON and POV [RR (95% CI)0.47 (0.26, 0.87) and 0.45 (0.21, 0.93), respectively] and overall (0 24 or 324 h) PON (RR 0.69; 95% CI 0.52, 0.92) were also reduced with metoclopramide. Extra-pyramidal side-effects were not reported in any patient. In conclusion, this review suggests that metoclopramide is effective and safe for IONV and PONV prophylaxis in this patient population. Given the quality of the studies and the infrequent use of neuraxial opioids, these results should be interpreted with caution in current practice and further studies are needed to conrm those ndings. Keywords: anaesthesia, spinal; Caesarean section; meta-analysis; metoclopramide; postoperative nausea and vomiting

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Intra- and postoperative nausea and vomiting (IONV and PONV) are common and can be distressing to patients undergoing Caesarean delivery (CD) under neuraxial anaesthesia. The incidence of IONV varied among different studies with rates up to 60 80% being reported.1 The aetiology of IONV is multifactorial, and include progesterone-induced reduction in the lower oesophageal sphincter tone, increased intra-gastric pressure,2 hypotension, exteriorization of the uterus, visceral stimulation, and the use of neuraxial opioids.1 Metoclopramide has multiple sites of action. It is a prokinetic drug that acts by increasing the tone of the lower oesophageal sphincter. It also has an antidopaminergic action on the chemoreceptor trigger zone and at higher doses has an anti-serotonergic activity.3 4 At a dose of 10 mg, it does not have a reliable anti-emetic effect when used for the prophylaxis of PONV in patients undergoing non-obstetric surgery under general

anaesthesia.5 This dose was reported to be safe in the parturient,2 6 and although it crosses the placental barrier, it is not associated with adverse neonatal effects.1 Metoclopramide is a generic inexpensive drug. It is currently rarely used in the UK for the management of nausea and vomiting associated with neuraxial anaesthesia, possibly due to a perceived lack of efcacy. On the other hand, some centres in North America use it regularly for this purpose. We, therefore, performed this systematic review and metaanalysis to assess the efcacy of metoclopramide for the prophylaxis against IONV and PONV in parturients undergoing CD under neuraxial anaesthesia.

Methods
We followed the recommendations of the PRISMA statement.7 We searched MEDLINE (1966 2011), the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE

& The Author [2012]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
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signicant. Continuous data were summarized as mean difference (MD) with 95% CI. If the 95% CI included a value of 0, we considered that the difference between metoclopramide and control was not statistically signicant. Analyses were performed using the Review Manager (RevMan; Version 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011). A random effects model was used. For statistically signicant differences in outcome, the number needed to treat (NNT) was calculated to estimate the overall clinical impact of the intervention. If the statistical test for heterogeneity was signicant (P,0.1) or the I2 test was .50%, the reason for heterogeneity was explored. Forest plots were used to graphically represent and evaluate treatment effects. Sensitivity analyses were performed for the primary endpoints of ION/IOV according to the use of spinal anaesthesia and receipt of spinal opioids. Another sensitivity analysis was performed according to the quality of the included studies by restricting the analysis to studies with a modied Oxford score of 4 or higher.

