Oral non‐steroidal anti‐inflammatory drugs (single dose) for perineal pain in the early postpartum period
Abstract
Background
Many women experience perineal pain after childbirth, especially after having sustained perineal trauma. Perineal pain‐management strategies are an important part of postnatal care. Non‐steroidal anti‐inflammatory drugs (NSAIDs) are a commonly‐used type of medication in the management of postpartum pain, and their effectiveness and safety should be assessed. This is an update of a review first published in 2016.
Objectives
To determine the effectiveness of a single dose of an oral NSAID for relief of acute perineal pain in the early postpartum period.
Search methods
For this update, we searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (9 December 2019), OpenSIGLE and ProQuest Dissertations and Theses (28 February 2020), and reference lists of retrieved studies.
Selection criteria
Randomised controlled trials (RCTs) assessing a single dose of a NSAID versus a single dose of placebo, paracetamol or another NSAID for women with perineal pain in the early postpartum period. We excluded quasi‐RCTs and cross‐over trials. We included papers in abstract format only if they had sufficient information to determine that they met the review’s prespecified inclusion criteria.
Data collection and analysis
Two review authors (FW and VS) independently assessed all identified papers for inclusion and risks of bias, resolving any discrepancies through discussion. Two review authors independently conducted data extraction, including calculations of pain relief scores, and checked it for accuracy. We assessed the certainty of the evidence using the GRADE approach.
Main results
We included 35 studies examining 16 different NSAIDs and involving 5136 women (none were breastfeeding). Studies were published between 1967 and 2013. Risk of bias due to random sequence generation, allocation concealment and blinding of outcome assessors was generally unclearly to poorly reported, but participants and caregivers were blinded, and outcome data were generally complete. We downgraded the certainty of evidence due to risk of bias, suspected publication bias, and imprecision for small numbers of participants.
NSAID versus placebo
Compared to women who receive a placebo, more women who receive a single‐dose NSAID may achieve adequate pain relief at four hours (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.64 to 2.23; 10 studies, 1573 women; low‐certainty evidence) and at six hours (RR 1.92, 95% CI 1.69 to 2.17; 17 studies, 2079 women; very low‐certainty evidence), although we are less certain about the effects at six hours. At four hours after administration, women who receive a NSAID are probably less likely to needadditional analgesia compared to women who receive placebo (RR 0.39, 95% CI 0.26 to 0.58; 4 studies, 486 women; moderate‐certainty evidence) and may be less likely to need additional analgesia at six hours after initial administration, although the evidence was less certain at six hours (RR 0.32, 95% CI 0.26 to 0.40; 10 studies, 1012 women; very low‐certainty evidence).
One study reported that no adverse events were observed at four hours post‐administration (90 women). There may be little or no difference in maternal adverse effects between NSAIDs and placebo at six hours post‐administration (RR 1.38, 95% CI 0.71 to 2.70; 13 studies, 1388 women; low‐certainty evidence). Fourteen maternal adverse effects were reported in the NSAID group (drowsiness (5), abdominal discomfort (2), weakness (1), dizziness (2), headache (2), moderate epigastralgia (1), not specified (1)) and eight in the placebo group (drowsiness (2), light‐headedness (1), nausea (1), backache (1), dizziness (1), epigastric pain (1), not specified (1)), although not all studies assessed adverse effects. Neonatal adverse effects were not assessed in any of the studies.
NSAID versus paracetamol
NSAIDs may lead to more women achieving adequate pain relief at four hours, compared with paracetamol (RR 1.54, 95% CI 1.07 to 2.22; 3 studies, 342 women; low‐certainty evidence). We are uncertain if there is any difference in adequate pain relief between NSAIDs and paracetamol at six hours post‐administration (RR 1.82, 95% CI 0.61 to 5.47; 2 studies, 99 women; very low‐certainty evidence) or in the need foradditional analgesia at four hours (RR 0.55, 95% CI 0.27 to 1.13; 1 study, 73 women; very low‐certainty evidence). NSAIDs may reduce the risk of requiring additional analgesia at six hours compared with paracetamol (RR 0.28, 95% CI 0.12 to 0.67; 1 study, 59 women; low‐certainty evidence).
