Patient‐controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour

Stephanie Weibel; Yvonne Jelting; Arash Afshari; Nathan Leon Pace; Leopold HJ Eberhart; Johanna Jokinen; Thorsten Artmann; Peter Kranke

doi:10.1002/14651858.CD011989.pub2

. 2017 Apr 13;2017(4):CD011989. doi: 10.1002/14651858.CD011989.pub2

Patient‐controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour

Stephanie Weibel ¹, Yvonne Jelting ¹, Arash Afshari ², Nathan Leon Pace ³, Leopold HJ Eberhart ⁴, Johanna Jokinen ¹, Thorsten Artmann ⁵, Peter Kranke ^1,^✉

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC6478102 PMID: 28407220

Abstract

Background

Multiple analgesic strategies for pain relief during labour are available. Recently remifentanil, a short‐acting opioid, has recently been used as an alternative analgesic due to its unique pharmacological properties.

Objectives

To systematically assess the effectiveness of remifentanil intravenous patient‐controlled analgesia (PCA) for labour pain, along with any potential harms to the mother and the newborn.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (9 December 2015), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP), handsearched congress abstracts (November 2015), and reference lists of retrieved studies.

Selection criteria

Randomised controlled trials (RCTs) and cluster‐randomised trials comparing remifentanil (PCA) with another opioid (intravenous (IV)/intramuscular (IM)), or with another opioid (PCA), or with epidural analgesia, or with remifentanil (continuous IV), or with remifentanil (PCA, different regimen), or with inhalational analgesia, or with placebo/no treatment in all women in labour including high‐risk groups with planned vaginal delivery.

Data collection and analysis

Two review authors independently assessed trials for inclusion, extracted data, and appraised study quality.

We contacted study authors for additional information other than incomplete outcome data. We performed random‐effects meta‐analysis.

To reduce the risk of random error in meta‐analysis we performed trial sequential analysis. We included total zero event trials and used a constant continuity correction of 0.01 (ccc 0.01) for meta‐analysis. We applied the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach to assess the quality of evidence.

Main results

Twenty RCTs with 3569 women were included. Of those, 10 trials (2983 participants) compared remifentanil (PCA) to an epidural, four trials (216 participants) to another opioid (IV/IM), three trials (215 participants) to another opioid (PCA), two trials (135 participants) to remifentanil (continuous IV), and one trial (20 participants) to remifentanil (PCA, different regimen). No trials were identified for the remaining comparisons.

Methodological quality of studies was moderate to poor. We assessed risk of bias as high for blinding issues and incomplete outcome data in 65% and 45% of the included studies, respectively.

There is evidence of effect that women in the remifentanil (PCA) group were more satisfied with pain relief than women in the other opioids (IV/IM) group (standardised mean difference (SMD) 2.11, 95% confidence interval (CI) 0.72 to 3.49, four trials, very low‐quality evidence), and that women were less satisfied compared to women in the epidural group (SMD ‐0.22, 95% CI ‐0.40 to ‐0.04, seven trials, very low‐quality evidence).

There is evidence of effect that remifentanil (PCA) provided stronger pain relief at one hour than other opioids administered IV/IM (SMD ‐1.58, 95% CI ‐2.69 to ‐0.48, three trials, very low‐quality evidence) or via PCA (SMD ‐0.51, 95% CI ‐1.01 to ‐0.00, three trials, very low‐quality evidence). Pain intensity was higher in the remifentanil (PCA) group compared to the epidural group (SMD 0.57, 95% CI 0.31 to 0.84, six trials, low‐quality evidence).

Data were limited on safety aspects for both the women and the newborns. Only one study analysed maternal apnoea in a comparison of remifentanil (PCA) versus epidural and reported that half of the women in the remifentanil and none in the epidural group had an apnoea (very low‐quality evidence). There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for maternal respiratory depression when compared to epidural analgesia (RR 0.91, 95% CI 0.51 to 1.62, ccc 0.01, three trials, low‐quality evidence) and no reliable conclusion might be reached compared to remifentanil (continuous IV) (all study arms included zero events, two trials, low‐quality evidence). In one trial of remifentanil (PCA) versus another opioid (IM) three out of 18 women in the remifentanil and none out of 18 in the control group had a respiratory depression (very low‐quality evidence).

There is no evidence of effect that remifentanil (PCA) was associated with an increased risk for newborns with Apgar scores less than seven at five minutes compared to epidural analgesia (RR 1.26, 95% CI 0.62 to 2.57, ccc 0.01, five trials, low‐quality evidence) and no reliable conclusion might be reached compared to another opioid (IV) and compared to remifentanil (PCA, different regimen) both with zero events in all study arms (one trial, very‐low quality evidence). In one trial of remifentanil (PCA) versus another opioid (PCA) none out of nine newborns in the remifentanil and three out of eight in the opioid (PCA) group had Apgar scores less than seven (very‐low quality evidence).

There is evidence that remifentanil (PCA) was associated with a lower risk for the requirement of additional analgesia when compared to other opioids (IV/IM) (RR 0.57, 95% CI 0.40 to 0.81, three trials, moderate‐quality evidence) and that it was associated with a higher risk compared to epidural analgesia (RR 9.27, 95% CI 3.73 to 23.03, ccc 0.01, six trials, moderate‐quality evidence). There is no evidence of effect that remifentanil (PCA) reduced the requirement for additional analgesia compared to other opioids (PCA) (RR 0.76, 95% CI 0.45 to 1.28, three trials, low‐quality evidence).

There is evidence that there was no difference in the risk for caesarean delivery between remifentanil (PCA) and other opioids (IV/IM) (RR 0.63, 95% CI 0.30 to 1.32, ccc 0.01, four trials, low‐quality evidence) and epidural analgesia (RR 1.0, 95% CI 0.82 to 1.22, ccc 0.01, nine trials, moderate‐quality evidence), respectively. Pooled meta‐analysis revealed an increased risk for caesarean section under remifentanil (PCA) compared to other opioids (PCA) (RR 2.78, 95% CI 0.99 to 7.82, two trials, very low‐quality evidence). However, a wide range of clinically relevant and non‐relevant treatment effects is compatible with this result.

Authors' conclusions

Based on the current systematic review, there is mostly low‐quality evidence to inform practice and future research may significantly alter the current situation. The quality of evidence is mainly limited by poor quality of the studies, inconsistency, and imprecision. More research is needed on maternal and neonatal safety outcomes (maternal apnoea and respiratory depression, Apgar score) and on the optimal mode and regimen of remifentanil administration to provide highest efficacy with reasonable adverse effects for mothers and their newborns.

Plain language summary

Patient‐controlled analgesia with remifentanil versus alternative analgesic methods for pain relief in labour

What is the issue

Pain relief during labour can be provided in a number of different ways. These include epidural analgesia, by injection of anaesthetic medication around the nerve roots in the spine, intramuscular or continuous intravenous opioids, and inhalational analgesia such as with nitrous oxide. Remifentanil is a relatively recently introduced potent, short‐acting opioid, which gives control over pain relief.

Why is this important

Labour pain may be associated with adverse effects for the mother and her baby and can result in prolonged labour.

This review aimed to compare remifentanil given via a patient‐controlled analgesia (PCA) device with other opioids given via the same way or via an intramuscular or intravenous injection, with epidural analgesia, with different regimens of remifentanil (PCA) or with remifentanil as a continuous intravenous infusion, with inhalational analgesia, or with no treatment for women during normal vaginal birth. Our main outcomes of interest were satisfaction with pain relief, pain scores, side effects for the women and their babies, need for additional analgesia and the risk for a caesarean section.

What evidence did we find

A search of the literature was performed in November/December 2015 and updated in December 2016. We found 20 randomised controlled trials with 3569 women. The methodological quality of studies was moderate to poor.

Women who received PCA with remifentanil were more satisfied with their pain relief than women receiving other opioids either by intravenous or intramuscular injection (four trials, 216 women, very low‐quality evidence). Remifentanil (PCA) provided stronger pain relief at one hour than the other opioids by intravenous or intramuscular injection (three trials, 180 women) and using PCA (three trials, 215 women), both very low‐quality evidence but with moderate‐quality evidence that remifentanil (PCA) was associated with a reduced need for additional analgesia compared to other intravenous or intramuscular opioids (three trials, 190 women). The number of women with need for additional analgesia was not different with remifentanil (PCA) or opioids (PCA) (three trials, 215 women, low‐quality evidence). Remifentanil (PCA) increased the risk for a maternal respiratory depression compared to other intramuscular opioids (one trial, 36 women, very low‐quality evidence). The newborn babies were not more likely to have low Apgar scores at five minutes after birth under remifentanil (PCA) compared to other intravenous or intramuscular opioids (one trial, 88 newborns, very low‐quality evidence), but newborns have a lower risk under remifentanil (PCA) compared to other opioids (PCA) (one trial, 17 newborns, very low‐quality evidence). Remifentanil (PCA) was not associated with an increased risk for caesarean section when compared with intravenous or intramuscular opioids (four trials, 215 women, low‐quality evidence), but compared to other opioids (PCA) (two trials, 143 women, very low‐quality evidence).

Women were slightly less satisfied with remifentanil (PCA) compared to an epidural for pain relief (seven trials, 2135 women, very low‐quality evidence). Pain intensity was higher in the remifentanil (PCA) group compared to the epidural group (six trials, 235 women, low‐quality evidence), with a higher need for additional analgesia (six studies, 1037 women, moderate‐quality evidence). Remifentanil (PCA) increased the risk for a maternal respiratory arrest compared to an epidural (one trial, 38 women, very low‐quality evidence). Remifentanil (PCA) was not associated with an increased risk of respiratory depression in mothers compared to an epidural (three trials, 687 women, low‐quality evidence). The newborn babies were not more likely to have low Apgar scores at five minutes after birth (five trials, 1322 newborns, low‐quality evidence). The number of women requiring caesarean section was not different with remifentanil (PCA) or epidural analgesia (moderate‐quality evidence).

What does this mean

Our confidence in the results of the current review is limited since the quality of evidence is mostly low. No definite conclusion can be drawn with respect to side effects for women and newborns as well as for the comparators remifentanil given via a continuous infusion or via PCA with a different regimen since there are too few studies with few participants that reported on these. No eligible study examined remifentanil (PCA) versus inhalational analgesia or no treatment. More research is needed, especially on side effects of remifentanil (PCA) for women and newborns.

Summary of findings

Background

Nowadays, multiple strategies are available to provide pain relief during labour, such as central neuraxial analgesia (e.g. epidural analgesia), parenteral opioids, and inhalational analgesia. According to the guidelines of the American Society of Anaesthesiologists (ASA) and the College of Obstetricians and Gynaecologists (ACOG), epidural analgesia is recommended as the most flexible, effective and least depressing to the central nervous system analgesic modality in obstetrics (Goetzl 2002). However, obstetric anaesthesiologists are occasionally faced with women who cannot receive this type of labour analgesia due to absolute or relative contraindications, e.g. woman receiving prophylactic anticoagulants (Moghbeli 2008), or women with significant coagulation disorders. Pregnant women may also ask for alternatives to central neuraxial analgesia for personal reasons. Moreover, central neuraxial analgesia may also technically not be possible to perform in women requesting pain relief for labour. Finally, there are many places in the world which do not offer epidural pain relief either at all, or only on a very limited basis (Saravanakumar 2007).

A common method for pain relief in labour is the use of opioids (e.g. pethidine) administered either via the intravenous (IV) or intramuscular (IM) route. In 2008, a survey in the United Kingdom on the prescription of IM opioids (e.g. pethidine) for labour analgesia concluded that pethidine lacks efficacy as an analgesic and has adverse effects on both the mother and the neonate (Tuckey 2008). Nevertheless, pethidine, morphine or diamorphine, and other long‐acting opioids are still frequently used (Tuckey 2008); a situation that does not differ markedly when compared with other European countries (Schnabel 2011).

These findings are in notable contrast to German and other European countries' guidelines on acute pain relief. Concerning the use of pethidine, the German guidelines on the management of acute pain relief in labour recommend that pethidine is not suited due to neurotoxic effects. Especially for the IM application route of pethidine, a negative recommendation (“Grade of Recommendation: A”) was stated (AWMF guidelines 2009, AWMF‐Register Nr. 001 ‐ 025, download on 29 November 2011).

Another alternative for labour analgesia is achieved by inhalational analgesia using, e.g. nitrous oxide. In principle, this method ensures that the mother stays awake and laryngeal reflexes remain intact. The fact that inhaled interventions for pain relief are usually easy to administer with limited preparation time and fast onset account for their popularity in some countries (Irestedt 1994; Kranke 2013). However, the existing body of evidence with respect to nitrous oxide and other inhaled molecules has been the subject of two systematic reviews with controversial results concerning the effectiveness as a labour analgesic (Klomp 2012; Rosen 2002).

The described discrepancy between scientific evidence and recommendations on the one hand, and the current clinical practice on the other hand, demands a closer look at the current body of evidence to discover alternative techniques that might be promising in view of efficacy (pain relief) and safety for both the mother and the neonate. For several reasons described above, there is a need for an effective and safe systemic analgesic for labour pain, which can be used as an alternative to central neuraxial analgesia in obstetrics. Due to its unique pharmacodynamic and pharmacokinetic profile (fast on‐ and offset), remifentanil might be an alternative opioid for labour analgesia (Egan 1993). Several surveys and narrative reviews focusing on opioids in obstetrics showed that remifentanil is gaining popularity (Lavand'homme 2009).

Proponents of the use of remifentanil for labour analgesia claim that it should be routinely available as an alternative for labour analgesia in those women who either do not want, can not have, or do not need, epidural analgesia (Hill 2008). However, opponents argue that not only does remifentanil produce negative respiratory effects for both the mother and the neonate, but also that the available evidence supporting the use of remifentanil is limited (Van de Velde 2008).

Therefore, it is essential to develop an evidence‐based decision basis for labour pain management and to promote a shared decision‐making process with parturients. In case of superiority of newer, more efficient and safer techniques, these techniques should be implemented when possible and safe to avoid unnecessary suffering and decrease potential negative impact on parental as well as neonatal outcomes.

Description of the condition

Pain during labour can be very intense and many pregnant women are anxious about the pain they will experience. This holds true also for women who have received prepared childbirth training (Melzack 1984). The anatomic and neurophysiologic basis underlying the pain of childbirth along with different pain‐management strategies are described in detail in an overview of systematic reviews dealing with pain management for women in labour (Jones 2012). The choice and demands of pain relief differ between countries and cultures and likewise the willingness to face and endure labour pain (Callister 2003; Callister 2010; Kartchner 2003; Semenic 2004; Weber 1996; Wilkinson 2010). Labour pain may be associated with adverse effects on both the mother and the fetus, mainly by elevated plasma catecholamine levels, respiratory changes and associated shifts in pCO₂ and pH. Furthermore, intense pain may also result in prolonged labour (Reynolds 2011). Therefore, it is important to provide women with various options for pain control during labour.

Description of the intervention

Remifentanil, first described in 1991 (James 1991), is a very short‐acting opioid with an analgesic potency that is about 200 times higher compared to morphine (Westmoreland 1993). It acts as a specific agonist on the μ‐opioid‐receptor. The metabolisation of remifentanil through nonspecific tissue and plasma esterases decreases its half‐life to only a few minutes, leading to a rapid decline of action in the patient. The fast on‐ and offset of the drug action facilitates its controllability. Especially, when applied in a patient‐controlled manner, remifentanil analgesia allows enhanced flexibility and controllability for obstetrics. The action of remifentanil, as well as safety concerns are not affected by impaired liver or kidney function of the recipients (Bosilkovska 2012; Hohne 2004). Known side effects of remifentanil include respiratory depression, nausea, pruritus, and decreased heart rate and blood pressure. It is mostly used in anaesthesiology, e.g. as a component of total intravenous anaesthesia (TIVA) combined with propofol due to its predictable pharmacokinetics irrespective of organ function and the lack of accumulation. Owing to the unique pharmacodynamic and pharmacokinetic characteristics of remifentanil, it is increasingly used for labour pain relief. The comparable rapid metabolisation of IV‐administered remifentanil in adults and neonates suggests only a limited risk to cause prolonged side effects for the newborn.

How the intervention might work

Remifentanil has been used for anaesthesia for many years, providing effective and controllable analgesia for different kinds of surgical procedures by acting as a μ‐agonist. Due to its characteristics (fast onset, short half‐life), it can be administered in a patient‐controlled mode, giving the parturient the opportunity of pain relief when required. Therefore, remifentanil might be an alternative to other opioids and to epidural analgesia.

