Inhaled analgesia for pain management in labour
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The main objective will be to explore the efficacy and safety of inhaled analgesia as pain relief for women in labour planning a vaginal delivery. Although important to look at, the effects of occupational exposure and toxic effects on reproduction for maternity health care workers will only be found in large‐scale epidemiological studies. Since we will only include intervention studies (see Types of studies), we will not include this objective in this review.
Background
Description of the condition
Labour pain and methods to relieve it are major concerns for women, healthcare workers and the general public (Caton 2002). These concerns have implications for the course of labour, for the quality of maternal and infant obstetric outcomes as well as for the costs of obstetric health care. In our modern society, pain has a negative connotation for the general public. Fear of labour pain is strongly associated with the fear of pain in general (Lowe 2002; Rosen 2002). Different views about the importance of pain during labour are reflected in great differences between countries worldwide with regard to the numbers of women who receive pain relief during labour, as well as the type of pharmacological analgesia that is used. Culture plays a significant role in attitudes towards childbirth pain, the definition of the meaning of childbirth pain, perceptions of pain and coping mechanisms used to manage pain in childbirth.
Description of the intervention
Inhaled analgesia during labour involves the inhalation of sub‐anaesthetic concentrations of agents while the mother remains awake and her protective laryngeal reflexes remain intact. The use of inhaled analgesics for pain relief during labour dates back to 1847, when James Simpson used it for the first time for vaginal delivery (Rae 1997). Nitrous oxide was first used in 1881 by Stanislaw Klikovich, who studied the effects of pre‐mixed nitrous oxide 80% in oxygen on women in labour (Richards 1976). In 1934, Minnitt introduced an apparatus for the self‐administration of nitrous oxide (Minnitt 1934). Other possibilities for inhaled analgesia for pain relief in labour are isoflurane, sevoflurane, trichloroethylene in air, methoxyflurane and cyclopropane. Trichloroethylene cannot be administered through a CO2 absorber and is flammable, while cyclopropane is explosive even in sub‐anaesthetic concentrations. Both drugs are no longer used in the developed world and therefore must be seen as of historical interest only. Sevoflurane is not recommended as analgesia because it has no analgesic activity at sub‐anaesthetic concentrations. Sub‐anaesthetic concentrations of nitrous oxide, enflurane, isoflurane and methoxyflurane do not significantly decrease uterine contractions and are preferable for this reason. However, only the use of nitrous oxide is widespread in modern obstetric practice. The reason why is not clear but probably due to ease of administration, lack of flammability, lack of pungent odour, lack of effect on uterine contractions, lack of relation with pathologic temperature, minimal toxicity and minimal depression of the cardio‐vascular system (KNOV 2009; Rosen 2002). The evidence on the use of nitrous oxide for relief of labour pain has been summarised in a systematic review (Rosen 2002). Nitrous oxide mixed with oxygen is administered by inhalation. Entonox contains 50% nitrous oxide and 50% oxygen and is mixed in liquid state in a single pressured container. Alternatively, Entonox can be used by blending a fixed concentration of 50% nitrous oxide and 50% oxide by two separate cylinders or hospital pipeline supply; the distribution of Entonox is done through a small regulator apparatus (Nitronox™). The Midogas device is another way to inhale Entonox which allows adjustment of the nitrous oxide concentration within a narrow range. The cylinders are connected to a facemask or mouthpiece. The demand valve opens only when the user applies a negative pressure by inspiring through the mouthpiece or well‐sealed mask covering the parturient mouth and nose. The demand valve eliminates flow when the parturient is not inhaling to minimise environmental contamination. Unlike the Entonox apparatus, the Nitronox apparatus allows exhaled gas to be scavenged. In countries such as Canada, Denmark, Finland, New Zealand, the United Kingdom and the United States of America, midwives are allowed to 1) set up the equipment for nitrous oxide, 2) instruct the woman how to use it and 3) monitor her use of it. The woman can self‐administer it after initial supervision. Inhaled analgesia can be used by the woman either intermittently with discontinuation of use as the contraction pain eases or disappears, or continuously, by inhaling both during and between contractions. There is a rapid uptake/washout rate for most of the inhaled analgesia, which means a low blood/gas solubility ratio. The blood/gas solubility ratio for nitrous oxide is 0.47 at 37 degrees C; for Isoflurane: 1.4; for Sevoflurane: 0.69; for Enflurane: 1.64 and for Methoxuyflurane: 13. For Methoxyflurane, the onset of analgesia is relatively slow but in spite of the low solubility it is far more potent than any of these agents and is therefore still used for inhalational analgesia in some settings. Maximal effect for nitrous oxide is observed in 30 to 60 seconds and wash‐out effect can be obtained in three or four exhalations (Talebi 2009). However, there is controversy about the use of nitrous oxide because of concerns about the safety of nitrous oxide for the subfecundability of female maternity care professionals and an increased incidence of spontaneous abortions of the pregnant maternity care professionals (Ahlborg 1996; Axelsson 1996; Bodin 1999; Boivin 1997; Zielhuis 1999).