One study reported that no maternal adverse effects were observed at four hours post‐administration (210 women). Six hours post‐administration, we are uncertain if there is any difference between groups in the number of maternal adverse effects (RR 0.74, 95% CI 0.27 to 2.08; 3 studies, 300 women; very low‐certainty evidence), with one case of pruritis in the NSAID group and one case of sleepiness in the paracetamol group. Neonatal adverse effects were not assessed in any of the included studies.
Comparisons of different NSAIDs or doses did not demonstrate any differences in effectiveness for any primary outcome measures; however, few data were available on some NSAIDs.
None of the included studies reported on any of this review's secondary outcomes.
Authors' conclusions
In women who are not breastfeeding and who sustained perineal trauma, NSAIDs (compared to placebo or paracetamol) may provide greater pain relief for acute postpartum perineal pain and fewer women need additional analgesia, but uncertainty remains, as the evidence is rated as low‐ or very low‐certainty. The risk of bias was unclear for many studies, adverse effects were often not assessed and breastfeeding women were not included. While this review provides some indication of the likely effect, there is uncertainty in our conclusions. The main reasons for downgrading were the inclusion of studies at high risk of bias and inconsistency in the findings of individual studies.
Future studies could examine NSAIDs' adverse effects, including neonatal effects and the compatibility of NSAIDs with breastfeeding, and could assess other secondary outcomes. Future research could consider women with and without perineal trauma, including perineal tears. High‐quality studies could be conducted to further assess the efficacy of NSAIDs versus paracetamol and the efficacy of multimodal treatments.
PICOs
Plain language summary
Anti‐inflammatory drugs for relief of perineal pain after childbirth
What is the issue?
Following childbirth, many women experience pain in the perineum, an area between the anus and vagina. This Cochrane Review asked if this pain can be reduced by one dose of a non‐steroidal anti‐inflammatory drug (NSAID), such as aspirin or ibuprofen.
Why is this important?
The pain some women experience in the perineum after childbirth can be particularly acute if the perineum tears during the birth, or needs to be cut (known as an episiotomy). Even a woman without tearing or surgery often experiences discomfort in her perineum, which can affect her mobility as well as her ability to care for her baby. This review is part of a series of reviews on the effectiveness of different drugs for pain relief for perineal pain immediately after birth. We are looking specifically at NSAIDs, such as aspirin and ibuprofen.
What evidence did we find?
We found 35 studies with 5136 women that examined 16 different NSAIDs (aspirin, ibuprofen, etc.). We included studies up to 9 December 2019. The studies we found only included women who had trauma of the perineum and who were not breastfeeding. Studies were conducted between 1967 and 2013 and had few women in them.
The studies showed that a single dose of a NSAID may provide greater pain relief at four hours (low‐certainty evidence) after taking the drug when compared to a placebo (dummy pill) or no treatment in non‐breastfeeding women who had sustained perineal trauma during childbirth. We are uncertain if there is any difference between NSAID and placebo in achieving adequate pain relief at six hours.
Women who received a single dose of NSAID are probably less likely to need additional pain relief at four hours (moderate‐certainty evidence) after taking the drug compared to women who received placebo or no treatment. We are uncertain if there is any difference between NSAIDs and placebo for women needing additional pain relief at six hours (very low‐certainty evidence). Not all of the studies assessed adverse effects of the drugs, but some studies reported maternal adverse effects such as drowsiness, headache, weakness, nausea, gastric discomfort. The evidence is very uncertain about the difference in maternal adverse effects between NSAIDs and placebo at six hours after administration (very low‐certainty evidence). One small study (90 women) reported that there were no maternal adverse effects at four hours after administration. None of the studies measured possible adverse effects on the baby.