Why it is important to do this review

Remifentanil patient‐controlled analgesia (PCA) for labour analgesia is becoming increasingly popular in some countries, while in other countries there is a remaining reluctance towards its use due to the fear of possible adverse effects based on a few reported severe outcomes secondary to remifentanil administration for labour pain (Bonner 2012; Pruefer 2012). Previously, some of the published trials have been partially summarised in systematic reviews, which either deal with the comparison of remifentanil PCA versus epidural analgesia (Liu 2014), or remifentanil versus pethidine (Leong 2011), or both of those comparisons in addition to fentanyl and nitrous oxide as comparators (Schnabel 2011) in the obstetrics setting. However, none of those reviews, in contrast to the current review, defined adverse events associated with this intervention as their primary outcome. Moreover, an up‐to‐date systematic review with the comprehensive reporting and high‐quality standard of a Cochrane review, including the commitment for a subsequent update process, is still lacking.

Objectives

To systematically assess the effectiveness of remifentanil patient‐controlled analgesia (PCA) for labour analgesia, along with any potential harms to the mother and the baby.

Methods

Criteria for considering studies for this review

Types of studies

We included individually‐randomised controlled trials (RCTs) and planned to include cluster‐randomised trials. Cross‐over trials and quasi‐RCTs were not included. We planned to include trials which were only published in abstract form, if sufficient information in the abstract was available to allow an assured decision on inclusion.

Types of participants

All women in labour with planned vaginal delivery, including high‐risk groups, e.g. preterm labour or following induction of labour were eligible.

We did not include trials involving women scheduled for caesarean delivery.

Types of interventions

We compared remifentanil administered via a patient‐controlled analgesia (PCA) device versus:

another opioid using a different mode (nurse‐/midwife‐controlled intravenous infusion (IV)) or route (intramuscular (IM)/subcutaneous (SC)) of administration;
another opioid using the same mode of administration (PCA);
epidural analgesia or other central neuraxial blocks (e.g. combined spinal‐epidural analgesia (CSE));
remifentanil using a different mode (continuous IV administration) of administration;
remifentanil using the same mode (PCA), but different regimen (e.g. increasing bolus versus constant bolus);
nitrous oxide (or other forms of inhalational analgesia);
placebo or no treatment.

We included trials describing all modes of IV pain control with remifentanil using a PCA pump at any stage during labour. There were no restrictions regarding the lockout interval, the amount of remifentanil delivered with each bolus dose, whether adjusted doses due to the patient’s body weight, e.g. 0.5 μg/kg of actual/ideal body weight, or a dosing scheme, e.g. with increasing doses depending on the efficacy in order to find an appropriate dose. Further, we included trials investigating a regimen with only bolus doses as well as trials investigating regimen that combined a defined amount of continuous administration of remifentanil with additional bolus doses of remifentanil upon request.

Both the bolus doses as well as the basal rates could be steady or variable over the course of time. In the intervention group, no other analgesics were allowed for simultaneous administration. However, this did not exclude the prior use of other parenteral (opioid) analgesics or other methods of pain relief administered to the parturients during the conduct of the study (i.e. escape analgesia, e.g. Entonox).

Types of outcome measures

Primary outcomes

Satisfaction with pain relief (as defined by trialists).
Adverse events for women:
1. apnoea (≥ 20 s of zero respiratory rate);
2. respiratory depression (less than nine breaths/minute);
3. oxygen desaturation (SpO₂ ≤ 95%, ≤ 92%);
4. hypotension;
5. bradycardia;
6. nausea;
7. vomiting;
8. pruritus;
9. postpartum haemorrhage (≥ 1000 mL);
10. sedation at one hour after onset of analgesia.
Adverse events for newborns:
1. Apgar score less than seven at five minutes;
2. Apgar score at five minutes;
3. need for naloxone;
4. depressed baby;
5. fetal heart rate (FHR)/cardiotocography (CTG) abnormalities or non‐reassuring fetal status;
6. neonatal neurologic and adaptive capacity score (NACS).

Secondary outcomes

Pain intensity (as defined by trialists) at 30 minutes to one hour ('early') and at two hours ('late')
Additional analgesia required (escape analgesia)
Rate of unscheduled caesarean delivery
Rate of assisted vaginal birth
Augmented labour (e.g. use of oxytocin)
Satisfaction with childbirth experience (as defined by trialists)
Sense of control in labour
Effect (negative) on mother/baby interaction
Breastfeeding initiation (as defined by trialists)
Umbilical cord base excess (arterial and venous)
Umbilical cord pH (arterial and venous)
Need for neonatal resuscitation (e.g. CPAP (continuous positive airway pressure), bag or mask ventilation, intubation)
Long‐term childhood development (as defined by trialists)
Cost (as defined by trialists

Search methods for identification of studies

The following methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth with review‐specific modifications.

Electronic searches

We searched Cochrane Pregnancy and Childbirth’s Trials Register by contacting their Information Specialist (9 December 2015). We updated this search on 10 December 2016 and added the results to Studies awaiting classification.

The Register is a database containing over 23,000 reports of controlled trials in the field of pregnancy and childbirth. For full search methods used to populate Pregnancy and Childbirth’s Trials Register including the detailed search strategies for CENTRAL, MEDLINE, Embase and CINAHL; the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service, please follow this link to the editorial information about the Cochrane Pregnancy and Childbirth in the Cochrane Library and select the ‘Specialized Register ’ section from the options on the left side of the screen.

Briefly, the Cochrane Pregnancy and Childbirth’s Trials Register is maintained by their Information Specialist and contains trials identified from:

monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
weekly searches of MEDLINE (Ovid);
weekly searches of Embase (Ovid);
monthly searches of CINAHL (EBSCO);
handsearches of 30 journals and the proceedings of major conferences;
weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Search results are screened by two people and the full text of all relevant trial reports identified through the searching activities described above is reviewed. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set which has been fully accounted for in the relevant review sections (Included studies; Excluded studies; Studies awaiting classification; Ongoing studies).

Search results were screened by two people (SW, YJ) and the full texts of all relevant trial reports identified through the searching activities described above were reviewed.

In addition, we searched ClinicalTrials.gov (26 November 2015) and the WHO International Clinical Trials Registry Platform (ICTRP) (27 November 2015) for unpublished, planned and ongoing trial reports. Our search terms were detailed in Appendix 1. We updated this search in December 2016 and added the results to Studies awaiting classification.

Searching other resources

We handsearched the congress abstracts of the American Society of Anesthesiologists (ASA), from 2000 to 18 November 2015, the International Anesthesia Research Society (IARS), from 2003 to 26 November 2015, and the European Society of Anaesthesiology (ESA), from 2004 to 26 November 2015. We updated this search in December 2016

We also searched the reference lists of retrieved studies. We did not apply any language or date restrictions.

Data collection and analysis

Selection of studies

Two review authors (SW, YJ) independently assessed for inclusion all the potential studies that were identified as a result of the search strategy (Appendix 2). We resolved any disagreement through discussion or, if required, we consulted a third review author (PK).

We created a study flow diagram to map the number of records identified, included and excluded.

Data extraction and management

We used a form to extract data (Appendix 3). For eligible studies, two review authors (SW, YJ) extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third review author (PK). When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details. We entered data into Review Manager 5 software (RevMan 2014) and checked for accuracy. A detailed description of the included studies is provided under the section Characteristics of included studies.

Assessment of risk of bias in included studies

Two review authors (SW, YJ) independently assessed risk of bias (RoB) for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (Appendix 4). We resolved any disagreement by discussion or by involving further review authors (PK, AA).

(1) Random sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

low risk of bias (any truly random process, e.g. random number table; computer random number generator);
high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether the intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

low risk of bias (e.g. telephone or central randomisation; sequentially numbered opaque sealed envelopes);
high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were efficiently blinded (methods used for blinding were plausible), or if we judged that the lack of blinding would be unlikely to affect results. We assessed blinding separately for subjective and objective outcomes. Most of the outcomes being assessed were defined as subjective outcomes with the exception of umbilical cord base excess/pH, vomiting and postpartum haemorrhage which were defined as objective outcomes. All GRADE‐relevant outcomes were subjective outcomes.

We assessed the methods as:

low, high or unclear risk of bias for participants;
low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for subjective and objective outcomes.

We assessed methods used to blind outcome assessment as:

low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We described for each included study, and for each outcome or class of outcomes (adverse events for mothers and newborns), the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes (see Characteristics of included studies, 'Risk of bias' table). We further assessed for each included study the cross‐over rates, escape rates (rescue analgesia), type of data analysis (full‐intention‐to‐treat (F‐ITT), partial‐ITT, per‐protocol‐analysis, as‐treated analysis), and the methods used for imputation of missing data. We assessed attrition bias separately for each outcome or class of outcome (Table 6).

1. Attrition bias: Outcome level (GRADE‐relevant outcomes).

Study	No. randomised (Remifentanil/ control)	No. analysed (Remifentanil/ control)	Overall assessment for risk of attrition bias	Outcome level_Risk of bias
Study	No. randomised (Remifentanil/ control)	No. analysed (Remifentanil/ control)	Overall assessment for risk of attrition bias	Satisfaction with pain relief	AE for women	AE for newborns	Pain intensity	Additional analgesia	Rate of CS
Balki 2007	10/ 10	10/ 10	Low	Low	Low	Low	Low	Low	Low
Blair 2005	20/ 20	20/ 19	High	High	High	High	Unclear	Unclear
Calderon 2006	12/ 12	12/ 12	Low	Low	Low	Low	Low		Low
Douma 2010	60/ 60/ 60	52/ 53/ 54	High	High	High	High	Low	Low	High
Douma 2011	14/ 12	10/ 10	High	High	Low	High	High	Low	Low
Douma 2015	57/ 59	49/ 49	High	High	High	High	Unclear	Unclear	High
El‐Kerdawy 2010	15/ 15	15/ 15	Low	Low	Low	Low	Low		Low
Evron 2005	43/ 45	43/ 45	Unclear	Low	High	Low	Low	Low	Low
Evron 2008	213 NA/ NA/ NA/ NA	192 44/ 50/ 49/ 49	Low				Low	Low	Low
Freeman 2015	709/ 705	687/ 671	High	High	High	High	High	High	High
Ismail 2012	380/ 380/ 380	380/ 380/ 380	Low	Low	Low	Low	Low		Low
Khooshideh 2015	41/ 41	41/ 41	Low	Low	Low	Low	Low
Ng 2011	34/ 34	34/ 34	Low	Low	Low	Low	Low	Low	Low
Shen 2013	30/ 30	27/ 26	High	High	High	High	High	High
Stocki 2014	20/ 20	19/ 20	Low	Low	Low	Low	Low	Low	Low
Stourac 2014	13/ 15	12/ 12	High	High	High	Low	High		Low
Thurlow 2002	18/ 18	18/ 18	Unclear	Low	Low		Low	High	High
Tveit 2012	19/ 20	17/ 20	High	High	High	High	High	Low	High
Volikas 2001	9/ 8	9/ 8	Low		Low	Low	Low	Low	Low
Volmanen 2008	27/ 25	24/ 21	High	High	High	High	High	High	High

Sensitivity analysis: Selection bias	Statistical method	All studies		'high risk of bias'‐studies excluded		Impact on robustness (95% CI)
Sensitivity analysis: Selection bias	Statistical method	n	Effect estimate	n	Effect estimate	Impact on robustness (95% CI)
1. Remifentanil (PCA) versus another opioid (IV/IM)
1.1 Satisfaction with pain relief	SMD (IV, Random), 95% CI	4, all at low risk of bias
1.3 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	2, all at low risk of bias
1.4 Nausea (and vomiting)	RR (MH, Random), 95% CI	4, all at low risk of bias
1.6 Pruritus	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
1.10 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH, Random), 95% CI	2, all at low risk of bias
1.11 Pain intensity 'early' (30 min/1 h)	SMD (IV, Random), 95% CI	3, all at low risk of bias
1.13 Additional analgesia required (escape analgesia)	RR (MH, Random), 95% CI	3, all at low risk of bias
1.14 Rate of caesarean delivery	RR (MH, Random), 95% CI	4, all at low risk of bias
2. Remifentanil (PCA) versus another opioid (PCA)
2.2 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	2, all at low risk of bias
2.10 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
2.12 NACS at 15/30 min	MD (IV, Random), 95% CI	2, all at low risk of bias
2.13 Pain intensity 'early' (30 min/1 h)	SMD (IV, Random), 95% CI	3, all at low risk of bias
2.15 Additional analgesia required (escape analgesia)	RR (MH, Random), 95% CI	3, all at low risk of bias
2.16 Rate of caesarean delivery	RR (MH, Random), 95% CI	2, all at low risk of bias
3. Remifentanil (PCA) versus epidural/combined spinal‐epidural analgesia (CSE)
3.1 Satisfaction with pain relief	SMD (IV, Random), 95% CI	7	‐0.22 [‐0.40, ‐0.04]	6	‐0.20 [‐0.46, 0.07]	Yes (CI includes 0)
3.3 Respiratory depression (< 9, < 8 breaths/min)	RR (IV, Random), 95% CI, 0/0 cell counts	3	0.91 [0.51, 1.62]	2	0.91 [0.52, 1.61]	No
3.4 Oxygen desaturation (SpO₂ < 92%)	RR (MH, Random), 95% CI	3	3.24 [1.66, 6.32]	2	5.83 [0.40, 84.06]	Yes (CI includes 1)
3.5 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	3	3.27 [2.32, 4.61]	2	5.44 [2.11, 14.02]	Yes (effect and CI increased)
3.6 Hypotension	RR (IV, Random), 95% CI, 0/0 cell counts	4	0.59 [0.37, 0.94]	3	0.57 [0.00, 2.4E⁷]	Yes (CI includes 1)
3.7 Bradycardia	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
3.8 Nausea	RR (MH, Random), 95% CI	8	1.49 [1.19, 1.86]	7	1.41 [1.09, 1.83]	No
3.9 Vomiting	RR (MH, Random), 95% CI	6	1.63 [1.25, 2.13]	5	1.82 [1.29, 2.57]	No
3.10 Pruritus	RR (MH, Random), 95% CI	7	0.75 [0.48, 1.18]	6	0.81 [0.45, 1.45]	No
3.11 Sedation (1 h)	MD (IV, Random), 95% CI	3, all at low risk of bias
3.12 Apgarscore ≤ 7 (< 7) at 5 min	RR (IV, Random), 95% CI, 0/0 cell counts	5, all at low risk of bias
3.13 Apgarscore at 5 min	MD (IV,), 95% CI	3, all at low risk of bias
3.14 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
3.15 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH, Random), 95% CI	5, all at low risk of bias
3.16 Pain intensity 'early' (1 h)	SMD (IV, Random), 95% CI	6, all at low risk of bias
3.18 Additional analgesia required	RR (IV, Random), 95% CI, 0/0 cell counts	6	9.27 [3.73, 23.03]	5	5.29 [1.2, 23.3]	No
3.19 Rate of caesarean delivery	RR (MH, Random), 95% CI	9, all at low risk of bias
4. Remifentanil (PCA) versus remifentanil (continuous IV)
4.1 Respiratory depression (< 8 breaths/min)	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
4.3 Hypotension	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
4.4 Bradycardia	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
4.5 Nausea (and vomiting)	RR (MH, Random), 95% CI	2, all at low risk of bias
4.8 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias

Sensitivity analysis: Blinding (performance and detection bias)	Statistical method	All studies		'high risk of bias'‐studies excluded		Impact on robustness (95% CI)
	Statistical method	n	Effect estimate	n	Effect estimate	Impact on robustness (95% CI)
1. Remifentanil (PCA) versus another opioid (IV/IM)
1.1 Satisfaction with pain relief	SMD (IV, Random), 95% CI	4	2.11 [0.72, 3.49]	2	2.46 [‐0.34, 5.26]	Yes (CI includes 0)
1.3 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	2	0.48 [0.00, 47.37]	1	0.05 [0.00, 0.82]	Yes (CI < 1: favours RPCA)
1.4 Nausea (and vomiting)	RR (MH, Random), 95% CI	4	0.54 [0.29, 0.99]	2	0.36 [0.06, 2.29]	Yes (CI includes 1)
1.6 Pruritus	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
1.10 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH, Random), 95% CI	2, all at low risk of bias
1.11 Pain intensity 'early' (30 min/1 h)	SMD (IV, Random), 95% CI	3	‐1.58 [‐2.69, ‐0.48]	2	‐1.28 [‐2.62, 0.07]	Yes (CI includes 0)
1.13 Additional analgesia required (escape analgesia)	RR (MH, Random), 95% CI	3	0.57 [0.40, 0.81]	2	0.48 [0.25, 0.91]	No
1.14 Rate of caesarean delivery	RR (MH, Random), 95% CI	4	0.70 [0.34, 1.41]	2	0.63 [0.30, 1.31]	No
2. Remifentanil (PCA) versus another opioid (PCA)
2.2 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	2	1.28 [0.49, 3.30]	1	1.64 [1.25, 2.15]	Yes (CI > 1: favours opioid)
2.10 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.03 [0.00, 1.8E⁸]	1	0.00 [0.00, 0.06]	Yes (CI < 1: favours RPCA)
2.12 NACS at 15/30 min	MD (IV, Random), 95% CI	2	1.11 [‐0.65, 2.87]	1	0.20 [‐0.93, 1.33]	Yes (direction of effect changed, CI decreased)
2.13 Pain intensity 'early' (30 min/1 h)	SMD (IV, Random), 95% CI	3	‐0.51 [‐1.01, ‐0.00]	2	‐0.73 [‐1.05, ‐0.40]	Yes (lower CI: clinically relevant moderate effect)
2.15 Additional analgesia required (escape analgesia)	RR (MH, Random), 95% CI	3	0.76 [0.45, 1.28]	2	0.65 [0.39, 1.09]	No
2.16 Rate of caesarean delivery	RR (MH, Random), 95% CI	2, all at low risk of bias
3. Remifentanil (PCA) versus epidural/combined spinal‐epidural analgesia (CSE)
3.1 Satisfaction with pain relief	SMD (IV, Random), 95% CI	7	‐0.22 [‐0.40, ‐0.04]	1	0.27 [‐0.31, 0.86]	Yes (CI includes 0)
3.3 Respiratory depression (< 9, < 8 breaths/min)	RR (IV, Random), 95% CI, 0/0 cell counts	3	0.91 [0.51, 1.62]	0	Not estimable	All studies at high risk
3.4 Oxygen desaturation (SpO₂ < 92%)	RR (MH, Random), 95% CI	3	3.24 [1.66, 6.32]	0	Not estimable	All studies at high risk
3.5 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	3	3.27 [2.32, 4.61]	1	11.38 [1.62, 79.78]	Yes (effect and CI increased)
3.6 Hypotension	RR (IV, Random), 95% CI, 0/0 cell counts	4	0.59 [0.37, 0.94]	0	Not estimable	All studies at high risk
3.7 Bradycardia	RR (IV, Random), 95% CI, 0/0 cell counts	2	1.0 [0.00, 1.0E¹²]	0	Not estimable	All studies at high risk
3.8 Nausea	RR (MH, Random), 95% CI	8	1.49 [1.19, 1.86]	1	3.94 [0.96, 16.22]	Yes (CI includes 1)
3.9 Vomiting	RR (MH, Random), 95% CI	6	1.63 [1.25, 2.13]	0	Not estimable	All studies at high risk
3.10 Pruritus	RR (MH, Random), 95% CI	7	0.75 [0.48, 1.18]	0	Not estimable	All studies at high risk
3.11 Sedation (1 h)	MD (IV, Random), 95% CI	3	0.71 [0.03, 1.39]	0	Not estimable	All studies at high risk
3.12 Apgarscore ≤ 7 (< 7) at 5 min	RR (IV, Random), 95% CI, 0/0 cell counts	5	1.26 [0.62, 2.57]	0	Not estimable	All studies at high risk
3.13 Apgarscore at 5 min	MD (IV,), 95% CI	3	0.06 [‐0.27, 0.39]	0	Not estimable	All studies at high risk
3.14 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.02 [0.00, 1.6E⁸]	0	Not estimable	All studies at high risk
3.15 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH, Random), 95% CI	5	1.55 [0.49, 4.92]	1	11.38 [1.62, 79.78]	Yes (CI > 1: favours epidural)
3.16 Pain intensity 'early' (1 h)	SMD (IV, Random), 95% CI	6	0.57 [0.31, 0.84]	0	Not estimable	All studies at high risk
3.18 Additional analgesia required	RR (IV, Random), 95% CI, 0/0 cell counts	6	9.27 [3.73, 23.07]	0	Not estimable	All studies at high risk
3.19 Rate of caesarean delivery	RR (MH, Random), 95% CI	9	0.99 [0.81, 1.21]	1	0.88 [0.06, 13.14]	Yes (CI increased)
4. Remifentanil (PCA) versus remifentanil (continuous IV)
4.1 Respiratory depression (< 8 breaths/min)	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No
4.3 Hypotension	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No
4.4 Bradycardia	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No
4.5 Nausea (and vomiting)	RR (MH, Random), 95% CI	2	0.85 [0.28, 2.54]	1	0.53 [0.21, 1.39]	No
4.8 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No

Sensitivity analysis: Attrition bias	Statistical method	All studies		'high risk of bias'‐studies excluded		Impact on robustness (95% CI)
Sensitivity analysis: Attrition bias	Statistical method	n	Effect estimate	n	Effect estimate	Impact on robustness (95% CI)
1. Remifentanil (PCA) versus another opioid (IV/IM)
1.1 Satisfaction with pain relief	SMD (IV, Random), 95% CI	4, all at low risk of bias
1.3 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	2	0.48 [0.00, 47.37]	1	3.50 [0.84, 14.61]	Yes (CI + effect moved to favour of opioid)
1.4 Nausea (and vomiting)	RR (MH, Random), 95% CI	4, all at low risk of bias
1.6 Pruritus	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
1.10 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH, Random), 95% CI	2, all at low risk of bias
1.11 Pain intensity 'early' (30 min/1 h)	SMD (IV, Random), 95% CI	3, all at low risk of bias
1.13 Additional analgesia required (escape analgesia)	RR (MH, Random), 95% CI	3	0.57 [0.40, 0.81]	2	0.48 [0.25, 0.91]	No
1.14 Rate of caesarean delivery	RR (MH, Random), 95% CI	4	0.70 [0.34, 1.41]	3	0.60 [0.29, 1.24]	No
2. Remifentanil (PCA) versus another opioid (PCA)
2.2 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	2	1.28 [0.49, 3.30]	0	Not estimable	All studies at high risk
2.10 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.03 [0.00, 1.8E⁸]	1	0.00 [0.00, 0.06]	Yes (CI moved to favour RPCA)
2.12 NACS at 15/30 min	MD (IV, Random), 95% CI	2	1.11 [‐0.65, 2.87]	0	Not estimable	All studies at high risk
2.13 Pain intensity 'early' (30 min/1 h)	SMD (IV, Random), 95% CI	3, all at low risk of bias
2.15 Additional analgesia required (escape analgesia)	RR (MH, Random), 95% CI	3, all at low risk of bias
2.16 Rate of caesarean delivery	RR (MH, Random), 95% CI	2	2.78 [0.99, 7.82]	1	1.78 [0.20, 16.10]	Yes (CI increased)
3. Remifentanil (PCA) versus epidural/combined spinal‐epidural analgesia (CSE)
3.1 Satisfaction with pain relief	SMD (IV, Random), 95% CI	7	‐0.22 [‐0.40, ‐0.04]	3	‐0.27 [‐0.64, 0.10]	Yes (CI includes 0)
3.3 Respiratory depression (< 9, < 8 breaths/min)	RR (IV, Random), 95% CI, 0/0 cell counts	3	0.91 [0.51, 1.62]	1	0.91 [0.39, 2.10]	No
3.4 Oxygen desaturation (SpO₂ < 92%)	RR (MH, Random), 95% CI	3	3.24 [1.66, 6.32]	0	Not estimable	All studies at high risk
3.5 Oxygen desaturation (SpO₂ < 95%)	RR (MH, Random), 95% CI	3	3.27 [2.32, 4.61]	1	4.33 [1.47, 12.79]	Yes (effect and CI increased)
3.6 Hypotension	RR (IV, Random), 95% CI, 0/0 cell counts	4	0.59 [0.37, 0.94]	2	0.01 [0.00, 7.8E⁷]	Yes (CI includes 1)
3.7 Bradycardia	RR (IV, Random), 95% CI, 0/0 cell counts	2	1.0 [0.00, 1.0E¹²]	1	1.0 [0.00, ∞]	No
3.8 Nausea	RR (MH, Random), 95% CI	8	1.49 [1.19, 1.86]	4	1.27 [0.82, 1.98]	Yes (CI includes 1)
3.9 Vomiting	RR (MH, Random), 95% CI	6	1.63 [1.25, 2.13]	3	1.54 [0.75, 3.14]	Yes (CI includes 1)
3.10 Pruritus	RR (MH, Random), 95% CI	7	0.75 [0.48, 1.18]	5	0.86 [0.48, 1.56]	No
3.11 Sedation (1 h)	MD (IV, Random), 95% CI	3, all at low risk of bias
3.12 Apgarscore ≤ 7 (< 7) at 5 min	RR (IV, Random), 95% CI, 0/0 cell counts	5	1.26 [0.62, 2.57]	3	1.26 [0.62, 2.57]	No
3.13 Apgarscore at 5 min	MD (IV,), 95% CI	3	0.06 [‐0.27, 0.39]	0	Not estimable	All studies at high risk
3.14 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2, all at low risk of bias
3.15 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH, Random), 95% CI	5	1.55 [0.49, 4.92]	2	0.87 [0.41, 1.87]	Yes (CI decreased, effect changed)
3.16 Pain intensity 'early' (1 h)	SMD (IV, Random), 95% CI	6	0.57 [0.31, 0.84]	3	0.57 [0.25, 0.89]	No
3.18 Additional analgesia required	RR (IV, Random), 95% CI, 0/0 cell counts	6	9.27 [3.73, 23.03]	5	5.29 [1.2, 23.3]	No
3.19 Rate of caesarean delivery	RR (MH, Random), 95% CI	9	0.99 [0.81, 1.21]	6	1.02 [0.83, 1.25]	No
4. Remifentanil (PCA) versus remifentanil (continuous IV)
4.1 Respiratory depression (< 8 breaths/min)	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No
4.3 Hypotension	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No
4.4 Bradycardia	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No
4.5 Nausea (and vomiting)	RR (MH, Random), 95% CI	2	0.85 [0.28, 2.54]	1	1.67 [0.43, 6.52]	No
4.8 Need for naloxone	RR (IV, Random), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	1	0.98 [0.00, ∞]	No

	EE [95% CI], P value, I² (%), n	TSA_Low risk of bias‐based (all low)
	EE [95% CI], P value, I² (%), n	RRR (%)	CER (%)	H (%)	RIS	evidence
1.13 Additional analgesia	0.58 [0.42, 0.79], 0.0005, 15%, 190	51.21	58	25	156	evidence of effect (intervention)
	low risk of bias studies: Evron 2005 + Ng 2011 (best)
1.14 Rate of caesarean delivery	0.63 [0.30, 1.32], 0.22, 0%,215	37.47	19	25	1444	absence of evidence
	low risk of bias studies: Evron 2005 + Ng 2011 (best)
2.15 Additional analgesia	0.87 [0.74, 1.03], 0.11, 0%, 215	35.21	28	25	1024	absence of evidence
	low risk of bias studies: Douma 2010 (best) + Volikas 2001
2.16 Rate of caesarean delivery	2.78 [0.99, 7.82], 0.05, 0%, 143	‐77.76	12.5	25	852	absence of evidence
	only low risk of bias study: Volikas 2001
3.3 Respiratory depression	0.91 [0.51, 1.62], 0.75, 0%,687	9.09	58	25	4986	absence of evidence
	best study (high risk): Stocki‐2014
3.12 Apgarscore < 7 at 5 min	1.26 [0.62, 2.57], 0.52, 0%, 1322	‐26.33	3	25	2.9E⁴	absence of evidence
	not best study (0/0 events), but largest (high risk): Ismail 2012
3.18 Additional analgesia	9.27 [3.73, 23.03], < 0.0001, 0%, 1037	‐218.8	5	25	449	evidence of effect (control)
	Not best study (0/0 events), but second best (high risk): Stocki 2014
3.19 Rate of caesarean delivery	1.0 [0.82, 1.22], 0.9857, 0%, 1578	‐12.5	8	25	4.4E⁴	absence of evidence
	best study (high risk): Evron 2008 clinically relevant (RRR) assumptions: RRR = ‐ 50%, CER (empirical) = 22%, H (empirical) = 0% → IS = 924 (lack of effect)
4.1 Respiratory depression	0.98 [0.06, 15.37], 0.9896, 0%, 135	4	1	25	3.4E⁶	absence of evidence
	best study (high risk): Shen 2013

	EE [95% CI], P value, I² (%), n	TSA_Empirical (with all studies)
	EE [95% CI], P value, I² (%), n	RRR (%)	CER (%)	H (%)	RIS	evidence
1.13 Additional analgesia	0.58 [0.42, 0.79], 0.0005, 15%, 190	42.39	62	21.39	194	evidence of effect, TSMB, (intervention)
1.14 Rate of caesarean delivery	0.63 [0.30, 1.32], 0.22, 0%,215	30.4	15	0	2245	absence of evidence
2.15 Additional analgesia	0.87 [0.74, 1.03], 0.11, 0%, 215	12.58	38	0	4218	absence of evidence
2.16 Rate of caesarean delivery	2.78 [0.99, 7.82], 0.05, 0%, 143	‐177.7	6	0	372	absence of evidence
3.3 Respiratory depression	0.91 [0.51, 1.62], 0.75, 0%,687	2	4	0	2.5E⁶	absence of evidence
3.12 Apgarscore < 7 at 5 min	1.26 [0.62, 2.57], 0.52, 0%, 1322	‐26	2	0	3.4E⁴	absence of evidence
3.18 Additional analgesia	9.27 [3.73, 23.03], < 0.0001, 0%, 1037	‐665	1	0	394	evidence of effect (control)
3.19 Rate of caesarean delivery	1.0 [0.82, 1.22], 0.9857, 0%, 1578	1.18	22	0	1.1E⁶	absence of evidence
4.1 Respiratory depression	0.98 [0.06, 15.37], 0.9896, 0%, 135	2	1	0	1.0E⁷	absence of evidence

	EE [95% CI], P value, I², n	OIS_minimal clinically relevant difference¹
	EE [95% CI], P value, I², n	mean₁	mean₂	SD_largest	OIS	evidence
1.1 Satisfaction with pain relief	2.11 [0.72, 3.49], 0.003, 93%, 216	7	6	2.22	208	evidence of effect (intervention)
	best low risk of bias study: Ng 2011
1.11 Pain intensity 'early'	‐1.58 [‐2.69, ‐0.48], 0.005, 89%, 180	25.6	35.6	26.6	298	absence of evidence
	best low risk of bias study: Ng 2011
2.13 Pain intensity 'early'	‐0.51 [‐1.01, ‐0.00], 0.05, 52%, 215	5.282	6.282	2.414	246	absence of evidence
	best low risk of bias study: Douma 2010
3.1 Satisfaction with pain relief	‐0.22 [‐0.40, ‐0.04], 0.02, 52%, 2135	8.1	9.1	1.5	96	evidence of effect (control)
	best study (high risk): Stocki 2014
3.16 Pain intensity 'early'	0.57 [0.31, 0.84], < 0.0001, 0%, 235	3.3	2.3	3.3	458	absence of evidence
	best study (high risk): Stocki 2014

	EE [95% CI], P value, I², n	OIS_low risk of bias‐based (best)
	EE [95% CI], P value, I², n	mean₁	mean₂	SD_largest	OIS	evidence
1.1 Satisfaction with pain relief	2.11 [0.72, 3.49], 0.003, 93%, 216	8	6	2.22	52	evidence of effect (intervention)
	best low risk of bias study: Ng 2011
1.11 Pain intensity 'early'	‐1.58 [‐2.69, ‐0.48], 0.005, 89%, 180	22.1	35.6	26.6	164	evidence of effect (intervention)
	best low risk of bias study: Ng 2011
2.13 Pain intensity 'early'	‐0.51 [‐1.01, ‐0.00], 0.05, 52%, 215	4.56	6.282	2.414	82	lack of effect
	best low risk of bias study: Douma 2010
3.1 Satisfaction with pain relief	‐0.22 [‐0.40, ‐0.04], 0.02, 52%, 2135	8.6	9.1	1.5	380	evidence of effect (control)
	best study (high risk): Stocki 2014
3.16 Pain intensity 'early'	0.57 [0.31, 0.84], < 0.0001, 0%, 235	4	2.3	3.3	160	evidence of effect (control)
	best study (high risk): Stocki 2014