(1947 2011), Google scholar, and CINAHL for randomized controlled trials (RCTs) which compared metoclopramide with placebo in women having CD under neuraxial anaesthesia. The following terms and combination of terms were used for the search: metoclopramide, caesarean section, spinal anaesthesia, and epidural anaesthesia. The search was done without language restrictions. The last computer search was done in June 2011. In addition, the bibliographies of retrieved articles were searched for additional studies. We searched for RCTs that compared metoclopramide with placebo in women undergoing CD under neuraxial anaesthesia and reported on the incidence of ION, IOV, PON, and/or POV. A study was excluded if the anaesthetic technique was not standardized or if metoclopramide was combined with another anti-emetic. Reviews, abstracts, letters to the editor, and retrospective studies were excluded. The articles that met the selection criteria were assessed separately by two authors using the seven-point modied Oxford scale.8 9 Any discrepancies were resolved by discussion. The two reviewers extracted data independently. A data collection sheet was created and included data on: (i) anaesthetic technique, (ii) neuraxial opioid use, (iii) number of patients included, (iv) time of administration and dose of metoclopramide, (v) method of nausea and vomiting assessment, (vi) threshold for treating hypotension, (vii) vasopressor used to treat hypotension, (viii) level of block, (ix) need for additional analgesia, (x) incidence of intraoperative hypotension, (xi) exteriorization of the uterus, (xii) ION/IOV, (xiii) PON/POV, (xiv) need for rescue anti-emetics, and (xv) side-effects. The primary outcomes for this meta-analysis were ION and IOV. Secondary outcomes were PON, POV, need for rescue anti-emetics, and side-effects. The method of nausea and vomiting assessment was considered adequate, if the patients were directly questioned about emetic symptoms and either a clear denition for nausea and vomiting or a scale for nausea severity was included in the Methods section. For ION and IOV, separate analyses were performed according to whether metoclopramide was administered before block placement or after cord clamping. For the latter analysis, data include events occurring after delivery, whereas results cover the entire intraoperative period when metoclopramide was given before block placement. For PON and POV, data were pooled as early PON/POV (0 3 or 04 h) and overall PON/POV (024 or 3 24 h). Visual analogue scale (VAS) scores for sedation reported as 0100 scale were converted to a 010-point scale for analysis. If the studies had more than two groups, only data from the metoclopramide and placebo groups were extracted. Dichotomous data were summarized using relative risk (RR) with 95% condence interval (CI). If the 95% CI included a value of 1, we considered that the difference between metoclopramide and placebo was not statistically

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Results
Forty-six studies were identied and assessed for inclusion in this review (Fig. 1). Of those, 35 were excluded. A total of 11 studies with 702 patients (349 received metoclopramide and 353 received placebo) were included in the nal analysis2 10 19 (Table 1). The minimum modied Oxford score of an included study was 1 and the maximum score was 6 with a median score of 4. Spinal anaesthesia was used in nine studies,2 10 12 17 19 while epidural anaesthesia was used in two studies.11 18 Metoclopramide was given at a dose of 10 mg in 10 studies,2 10 12 19 while one study11 used a dose of 0.15 mg kg21. Metoclopramide was given before block placement in four studies2 10 12 19 and after clamping of the umbilical cord in seven studies.11 13 18 Intraoperative data were reported in three studies when metoclopramide was given before block placement,2 12 19 and six studies when it was given after cord clamping.11 14 18 PON and POV were reported in six studies.10 14 18 Spinal opioids were used in four studies with three studies2 15 19 using fentanyl 10 mg and one study13 using a combination of fentanyl 20 mg with morphine 200 mg. Epidural opioids were used in one study18 where fentanyl 100 mg was given at the time of epidural local anaesthetic administration. The method of nausea and vomiting assessment was considered adequate in six studies11 13 14 17 19 and inadequate in ve studies.2 10 12 15 16

Risk factors for IONV

Adequacy of block
Four studies12 14 17 19 reported on the level of block and the need for additional analgesia, four studies2 15 16 18 reported on the level of block alone, and one study11 reported on the need for additional analgesia alone with no differences between the groups in those outcomes in any of those

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Literature search Databases: MEDLINE, CENTRAL, Google Scholar, and EMBASE

Mishriky and Habib

Combining search databases resulted in 475 publications

46 publications accessed for inclusion

429 excluded 269 duplicates 115 metoclopramide not used 17 reviews 12 case reports 11 abstracts 2 surveys 1 non-human studies 1 letter to the editor 1 commentary 33 excluded 12 non-Caesarean 8 no control group 7 general anaesthesia 3 endpoints other than nausea/vomiting 2 in Persian 1 anaesthesia not standardized

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13 RCTs considered for inclusion 2 excluded 1 combined nausea/vomiting results 1 duplicate publication 11 RCTs included in the final analysis

Fig 1 Flow diagram of screened, excluded, and analysed publications. RCTs, randomized, controlled trials.

studies. The remaining two studies10 13 did not report on either the level of block or the need for additional analgesia.

Intra- and postoperative results

Metoclopramide given before block placement
Three studies2 12 19 administered metoclopramide before block placement and reported on ION and IOV. All three studies used spinal anaesthesia. Combining results from the three studies showed that metoclopramide caused a statistically signicant reduction in the incidence of ION (RR 0.27; 95% CI 0.16, 0.45) and IOV (RR 0.14; 95% CI 0.03, 0.56) when compared with placebo. The NNT for ION and IOV was 2 and 5, respectively (Figs 2 and 3).