A NSAID may also be better than paracetamol in providing pain relief at four hours after administration. We are uncertain if there is any difference between NSAID and paracetamol in achieving adequate pain relief at six hours or in the number of women who need additional pain relief at four hours after administration. Women who receive NSAID may be less likely to need additional pain relief at six hours compared to women who received paracetamol. One study reported that no maternal adverse effects were observed at four hours (210 women). Three small studies reported maternal adverse effects at six hours after administration but we are uncertain if there is any difference between the groups. Adverse effects on the baby were not reported in any of the included studies and all studies excluded women who were breastfeeding.
Comparisons of different NSAIDs and different doses of the same NSAID did not demonstrate any clear differences in their effectiveness on any of the main outcomes measured in this review. However, little information was available for some NSAIDs.
None of the included studies reported on any of this review's secondary outcomes, including: extended hospital stay or readmission to hospital for perineal pain; breastfeeding; perineal pain at six weeks after having the baby; women's views, postpartum depression or measures of disability due to perineal pain.
What does this mean?
For women who are not breastfeeding, a single dose of a NSAID may be better than placebo or paracetamol for perineal pain at four hours. No serious side effects were reported, but not all studies examined these. For women who breastfeed, there are no data and these women should seek help, as some NSAIDs are not recommended for women who breastfeed.
Authors' conclusions
Summary of findings
| NSAID compared with placebo for perineal pain in the early postpartum period | ||||||
| Patient or population: women with perineal pain in the early postpartum period | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | NSAID | |||||
| Adequate pain relief | 284 per 1000 | 543 per 1000 | RR 1.91 | 1573 | ⊕⊕⊝⊝ | ‐ |
| Adequate pain relief | 321 per 1000 | 615 per 1000 | RR 1.92 | 2079 | ⊕⊝⊝⊝ | ‐ |
| Need for additional analgesia | 305 per 1000 | 119 per 1000 | RR 0.39 | 486 | ⊕⊕⊕⊝ | ‐ |
| Need for additional analgesia (6 hours after administration) | 438 per 1000 | 140 per 1000 | RR 0.32 | 1012 | ⊕⊝⊝⊝ | ‐ |
| Maternal drug adverse effects | See comment | Not estimable | 90 (1 RCT) | One small study (90 women) reported no maternal drug adverse events in either the intervention or control group | ||
| Maternal drug adverse effects | 22 per 1000 | 31 per 1000 | RR 1.38 | 1388 | ⊕⊕⊝⊝ | ‐ |
| Neonatal drug adverse effects | Not reported | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level for serious risk of bias: two studies included in this outcome had instances of high risk of bias. The remaining studies had a mix of low and unclear risk of bias. eDowngraded one level for imprecision (few events); 95% CI around the pooled estimate includes no effect. | ||||||
| NSAID (single administration, any dose) compared to paracetamol for perineal pain in the early postpartum period | ||||||
| Patient or population: women with perineal pain in the early postpartum period | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with paracetamol | Risk with NSAID (single administration, any dose) | |||||
| Adequate pain relief (4 hours after administration) | Study population | RR 1.54 | 342 | ⊕⊕⊝⊝ | ‐ | |
| 205 per 1000 | 315 per 1000 | |||||
| Adequate pain relief (6 hours after administration) | Study population | RR 1.82 | 99 | ⊕⊝⊝⊝ | ‐ | |
| 200 per 1000 | 364 per 1000 | |||||
| Need for additional analgesia (4 hours after administration) | Study population | RR 0.55 | 73 | ⊕⊝⊝⊝ | ‐ | |
| 405 per 1000 | 223 per 1000 | |||||
| Need for additional analgesia (6 hours after administration) | Study population | RR 0.28 | 59 | ⊕⊕⊝⊝ | ‐ | |
| 571 per 1000 | 160 per 1000 | |||||
| Maternal drug adverse effects (4 hours after administration) | See comment | not estimable | 210 | 1 study (210 women) reported no maternal drug adverse events in either the intervention or control group | ||
| Maternal drug adverse effects (6 hours after administration) | Study population | RR 0.74 | 300 | ⊕⊝⊝⊝ | ‐ | |
| 53 per 1000 | 39 per 1000 | |||||