Sensitivity analysis: Random‐effects versus fixed‐effect model	Statistical method	Random‐effects model		Fixed‐effect model			Impact on robustness (95% CI) (fixed‐effect model)
	Statistical method	n	Effect estimate	n	Effect estimate		Impact on robustness (95% CI) (fixed‐effect model)
1. Remifentanil (PCA) versus another opioid (IV/IM)
1.1 Satisfaction with pain relief	SMD (IV), 95% CI	4	2.11 [0.72, 3.49]	4		1.85 [1.51, 2.19]	Yes (CI decreased, large effect)
1.3 Oxygen desaturation (SpO₂ < 95%)	RR (MH), 95% CI	2	0.48 [0.00, 47.37]	2		0.66 [0.28, 1.57]	Yes (CI decreased)
1.4 Nausea (and vomiting)	RR (MH), 95% CI	4	0.54 [0.29, 0.99]	4		0.51 [0.28, 0.95]	No
1.6 Pruritus	RR (IV), 95% CI, 0/0 cell counts	2	1.02 [0.00, 1.1E¹²]	2		1.02 [0.00, 1.1E¹²]	No
1.10 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH), 95% CI	2	0.30 [0.10, 0.90]	2		0.30 [0.10, 0.85]	No
1.11 Pain intensity 'early' (30 min/1 h)	SMD (IV), 95% CI	3	‐1.58 [‐2.69, ‐0.48]	3		‐1.35 [‐1.68, ‐1.01]	Yes (CI decreased, large effect)
1.13 Additional analgesia required (escape analgesia)	RR (MH), 95% CI	3	0.57 [0.40, 0.81]	3		0.53 [0.39, 0.71]	No
1.14 Rate of caesarean delivery	RR (MH), 95% CI	4	0.70 [0.34, 1.41]	4		0.77 [0.39, 1.49]	No
2. Remifentanil (PCA) versus another opioid (PCA)
2.2 Oxygen desaturation (SpO₂ < 95%)	RR (MH), 95% CI	2	1.28 [0.49, 3.30]	2	1.39 [1.16, 1.67]		Yes (CI > 1: favours opioid)
2.10 Need for naloxone	RR (IV,), 95% CI, 0/0 cell counts	2	0.03 [0.00, 1.8E⁸]	2	0.01 [0.00, 2.4E⁶]		No
2.12 NACS at 15/30 min	MD (IV), 95% CI	2	1.11 [‐0.65, 2.87]	2	1.15 [0.38, 1.93]		Yes (CI > 0: favours RPCA)
2.13 Pain intensity 'early' (30 min/1 h)	SMD (IV), 95% CI	3	‐0.51 [‐1.01, ‐0.00]	3	‐0.57 [‐0.86, ‐0.29]		Yes (CI < 0: favours RPCA)
2.15 Additional analgesia required (escape analgesia)	RR (MH), 95% CI	3	0.76 [0.45, 1.28]	3	0.74 [0.55, 1.00]		No
2.16 Rate of caesarean delivery	RR (MH), 95% CI	2	2.78 [0.99, 7.82]	2		2.78 [0.99, 7.77]	No
3. Remifentanil (PCA) versus epidural/combined spinal‐epidural analgesia (CSE)
3.1 Satisfaction with pain relief	SMD (IV), 95% CI	7	‐0.22 [‐0.40, ‐0.04]	7	‐0.29 [‐0.38, ‐0.20]		No
3.3 Respiratory depression (< 9, < 8 breaths/min)	RR (IV), 95% CI, 0/0 cell counts	3	0.91 [0.51, 1.62]	3	1.2 [0.67, 2.17]		No
3.4 Oxygen desaturation (SpO₂ < 92%)	RR (MH), 95% CI	3	3.24 [1.66, 6.32]	3	3.46 [2.32, 5.16]		No
3.5 Oxygen desaturation (SpO₂ < 95%)	RR (MH), 95% CI	3	3.27 [2.32, 4.61]	3	3.30 [2.43, 4.49]		No
3.6 Hypotension	RR (IV,), 95% CI, 0/0 cell counts	4	0.59 [0.37, 0.94]	4	0.57 [0.36, 0.89]		No
3.7 Bradycardia	RR (IV,), 95% CI, 0/0 cell counts	2	1.0 [0.00, 1.0E¹²]	2	1.0 [0.00, 1.0E¹²]		No
3.8 Nausea	RR (MH), 95% CI	8	1.49 [1.19, 1.86]	8	1.53 [1.22, 1.91]		No
3.9 Vomiting	RR (MH), 95% CI	6	1.63 [1.25, 2.13]	6	1.62 [1.24, 2.10]		No
3.10 Pruritus	RR (MH), 95% CI	7	0.75 [0.48, 1.18]	7	0.76 [0.54, 1.07]		No
3.11 Sedation (1 h)	MD (IV), 95% CI	3	0.71 [0.03, 1.39]	3	0.91 [0.57, 1.25]		No
3.12 Apgarscore ≤ 7 (< 7) at 5 min	RR (IV,), 95% CI, 0/0 cell counts	5	1.26 [0.62, 2.57]	5	1.22 [0.67, 2.62]		No
3.13 Apgarscore at 5 min	MD (IV,), 95% CI	3	0.06 [‐0.27, 0.39]	3	0.06 [‐0.27, 0.39]		No
3.14 Need for naloxone	RR (IV,), 95% CI, 0/0 cell counts	2	0.02 [0.00, 1.6E⁸]	2	0.01 [0.00, 4.6E⁵]		No
3.15 FHR/CTG abnormalities, non‐reassuring fetal status	RR (MH), 95% CI	5	1.55 [0.49, 4.92]	5	1.38 [0.84, 2.25]		No
3.16 Pain intensity 'early' (1 h)	SMD (IV), 95% CI	6	0.57 [0.31, 0.84]	6	0.57 [0.31, 0.84]		No
3.18 Additional analgesia required	RR (IV,), 95% CI, 0/0 cell counts	6	9.27 [3.73, 23.03]	6	10.86 [4.37, 26.95]		No
3.19 Rate of caesarean delivery	RR (MH), 95% CI	9	0.99 [0.81, 1.21]	9	0.96 [0.79, 1.18]		No
4. Remifentanil (PCA) versus remifentanil (continuous IV)
4.1 Respiratory depression (< 8 breaths/min)	RR (IV,), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	2	0.98 [0.00, 1.0E¹²]]		No
4.3 Hypotension	RR (IV,), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	2	0.98 [0.00, 1.0E¹²]		No
4.4 Bradycardia	RR (IV,), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	2	0.98 [0.00, 1.0E¹²]		No
4.5 Nausea (and vomiting)	RR (MH), 95% CI	2	0.85 [0.28, 2.54]	2	0.81 [0.38, 1.73]		No
4.8 Need for naloxone	RR (IV,), 95% CI, 0/0 cell counts	2	0.98 [0.00, 1.0E¹²]	2	0.98 [0.00, 1.0E¹²]		No

Data			0‐ and 0/0‐event trials included (TSA)						0‐event trials included and 0/0‐event trials excluded (RevMan)¹
Outcome (n, studies)	0‐events, 0/0‐events, imbalance (Yes/No)	Summary statistic	Reciprocal (1.0)	Reciprocal (0.01)	Empirical (1.0)	Empirical (0.01)	Constant (1.0)	Constant (0.01)	Constant (1.0)
1.3 Oxygen desaturation (2)	1, 0 (Yes)	RR [95% CI], P value, I²	0.51 [0.01, 30.22], 0.7471, 86%	3.41 [0.82, 14.22] 0.0918, 0%	0.57 [0.01, 24.87] 0.7699, 87%	3.39 [0.81, 14.10], 0.0938, 0%	0.5 [0.01, 31.95], 0.7421, 86%	3.42 [0.82, 14.25], 0.0914, 0%	0.5 [0.01, 31.95], 0.7421, 86%
1.4 Nausea (and vomiting) (4)	1, 0 (No)	RR [95% CI], P value, I²	0.54 [0.29, 0.99], 0.0460, 0%	0.56 [0.30, 1.04], 0.0665, 0%	0.54 [0.29, 0.99], 0.0463, 0%	0.56 [0.30, 1.04], 0.0667, 0%	0.54 [0.29, 0.99], 0.0461, 0%	0.56 [0.30, 1.04], 0.0664, 0%	0.54 [0.29, 0.99], 0.0461, 0%
1.6 Pruritus (2)	0, 2 (No)	RR [95% CI], P value, I²	1.0 [0.06, 15.71], 1.0, 0%	1.0 [0.00, 1.0E¹²], 1.0, 0%	NA	NA	1.02 [0.07, 16.06], 0.9874, 0%	1.02 [0.00, 1.1E¹²], 0.9987, 0%	NA
1.14 Rate of caesarean delivery (4)	2, 0 (No)	RR [95% CI], P value, I²	0.69 [0.34, 1,40], 0.3084, 0%	0.63 [0.30, 1.32], 0.2164, 0%	0.7 [0.34, 1.43], 0.3268, 1%	0.63 [0.30, 1.32], 0.2182, 0%	0.70 [0.35, 1.40], 0.3103, 0%	0.63 [0.30, 1.32], 0.2165, 0%	0.70 [0.35, 1.40], 0.3103, 0%
2.10 Need for naloxone (2)	1, 1 (No)	RR [95% CI], P value, I²	0.49 [0.05, 5.29], 0.5580, 0%,	0.03 [0.00, 1.1E⁸], 0.7484, 0%	NA	NA	0.48 [0.04, 5.30], 0.5473, 0%	0.03 [0.00, 1.8E⁸], 0.7549, 0%	0.3 [0.03, 2.72], 0.2847, 0%
3.3 Respiratory depression (3)	1, 1 (Yes)	RR [95% CI], P value, I²	0.97 [0.56, 1.70] 0.9206, 0%	0.91 [0.51, 1.62] 0.7506, 0%	0.98 [0.57, 1.71] 0.9550, 0%	0.91 [0.51, 1.62] 0.7532, 0%	0.98 [0.56, 1.71] 0.9424, 0%	0.91 [0.51, 1.62] 0.7518, 0%	1.35 [0.30, 6.18], 0.6967, 37%
3.4 Oxygen desaturation (3)	1, 0 (Yes)	RR [95% CI], P value, I²	3.2 [1.72, 5.94], 0.0002, 46%	2.88 [1.94, 4.27], < 0.0001, 0%	3.04 [1.70, 5.43], 0.0002, 38%	2.88 [1.94, 4.27], < 0.0001, 0%	3.19 [1.72, 5.91], 0.0002, 46%	2.88 [1.94, 4.27], < 0.0001, 0%	3.19 [1.72, 5.91], 0.0002, 46%
3.6 Hypotension (4)	2, 1 (No)	RR [95% CI], P value, I²	0.59 [0.38, 0.93], 0.0225, 0%	0.59 [0.37, 0.94], 0.0271, 0%	0.59 [0.38, 0.93], 0.0219, 0%	0.59 [0.38, 0.94], 0.0273, 0%	0.59 [0.38, 0.93], 0.0225, 0%	0.59 [0.37, 0.94], 0.0271, 0%	0.58 [0.23, 1.48], 0.2517, 16%
3.7 Bradycardia (2)	0, 2 (No)	RR [95% CI], P value, I²	1.0 [0.07, 15.07], 1.0, 0%	1.0 [0.00, 1.0E¹²], 1.0, 0%	NA	NA	1.0 [0.07, 15.07], 1.0, 0%	1.0 [0.00, 1.0E¹²], 1.0, 0%	NA
3.10 Pruritus (7)	1, 0 (Yes)	RR [95% CI], P value, I²	0.75 [0.48, 1.18], 0.2182, 29%	0.78 [0.51, 1.18], 0.2366, 21%	0.75 [0.48, 1.18], 0.2170, 29%	0.78 [0.51, 1.18], 0.2368, 21%	0.75 [0.48, 1.18], 0.2154, 29%	0.78 [0.51, 1.18], 0.2370, 21%	0.75 [0.48, 1.18], 0.2154, 29%
3.12 Apgarscore < 7 at 5 min (5)	2, 2 (No)	RR [95% CI], P value, I²	1.26 [0.65, 2.43], 0.4944, 0%	1.26 [0.62, 2.57], 0.5193, 0%	1.28 [0.66, 2.47], 0.4596, 0%	1.26 [0.62, 2.57], 0.5209, 0%	1.26 [0.65, 2.43], 0.4904, 0%	1.26 [0.62, 2.57], 0.5197, 0%	1.28 [0.65, 2.51], 0.4801, 0%
3.14 Need for naloxone (2)	1, 1 (Yes)	RR [95% CI], P value, I²	0.34 [0.03, 3.82], 0.3846, 0%	0.02 [0.00, 1.6E⁸], 0.7247, 0%	NA	NA	0.46 [0.04, 4.88], 0.5200, 0%	0.02 [0.00, 1.6E⁸], 0.7447, 0%	0.2 [0.03, 1.15], 0.0720, 0%
3.15 FHR/CTG abnormalities (5)	1, 0 (No)	RR [95% CI], P value, I²	1.54 [0.50, 4.75], 0.4499, 46%	1.88 [0.63, 5.61], 0.2578, 35%	1.53 [0.52, 4.54], 0.4410, 44%	1.88 [0.63, 5.64], 0.2600, 35%	1.54 [0.50, 4.75], 0.4499, 46%	1.88 [0.63, 5.61], 0.2578, 35%	1.54 [0.50, 4.75], 0.4499, 46%
3.18 Additional analgesia required (6)	2, 1 (No)	RR [95% CI], P value, I²	7.47 [3.28, 16.99] < 0.0001, 0%	9.26 [3.73, 23.03] < 0.0001, 0%	9.66 [3.97, 23.52] < 0.0001, 0%	9.23 [3.71, 22.95] < 0.0001, 0%	7.65 [3.37, 17.38] < 0.0001, 0%	9.27 [3.73, 23.03] < 0.0001, 0%	8.1 [3.5, 18.75], < 0.0001, 0%
3.19 Rate of caesarean delivery (9)	1, 0 (No)	RR [95% CI], P value, I²	0.99 [0.81, 1.21], 0.9076, 0%	1.0 [0.82, 1.22], 0.9858, 0%	0.99 [0.81, 1.21], 0.9058, 0%	1.0 [0.82, 1.22], 0.9857, 0%	0.99 [0.81, 1.21], 0.9067, 0%	1.0 [0.82, 1.22], 0.9857, 0%	0.99 [0.81, 1.21], 0.9067, 0%
3.20 Rate of assisted birth (8)	1, 0 (No)	RR [95% CI], P value, I²	0.92 [0.66, 1.26], 0.5914, 0%	0.94 [0.68, 1.30], 0.6917, 0%	0.92 [0.66, 1.26], 0.5926, 0%	0.94 [0.68, 1.30], 0.6918, 0%	0.92 [0.66, 1.26], 0.5914, 0%	0.94 [0.68, 1.30], 0.6917, 0%	0.92 [0.66, 1.26], 0.5914, 0%
3.26 Neonatal resuscitation (2)	2, 0 (No)	RR [95% CI], P value, I²	1.01 [0.04, 24.25], 0.9933, 57%	1.09 [0.00, 3.1E⁸], 0.9929, 0%	NA	NA	1.02 [0.04, 25.09], 0.9901, 57%	1.03 [0.00, 3.4E⁸], 0.9980, 0%	1.02 [0.04, 25.09], 0.9901, 57%
4.1 Respiratory depression (2)	0, 2 (No)	RR [95% CI], P value, I²	1.0 [0.06, 15.66], 1.0, 0%	1.0 [0.00, 1.0E¹²], 1.0, 0%	NA	NA	0.98 [0.06, 15.37], 0.9896, 0%	0.98 [0.00, 1.0E¹²], 0.9989, 0%	NA
4.3 Hypotension (2)	0, 2 (No)	RR [95% CI], P value, I²	1.0 [0.06, 15.66], 1.0, 0%	1.0 [0.00, 1.0E¹²], 1.0, 0%	NA	NA	0.98 [0.06, 15.37], 0.9896, 0%	0.98 [0.00, 1.0E¹²], 0.9989, 0%	NA
4.4 Bradycardia (2)	0, 2 (No)	RR [95% CI], P value, I²	1.0 [0.06, 15.66], 1.0, 0%	1.0 [0.00, 1.0E¹²], 1.0, 0%	NA	NA	0.98 [0.06, 15.37], 0.9896, 0%	0.98 [0.00, 1.0E¹²], 0.9989, 0%	NA
4.8 Need for naloxone (2)	0, 2 (No)	RR [95% CI], P value, I²	1.0 [0.06, 15.66], 1.0, 0%	1.0 [0.00, 1.0E¹²], 1.0, 0%	NA	NA	0.98 [0.06, 15.37], 0.9896, 0%	0.98 [0.00, 1.0E¹²], 0.9989, 0%	NA