Intraoperative hypotension
Ten studies reported a threshold for treating intraoperative hypotension with boluses of ephedrine (Table 1).2 10 15 17 19 The threshold to treat hypotension was dened as a decrease in systolic arterial pressure (SAP) more than 20% from baseline or below 100 mm Hg in four studies,2 11 17 19 a decrease of .20% or below 90 mm Hg in three studies,10 15 18 a decrease of .20% or below 80 mm Hg in one study,14 a decrease of .20% in one study,16 and an SAP below 90 mm Hg in one study.13 There was no difference between the groups in the incidence of hypotension in any of those studies.

Metoclopramide given after delivery

Six studies11 14 18 gave metoclopramide after delivery and reported on ION and IOV. Four studies14 17 used spinal anaesthesia, while two used epidural anaesthesia.11 18 Pooled results from the six studies showed a statistically signicant reduction in the incidence of post-delivery ION (RR 0.38; 95% CI 0.20, 0.75) and IOV (RR 0.34; 95% CI 0.18, 0.66) in the metoclopramide group (Figs 2 and 3). The NNT for ION and IOV was 4 and 7, respectively. There was a signicant heterogeneity for the outcome of ION (P0.007, I 2 69%). Three studies15 16 18 had a higher control rate of

Exteriorization of the uterus

Exteriorization of the uterus was reported in six studies,2 11 14 17 19 with no differences between the groups in the incidence of exteriorization of the uterus in any of the studies (Table 1). The other ve studies10 12 13 15 16 did not report on exteriorization of the uterus.

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Table 1 Characteristics of the included studies. MOS, modied Oxford scale; (R/C/B/F), randomization/concealment of allocation/double-blinding/ow of patients; n, number of patients per group; ION-IOV/PON-POV, intra-/postoperative nausea and vomiting; M, metoclopramide; C, control; SAP, systolic arterial pressure; VAS, visual/verbal analogue scale
Reference MOS (R/C/ n B/F) Time of Spinal Threshold to administration or treat epidural hypotension Vasopressor Neuraxial opioids Hypotension (%) Uterus; exteriorization (%) Data reported Primary outcome assessment Denition of nausea and vomiting and/ or nausea score Nausea score described VAS 0 100

Chestnut and colleagues11

3 (2/0/1/0) M: 34; C: 33

After delivery

Epidural

SAP decrease I.V. .20% from ephedrine baseline or below 100 mm Hg

M: 29; C: 18

M: 94; C: 79

ION IOV/ PON POV

Observation intraoperatively and direct questioning about worst intraoperative nausea score after transfer to recovery Not reported

Maranhao and 1 (1/0/0/0) M: 20; colleagues16 C: 20 Lussos and colleagues2 2 (1/0/1/0) M: 21; C: 21

After delivery

Spinal

AP decrease .20% from baseline SAP 20% below 5 10 mg i.v. 10 mg baseline or below ephedrine fentanyl 100 mm Hg

M: 30; C: 30

ION IOV

Not reported

Before block placement

Spinal

M: 19; C: 5

M: 100; C: 100

ION IOV

Reporting by patients Not reported either spontaneously or after asked regularly about general well-being Direct questioning Nausea score described VAS 0 10 Not reported Nausea and vomiting dened Not reported

Stein and colleagues19

4 (1/1/2/0) M: 25; C: 25

Before block placement

Spinal

SAP decrease 5 10 mg i.v. 10 mg .20% from ephedrine fentanyl baseline or below 100 mm Hg I.V. ephedrine SAP decrease 5 10 mg i.v. .20% from ephedrine baseline or below 80 mm Hg SAP decrease 10 mg i.v. .20% from ephedrine baseline or below 90 mm Hg SAP decrease 10 mg i.v. .20% from ephedrine baseline or below 90 mm Hg SAP decrease 5 10 mg i.v. .20% from ephedrine baseline or below 100 mm Hg 10 mg fentanyl