| Neonatal drug adverse effects ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐‐ | ‐ |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level for serious risk of bias: unclear risk of selection bias. | ||||||
Background
Description of the condition
The perineum in women is a diamond‐shaped area between the vagina and the anus (Chou 2009). Pain in this area is particularly common following childbirth. A study conducted in the UK found that 92% of all women, with or without perineal trauma, reported perineal pain in the first day after birth, although this resolved for 88% of women at two months postpartum (Andrews 2008). Macarthur 2004, in a prospective cohort study involving 447 women in Canada, reported an incidence of perineal pain in the first day after birth of 75% in women with an intact perineum. This shows that perineal pain is not limited to women who sustain perineal trauma. However, women who have perineal trauma, which is approximately 70% of women giving birth, more commonly experience perineal pain (Laws 2009), report more severe pain and are more likely to use analgesic medicines (Leeman 2009). Spontaneous trauma to the perineum during childbirth has a four‐degree classification system depending on the tissues affected, varying from tearing of only the skin, subcutaneous tissue and/or vaginal mucosa in a first‐degree tear, to tearing of the deep and superficial perineal muscles and anal sphincter in a third‐degree tear. In a fourth‐degree tear, the ano‐rectal epithelium is also disrupted (Kettle 2004). Episiotomy is another type of trauma to the perineum and involves a surgical incision of the perineum to increase the diameter of the vulval outlet (Kettle 2004). In Macarthur 2004, perineal pain was experienced by 95% (210/220) of women with first‐/second‐degree tears, 97% (94/96) of those who had undergone episiotomies, and 100% (46/46) of women with third‐/fourth‐degree tears, but by six weeks postpartum, the frequency of perineal pain was not different between trauma groups. Preventing perineal trauma, as far as is possible, is thus vital for minimising the experience of perineal pain. A Cochrane Review evaluating perineal techniques to avoid perineal trauma during childbirth (Aasheim 2017) found that the use of warm compresses reduces third‐ and fourth‐degree tears. However, perineal trauma is not fully preventable and women without perineal trauma also frequently experience perineal pain (Andrews 2008; Macarthur 2004). Consequently, pain‐management strategies for perineal pain are an important part of postpartum care, particularly as perineal pain can interfere with a woman’s mobility, affect her ability to care for her baby (East 2012a), and, if the pain persists, may be associated with urinary/faecal incontinence and dyspareunia (Andrews 2008; Thompson 2002).
Most women experience short‐term perineal pain following childbirth, but between 6% to 30% of women continue to report perineal pain at one year postpartum (Schytt 2007; Williams 2007). Definitions of acute and chronic pain vary in the literature, but chronic pain is often described as pain present for more than 12 weeks (Airaksinen 2006). Pain of up to 12 weeks duration is generally considered acute pain, although pain lasting between six and 12 weeks has been further classified as sub‐acute (Van Tulder 2006). More recently, rather than defining pain according to set time‐frames of duration, chronic pain has been defined as pain that persists longer than the usual course (Loeser 2011). Acute pain presenting in the early postpartum period should be differentiated from chronic perineal pain in this context (Chou 2009), because of different pathophysiological processes that occur when acute pain becomes chronic (Voscopoulus 2010). The term 'early postpartum period' is equally challenging to define and varies in time‐frame durations in the literature. Early postpartum period has previously been defined as a time period of between three and 12 weeks after a baby's birth (Moodley 2003; Nicklas 2013; O'Brien 2003), a time period of one week's duration (Abou Saleh 1997), a time period of up to six months postpartum (Goodman 2003; Teich 2014), or without any specified time limit. In this review, for consistency with previous Cochrane Reviews examining interventions for early postpartum perineal pain (Chou 2009; Chou 2013), we consider the first four weeks after the birth to be the 'early postpartum period'. When women experience postpartum perineal pain in this period, it can thus be considered acute pain.