Study	Comparator	Analgesia duration (mean ± SD, median (range)) [min]	*Background infusion [µg/(kgmin)]**	Bolus dose	Bolus application speed (calculated)	Bolus dose escalation on request	Lockout time [min]	Maximum dose	Total dose administered (mean ± SD, median (range [IQR])
Balki 2007	Remifentanil variable infusion, fixed bolus	463	0.025	0.25 µg/kg	NA	0.5 ‐ 1 µg/kg, every 15 min	2	3000 µg in 4 h	474 (188 ‐ 925) µg/h
Blair 2005	Pethidine PCA	147.5 ± 79	no	40 µg	133.33 µg/min	no	2	NA	NA
Calderon 2006	Meperidine IM	280 ± 55	0.025	50 µg	2 µg/min	no	30	NA	NA
Douma 2010	(1) Meperidine PCA (2) Fentanyl PCA	234 ± 136	no	40 µg	NA	no	2	1200 µg/h	1840 ± 1090 µg
Douma 2011	epidural	286 ± 145	no	40µg	66.67 µg/min	no	2	1200 µg/h	2817 ± 1564 µg
Douma 2015	epidural	192 ± 116	no	40µg	66.67 µg/min	no	2	1200 µg/h	1417 µg
El‐Kerdawy 2010	epidural	NA	0.0	0.25 µg/kg	1.5 µg/(kg*min)	no	5	3000 µg in 4 h	NA
Evron 2005	Meperidine IV	NA	no	20 µg	NA	5 µg increments, every 15 ‐ 20 min	3	1500 µg/h	1034.5 (133 ‐ 4021) µg
Evron 2008	epidural	NA	0.025	20 µg	NA	25% increase every 15 ‐ 20 min	3	NA	8.5 ± 2.2 µg/(kg*h)
Freeman 2015	epidural	236 (128 ‐ 376)	no	30 µg	NA	increase to 40 µg or decrease to 20 µg	3	40 µg per bolus	NA
Ismail 2012	epidural/CSE	NA	no	25 µg	25 µg/min	escalation scheme (0.1 – 0.2 – 0.3 – 0.5 – 0.7 – 0.9 µg/kg) until the maximum dose of 0.9 µg/kg	1	25 µg/mL + 0.9 µg/kg per bolus	NA
Khooshideh 2015	Remifentanil IV	NA	no	0.25 µg/kg	NA	increased to 0.4 µg/kg (if VNRS ≥ 7)	4	0.4 µg/kg per bolus	942.6 ± 86.4 µg
Ng 2011	Pethidine IM	NA	no	25 µg (< 60 kg) or 30 µg (≥ 60 kg)	6.67 µg/min	no	3.75‐4.50	500 µg/h (calculated)	NA
Shen 2013	Remifentanil IV	151¹	no	0.1 µg/kg	0.2 µg/(kg*min)	increments of 0.1 µg/kg to 0.4 µg/kg	2	0.4 µg/kg per bolus	1340 (1220 ‐ 1480 [890 ‐ 1680]) µg
Stocki 2014	epidural	NA	no	20 µg	NA	up to 60 µg	2 min, 1 min on request	60 µg per bolus	1725 ± 1392 µg
Stourac 2014	epidural	162.75 ± 77.15	no	20 µg	NA	10 µg increments (if VAS decrease < 2)	3	NA	NA
Thurlow 2002	Meperidine IM	NA	no	20 µg	60 µg/min	NA	3	NA	NA
Tveit 2012	epidural	225 ± 117.2	no	0.15 µg/kg	100 µg/min	0.15 µg/kg increments every 15 min	2	No limit	NA
Volikas 2001	Pethidine PCA	334 ± 260	no	0.5 µg/kg	NA	no	2	No limit	3670 (120 ‐ 4880) µg (mean (range))
Volmanen 2008	epidural	Max. 60	no	25 µg	25 µg/min	escalation scheme (0.1 – 0.2 – 0.33 – 0.5 – 0.7 – 0.9 µg/kg) until the maximum dose of 0.9 µg/kg	1	25 µg/mL + 0.9 µg/kg per bolus	0.14 (0.08 ‐ 0.18 [0.03 ‐ 0.32]) µg/(kg*min)

Author (Year)
Study design/Methods	RCT, blinding, randomisation, purpose, when and were was the study conducted?, trial identifier
Participant flow
	Experimental	Control
Number of participants assessed for eligibility
Number of participants randomised
Number of participants receiving treatment
Number of participants analysed
Inclusion criteria
Exclusion criteria
Population/Baseline details	Experimental	Control
Mean age/Median age
Mean weight/Median weight
ASA I/II
Type of delivery (spontaneous delivery/instrumental/caesarean section)
Week of gestation
Singleton, twin, multiple pregnancy
Parity
Duration of labour (first stage of labour, second stage of labour)
Interventions
Outcomes (primary endpoint, dichotomous, continuous)
Notes	sample size, power analysis, concomitant medications, funding

Dichotomous outcome data	Experimental		Control
Dichotomous outcome data	(n) Number assessed	(n) Number with outcome	(n) Number assessed	(n) Number with outcome
Additional analgesia required (e.g. conversion to epidural analgesia)
Conversion to caesarean delivery
Breastfeeding initiation
Assisted vaginal birth
Need for neonatal resuscitation
Adverse events for women (e.g. apnoea, respiratory depression, oxygen desaturation, hypotension, bradycardia, nausea, vomiting, postpartum haemorrhage, maternal somnolence)
Adverse events for the newborn (e.g. Apgar scores less than 7 at 5 minutes, need for naloxone, depressed baby, opioid‐induced loss of fetal heart rate variability)
Continuous outcome data   (Unit of measurement)	Experimental		Control
Continuous outcome data   (Unit of measurement)	n	Mean (SD)	n	Mean (SD)
Satisfaction with pain relief
Sense of control in labour
Effect (negative) on mother/baby interaction
Pain scores
Satisfaction with childbirth experience
Long‐term childhood development
Cost
Umbilical cord base excess (arterial)
Umbilical cord base excess (venous)
Umbilical cord pH (arterial)
Umbilical cord pH (venous)
Apgar scores at 1, 5, 10 min
Sedation scores

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Satisfaction with pain relief	4	216	Std. Mean Difference (IV, Random, 95% CI)	2.11 [0.72, 3.49]
2 Respiratory depression (< 8 breaths/min)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Oxygen desaturation (SpO₂ < 95%)	2	113	Risk Ratio (M‐H, Random, 95% CI)	0.48 [0.00, 47.37]
4 Nausea (and vomiting)	4	216	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.29, 0.99]
5 Vomiting	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6 Pruritus	2	156	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7 Sedation (1 h)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
8 Apgar score < 7 at 5 min	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9 Apgar score at 5 min	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
10 FHR/CTG abnormalities, non‐reassuring fetal status	2	156	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.10, 0.90]
11 Pain intensity 'early' (1 h)	3	180	Std. Mean Difference (IV, Random, 95% CI)	‐1.58 [‐2.69, ‐0.48]
12 Pain intensity 'late' (2 h)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
13 Additional analgesia required (escape analgesia)	3	190	Risk Ratio (M‐H, Random, 95% CI)	0.57 [0.40, 0.81]
14 Rate of caesarean delivery	4	215	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.34, 1.41]
15 Rate of assisted birth	4	215	Risk Ratio (M‐H, Random, 95% CI)	0.82 [0.32, 2.09]
16 Augmented labour	3	190	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.72, 1.29]
17 Breastfeeding initiation (feeding difficulties)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Satisfaction with pain relief	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
2 Oxygen desaturation (SpO₂ < 95%)	2	190	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.49, 3.30]
3 Hypotension	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4 Bradycardia	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5 Nausea (and vomiting)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
6 Pruritus	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7 Sedation (1 h)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
8 Apgar score < 7 at 5 min	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
9 Apgar score at 5 min	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
10 Need for naloxone	2	55	Risk Ratio (M‐H, Random, 95% CI)	0.30 [0.01, 6.47]
11 FHR/CTG abnormalities, non‐reassuring fetal status	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
12 NACS at 15/30 min	2	94	Mean Difference (IV, Random, 95% CI)	1.11 [‐0.65, 2.87]
13 Pain intensity 'early' (30 min/1 h)	3	215	Std. Mean Difference (IV, Random, 95% CI)	‐0.51 [‐1.01, ‐0.00]
14 Pain intensity 'late' (2 h)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
15 Additional analgesia required (escape analgesia)	3	215	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.45, 1.28]
16 Rate of caesarean delivery	2	143	Risk Ratio (M‐H, Random, 95% CI)	2.78 [0.99, 7.82]
17 Rate of assisted birth	2	143	Risk Ratio (M‐H, Random, 95% CI)	1.22 [0.62, 2.37]
18 Augmented labour	2	152	Risk Ratio (M‐H, Random, 95% CI)	1.37 [0.59, 3.15]

Remifentanil (PCA) compared to another opioid (IV/IM) for pain management in labour
Patient or population: women in labour with planned vaginal delivery  Setting: labour wards in Europe (two studies), Middle East (one study), and Asia (one study)  Intervention: remifentanil (PCA)  Comparison: another opioid (IV/IM)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with another opioid (IV/IM)	Risk with remifentanil (PCA)
Satisfaction (overall) with pain relief (VAS 0 to 10 cm, NRS 1 to 4, NRS 0 to 10, VRS 0 to 5)	see comment	The standardised mean satisfaction score in the intervention group was 2.11 higher (0.72 higher to 3.49 higher)**	‐	216  (4 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 2}	A SMD of 2.11 higher is equivalent to a range of 2.74 cm higher (SD = 1.3) to 4.68 cm higher (SD = 2.22) on a VAS 0 to 10 cm scale in the intervention group. The mean satisfaction scores in the control group range from 4.23 to 6.0 cm.^{# **}
Pain intensity 'early' (30 min/1 h) (VAS 0 to 10 cm, VAS 0 to 100 cm)	see comment	The standardised mean pain score 'early' in the intervention group was 1.58 fewer (2.69 fewer to 0.48 fewer)***	‐	180  (3 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 2 3}	A SMD of 1.58 fewer is equivalent to a range of 1.26 cm fewer (SD = 0.8) to 2.8 cm fewer (SD = 1.77) on a VAS 0 to 10 cm scale in the intervention group. The mean pain scores in the control group range from 3.56 to 6.3 cm (VAS 0 to 10 cm).^{# ***}
Additional analgesia required (escape analgesia)	Study population		RR 0.57  (0.40 to 0.81)	190  (3 RCTs)	⊕⊕⊕⊝  MODERATE ⁴
	621 per 1.000	354 per 1.000  (248 to 503)
Rate of caesarean delivery	Study population		RR 0.63  (0.30 to 1.32)	215  (4 RCTs)	⊕⊕⊝⊝  LOW ^{4 5}	Two studies includes zero events in one arm (constant continuity correction of 0.01).⁷
	148 per 1.000	93 per 1.000  (44 to 195)
Maternal apnoea	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
Maternal respiratory depression (< 8 breaths/min)	None out of 18 women in the control group and three out of 18 in the remifentanil group had a respiratory depression.		not estimable	36  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{4 6}	Only one trial assessed this outcome.
Apgar score < 7 at 5 min	None of the newborns in both groups had an Apgar score < 7 at 5 min.		not estimable	88  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{4 6}	Only one trial assessed this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; RR: risk ratio; SMD: standardised mean difference; SD: standard deviation; RoB: Risk of bias; RIS: required information size; OIS: optimal information size
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Remifentanil (PCA) compared to epidural/CSE for pain management in labour
Patient or population: women in labour with planned vaginal delivery  Setting: labour wards in Europe (six studies) and Middle East (four studies)  Intervention: remifentanil (PCA)  Comparison: epidural analgesia/central neuraxial blocks (CSE)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Risk with epidural analgesia/central neuraxial blocks (CSE)	Risk with remifentanil (PCA)
Satisfaction (overall) with pain relief (NRS 0 to 4, 1 to 4, 0 to 10, 1 to 10, VRS 1 to 4)	see comment	The standardised mean satisfaction score in the intervention group was 0.22 fewer (0.40 fewer to 0.04 fewer)**	‐	2135  (7 RCTs)	⊕⊝⊝⊝  VERY LOW ^{1 2}	A SMD of 0.22 fewer is equivalent to a range of 0.15 cm fewer (SD = 0.7) to 0.61 cm fewer (SD = 2.78) on a VAS 0 to 10 cm scale in the intervention group. Mean satisfaction scores in the control group range from 6.7 to 9.1 cm (VAS 0 to 10 cm).^{# **}
Pain intensity 'early' (1 h) (VAS 0 to 10 cm, VAS 0 to 100 cm, NRS 0 to 10)	see comment	The standardised mean pain score 'early' in the intervention group was 0.57 higher (0.31 higher to 0.84 higher)***	‐	235  (6 RCTs)	⊕⊕⊝⊝  LOW ^{3 4}	A SMD of 0.57 higher is equivalent to a range of 0.57 cm higher (SD = 1.0) to 1.43 cm higher (SD = 2.5) on a VAS 0 to 10 cm scale in the intervention group. The mean pain scores in the control group range from 1.6 to 4.14 cm (VAS 0 to 10 cm).^{# ***}
Additional analgesia required	Study population		RR 9.27  (3.73 to 23.03)	1037  (6 RCTs)	⊕⊕⊕⊝  MODERATE ³	One study includes zero events in both arms; two studies include zero events in one arm (constant continuity correction of 0.01). ⁸
	10 per 1.000	93 per 1.000  (34 to 230)
Rate of caesarean delivery	Study population		RR 1.0  (0.82 to 1.22)	1578  (9 RCTs)	⊕⊕⊕⊝  MODERATE ³	One study includes zero events in one arm (constant continuity correction of 0.01). ⁹
	215 per 1.000	215 per 1.000  (176 to 262)
Maternal apnoea	None out of 19 women in the control group and nine out of 19 in the remifentanil group had an apnoea.		not estimable	38  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{5 7}	Only one trial assessed this outcome.
Maternal respiratory depression (< 9, < 8 breaths/min)	Study population		RR 0.91  (0.51 to 1.62)	687  (3 RCTs)	⊕⊕⊝⊝  LOW ^{3 6}	One study includes zero events in both arms; one study includes zero events in one arm (constant continuity correction of 0.01). ¹⁰
	38 per 1.000	35 per 1.000  (19 to 62)
Apgar score ≤ 7 (< 7) at 5 min	Study population		RR 1.26  (0.62 to 2.57)	1322  (5 RCTs)	⊕⊕⊝⊝  LOW ^{3 6}	Two studies include zero events in both arms; two studies include zero events in one arm (constant continuity correction of 0.01). ¹¹
	23 per 1.000	30 per 1.000  (14 to 59)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; OIS: optimal information size; RIS: required information size; RoB: Risk of Bias; RR: risk ratio; SD: standard deviation; SMD: standardised mean difference
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Remifentanil (PCA) compared to remifentanil (continuous IV) for pain management in labour
Patient or population: women in labour with planned vaginal delivery  Setting: labour wards in Asia (one study) and Middle East (one study)  Intervention: remifentanil (PCA)  Comparison: remifentanil (continuous IV)
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with remifentanil (continuous IV)	Risk with remifentanil (PCA)	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Satisfaction (overall) with pain relief	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
Pain intensity 'early' (30 min/1 h) (VAS 0 to 10 cm)	The mean pain score in the remifentanil (continuous IV) group was 4.0 cm on a VAS 0 to 10 cm scale.	Mean pain score in the remifentanil (PCA) group was 1.0 cm fewer (1.8 fewer to 0.2 fewer).***	not estimable	53  (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 2}	Only one trial assessed this outcome.
Additional analgesia required (escape analgesia)	Two out of 29 women in the remifentanil (PCA) group and four out of 30 participants in the remifentanil (continuous IV) group required additional epidural analgesia.		not estimable	59 (1 RCT)	⊕⊝⊝⊝  VERY LOW ^{1 2}	Only one trial assessed this outcome.
Rate of caesarean delivery	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
Maternal apnoea	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
Maternal respiratory depression (< 8 breaths/min)	see comment	see comment	RR 0.98  (0.00 to 1.0E¹²)	135  (2 RCTs)	⊕⊕⊝⊝  LOW ^{3 4}	All study arms include zero events (constant continuity correction of 0.01). ⁵
Apgar score < 7 at 5 min	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; OIS: optimal information size; RIS: required information size; RoB: Risk of bias
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Remifentanil (PCA, increasing bolus dose) compared to remifentanil (PCA, increasing infusion dose) for pain management in labour
Patient or population: women in labour with planned vaginal delivery  Setting: labour ward in North America (one study)  Intervention: remifentanil (PCA, IB (increasing bolus dose))  Comparison: remifentanil (PCA, IF (increasing infusion dose))
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Outcomes	Risk with remifentanil (continuous IV)	Risk with remifentanil (PCA)	Relative effect  (95% CI)	№ of participants  (studies)	Quality of the evidence  (GRADE)	Comments
Satisfaction (overall) with pain relief (VNRS 0 to 10)	The mean satisfaction scores in the remifentanil (PCA, IF) group was 8.4 on a VNRS 0 to 10 scale.	Mean satisfaction scores in the remifentanil (PCA, IB) group was 0.2 higher (0.81 fewer to 1.21 higher).**	not estimable	20 (1 RCT)	⊕⊕⊝⊝  LOW ¹	Only one trial assessed this outcome.
Pain intensity 'early' (30 min/1 h)	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
Additional analgesia required (escape analgesia)	Only one out of 10 woman in the remifentanil (PCA, IF) group crossed over to the epidural group.		not estimable	20 (1 RCT)	⊕⊕⊝⊝  LOW ¹	Only one trial assessed this outcome.
Rate of caesarean delivery	Four out of 10 women in each group delivered by caesarean section.		not estimable	20 (1 RCT)	⊕⊕⊝⊝  LOW ¹	Only one trial assessed this outcome.
Maternal apnoea	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
Maternal respiratory depression (< 8 breaths/min)	see comment	see comment	‐	(0 studies)	‐	No trial assessed this outcome.
Apgar score < 7 at 5 min	None of the newborns in both groups had an Apgar score < 7 at 5 min.		not estimable	20 (1 RCT)	⊕⊕⊝⊝  LOW ¹	Only 1 trial assessed this outcome.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).    CI: confidence interval; IB: increasing bolus dose; IF: increasing infusion dose; RR: risk ratio
GRADE Working Group grades of evidence   High quality: We are very confident that the true effect lies close to that of the estimate of the effect  Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different  Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect  Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Author (Year)
Public Title
Scientific Title
Identified through	Main search/references/additional searches.
Study status	Active/recruiting/ongoing/finished
Relevant study design	Randomised controlled trial	Yes/No/Unclear
Relevant population	Women in labour with planned vaginal delivery including women of high‐risk groups. Specifically excluded are women undergoing caesarean section.	Yes/No/Unclear
Relevant intervention	Experimental group must have received remifentanil administered via a patient‐controlled analgesia device for pain relief in labour. No other analgesics are allowed for simultaneous administration. Control group must have placebo treatment, no treatment, or any other intervention for pain relief in labour.	Yes/No/Unclear
Intervention experimental
Intervention control
If you have not answered Yes to all of the questions, please exclude the study. If you answered Yes to all questions, please continue to data extraction form and critical appraisal.