M: 68; C: 76

M: 100; C: 100

ION IOV

Danzer and colleagues12 Fujii and colleagues14

5 (1/1/2/1) M: 17; C: 15 4 (2/0/2/0) M: 30; C: 30

Before block placement After delivery

Spinal Spinal

ION IOV/ PON POV M: 93; C: 93 ION IOV/ PON POV

Not reported Direct questioning

Garcia-Miguel and colleagues15 Pan and Moore18

4 (2/0/1/1) M: 48; C: 50

After delivery

Spinal

M: 31; C: 26

ION IOV

Not reported

4 (2/0/1/1) M: 51; C: 51

After delivery

Epidural

100 mg fentanyl

M: 84; C: 86

ION IOV/ PON POV

Direct questioning

Nausea score described VAS 0 10 Nausea and vomiting dened, and nausea score described (linear numerical scale 0-10)

Numazaki and 4 (2/0/2/0) M: 25; Fujii17 C: 25

After delivery

Spinal

M: 40; C: 40

M: 92; C: 92

ION IOV

Direct questioning

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Denition of nausea and vomiting and/ or nausea score Nausea and vomiting dened, and nausea score described (four-point scale) Not reported

Mishriky and Habib

ION of 50% or higher compared with the other studies with control rates of 2336%.11 14 17 Excluding those studies eliminated this heterogeneity (P0.55, I 2 0%) and the pooled result was still statistically signicant (RR 0.47; 95% CI 0.25, 0.88).

Direct questioning

Primary outcome assessment

Intraoperative need for rescue anti-emetics

Only one study12 where metoclopramide was given before block placement reported on the use of rescue anti-emetics with no difference between the groups. Combining results from the two studies15 18 that reported on the need for intraoperative rescue anti-emetics when metoclopramide was given after cord clamping showed a statistically signicant reduction with metoclopramide when compared with placebo (RR 0.22; 95% CI 0.06, 0.73), with an NNT of 10.

PON POV

Not reported

Uterus; exteriorization (%)

PON POV

Data reported

Early postoperative results

Three studies10 11 14 reported on early PON and POV. Two studies10 14 used spinal anaesthesia, while one study11 used epidural anaesthesia. Combining results from the three studies showed a statistically signicant reduction in the incidence of both PON (RR 0.47; 95% CI 0.26, 0.87) and POV (RR 0.45; 95% CI 0.21, 0.93) in metoclopramide-treated patients (Fig. 4). The NNT for early PON and POV was 7 and 8, respectively.
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Hypotension (%)

M: 45; C: 40

Vasopressor Neuraxial opioids

20 mg M:30; C: 45 fentanyl and 200 mg morphine

Overall postoperative results

Four studies12 14 18 reported on overall PON and POV. Three studies12 14 used spinal anaesthesia, while one study18 used epidural anaesthesia. Combining results from the four studies showed that metoclopramide caused a statistically signicant reduction in the incidence of PON (RR 0.69; 95% CI 0.52, 0.92) when compared with placebo. For POV, no conclusion can be made due to the wide CIs (RR 0.74; 95% CI 0.33, 1.68). The NNT for overall PON was 8. Statistical heterogeneity was observed with POV (P0.09, I 2 58%). One study18 had a higher rate of POV (37%) compared with the other studies (13 16%).13 14 Excluding this study18 eliminated the statistical heterogeneity (P0.25, I 2 24%) with no change in overall results (RR 1.09; 95% CI 0.45, 2.64).

SAP decrease 3 mg i.v. .20% from ephedrine baseline or below 90 mm Hg Spinal

Time of Spinal Threshold to administration or treat epidural hypotension

After delivery

Spinal

SAP below 90 mm 5 mg i.v. Hg ephedrine

Before block placement

Postoperative need for anti-emetics

Two studies13 18 reported on the need for rescue anti-emetics after operation. No conclusion can be made when pooling the results of those two studies due to the wide CIs (RR 0.56; 95% CI 0.11, 2.82). Statistical heterogeneity was observed between the two studies (P0.02, I 2 82%).13 18 This is likely related to the use of neuraxial morphine in one study,13 where no reduction in the need for rescue was reported, but not in the other study,18 where the metoclopramide group required signicantly less rescue compared with control.