Several methods of pharmacological and non‐pharmacological pain relief are currently being used in managing acute postpartum perineal pain. These include cooling treatments, topical anaesthetics, analgesics and non‐steroidal anti‐inflammatory drugs (NSAIDs). Previous Cochrane Reviews evaluating the effectiveness of several treatment strategies for acute perineal pain postpartum concluded that rectal NSAID suppositories are associated with less pain up to 24 hours postpartum compared to placebo (Hedayati 2003) and paracetamol provides more pain relief to women compared to placebo (Chou 2013). In addition, there is non‐compelling evidence for the use of topical anaesthesia (Hedayati 2005), limited evidence for the use of local cooling treatments (East 2012b), and a lack of evidence to support the use of therapeutic ultrasound (Hay‐Smith 1998).
In this review we focus on oral NSAIDs (single‐dose) for alleviating perineal pain in the early postpartum period, that is, during the first four weeks after birth.
Description of the intervention
NSAIDs are a group of medicines that have been used for centuries for their analgesic, anti‐pyretic and anti‐inflammatory properties. Salicin was first extracted from willow bark in 1829 by Leroux (Brunton 2011), and the derivative aspirin was produced in 1899 (Rao 2008). In the 20th century, many NSAIDs were developed, but it was not until the 1970s that a mechanism of action was identified (Rainsford 2007; Vane 1971), and our understanding of their effects as well as their use in the treatment and management of various conditions continue to evolve. NSAIDs are mainly categorised according to their inhibitory effects on two isoforms of cyclo‐oxygenase (COX1 and COX2), as described below.
Various routes for NSAID administration are available, including intra‐muscular injection, intravenously, per rectum, topically and orally (Tramèr 1998). This review examines the effectiveness of NSAIDs taken orally. More specifically, this review evaluates the effectiveness of a single oral dose of a NSAID, defining a single dose as a dose taken at one time rather than dosage regimens that would involve more than one dose of a given NSAID over time (Howard 2013). The speed at which an oral NSAID is absorbed into the bloodstream varies for different NSAIDs. For example, for ibuprofen, peak plasma concentrations are observed 15 to 30 minutes after ingesting the drug, with a half‐life in the plasma of approximately two hours (Davies 1998). This is an example of a fast‐acting NSAID, whereas slow‐acting NSAIDs such as naproxen show later peak plasma concentrations and have a longer half‐life (Vree 1993). The recommended dosage at which NSAIDs are administered also depends on the individual NSAID, as well as the route of administration and the reason for taking the drug. For acute pain, for instance, a single oral dose of 400 mg of ibuprofen is generally taken, which can be repeated every four to six hours up to a maximum daily dose of 2400 mg. Naproxen, as another example, has a maximum daily dose of 1250 mg and is given orally for acute pain in an initial dose of 500 mg followed by 250 mg doses every six to eight hours afterwards, as required (BNF 2014).
The most common adverse effects of NSAIDs include abdominal pain, nausea, dyspepsia, headache, pruritis, urticaria and other skin rashes. Rarely, NSAIDs can lead to perforation of gastric ulcers and gastrointestinal bleeding, hypersensitivity reactions, bronchospasm, haematopoietic disorders, hypertension, cardiac failure and renal failure. Adverse effects are more likely in elderly people and may be minimised by using the lowest effective dose for the shortest duration necessary (Irish Pharmaceutical Healthcare Association 2014).