Intervention
Analgesia duration
Background infusion
Bolus dose
Bolus application speed
Bolus dose escalation on request
Lockout time
Maximum dose
Total administered dose of remifentanil (if stated)

Author (Year)
Journal
Title
Random sequence generation (selection bias)
State here the method used to generate allocation and reasons for grading		Adequate/Inadequate/Unclear
Allocation concealment (selection bias)
State here the method used to conceal allocation and reasons for grading		Adequate/Inadequate/Unclear
Blinding of participants and personnel (performance bias)
Person responsible for participants care		Low risk/High risk/Unclear
Participant		Low risk/High risk/Unclear
Blinding of outcome assessment (detection bias)
Outcome assessor		Low risk/High risk/Unclear
Incomplete outcome data (attrition bias)
Drop‐out rate > 15%		Yes/No/Unclear
Missing values reported, balanced across groups, and unrelated to true outcome		Yes/No/Unclear
Escape rate > 15%		Yes/No/Unclear
Cross‐over rate > 15%		Yes/No/Unclear
Data analysis described		Yes/No/Unclear
Imputation methods correct		Yes/No/Unclear
Selective reporting (reporting bias)
Free of selective outcome reporting?		Yes/No/Unclear
Other bias
Other sources of bias		Yes/No/Unclear

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Satisfaction with pain relief	7	2135	Std. Mean Difference (IV, Random, 95% CI)	‐0.22 [‐0.40, ‐0.04]
2 Apnoea	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Respiratory depression (< 9, < 8 breaths/min)	3	687	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.23, 9.90]
4 Oxygen desaturation (SpO₂ < 92%)	3	774	Risk Ratio (M‐H, Random, 95% CI)	3.24 [1.66, 6.32]
5 Oxygen desaturation (SpO₂ < 95%)	3	800	Risk Ratio (M‐H, Random, 95% CI)	3.27 [2.32, 4.61]
6 Hypotension	4	823	Risk Ratio (M‐H, Random, 95% CI)	0.58 [0.22, 1.49]
7 Bradycardia	2	44	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
8 Nausea	8	1909	Risk Ratio (M‐H, Random, 95% CI)	1.49 [1.19, 1.86]
9 Vomiting	6	1840	Risk Ratio (M‐H, Random, 95% CI)	1.63 [1.25, 2.13]
10 Pruritus	7	1852	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.48, 1.18]
11 Sedation (1 h)	3	148	Std. Mean Difference (IV, Random, 95% CI)	0.71 [0.03, 1.39]
12 Apgar score ≤ 7 (< 7) at 5 min	5	1322	Risk Ratio (M‐H, Random, 95% CI)	1.28 [0.65, 2.51]
13 Apgar score at 5 min	3	137	Mean Difference (IV, Random, 95% CI)	0.06 [‐0.27, 0.39]
14 Need for naloxone	2	1170	Risk Ratio (M‐H, Random, 95% CI)	0.20 [0.01, 3.85]
15 FHR/CTG abnormalities, non‐reassuring fetal status	5	1280	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.49, 4.92]
16 Pain intensity 'early' (1 h)	6	235	Std. Mean Difference (IV, Random, 95% CI)	0.57 [0.31, 0.84]
17 Pain intensity 'late' (2 h)	4	143	Std. Mean Difference (IV, Random, 95% CI)	1.46 [0.66, 2.26]
18 Additional analgesia required	6	1037	Risk Ratio (M‐H, Random, 95% CI)	8.10 [3.50, 18.75]
19 Rate of caesarean delivery	9	1578	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.81, 1.21]
20 Rate of assisted birth	8	1550	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.66, 1.26]
21 Augmented labour	6	1379	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.82, 1.02]
22 Umbilical cord base excess (artery)	3	75	Mean Difference (IV, Random, 95% CI)	‐0.97 [‐2.65, 0.72]
23 Umbilical cord base excess (venous)	2	129	Mean Difference (IV, Random, 95% CI)	‐0.05 [‐2.39, 2.30]
24 Umbilical cord pH (artery)	5	1245	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐0.02, ‐0.00]
25 Umbilical cord pH (venous)	4	1299	Mean Difference (IV, Random, 95% CI)	0.01 [‐0.01, 0.02]
26 Neonatal resuscitation	2	69	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.04, 25.09]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Respiratory depression (< 8 breaths/min)	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
2 Oxygen desaturation (SpO₂ < 95%)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3 Hypotension	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Bradycardia	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
5 Nausea (and vomiting)	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.28, 2.54]
6 Pruritus	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
7 Sedation (1 h)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
8 Need for naloxone	2	135	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
9 FHR/CTG abnormalities, non‐reassuring fetal status	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
10 Pain intensity 'early' (1 h)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
11 Pain intensity 'late' (2 h)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
12 Additional analgesia required (escape analgesia)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
13 Neonatal resuscitation	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Methods	Randomised, controlled trial. Double‐blinded. No statement on time of randomisation. The purpose of this pilot study was to compare two regimens of IV remifentanil PCA, along with continuous background infusion, for labour analgesia. The study was conducted in Mount Sinai Hospital, Toronto, Canada, from September 2005 to December 2006. Trial Identifier: NA
Participants	Participant flow: Number assessed for eligibility: 22 Number randomised: 20 (10/10) Number receiving treatment: 20 (10/10) Number analysed: 20 (10/10) Inclusion criteria: Term pregnancy, ASA I and II women in active labour, who requested systemic analgesia with or without contraindications to epidural analgesia Exclusion criteria: Allergy or hypersensitivity to remifentanil, opioid dependence or addiction, consumption of narcotics within 24 h of the study period, FHR abnormalities, fetal compromise and/or language barrier Baseline details: Fixed bolus group (n = 10): Age (years, mean (SD)): 32.7 (5.9) Weight (kg, mean (SD)): 85 (30) ASA I/II (n/n): NA Type of delivery (n): vaginal (6), CS (4) Week of gestation: 39.2 ± 1.5 Singleton, twin, multiple pregnancy: NA Parity (n): Primipara (5) Duration of labour: ‐ First stage of labour (min, mean (SD)): NA ‐ Second stage of labour (min, mean (SD)): NA Fixed infusion group (n = 10): Age (years, mean (SD)): 30.4 (5.8) Weight (kg, mean (SD)): 77.1 (14.1) ASA I/II (n/n): NA Type of delivery (n): vaginal (6), CS (4) Week of gestation: 39.0 ± 1.4 Singleton, twin, multiple pregnancy: NA Parity (n): Primipara (7) Duration of labour: ‐ First stage of labour (min, mean (SD)): NA ‐ Second stage of labour (min, mean (SD)): NA
Interventions	Initially, all women received a standard regimen of remifentanil with an infusion of 0.025 µg/(kgmin) and a PCA bolus of 0.25 µg/kg. The PCA lockout interval was set at 2 min, and the 4 h limit was 3 mg. As labour progressed and women required additional analgesia, they received higher doses of either the infusion (group: constant bolus) or the PCA boluses (group: constant infusion). (At the woman’s request, if there was either no change or worsening of pain scores; each step was maintained for at least 15 min before progressing to the subsequent one.) Fixed bolus group (n = 10):* The infusion rate was increased stepwise from 0.025 µg/(kgmin) to 0.05 µg/(kgmin), 0.075 µg/(kgmin) and 0.1 µg/(kgmin), while the bolus of 0.25 µg/kg was maintained. Fixed infusion group (n = 10): The bolus dose was increased stepwise from 0.25 µg/kg to 0.5 µg/kg, 0.75 µg/kg and 1 µg/kg, while the infusion rate of 0.025 µg/(kg*min) was kept constant.
Outcomes	The primary outcome variables were maternal pain and desaturation. Continuous: ‐ overall satisfaction (VNRS 0 to 10, within 2 h after delivery) ‐ pain intensity (VNRS 0 to 10, at 0, every 30 min until delivery), overall pain score (VNRS 0 to 10, within 2 h of delivery) ‐ umbilical cord BE (artery, vein), umbilical cord pH (artery, vein) ‐ sedation score (observer, 5 to 0, at baseline and lowest sedation) Dichotomous: ‐ additional analgesia (epidural) ‐ rate of CS ‐ need for neonatal resuscitation ‐ augmented labour (no substance indicated) ‐ women: oxygen desaturation (< 95%, < 90%), hypotension, bradycardia, nausea, vomiting, pruritus, drowsiness, dizziness, confusion ‐ newborns: Apgar score ≥ 7 at 1 and 5 min, non‐reassuring FHR, need for naloxone
Notes	‐ Small trial sample size (< 200 participants) ‐ Power analysis performed (VNRS pain, n = 10 per group) Concomitant medication: Nausea or vomiting was treated with dimenhydrinate, and diphenhydramine was administered for pruritus. The woman could choose to cross over to epidural analgesia at any time during labour, unless there was a contraindication to a regional technique. Funding: NA
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “The patients were randomized, via a computer‐generated randomisation scheme, into one of the two study groups.”
Allocation concealment (selection bias)	Unclear risk	Quote: “The group allocation was blinded via sealed envelopes until the time of PCA administration.” Not specifically mentioned sequentially numbered, opaque envelopes (SNOSE).
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Quote: “The patient and the obstetrician, as well as the registered nurse collecting the data, were all blinded to the study group. The group allocation was known only to the anaesthesiologist who was making changes to the pump settings when needed.” Blinding for participants and personnel adequate.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Quote: “The patient and the obstetrician, as well as the registered nurse collecting the data, were all blinded to the study group. The group allocation was known only to the anaesthesiologist who was making changes to the pump settings when needed.”, “Fetal heart rate tracings were analysed by an obstetrician (P.B.) who was blinded to the study group.” Blinding for outcome assessment adequate.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	‐ No missing outcome data after randomisation. ‐ Rate of escape (epidural): 10%/0% ‐ Rate of cross‐over: NA ‐ Data‐analysis: Full‐ITT
Selective reporting (reporting bias)	Unclear risk	There is no reference to a trial registry and no published study protocol.
Other bias	Low risk	The study appears to be free of other sources of bias.

PERMALINK

Patient‐controlled analgesia with remifentanil versus alternative parenteral methods for pain management in labour

Stephanie Weibel

Yvonne Jelting

Arash Afshari

Nathan Leon Pace

Leopold HJ Eberhart

Johanna Jokinen

Thorsten Artmann

Peter Kranke

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

(1) Random sequence generation (checking for possible selection bias)

(2) Allocation concealment (checking for possible selection bias)

(3.1) Blinding of participants and personnel (checking for possible performance bias)

(3.2) Blinding of outcome assessment (checking for possible detection bias)

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

1. Attrition bias: Outcome level (GRADE‐relevant outcomes).

(5) Selective reporting (checking for reporting bias)