2 (1/0/1/0) M: 20; C: 20

Table 1 Continued

MOS (R/C/ n B/F)

Biswas and colleagues10

Reference

Duman and colleagues13

6 (2/0/2/2) M: 58; C: 63

Side-effects
Extra-pyramidal side-effects were evaluated in six studies,2 11 13 14 17 18 with no reported occurrence in any of the patients. Sedation was investigated in three

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Risk ratio MH, random 95% Cl

Study or subgroup

Metoclopramide Control Risk ratio Events Total Events Total Weight MH, random 95% Cl 0.40 (0.18, 0.89) 0.18 (0.06, 0.51) 0.21 (0.08, 0.53) 0.27 (0.16, 0.45)

1.1.1 Overall nausea (metoclopramide before block) 15 43.5% 17 11 5 Danzer 21 24.2% 21 17 3 Lussos Stein 25 32.3% 25 19 4 Subtotal (95% Cl) 61 100.0% 63 Total events 47 12 Heterogeneity: 2 = 0.00; 2 = 1.93, df = 2 (P = 0.38); l 2 = 0% Test for overall effect: Z = 4.92 (P < 0.00001) 1.1.2 Postdelivery nausea (metoclopramide after delivery) Chestnut 4 34 12 33 16.3% 30 7 30 13.7% Fujii 3 30 50 17.0% Garcia-Miguel 4 48 Maranhao 10 20 12.4% 20 2 7 25 16.5% 25 Numazaki 5 29 51 24.1% 51 Pan 22 209 100.0% 208 Subtotal (95% Cl) Total events 40 95 Heterogeneity: 2 = 0.45; 2 = 15.91, df = 2 (P = 0.007); l 2 = 69% Test for overall effect: Z = 2.79 (P = 0.005)

0.32 (0.12, 0.90) 0.43 (0.12, 1.50) 0.14 (0.05, 0.36) 0.20 (0.05, 0.80) 0.71 (0.26, 1.95) 0.76 (0.51, 1.13) 0.38 (0.20, 0.75)

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0.1 1 0.01 Favours metoclopramide

10 100 Favours control

Fig 2 Forest plot of meta-analysis: intraoperative nausea. CI, condence interval.

Study or subgroup

Metoclopramide Control Events Total Events Total Weight

Risk ratio MH, random 95% Cl Not estimable 0.11 (0.02, 0.80) 0.17 (0.02, 1.29) 0.14 (0.03, 0.56)

Risk ratio MH, random 95% Cl

1.4.1 Overall vomiting (metoclopramide before block) 0 17 0 15 Danzer 21 51.7% 1 21 9 Lussos Stein 1 25 6 25 48.3% Subtotal (95% Cl) 61 100.0% 63 Total events 2 15 Heterogeneity: 2 = 0.00; 2 = 0.08, df = 1 (P = 0.78); l 2 = 0% Test for overall effect: Z = 2.76 (P = 0.006) 1.4.2 Postdelivery vomiting (metoclopramide after delivery) Chestnut 0 34 5 33 5.0% 2 30 7 30 16.0% Fujii Garcia-Miguel 1 48 9 50 9.4% 9 20 9.8% Maranhao 1 20 6 25 20.6% 3 25 Numazaki 13 Pan 8 51 51 39.3% 209 100.0% Subtotal (95% Cl) 208 Total events 15 49 Heterogeneity: 2 = 0.12; 2 = 6.07, df = 5 (P = 0.030); l 2 = 18% Test for overall effect: Z = 3.21 (P = 0.001)

0.09 (0.01, 1.54) 0.29 (0.06, 1.26) 0.12 (0.02, 0.88) 0.11 (0.02, 0.80) 0.50 (0.14, 1.78) 0.62 (0.28, 1.36) 0.34 [0.18, 0.66]

0.1 1 0.01 Favours metoclopramide

10 100 Favours control

Fig 3 Forest plot of meta-analysis: intraoperative vomiting. CI, condence interval.

studies,11 17 18 with no difference in pooled results between the groups [mean (SD) sedation score for the metoclopramide group 3.09 (2.1), the placebo group 2.66 (2.1), and MD 0.47; 95% CI 20.40, 1.34]. Headache was investigated in two studies;14 18 however, due to the wide CI of the pooled

results (RR 0.75; 95% CI 0.15, 3.81), no conclusion can be made regarding the comparison with the placebo group. Anxiety was reported in two studies; one study reported the mean anxiety scores with no differences between metoclopramide and control,11 while the second reported the