The underlying cause is thought to be inactivation of methionine synthase by nitrous oxide (Sanders 2008). Cellular‐level damage can begin during a maternity‐care worker’s shift in a poorly ventilated hospital where nitrous oxide is used without scavenging. The damage‐producing process stops when the maternity‐care worker leaves the hospital’s contaminated environment. While she is away from the hospital, her body begins to repair any cellular‐level damage. The healing of damage that has not caused actual pathology is referred to as restitution. If she returns to work in a nitrous oxide‐polluted environment before restitution is complete, the damage‐producing process resumes and restitution will be incomplete. Over time, the damage may accumulate enough to produce pathology.
Subfecundability in the form of maternal absorption of malformed conceptions has been found in animal studies of the reproductive effects of very prolonged exposures to very high doses of nitrous oxide (Sanders 2008). Nitrous oxide‐induced fertility problems occur in rats at 1,000 ppm but not at 500 ppm or lower. Rats are known to be particularly sensitive to damage from nitrous oxide.
More months on average to conceive was found in a study of dental assistants working in settings that did not use scavenging of exhaled nitrous oxide (Rowland 1992). It was estimated that the ambient air in which they worked was contaminated by greater than 1,000 parts per million (ppm) of nitrous oxide.
Current standards in the Netherlands and United States call for limiting occupational exposure to nitrous oxide to not more than an eight‐hour time‐weighted average (TWA) concentration of 25 ppm (KNOV 2009). The UK, Finland, Germany and Sweden have set 100 ppm as their upper limits. The United States' 25 ppm standard was set arbitrarily during the 1970s without benefit of actual data. Nevertheless, the American Society of Anesthesiologists (ASA), the National Institute of Occupational Safety and Health (NIOSH) and the US Occupational Safety and Health Administration (OSHA) all believe that this standard has been effective in protecting American health workers. Concerns about reproductive toxicity from occupational exposure to nitrous oxide at levels below the 25‐ppm standard are not supported by the available data, which, however, do not include findings from prospective studies.
The risk of reproductive failure related to occupational exposure to nitrous oxide is essentially eliminated when nitrous oxide labor analgesia is used in well‐ventilated modern hospitals and “scavenging” is used. The Boivin 1997 meta‐analysis reached the same conclusion as the Rosen 2002 review: scavenging solves the problem. Epidemiological studies based on data obtained in the pre‐scavenging era indicated an increased risk of spontaneous abortion.
Other side effects are maternal drowsiness, nausea and vomiting when nitrous oxide is used too long or extensively, especially if the rule of self‐administration is violated. Renal and hepatic toxicity and uterine relaxation are usually not of concern at analgesic levels of inhaled analgesia but we will include them if possible.
How the intervention might work
The precise mechanism of action of pain relief by inhaled analgesia remains uncertain. Maze and Fuginaga hypothesised that nitrous oxide induces the release of endogenous opioid peptides in the peri‐aqueductual grey area of the midbrain (Maze 2000). The release of this substance in the midbrain could modulate pain stimuli through the descending spinal cord nerve pathways.