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

(7) Overall risk of bias

2. Sensitivity analysis: Selection bias (random sequence generation, allocation concealment).

3. Sensitivity analysis: Blinding (performance and detection bias).

4. Sensitivity analysis: Attrition bias.

Assessing the quality of the body of evidence using the GRADE approach

5. Trial sequential analysis (low risk of bias‐based) for dichotomous GRADE‐relevant outcomes.

6. Trial sequential analysis (empirical) for dichotomous GRADE‐relevant outcomes.

7. Optimal information size calculation (minimal clinically relevant difference) for GRADE‐relevant continuous outcomes.

8. Optimal information size calculation (low risk of bias‐based) for GRADE‐relevant continuous outcomes.

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Multi‐armed studies

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

9. Sensitivity analysis: Random‐effects versus fixed‐effect model.

10. Zero event handling: Continuity corrections.

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

Trial characteristics

Comparisons and interventions

11. Interventions.

Methods	Randomised, controlled trial. Single‐blinded. No statement on time of randomisation. The purpose of this trial was to determine the analgesic efficacy and safety of remifentanil versus pethidine via PCA for women in established uncomplicated labour. There are no details where or when the study was conducted. The authors’ origin is United Kingdom. Trial Identifier: NA
Participants	Participant flow: Number assessed for eligibility: NA Number randomised: 40 (20/20) Number receiving treatment: 40 (20/20) Number analysed: 39 (20/19) Inclusion criteria: Women with ASA I or II, either before the onset of labour in the antenatal ward or in early labour before any analgesia had been requested Exclusion criteria: Women were excluded from the study if they planned to use epidural analgesia or had pre‐eclampsia, multiple pregnancy, premature labour or allergy to any agent under investigation. Baseline details: Remifentanil group (n = 20): Age (years, mean (SD)): 29 (5.2) Weight (kg, mean (SD)): 76 (9) ASA I/II (n/n): NA Type of delivery (n): spontaneous (NA) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity (median (IQR [range])): 1 (1 ‐ 2 [0 ‐ 5]) Duration of labour: ‐ before PCA use (min, mean (SD)): 125 (98) ‐ first stage of labour (min, mean (SD)): 260 (97) ‐ second stage of labour (min, mean (SD)): 22 (22) Pethidine group (n = 19): Age (years, mean (SD)): 29 (5.4) Weight (kg, mean (SD)): 76 (12) ASA I/II (n/n): NA Type of delivery (n): spontaneous labour (NA) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity (median (IQR [range])): 1 (0 ‐ 2 [0 ‐ 3]) Duration of labour: ‐ before PCA use (min, mean (SD)): 191 (205) ‐ first stage of labour (min, mean (SD)): 296 (158) ‐ second stage of labour (min, mean (SD)): 20 (12)
Interventions	Remifentanil group (n = 20): Women received a remifentanil PCA using 40 µg remifentanil with a lockout of 2 min. The bolus dose and lockout period for the remifentanil PCA were based on an average maternal weight (80 kg) and a bolus of 0.5 µg/kg. Pethidine group (n = 19): Control participants received PCA using pethidine 15 mg with a lockout of 10 min.
Outcomes	The primary endpoint of the study was overall pain. Continuous: ‐ satisfaction with analgesia (VAS 0 to 10, at 0, 30 min until 120 min, median + IQR + range (symmetric)) ‐ pain intensity (VAS 0 to 10, at 0, every 30 min until 120 min, median + IQR (asymmetric)), overall pain score (VAS 0 to 10, at 2 h after delivery) ‐ umbilical cord pH (not specified) ‐ sedation score (observer, 5 to 1, and parturient score, VAS 0 to 10, at 0, 30, 60, 90, 120 min, respectively, median + IQR + range (asymmetric)) ‐ women: mean respiratory rate, mean SBP, mean HR, median nausea score (VAS 0 to 10) (at 0, 30, 60, 90, 120 min, respectively) ‐ newborns: mean FHR (at 0, 30, 60, 90, 120 min), Apgar score at 1 and 5 min (median + IQR + range (asymmetric)), NACS at 30 and 120 min (median + IQR + range (symmetric)) Dichotomous: ‐ additional analgesia (Entonox) ‐ women: oxygen desaturation (% total PCA time spent with < 94% and < 90%, diagrammed) ‐ newborns: need for naloxone
Notes	‐ Small trial sample size (< 200 participants) ‐ Power analysis performed (VAS overall pain, n = 20 per group) Concomitant medication: All women were free to change to regional analgesia at any time if so desired. Entonox was available to all women throughout the study. Funding: NA
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “The women were randomly allocated to receive PCA using either remifentanil […] or pethidine […].” No method described.
Allocation concealment (selection bias)	Unclear risk	No statement on allocation concealment.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: “[…] women, who were unaware of which treatment they were receiving.” No statement on whether key study personnel were blinded. We assume that participants and attending personnel might be able to uncover group allocation due to the different pharmacokinetics of the two interventions. The used method of blinding may only work for the outcome assessors (which was not mentioned in the published report for most of the relevant outcomes).
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Quote: “Baseline non‐invasive blood pressure, heart rate, SpO₂, respiratory rate, observer sedation score […] and fetal heart rate were recorded by a blinded investigator. Baseline visual analogue scale (VAS) measurements were also recorded for the pain of contractions, satisfaction with current analgesia, nausea, anxiety and sedation.”, “At delivery, Apgar scores at 1 and 5 min were recorded, cord blood was taken for blood gas analysis and the fetal requirement for naloxone was noted.”, "The cardiotocograph (CTG) was recorded for a minimum of 1 h after starting the PCA and was subsequently analysed by a blinded obstetrician […].” It is unclear from the description whether assessment for most of the outcomes after treatment (during study) was blinded. The study did address this issue only for the assessment of FHR patterns. We do not know who was responsible for outcome assessment and participants and attending personnel may be able to uncover group allocation. The subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding. Therefore, insufficient information exists to judge "yes" or "no".
Incomplete outcome data (attrition bias)   All outcomes	High risk	‐ Dropout rate: 0%/5% Quote: “There was one protocol violation in the pethidine group and no data were included from this patient.” The protocol violation was not described. ‐ No statement on why 1 woman in the Remifentanil group was not analysed for all outcomes (satisfaction with pain relief, AE for newborn) ‐ Rate of escape (Entonox): 90%/100% (may influence data on AE, satisfaction and pain) ‐ Rate of cross‐over: NA ‐ Data‐analysis: Per‐protocol (protocol violation)
Selective reporting (reporting bias)	Unclear risk	There is no reference to a trial registry and no published study protocol.
Other bias	Low risk	The study appears to be free of other sources of bias.

Methods	Randomised, controlled trial. No statement on blinding. No statement on time of randomisation. The purpose of this trial was to evaluate the effectiveness and security of remifentanil administered by means of elastomeric infusor with PCA IV compared with IM meperidine in obstetric women with contraindication for epidural analgesia. There are no details where or when the study was conducted. The authors’ origin is Spain. Trial Identifier: NA
Participants	Participant flow: Number assessed for eligibility: NA Number randomised: 24 (12/12) Number receiving treatment: 24 (12/12) Number analysed: 24 (12/12) Inclusion criteria: ASA I to III, aged 20 to 40 years, requesting analgesia Exclusion criteria: NA Baseline details: Remifentanil group (n = 12): Age (years, mean (SD)): 28 (5) Weight (kg, mean (SD)): 72 (8) ASA I/II (n/n): 8/2 Type of delivery (n): spontaneous (NA), instrumental (1), CS (0) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity: NA Duration of labour: ‐ First stage of labour (min, mean (SD)): NA ‐ Second stage of labour (min, mean (SD)): NA Meperidine group (n = 12): Age (years, mean (SD)): 30 (3) Weight (kg, mean (SD)): 75 (6) ASA I/II (n/n): 7/3 Type of delivery (n): spontaneous (NA), instrumental (2), CS (1) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity: NA Duration of labour: ‐ First stage of labour (min, mean (SD)): NA ‐ Second stage of labour (min, mean (SD)): NA
Interventions	Remifentanil group (n = 12): An elastomeric infusor with a capacity of 250 mL was filled with 2.5 mg of remifentanil and a 12 mL/h was started (average infusion of 0.025 µg/(kgmin) of remifentanil and boluses of 5 mL with a time of closing of 30 min). Meperidine group (n = 12):* Women were given 1 mg/kg of meperidine and 2.5 mg of haloperidol every 4 h by IM route.
Outcomes	The primary endpoint of the study was not defined. Continuous: ‐ overall satisfaction (VAS 0 to 10, time point unclear) ‐ pain intensity (VAS 0 to 100, at 0, every 30 min until 280 min, "expulsivo") ‐ newborns: Apgar score at 1 and 5 min Dichotomous: ‐ rate of CS, rate of assisted birth (instrumental) ‐ women: nausea + vomiting
Notes	‐ Small trial sample size (< 200 participants) ‐ Power analysis not performed Concomitant medication: NA Funding: NA Intervention: Lockout time of 30 min seems too long for adequate analgesia. Contact to the authors: We contacted Dr. Torres via e‐mail (23 June 2016) to inquire the number of women who reported 'pain intensity at 2 hours'. We did not receive any answer.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: “24 patients were randomized […].” No method described.
Allocation concealment (selection bias)	Unclear risk	No statement on allocation concealment.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	The study did not address this issue. However, we assume that blinding of parturients and personnel did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	The study did not address this issue. However, we assume that blinding of outcome assessment did not occur due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	‐ No missing outcome data after randomisation ‐ Rate of escape: NA ‐ Rate of cross‐over: NA ‐ Data‐analysis: Full‐ITT
Selective reporting (reporting bias)	Unclear risk	There is no reference to a trial registry and no published study protocol.
Other bias	Low risk	The study appears to be free of other sources of bias.

Methods	2‐arm randomised, controlled trial with a third‐arm observational cohort. Not blinded. Randomisation after onset of labour. The purpose of this trial was to compare the incidence of maternal fever (temperature ≥ 38°C) in parturients receiving IV remifentanil by PCA, with those receiving either epidural analgesia or no analgesia. The study was conducted in Leiden University Medical Center (period unknown). Trial Identifier: NTR1498
Participants	Participant flow: Number assessed for eligibility: 250 Number randomised: 116 (57/59) Number receiving treatment: 114 (57/57) Number analysed: 98 (49/49) + 42 control group Inclusion criteria: ASA I or II parturients with a singleton pregnancy, between 37 and 42 weeks of gestation Exclusion criteria: BMI ≥ 40 kg/m², insulin‐dependent diabetes, severe pre‐eclampsia (proteinuria ≥ 5 g/24 h), use of antibiotics during delivery, initial maternal SpO₂ < 98%, initial maternal temperature ≥ 38°C, cervical dilation of > 7 cm and ruptured membranes for > 24 h at the time of inclusion. If delivery occurred within 1 h of starting the study, women were excluded from analysis. Baseline details: Remifentanil group (n = 49): Age (years, mean (SD)): 32 (4.8) Weight (kg, mean (SD)): 81 (17.2) ASA I/II (n/n): NA Type of delivery (n): spontaneous (32), instrumental (9), CS (7), missing (1) Week of gestation: 39 Singleton, twin, multiple pregnancy: singleton Parity (n): Nulliparous (25) Duration of labour: ‐ First stage of labour (min, mean (SD)): 355 (179) ‐ Second stage of labour (min, mean (SD)): 35 (29.9) Epidural group (n = 49): Age (years, mean (SD)): 31 (5.6) Weight (kg, mean (SD)): 81 (12.6) ASA I/II (n/n): NA Type of delivery(n): spontaneous (29), instrumental (9), CS (10), missing (1) Week of gestation: 40 Singleton, twin, multiple pregnancy: singleton Parity (n): Nulliparous (27) Duration of labour: ‐ First stage of labour (min, mean (SD)): 434 (158) ‐ Second stage of labour (min, mean (SD)): 40 (28.9) Control group (n = 42): Age (years, mean (SD)): 33 (4.5) Weight (kg, mean (SD)): 83 (13.3) ASA I/II (n/n): NA Type of delivery (n): spontaneous (34), instrumental (3), CS (5) Week of gestation: 40 Singleton, twin, multiple pregnancy: singleton Parity (n): Nulliparous (11) Duration of labour: ‐ First stage of labour (min, mean (SD)): 224 (131) ‐ Second stage of labour (min, mean (SD)): 24 (24.1)
Interventions	Remifentanil group (n = 49): Women in the remifentanil (PCA) group received a 40 µg bolus (lockout 2 min, bolus duration 36 s) using a Graseby 3300 syringe pump (Smiths Medical Int., Luton, UK). The maximum dose permitted was 1200 µg/h. No background infusion was added. Because of concerns about the potential for neonatal respiratory depression, the pump was stopped when the woman reached full cervical dilatation. Epidural group (n = 49): A catheter was inserted at the L2–3 or L3–4 interspace using a 17‐gauge Tuohy needle. Parturients received a loading dose of ropivacaine 25 mg (0.2% ropivacaine 12.5 mL), followed by a continuous infusion of 0.1% ropivacaine and sufentanil 0.5 µg/mL at 10 mL/h. In case of inadequate analgesia, additional 10 mL boluses could be given. In case of epidural catheter dislodgement, the catheter was replaced. Control group (n = 42): No intervention
Outcomes	The primary outcome variable was the proportion of women who developed a temperature ≥ 38°C before delivery. Continuous: ‐ overall satisfaction (NRS 1 to 10, after delivery) ‐ pain intensity (VAS 0 to 10, at 0, 1, 2, 3, 4 h after starting analgesia, diagrammed) ‐ umbilical cord BE (venous), umbilical cord pH (venous) ‐ sedation score (observer, 1 to 5, at 0, 1, 2, 3, 4 h after starting analgesia) ‐ newborns: Apgar score at 1 and 5 min Dichotomous: ‐ additional analgesia (escape analgesia) ‐ rate of CS, rate of assisted birth (instrumental) ‐ oxytocin use ‐ women: oxygen desaturation (< 92%, < 90%, for 1, 2 or 5 min), nausea, vomiting, pruritus ‐ newborns: Apgar score ≤ 7 at 5 min, CTG reactive
Notes	‐ Small trial sample size (< 200 participants) ‐ Power analysis performed (incidence of fever, n = 175 in total) Concomitant medication: When parturients were dissatisfied with analgesia, an epidural was offered as alternative. When SpO₂ dropped < 92% for more than 60 s, oxygen was administered by facemask. Intrapartum fever was defined as maternal tympanic temperature ≥ 38°C. In cases of fever, antibiotics could be administered to the parturient. Hypotension (SBP < 90 mmHg or > 25% below pre‐analgesia values) was treated with IV fluids and/or IV ephedrine or phenylephrine. Funding: NA Contact to the authors: We contacted Dr. Douma via e‐mail (15 March 2016) to inquire the number of women who reported 'satisfaction with pain relief' and 'pain intensity at 1, 2, 3, and 4 hours'. We received the missing data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomisation was performed using a computer‐ generated randomisation list and treatments (RPCA or EA) […]”
Allocation concealment (selection bias)	Low risk	Quote: “…were presented in a numbered opaque sealed envelope that was opened upon the request for analgesia.”
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: “The study was not blinded.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: “The study was not blinded.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)   All outcomes	High risk	‐ Dropout rate: 14%/17% Quote: “We assessed the eligibility of 250 women, of whom 164 were enrolled in the study […]. After excluding women who delivered within one hour, [2 failed epidural, 2 withdrawals, 13 delivered within 1 hour, 5 exclusion criterion] 140 women were analysed, 49 received RPCA, 49 received EA and 42 were in the observational control group." No reasons declared for exclusion of the 5 women (exclusion criterion). ‐ Quote: “Due to technical difficulties, continuous saturation data were not always available and this information is reported for only 114 women.”; Data on type of delivery from one woman each group were missing with no reasons declared. ‐ Rate of escape: NA ‐ Rate of cross‐over: 16%/2%, cross‐over participants were analysed as randomised ‐ Data‐analysis: Per‐protocol (women who delivered within 1 h were excluded)
Selective reporting (reporting bias)	High risk	2 protocols are available (NTR1498 and EUCTR2008‐002792‐28‐NL) and there are several deviations. In the protocol maternal temperature and maternal saturation were defined as primary outcomes. In the published report, however, maternal saturation was reported as a secondary outcome. The secondary outcomes pain and overall satisfaction were not pre‐specified in the protocol. The pre‐specified outcomes NACS and requirement for naloxone were not reported in the published report. The study protocol was prospectively registered: Study registration (NTR1498): 10/2008. First enrolment: 11/2008
Other bias	Low risk	The study appears to be free of other sources of bias.