How the intervention might work
During childbirth, due to pressure on or trauma of the perineum, a local inflammatory response occurs causing perineal pain. NSAIDs may improve perineal pain through their anti‐inflammatory action. Moreover, they have a known analgesic effect, particularly for pain that is associated with tissue trauma/injury and inflammation (Rao 2008). This review focuses on the effectiveness of a single dose of a NSAID in relieving perineal pain, which, if effective, will mainly be due to its early analgesic properties as its anti‐inflammatory effect will be minimal at this dosage. NSAIDs are believed to act peripherally by inhibiting COX enzymes that catalyse the conversion of arachidonic acid into prostaglandin (PG) (Rao 2008). There are two main isoforms of COX: COX1 and COX2. COX1 is normally present in most tissues and cells and is not related to inflammation, whereas COX2 is induced by inflammatory mediators and is only found in tissues in the presence of inflammation. In addition, COX2 catalyses the production of pro‐inflammatory prostaglandin G2 (Seibert 1994; Smith 1998). Selective COX2 inhibitors were developed to diminish the side effects of non‐selective NSAIDs that result from COX1 inhibition, particularly the inhibition of gastro‐protective prostaglandin synthesis. However, selective COX2 NSAIDs exhibit cardiovascular adverse effects (Solomon 2004).
Pain experienced in the perineal area is transmitted through the pudendal nerve to the spinal segments S2 to S4. NSAIDs thus act peripherally by inhibiting pro‐inflammatory prostaglandin production and by subsequently reducing inflammation in the perineal area and decreasing pudendal pain nerve fibres excitation.
This review examines the effectiveness of a single dose of any NSAID for the management of perineal pain in the early postpartum period.
Why it is important to do this review
Postpartum perineal pain is a very common post‐childbirth complaint. It can have negative consequences for mother and child, including disability in daily functioning for the mother; for example, it can interfere in her taking care of her infant and in breastfeeding. Early pain management is thus relevant to provide relief and prevent chronicity.
NSAIDs are commonly used in the management of postpartum pain (Leeman 2009). It is therefore important to consider their effectiveness and safety, including their safety for the neonate in breastfeeding mothers. The use of NSAID rectal suppositories has been examined in a previous Cochrane Review (Hedayati 2003). Adding to the evidence from previous Cochrane Reviews evaluating alternative management strategies for postpartum perineal pain, this systematic review evaluates and synthesises studies examining the effectiveness of NSAIDs that are administered orally and in a single dose.
Objectives
To determine the effectiveness of a single dose of an oral non‐steroidal anti‐inflammatory drug (NSAID) for relief of acute perineal pain in the early postpartum period.
Methods
Criteria for considering studies for this review
Types of studies
We include only randomised controlled trials (RCTs), comparing a non‐steroidal anti‐inflammatory drug (NSAID) with another NSAID, aspirin, paracetamol or placebo/no‐drug treatment. We exclude quasi‐RCTs and cross‐over trials. We included papers in abstract format only if they had sufficient information to determine that they met the review’s prespecified inclusion criteria. If they did not include this information, we excluded them, but first contacted authors to request the full‐text version.
Types of participants
All women who had acute perineal pain or who had been treated for acute perineal pain in the early postpartum period, i.e. the first four weeks after giving birth or as defined by the authors of the studies.
Types of interventions
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Single dose of a NSAID compared with placebo/no drug treatment
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Single dose of a NSAID compared with a single dose of paracetamol
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Single dose of a NSAID compared with a single dose of another NSAID/aspirin
We excluded studies examining NSAIDs administered as suppositories as these have been examined in another Cochrane Review (Hedayati 2003). Our review only includes studies examining the effectiveness of NSAIDs administered orally (single‐dose). Studies that evaluated more than one dose of NSAIDs were included in the review if data on the effectiveness of a single dose were collected and reported separately.