Why it is important to do this review
Approximately 20% of women who had a vaginal delivery in the UK (DOH 2005; Khor 2000), 59% to 61% of women in the USA (Declercq 2007; Osterman 2011) and 10% of women in the Netherlands (PRN 2008) used an epidural injection as pain relief in labour. The use of an epidural injection in labour has steadily increased until the last decade in modern high developed countries (Anim‐Somuah 2005). In some countries these figures still are expected to rise in the coming years, for example in the Netherlands. The use of epidural anaesthesia, especially within primary obstetric care, determines a higher rate of deliveries in secondary or tertiary obstetric care hospitals, which increases medicalisation as well as healthcare costs. Reported maternal complications of epidurals include hypotension ‐ a reduction in maternal blood pressure (BP). Severe sudden hypotension (more than 20% decrease in baseline BP) may result in a clinically significant decrease in utero‐placental blood flow, which could potentially affect delivery of oxygen to the baby. This may especially compromise a baby with inadequate reserves (Vincent 1998). For this reason intravenous fluids may be given before administering the epidural drugs (fluid preload) to attenuate the decrease in maternal blood pressure. Side effects such as itchiness, drowsiness, shivering and fever have also been reported (Buggy 1995; Eberle 1996). Women may develop urinary retention while using epidural analgesia. This may necessitate the insertion of a catheter to drain the bladder.
Urinary retention in the postpartum period has been attributed to long labours in women using epidural analgesia (Liang 2002). Epidural analgesia may influence the course of labour. There have been suggested associations with malpositions of the fetal head, prolonged labour, increased use of oxytocin and of instrumental deliveries (Eberle 1996); possible effects on the risk of caesarean section continue to be debated (Lieberman 2002). The systematic review of Anim‐Somuah 2005 found that epidural analgesia is associated with an increased risk of instrumental vaginal birth (relative risk (RR) 1.38, 95% CI 1.24 to 1.53, 17 trials, 6162 women).
A second reason why it is important to do this review is that all women should have access to some form of relatively effective and safe analgesia during labour and to provide analgesia when they need it during labour (Rooks 2007). Even in hospitals with full‐time obstetric anaesthesia coverage, no one may be available to place an epidural, provide another highly effective method of labour analgesia, or provide labour‐intensive non‐pharmacological method to help the woman in pain.
Inhaled pain relief during labour, especially by nitrous oxide, is relatively easy to administer, can be started in less than a minute and becomes effective within a minute. Since it does not affect the physiology of labour, it can be started whenever it is needed. However, the effectiveness and efficacy of nitrous oxide use for management of labour pain is hard to ascertain because of the few available data. The available data are out of date (Rosen 2002); thus a systematic assessment of the evidence regarding the safety and efficacy of inhaled analgesia for pain relief in labour is urgently needed.
This review is one in a series of Cochrane reviews examining pain management in labour. These reviews contribute to an overview of systematic reviews of pain management for women in labour (Jones 2011b), and share a generic protocol (Jones 2011a).
Objectives
The main objective will be to explore the efficacy and safety of inhaled analgesia as pain relief for women in labour planning a vaginal delivery. Although important to look at, the effects of occupational exposure and toxic effects on reproduction for maternity health care workers will only be found in large‐scale epidemiological studies. Since we will only include intervention studies (see Types of studies), we will not include this objective in this review.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) only, including studies with a crossover design. (We will not include results from quasi‐RCTs in the analyses but we may be discuss them in the text if little other evidence is available.)
Types of participants
Women in labour. (This will include women in high‐risk groups, e.g. preterm labour or following induction of labour. We will use subgroup analysis for any possible differences in the effect of interventions in these groups.)
Types of interventions
This review is one in a series of Cochrane reviews examining pain management in labour. These reviews contribute to an overview of systematic reviews of interventions for pain management in labour (Jones 2011b), and share a generic protocol (Jones 2011a). To avoid duplication, the different methods of pain management have been listed in a specific order, from 1 to 15. Individual reviews focusing on particular interventions include comparisons with only the interventions above it in the list. Methods of pain management identified in the future will be added to the end of the list. The current list is as follows.
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Placebo/no treatment
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Hypnosis
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Biofeedback (Barragán 2011)
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Intracutaneous or subcutaneous sterile water injection (Derry 2011)
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Immersion in water (Cluett 2009)
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Aromatherapy (Smith 2011a)
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Relaxation techniques (yoga, music, audio)*
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Acupuncture or acupressure (Smith 2011b)
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Manual methods (massage, reflexology)*
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TENS (Dowswell 2009)
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Inhaled analgesia (this review)
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Opioids (Ullman 2010)
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Non‐opioids (Othman 2011)
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Local anaesthetic nerve blocks (Novikova 2011)
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Epidural (including combined spinal epidural) (Anim‐Somuah 2005; Simmons 2007)
Accordingly, this review will only include comparisons of inhaled analgesia with other inhaled analgesia or with: 1. placebo/no treatment; 2. hypnosis; 3. biofeedback; 4. sterile water injection; 5. immersion in water; 6. aromatherapy; 7. relaxation techniques (yoga, music, audio); 8. acupuncture or acupressure; 9. manual methods (massage, reflexology); or 10. TENS.