Methods	Multicentre randomised, controlled equivalence trial. No blinding. Randomisation before start of actual labour. The purpose of this trial was to determine women’s satisfaction with pain relief using PCA with remifentanil compared with epidural analgesia during labour. The study was conducted in three academic hospitals, 11 teaching hospitals, and one general hospital in the Netherlands from 30 May 2011 to 24 October 2012. Trial Identifier: NTR2551
Participants	Participant flow: Number assessed for eligibility: NA Number randomised: 1414 (709/705) Number receiving treatment (of interest): 698 (402/296) Number analysed: 1358 (687/671) Inclusion criteria: Healthy women or those who have a mild systemic disease (ASA I or II), aged 18 or older, scheduled to deliver vaginally after 32 weeks Exclusion criteria: Contraindications for epidural analgesia or hypersensitivity to one of the drugs used Baseline details: Remifentanil group (n = 687): Age (years, mean (SD)): 31.5 (5.1) BMI (kg/m², median (IQR)): 23.7 (21.5‐26.9) ASA I/II (n/n): 491/196 Type of delivery (n): spontaneous (518), instrumental (63), CS (106) Week of gestation (median (IQR)): 37.8 (35.5 ‐ 39.2) Singleton, twin, multiple pregnancy (n): multiple pregnancy (24) Parity (n): 0 (323), ≥ 1 (364) Duration of labour: ‐ First stage of labour (min, mean (IQR)): 236 (128 ‐ 376) ‐ Second stage of labour (min, mean (IQR)): 20 (10 ‐ 46) Epidural group (n = 671): Age (years, mean (SD)): 31.7 (4.8) BMI (kg/m², median (IQR)): 23.8 (21.4 ‐ 27.6) ASA I/II (n/n): 461/210 Type of delivery (n): spontaneous (501), instrumental (70), CS (100) Week of gestation (median (IQR)): 37.1 (35.3 ‐ 39.0) Singleton, twin, multiple pregnancy (n): multiple pregnancy (30) Parity (n): 0 (329), ≥ 1 (342) Duration of labour: ‐ First stage of labour (min, mean (IQR)): 309 (181 ‐ 454) ‐ Second stage of labour (min, mean (IQR)): 24 (10 ‐ 53)
Interventions	Remifentanil group (n = 687): The patient‐controlled device was programmed to deliver 30 µg remifentanil (solution 20 µg/mL) on request with a lockout time of 3 min. The dose could be increased to 40 µg in case of insufficient pain relief or decreased to 20 µg in case of excessive side effects. No background infusion was allowed. Women who were treated with patient‐controlled remifentanil were instructed on how to use the device and to maximise analgesia by pressing the device’s button in anticipation of the next contraction. Epidural group (n = 671): Women randomised to epidural analgesia received this when they requested pain relief, according to local protocol.
Outcomes	The primary outcome measure was satisfaction with pain relief measured on a VAS ranging from 0 to 100 mm. Continuous: ‐ satisfaction with pain relief (VAS scale unclear, during active labour, after pain relief, at request, averaged), overall satisfaction (NRS 0 to 10, after birth) ‐ pain intensity (VAS scale unclear, during active labour, after pain relief, at request, averaged) Dichotomous: ‐ additional analgesia (escape analgesia) ‐ rate of CS, rate of assisted birth (instrumental) ‐ need for neonatal admission ‐ oxytocin use ‐ umbilical cord pH (artery), pH < 7.1 (twin 1) ‐ women: respiratory depression (< 8 breaths/min), oxygen desaturation (< 95%, < 92%), hypotension (< 90 mmHg), nausea, vomiting, pruritus, postpartum haemorrhage (≥ 1000 mL) ‐ newborns: Apgar score ≤ 7 at 5 min (twin 1)
Notes	‐ Power analysis performed (satisfaction with pain relief, n = 102 per group) Concomitant medication: If pain relief was inadequate, women could request epidural analgesia. They were advised to discontinue using the device during the second stage of labour to minimise the risk of neonatal side effects. If pain relief after epidural analgesia was judged inadequate by the woman, she could receive patient‐controlled remifentanil instead of epidural analgesia. No advice was given regarding continuing epidural analgesia during the second stage of labour. Funding: This study was funded by a grant from ZonMW (Dutch Organization for Health Care Research and Development) project No 80‐82310‐97‐11039. Intervention: Lockout time of 3 min seems too long for adequate analgesia (borderline).
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomisation was performed through a web based randomisation program. We randomised in fixed blocks of three, stratified for centre and parity.”
Allocation concealment (selection bias)	High risk	Quote (full‐text publication): “The allocation code appeared after a patient’s initials were entered into the randomisation program.” Quote (protocol: BMC Pregnancy and Childbirth 2012, 12: 63): "The consent form must be signed before performance of any study‐related activity. After obtaining informed consent women will be randomized and will be informed on the assigned method of pain relief before labour starts (as in usual care). They are only given pain relief during labour at their request or if a medical reason should arise." Allocation concealment was uncovered for participants and personnel before the start of treatment.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: “Blinding was not possible because of the nature of the two interventions.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: “Blinding was not possible because of the nature of the two interventions.” No blinding and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)   All outcomes	High risk	‐ Dropout rate: 3%/5% ‐ Large amount (5.5% to 41.5%) of data for maternal side effects and neonatal data were missing. No reasons reported. ‐ Randomisation occurred before onset of labour and only 65% and 52% received an analgesic intervention in the remifentanil and epidural group, respectively. Only 57% of women in the remifentanil group and only 42% in the epidural group received the allocated intervention. ‐ Rate of women with other pain relief (not escape, immediate use): 10%/15% ‐ Rate of cross‐over (insufficient pain relief): 13%/1% ‐ Rate of cross‐over (protocol violation): 9%/10% ‐ Data analysis: A partial ITT analysis with all women (including those without pain relief) was performed for rate of CS, assisted vaginal birth, postpartum haemorrhage, Apgar score < 7 at 5 min, and neonatal admission. A partial‐ITT with only women received pain relief (cross‐over participants as randomised) was performed for satisfaction, pain, cross‐over rate, and maternal side effects (SpO₂, BP, respiratory depression, PONV, pruritus). ‐ Study design: equivalence study (per‐protocol analysis recommended) ‐ Multiple imputation was used to correct missing primary outcome data
Selective reporting (reporting bias)	High risk	A published protocol (BMC Pregnancy and Childbirth 2012, 12: 63) and a registered protocol (NTR2551) are available and there are several deviations. In the registered protocol cost‐effectiveness was defined as the primary outcome and pain relief, woman's satisfaction, pain scores, and maternal and neonatal side effects were defined as secondary outcomes. In the published report, however, the authors stated: “Our published protocol stated that both effectiveness and cost effectiveness were primary outcome measures. Satisfaction with pain relief was the primary outcome measure for effectiveness from the start of the study [which was not reported in the protocol]. We planned to perform a cost effectiveness analysis as well, taking into account the primary outcome for effectiveness. Because this was not made clear enough in the original protocol and registry it was changed in the last amended protocol. This last amended protocol was submitted before the last randomised woman delivered and as a result we did not have access to the data.” The first protocol (NTR2551) was prospectively registered: Study registration: 10/2010 First enrolment: 05/2011 The second protocol (BMC Pregnancy and Childbirth 2012, 12: 63) was retrospectively registered: Protocol received: 04/2012 First enrolment: 05/2011
Other bias	Low risk	The study appears to be free of other sources of bias.

Methods	Randomised, controlled trial. Not blinded. Randomisation after onset of labour. The purpose of this trial was to compare the analgesia efficacy and maternal satisfaction of remifentanil labour analgesia with standard treatment (epidural analgesia). The study was conducted in a Jerusalem tertiary hospital labour and delivery suite from February 2010 to August 2010. Trial Identifier: NCT00801047
Participants	Participant flow: Number assessed for eligibility: 144 Number randomised: 40 (20/20) Number receiving treatment: 39 (19/20) Number analysed: 39 (19/20) Inclusion criteria: Healthy, ASA I or II, age 18 to 40 years, body weight < 110 kg, gestational age > 36 completed weeks, with singleton pregnancy and vertex presentation Exclusion criteria: Contraindication to epidural analgesia, opioid administration in the previous 2 h, previous uterine surgery, pre‐eclampsia, inability to understand the consent form, nasal obstruction for any reason, medical indication for epidural analgesia (e.g. cardiac disease, suspected difficult airway), or non‐reassuring FHR tracing Baseline details: Remifentanil group (n = 19): Age (years, mean (SD)): 31 (5) Weight (kg, mean (SD)): 72 (10) ASA I/II (n/n): NA Type of delivery (n): spontaneous (NA), vacuum delivery (2), CS (0) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity (median (IQR) or n): 1 (1‐1), Nulliparous (4) Duration of labour: ‐ First stage of labour (min, mean (SD)): 329 (215) ‐ Second stage of labour (min, mean (SD)): 35 (41) Epidural group (n = 20): Age (years, mean (SD)): 30 (6) Weight (kg, mean (SD)): 73 (13) ASA I/II (n/n): NA Type of delivery (n): spontaneous (NA), vacuum delivery (1), CS (4) Week of gestation: NA Singleton, twin, multiple pregnancy: NA Parity (median (IQR) or n): 1 (0‐1), Nulliparous (6) Duration of labour: ‐ First stage of labour (min, mean (SD)): 404 (259) ‐ Second stage of labour (min, mean (SD)): 69 (81)
Interventions	Remifentanil group (n = 19): PCA: The bolus dose was titrated to effect from 20 µg up to a maximum of 60 µg as required; the lockout interval was initially set at 2 min, without a background infusion. The PCIA bolus/lockout interval was titrated to an endpoint of either woman's comfort or a maximal bolus dose of 60 µg/minimal lockout interval of 1 min by the recruiting anaesthesiologist at any time during labour. The PCIA pump tubing was “piggybacked” into the distal most port of the mainline IV fluid tubing. The mainline tubing contained an antireflux valve designed to prevent remifentanil inadvertently backing up in the IV line during administration. Epidural group (n = 20): A 17‐gauge Tuohy needle was inserted by the midline approach using loss of resistance to air at intervertebral space L3‐4 or L2‐3. An incremental initial loading dose of 15 mL of 0.1% bupivacaine with 50 µg fentanyl was administered followed by patient‐controlled epidural analgesia infusion of 0.1% bupivacaine with 2 µg/mL fentanyl: basal infusion of 5 mL/h, patient‐controlled bolus 10 mL, and lockout interval 20 min. Additional epidural bolus doses (either 0.1% bupivacaine 10 mL during the first stage of labour or 1% lidocaine 8 mL during the second stage of labour) were administered by the anaesthesiologist to treat breakthrough pain. If epidural analgesia failed, the epidural catheter was reinserted.
Outcomes	The primary endpoint of the study was to demonstrate non‐inferiority of remifentanil labour analgesia compared with epidural analgesia in labouring women, measured by hourly assessment of NRS for pain throughout the duration of labour and maternal satisfaction. Continuous: ‐ satisfaction with pain relief (NRS 0 to 10, at 10 min and postpartum) ‐ pain intensity (NRS 0 to 10, at 0, 30 min, 1, 2, 3, 4, 5, 6 h) ‐ newborns: Apgar score at 1 and 5 min (median + IQR + range (symmetric), data for Apgar score at 5 min dichotomised: all newborn had an Apgar score of 10 at 5 min) Dichotomous: ‐ additional analgesia after 1 h (rescue), additional analgesia (cross‐over to the other treatment arm) ‐ rate of CS, rate for assisted birth (vacuum) ‐ need for neonatal resuscitation ‐ umbilical cord BE (artery), umbilical cord pH (artery) ‐ oxytocin use ‐ sedation score (observer, awake or easily arousable at 1 h) ‐ women: apnoea (> 20 s of zero respiratory rate), respiratory depression (< 8 breaths/min), oxygen desaturation (< 94%), nausea (at 1 h and postpartum), pruritus (at 1 h and postpartum)
Notes	‐ Small trial sample size (< 200 participants) ‐ Power analysis performed (NRS pain, n = 17 per group) Concomitant medication: Women were informed before study enrolment that conversion to the other treatment would be possible at any time during labour beginning 30 min after analgesia initiation with the study technique. All women received continuous supplementary oxygen (2 L/min) through an oral‐nasal cannula. Funding:  Hadassah Medical Organisation Contact to the authors: We contacted Dr. Weiniger via e‐mail (16 March 2016) to inquire the number of women who reported 'pain intensity at 30 min, 1, and 2 hours'. We received the missing data.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: “Randomization and group allocation were determined: cards were divided into groups of 8 cards. Each group contained 4 allocation cards for remifentanil and 4 allocation cards for epidural analgesia (ratio 1:1), and 8 opaque envelopes numbered in groups from 1 – 8, 9 – 16, etc. were assigned to each group of cards. The cards were placed face down, manually shuffled, randomly selected, and then inserted into the numbered, opaque envelopes by a person not involved in the study. These envelopes were then sealed. Treatment assignment was revealed by breaking the seal of an envelope in consecutive order from number 1.”
Allocation concealment (selection bias)	Low risk	Quote: “…inserted into the numbered, opaque envelopes by a person not involved in the study. These envelopes were then sealed. Treatment assignment was revealed by breaking the seal of an envelope in consecutive order from number 1.”
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Quote: “This randomized nonblinded controlled noninferiority study […].” The study was not blinded due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Blinding of outcome assessment (detection bias)   All outcomes	High risk	Quote: “The investigator inquired whether opioid side effects (i.e., pruritus and/or nausea and vomiting) were present or absent.”, “After delivery, face‐to‐face follow‐up was performed on the first postpartum day for both mother and child by one of the investigators”, “Hence, the mathematician was not blinded to group allocation. However, she was blinded to our study hypothesis that remifentanil was noninferior to epidural analgesia and that remifentanil may have respiratory effects different from those seen with epidural analgesia.” The study did not adequately report on blinding of outcome assessors. Therefore, we assume that the study was not blinded due to technical reasons and at least the subjective¹ outcomes or outcome measurements are likely to be influenced by lack of blinding.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	‐ Dropout rate: 5%/0% One woman was excluded after enrolment but before analgesia due to obstetrician request. Reasons for missing outcome data unlikely to be related to true outcome. ‐ Rate of escape (other pain relief after 1 h): 0%/17% (may influence data on AE, satisfaction and pain) ‐ Rate of cross‐over: 16%/5% ‐ Data‐analysis: Partial‐ITT ‐ Study design: non‐inferiority study (per‐protocol analysis recommended)
Selective reporting (reporting bias)	High risk	A registered protocol (NCT00801047) is available and there are several deviations. The VAS pain score was defined as primary outcome and no other primary or secondary outcomes were defined in the protocol. In the published report, however, the authors defined maternal satisfaction as another primary endpoint, and incidence of apnoea was defined as secondary outcome. The primary outcome pain score was reported on a 11‐point NRS scale in the final report. The authors further reported on SpO₂, sedation, pruritus, nausea, and adverse effects on the newborn. The protocol was prospectively registered: Protocol registration: 12/2008 First enrolment: 02/2010
Other bias	Low risk	The study appears to be free of other sources of bias.

Study	Reason for exclusion
Balcioglu 2007	Wrong intervention (PCA versus PCA)
Jost 2013	Cross‐over trial
Shahriari 2007	No patient‐controlled anaesthesia
Solek‐Pastuszka 2009	No randomisation
Varposhti 2013	Cross‐over trial
Volmanen 2004	Cross‐over trial
Volmanen 2005	Cross‐over trial
Volmanen 2009	Cross‐over trial
Volmanen 2011	Cross‐over trial

Methods	Randomised, controlled trial, double‐blinded. The purpose of this trial is to assess whether the combination of dexmedetomidine (DMET) with remifentanil produces a synergistic effect that results in lower analgesic requirements. The study was conducted in Ain Shams University Hospital, Cairo, Egypt. There are no details when the study was conducted. Trial identifier: NA
Participants	Inclusion criteria: pregnant women, ASA I‐II, full term (37‐40 weeks), singleton fetus with cephalic presentation, first stage of spontaneous labour Exclusion criteria: known relevant drug allergy, significant respiratory depression from previous exposure to opioids, obstetric complications
Interventions	Remifentanil PCA + DMET versus remifentanil PCA + placebo
Outcomes	VAS pain scores, maternal and fetal complications, patients' satisfaction
Notes	This study is expected to be excluded due to wrong intervention (PCA versus PCA, same regimen).

Methods	Case report: "Labour analgesia challenge ‐ when epidural is not possible, what can we do?" The author's origin is Portugal.
Participants	Pregnant 31 year‐old female, 86 kg, 1.63 m, with severe scoliosis
Interventions	Remifentanil PCA
Outcomes	Pain score, occurrence of vomiting, neonatal outcome (Apgar score)
Notes	This case report is expected to be excluded (not RCT).

Methods	Randomised, controlled trial. The purpose of this study is to compare two different remifentanil PCA protocols (bolus and bolus + infusion) with intramuscular meperidine for labour analgesia. The study was conducted in Cukurova University Medical Faculty, Turkey. There are no details when the study was conducted. Trial identifier: NA
Participants	Inclusion criteria: pregnant women, ASA I‐II, mean gestational age of 270 ± 10 days, planned for vaginal delivery Exclusion criteria: gestational pathology, obesity (BMI > 40 kg/m²), high risk cases (pre‐eclampsia, severe asthma, insulin‐dependent diabetes, hepatorenal disease), history of opioid allergy, long‐term opioid use or chronic pain
Interventions	remifentanil PCA bolus versus remifentanil PCA bolus + infusion versus meperidine IM
Outcomes	pain‐comfort and sedation scores, remifentanil consumption, side effects, Apgar scores
Notes	NA

Methods	Insufficient information about study design.
Participants	Inclusion criteria: pregnant women, spontaneous labour, ASA I
Interventions	Continuous epidural infusion versus remifentanil PCA
Outcomes	The primary outcome is maternal and neonatal safety. The secondary outcome is efficacy evaluated through hourly pain and satisfaction scores.
Notes	There is no full text available (abstract only).