Types of outcome measures
Primary outcomes
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Adequate pain relief as reported by the woman, or by determination of greater than 50% relief of pain (either as stated by the woman or as calculated using a formula)*
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Need for additional analgesia for relief of perineal pain
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Maternal drug adverse effects, e.g. nausea, vomiting, sedation, constipation, diarrhoea, drowsiness, sleepiness, psychological impact
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Neonatal drug adverse effects, e.g. nausea, vomiting, sedation, constipation, diarrhoea, drowsiness, sleepiness, psychological impact
* Assessment of 50% pain relief via Total Pain Relief (TOTPAR) and Summed Pain Intensity Difference (SPID) scores (see 'Assessment of pain' section)
Secondary outcomes
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Prolonged hospitalisation due to perineal pain (days)
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Rehospitalisation due to perineal pain
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Fully breastfeeding at discharge
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Mixed feeding at discharge
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Fully breastfeeding at six weeks
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Mixed feeding at six weeks
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Perineal pain at six weeks
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Maternal views (using a validated questionnaire), for example, women’s satisfaction with the intervention
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Maternal postpartum depression, measured using a validated depression scale, for example the Edinburgh Postnatal Depression (EPD) scale
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Instrumental measures of disability due to perineal pain/activities of daily living (ADLs)/quality of life (QoL), for example, 15D Health‐Related Quality of Life (HRQoL) instrument
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.
Electronic searches
For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register by contacting their Information Specialist (9 December 2019).
The Register is a database containing over 25,000 reports of controlled trials in the field of pregnancy and childbirth. It represents over 30 years of searching. For full current 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.
Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is maintained by their Information Specialist and contains trials identified from:
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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monthly searches of CINAHL (EBSCO);
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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.
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 that has been fully accounted for in the relevant review sections (Included studies; Excluded studies).
In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (9 December 2019) using the search methods detailed in Appendix 1.
We also searched the OpenSIGLE database to identify grey literature and the ProQuest Dissertations and Theses to retrieve dissertation theses related to our topic of interest (28 February 2020) (see: Appendix 1 for search methods used).
Searching other resources
We reviewed the reference lists of all selected papers to identify any additional potentially eligible studies not captured by the electronic searches. We also contacted experts in the field of pain relief and maternity care, and, where appropriate, authors of studies published in abstract format only, to identify any unpublished studies.
We did not apply any language or date restrictions.
Data collection and analysis
Assessment of pain
The number of women achieving adequate pain relief was defined as one of the following.
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The number of women reporting 'good' or 'excellent' pain relief when asked about their level of pain relief four to six hours after receiving their allocated treatment (the data were extracted as dichotomous data).
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The number of women who reported 50% pain relief or greater.
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The number of women who achieved 50% pain relief or greater, as calculated by using derived pain relief scores (TOTPAR (total pain relief) or SPID (summed pain intensity differences)) over four to six hours.
TOTPAR or SPID (or both) were calculated provided sufficient data were present. Examples of possible pain measures included the five‐point pain relief (PR) scale with standard or comparable wording (none, slight, moderate, good, complete), the four‐point pain intensity (PI) scale (none, mild, moderate, severe), or the visual analogue scale (VAS) or both for pain relief or pain intensity. From these categorical scales, it was possible to convert results into dichotomous data (the proportion of women achieving at least 50% or greater, max TOTPAR) using standard formulae (Moore 1996; Moore 1997b). Conversion of data in this way allowed the use of these data in a meta‐analysis (Moore 1997a; Moore 1997b). We used the following equations to estimate the proportions of women achieving at least 50% of maximum TOTPAR:
Proportion with greater than 50% maxTOTPAR = (1.33 x mean %maxTOTPAR – 11.5)
With %maxTOTPAR = mean TOTPAR x 100/(maximum score x number of hours)
Proportion with greater than 50% maxTOTPAR = (1.36 x mean %maxSPID – 2.3)
With %maxSPID = mean SPID x 100/(maximum score x number of hours)
We then calculated the number of women achieving at least 50% maxTOTPAR by multiplying the proportions of women with at least 50% maxTOTPAR by the total number of women in the treatment groups. We then used the number of women with at least 50% maxTOTPAR to calculate the relative benefit and the number needed to treat for an additional beneficial outcome. Where studies used more than one method of calculating adequate pain relief, we preferred for analyses and reporting purposes (in order of decreasing preference) as follows: i) the proportion with at least 50% maxTOTPAR calculated using SPID; ii) the proportion with at least 50% maxTOTPAR calculated using TOTPAR; and iii) the number of women reporting 'good' or 'excellent' pain relief/number of women reporting at least 50% pain relief. We also assessed the number of women who remedicated in the period of four to eight hours, as well as the median time to remedication, if the information was available.