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Study or subgroup 3.6.1 Early PON Metoclopramide Control Risk ratio Events Total Events Total Weight MH, Random 95% Cl 0.50 (0.18, 1.40) 0.40 (0.16, 1.02) 0.60 (0.16, 2.29) 0.47 (0.26, 0.87) Risk ratio MH, random 95% Cl

Mishriky and Habib

20 35.5% 20 8 4 Biswas 33 43.6% 34 12 5 Chestnut Fujii 30 20.9% 30 5 3 Subtotal (95% Cl) 83 100.0% 84 Total events 25 12 Heterogeneity: 2 = 0.00; 2 = 0.24, df = 2 (P = 0.89); l 2 = 0% Test for overall effect: Z = 2.39 (P = 0.02) 3.6.2 Early POV 2 20 3 20 19.0% Biswas 4 34 12 33 51.0% Chestnut 3 30 5 30 29.9% Fujii 83 100.0% 84 Subtotal (95% Cl) Total events 9 20 Heterogeneity: 2 = 0.00; 2 = 0.79, df = 2 (P = 0.68); l 2 = 0% Test for overall effect: Z = 2.16 (P = 0.03)

0.67 (0.12, 3.57) 0.32 (0.12, 0.90) 0.60 (0.16, 2.29) 0.45 (0.21, 0.93)

0.1 1 0.01 Favours metoclopramide

10 100 Favours control

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Fig 4 Forest plot of meta-analysis: early (0 3 or 0 4 h) postoperative nausea and postoperative vomiting. CI, condence interval; PON, postoperative nausea; POV, postoperative vomiting.

number of patients with anxiety19 (16% in the metoclopramide group compared with 4% in the placebo group, P0.20). Pruritus was reported in one study13 with no differences between the groups (29% metoclopramide group vs 37% placebo group). Respiratory depression was investigated in three studies11 13 18 with no reported occurrence in any of the patients.

Sensitivity analyses
Restricting the analysis to studies done under spinal anaesthesia2 12 14 17 19 or to those that used spinal opioids2 13 15 19 did not change the results regarding ION and IOV. Including only studies with a modied Oxford score of 4 or more did not change the direction of results; however, the pooled results for IOV when metoclopramide was given before block placement12 19 and ION when metoclopramide was given after cord clamping14 15 17 18 were no longer statistically signicant [RR (95% CI)0.17 (0.02 1.29) and 0.44 (0.19 1.05), respectively].

Discussion
This meta-analysis suggests that the administration of metoclopramide causes a signicant reduction in the incidence of IONV and PONV in women undergoing CD under neuraxial anaesthesia with no signicant side-effects. In the general surgical population, the anti-emetic effects of metoclopramide in a dose of 10 mg are uncertain with 50% of studies reporting this dose to be no better than placebo.20 This has led to decreased use and interest in this agent in the UK and other countries. Only four of the 11 studies included in this review were published in the last decade. Higher doses of 2050 mg, however, were reported

to be effective.21 22 In contrast to the patients undergoing non-obstetric surgery under general anaesthesia, this review suggests that the 10 mg dose of metoclopramide is effective for nausea and vomiting prophylaxis in women undergoing CD under neuraxial anaesthesia. The reasons for this difference are unclear, but may be related to the different risk factors for IONV compared with PONV and the impact of the physiological changes of pregnancy. Metoclopramide increases the tone of the lower oesophageal sphincter,6 23 which is reduced during pregnancy and accounts for the high incidence of gastro-oesophageal reux in parturients. Since reux can be associated with nausea,24 25 the increase in the lower oesophageal sphincter tone with metoclopramide might account for its effective anti-emetic effect in this patient population. Furthermore, the prokinetic effect of metoclopramide increases gastric and small intestinal motility, and causes relaxation of the pylorus during stomach contractions.26 Such effects might contribute to the effective anti-emetic effect of metoclopramide in the parturient where oesophageal peristalsis and intestinal transit time are slowed down.27 On the other hand, the effectiveness of metoclopramide in enhancing gastric emptying might be reduced by opioids28 which are commonly implicated as risk factors for PONV. Metoclopramide may also be less effective against nausea and vomiting induced by inhaled agents that contribute to early PONV in the general surgical population.29 Metoclopramide causes a reduction of gastric volume in labouring women. It also crosses the placenta with an umbilical venous/maternal plasma concentration ratio range of 0.59 0.84 when given to women undergoing Caesarean section.6 30 31 No adverse effects on the neonate were noted as assessed by Apgar scores,2 6 10 15 18 31