Interventions will include any inhaled analgesia during labour including isoflurane, methoxyflurane and nitrous oxide. We will include any frequency or duration of administration, any dosage/intensity, any combinations of inhaled analgesia and any timing of labour (first, second or third period) of inhaled analgesia.
Types of outcome measures
Primary outcomes
Effects of interventions
Pain intensity (as defined by trialists) Likert 1932
Satisfaction with pain relief (as defined by trialists) collected within 48 hours after birth
Sense of control in labour (as defined by trialists)
Satisfaction with childbirth experience (as defined by trialists)
Safety of interventions
Effect on mother/baby interaction (skin to skin contact of mother and baby within the first hour of birth)
Breastfeeding (at specified time points; within the first hour of birth, at discharge of the hospital)
Assisted vaginal birth
Caesarean section
Side effects (nausea, vomiting, drowsiness, renal and hepatic toxicity, uterine relaxation)
Admission to special care baby unit/neonatal intensive care unit (as defined by trialists)
Apgar score less than seven at five minutes
Need for rescue analgesia (mother or baby)
Poor infant outcomes at long‐term follow‐up (as defined by trialists)
Other outcomes
Cost (as defined by trialists)
Secondary outcomes
For the baby
1. Differences in the one, two, five or 10 minute Apgar scores
2. Neurological integrity scale of the newborn
For the professional
1. Occupational exposure
2. Toxic effects on reproduction
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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weekly searches of EMBASE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL, MEDLINE and EMBASE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords.
In addition, we will search ClinicalTrials.gov, and Current Controlled Trials to identify ongoing trials. We will give the search terms used for each of these in the review.
Searching other resources
We will manually search reference lists of identified studies and conference proceedings from the American Society of Clinical Anesthesia. One review author will screen conference proceedings and we will include studies if we can obtain adequate information either from the abstract or from personal communication. If we identify articles from other sources (experts or reference lists) as possibly eligible, two authors will assess for inclusion independently. We will contact content experts and trialists for relevant references.
We will not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion and, if we cannot achieve consensus, consult a third author. We will not apply any language restrictions.
Data extraction and management
We will design a form to extract data. For eligible studies, two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third author. We will enter data into Review Manager software (RevMan 2011) and check for accuracy.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We will resolve any disagreement by discussion or by involving a third assessor. To assess the risk of bias, we will evaluate the following items:
(1) Random sequence generation (checking for possible selection bias)
We will describe 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 will assess the method as:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number) or;
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We will describe for each included study the method used to conceal the allocation sequence and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.
We will assess the methods as:
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low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3) Blinding (checking for possible performance bias)
We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding could not have affected the results. We will assess blinding separately for different outcomes or classes of outcomes.
We will assess the methods as:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel;
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low, high or unclear risk of bias for outcome assessors.
We will use partial blinding as an option because many of the administered inhaled analgesia cannot be completely blinded because of their odour. We will also use partial blinding for self‐reported efficacy outcomes and when these outcomes are recorded by blinded personnel.
(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)
We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported, 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. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake. We will assess methods as:
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low risk of bias (20% or less missing data);
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high risk of bias;
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unclear risk of bias.
(5) Selective reporting bias
We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found (Sterne 2001).
We will assess the methods as:
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low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);
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high risk of bias (where not all the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other sources of bias
We have to look for concurrent or prior use of analgesia in the selected studies because the concurrent or prior use of analgesia can give some bias of the effects of the studied analgesia. Furthermore we will describe for each included study any other important concerns we have about other possible sources of bias.
We will assess whether each study was free of other problems that could put it at risk of bias:
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low risk of bias;
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high risk of bias;
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unclear risk of bias.
(7) Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses ‐ seeSensitivity analysis.
If we include crossover trials we will proceed to the next questions for assessing risk of bias.