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the presence of a small number of studies as is the case in our review.41 43 This systematic review has identied some areas for future research. Large studies with adequate power comparing metoclopramide with placebo in patients undergoing CD under spinal anaesthesia with both short- and long-acting spinal opioids administered and reporting on nausea and vomiting are required. The use of metoclopramide in women receiving phenylephrine infusions for haemodynamic support needs to be investigated since this technique was reported to be associated with less IONV compared with treatment of hypotension with boluses of vasopressors,44 45 as was used in all studies included in this review. Because of the multifactorial nature of IONV and PONV, the efcacy of metoclopramide when combined with other anti-emetics requires further investigation. In conclusion, this systematic review suggests that the administration of metoclopramide in a dose of 10 mg is effective and safe for the prophylaxis against IONV and early PONV in parturients undergoing CD under neuraxial anaesthesia. Since the use of metoclopramide has signicantly declined due to a presumed lack of efcacy, this information calls for reappraisal of the routine administration of this inexpensive drug for the management of the unpleasant symptoms of nausea and vomiting in the obstetric patient population.

haemodynamic variables,31 neurobehavioural scores,6 31 or umbilical cord gas analysis.2 6 Metoclopramide is excreted in breast milk. It is sometimes used as a galactagogue to increase milk supply.32 33 While no adverse effects on nursing infants are reported, the American Academy of paediatrics has classied metoclopramide as a drug for which the effect on nursing infants is unknown but may be of concern. This specically applies to its use for long periods due to its long half-life and impact on neurotransmitter function in the developing nervous system, creating a potential risk for neurodevelopmental effects.34 Studies comparing metoclopramide with other anti-emetics in this patient population are outside the scope of this meta-analysis, but there is evidence that metoclopramide has similar efcacy to both droperidol and ondansetron for IONV14 17 35 and PONV14 35 prophylaxis, and its price is signicantly lower than those agents.36 Although side-effects of metoclopramide are few when used in low doses (10 20 mg), only one of the studies14 included in this meta-analysis investigated other common side-effects of metoclopramide such as dizziness, drowsiness, and fatigue.1 With higher doses, rare but serious effects of metoclopramide include extra-pyramidal sideeffects and acute dystonia. While these side-effects have been reported in some case reports,37 39 they were not observed in any of the studies included in this analysis. Our systematic review has several limitations. First, neuraxial opioids were used in only ve studies with the older studies using local anaesthetics alone. Currently, neuraxial opioids are commonly used to enhance intra- and postoperative analgesia. The use of intrathecal fentanyl was reported to reduce the incidence of IONV as a result of improved analgesia.40 Restricting the analysis to studies that used intrathecal opioids did not change the overall results of this review with regard to IONV. Secondly, while long-acting intrathecal opioids such as morphine are now commonly used, only one study included in this review used intrathecal morphine as part of the anaesthetic technique and reported data on PONV. While the use of intrathecal morphine is unlikely to affect the incidence of IONV, it causes an increased risk for PONV. Indeed, the study13 using intrathecal morphine did not report a reduction in PONV with metoclopramide prophylaxis. Thirdly, the quality of some of the included studies was low as assessed by the modied Oxford score. Furthermore, the method of assessing the primary outcome was deemed inadequate in ve of the included studies. Limiting the analysis to studies with a modied Oxford score .4 still showed lower incidence of IONV with metoclopramide, but some of the differences were no longer statistically signicant. Fourthly, risk factors for PONV such as smoking status and history of PONV were not reported in most studies. Those risk factors were developed in patients undergoing general anaesthesia and it is not known if they are applicable to obstetric patients receiving neuraxial anaesthesia. Finally, publication bias cannot be excluded. We did not test for publication bias with funnel plots or other statistical tests since those are unreliable in

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Declaration of interest
None declared.

Funding
This article was supported solely by departmental funds.

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