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Was use of a cross‐over design appropriate (Elbourne 2002)?
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Is it clear that the order of receiving treatments was randomised?
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Can it be assumed that the trial was not biased from carry‐over effects? Inhaled analgesia has a relatively rapid uptake/washout effect. We take four exhalations as the save cut‐off point for no residual effect.
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Are unbiased data available (period effects)? Pain of uterine contractions are not consistent over time. The pain will become more intense when the labour will develop over time until the delivery start. We have to look for any control for labour progress at the start of the inhaled analgesia. If the start of the analgesia is not in the same period (first period from 0 cm dilation until 5 cm dilation and second period after 5 cm dilation until 10 cm) we have to report this risk of bias.
Measures of treatment effect
Dichotomous data
For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals and where relevant, as risk difference and number needed to treat.
Continuous data
For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods. Where appropriate, we will use standard inverse‐variance random‐effects meta‐analysis to combine the trials (DerSimonian 2007).
Unit of analysis issues
Crossover trials
Other unit of analysis issues
If neither carry‐over nor period effects are thought to be a problem, then an appropriate analysis of continuous data from a two‐period, two‐intervention cross‐over trial is a paired T‐test. This evaluates the value of ‘measurement on experimental intervention (E)’ minus ‘measurement on control intervention (C)’ separately for each participant. The mean and standard error of these difference measures are the building blocks of an effect estimate and a statistical test. The effect estimate may be included in a meta‐analysis using the generic inverse‐variance method in RevMan 2011.
Dealing with missing data
For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.
For all outcomes, we will carry out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and analyse all participants in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.
Assessment of heterogeneity
We will measure heterogeneity of treatment effects between trials using the Chi2 test and the I2 statistic (Deeks 2001; Higgins 2011), which describes the percentage of total variation across trials that is attributable to heterogeneity rather than to chance.
I2 values of 25%, 50% and 75% may be interpreted as low, moderate, and high between‐trial heterogeneity, although the interpretation of I2 depends on the size and number of trials included.
Assessment of reporting biases
If there are 10 or more studies in the meta‐analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually, and use formal tests for funnel plot asymmetry. For continuous outcomes we will use the test proposed by Egger 1997, and for dichotomous outcomes we will use the test proposed by Harbord 2006. If we detect asymmetry in any of these tests or by a visual assessment, we will perform exploratory analyses to investigate it.
Data synthesis
We will carry out statistical analysis using the Review Manager software (RevMan 2011). We will use fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. We will treat the random‐effects summary as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.
If we use random‐effects analyses, we will present the results as the average treatment effect with its 95% confidence interval, and the estimates of T² and I².
Subgroup analysis and investigation of heterogeneity
If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random‐effects analysis to produce it. We plan to carry out the following subgroup analyses.
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Spontaneous labour versus induced labour.
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Primiparous versus multiparous.
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Term versus preterm birth.
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Continuous support in labour versus no continuous support.
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Mode of delivery: spontaneous vaginal, operative vaginal, mode of delivery mixed or unclear.
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Different methods and doses of inhaled pain relief (inhalation agent regimen and doses).
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Obese versus not obese women
We will look separately at results of studies in which a 50%/50% blend of N2O and O2 was self‐administered by labouring women and distinguish the results of those studies from the results of studies in which
a. the ratio of N2O to O2 was higher than 50%,
b. the ratio of N2O to O2 was lower than 50%,
c. the ratio of the gases could be changed by a professional,
d. the ratio could be changed by the labouring woman
e. the ratio was 50%/50% but someone other than the woman who was inhaling it administered it to her.
We will restrict subgroup analysis to the primary outcomes.
For fixed‐effect inverse variance meta‐analyses we will assess differences between subgroups by interaction tests. For random‐effects and fixed‐effect meta‐analyses using methods other than inverse variance, we will assess differences between subgroups by inspection of the subgroups' confidence intervals; non‐overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.
Sensitivity analysis
We will carry out sensitivity analysis, where appropriate, to explore the effects of trial quality. We will exclude studies of poor quality, as assessed by concealment of allocation inadequate in the analysis in order to assess for any substantive difference to the overall result. If no substantive difference exists, we will leave the studies in for the main analysis. We will conduct this sensitivity analysis for the primary outcomes only.