Selection of studies
Two review authors (FW and VS) independently assessed for inclusion all of the potential studies identified by the search strategy. We resolved any disagreement through discussion or, if necessary, we would have consulted a third person, but this was not required. We included studies presented only as abstracts if they had sufficient information to confirm that they met the review's prespecified inclusion criteria.
We created a study flow diagram to map out the number of records identified, included and excluded (Figure 1).
Data extraction and management
We designed a form to extract data based on the Cochrane Pregnancy and Childbirth Group's data extraction template form. For eligible studies, two review authors (FW and VS) extracted the data independently using the agreed form. We resolved discrepancies through discussion or, if necessary, we would have consulted a third person, but this was not required. We entered data into Review Manager 5 software (RevMan 2020), and FW and VS independently checked these data for accuracy.
Where information about any of the above was unclear, we attempted to contact authors of the original reports to provide further details.
Assessment of risk of bias in included studies
Two review authors (FW and VS) independently assessed risks of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreement by discussion or, if necessary, we would have involved a third assessor, but this was not required.
(1) Random sequence generation (checking for possible selection bias)
We 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 assessed 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);
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We describe for each included study the methods used to conceal allocation to interventions prior to assignment, and assessed whether intervention allocation could have been foreseen in advance of or during recruitment, or changed after assignment.
We assessed 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.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We 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 considered that studies were at low risk of bias if they were blinded, or if we judged that a lack of blinding would be unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed 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.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We describe 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 different outcomes or classes of outcomes.
We assessed the methods used to blind outcome assessment as:
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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 describe for each included study, and for each outcome, the completeness of data including attrition and exclusions from the analysis. We state 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. Where sufficient information was reported, or could be supplied by the trial authors, we re‐included missing data in the relevant analyses.
We assessed the methods as:
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low risk of bias (e.g. no missing outcome data, missing outcome data balanced across groups);
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high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups, ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);
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unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk of bias (where it is clear that all of the study’s prespecified 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 prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; 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 bias (checking for bias due to problems not covered by (1) to (5) above)
We describe for each included study any important concerns we had about other possible sources of bias.
We assessed whether each study was free of other problems that could put it at risk of bias:
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low risk of other bias;
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high risk of other bias;
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unclear whether there is risk of other bias.
(7) Overall risk of bias
We made explicit judgements about whether studies were at high risk of bias, according to the criteria described in the Handbook (Higgins 2011). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings. We intended to explore the impact of the level of bias in sensitivity analyses ‐ seeSensitivity analysis.
Measures of treatment effect
We carried out statistical analyses using the Review Manager 5 software (RevMan 2020).
Dichotomous data
For dichotomous data, we presented the results as the summary risk ratio (RR) with a 95% confidence interval (CI).
Continuous data
For continuous data, we planned to use the mean difference (MD) if outcomes were measured in the same way between trials. We also planned to use the standardised mean difference (SMD) to combine trials that measured the same outcome, but used different methods; however, these were not required as there were no continuous data in the included studies.
Unit of analysis issues
Cluster‐randomised trials
We did not identify any cluster‐randomised trials on the topic. However, if we had found any, we would have included them using the guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).
Multi‐arm trials
For multi‐armed trials, only the comparisons of intervention arms that were relevant to this review were included. For example, if a study compared ibuprofen, codeine and placebo, we included only the ibuprofen versus placebo comparison.
If comparisons shared intervention or control groups then we divided the number of participants approximately evenly among the comparisons (Deeks 2020). For example, in the studies with two (or more) intervention groups and one control group we divided the number of participants and the number of events in the control group by half (or more where there were more intervention groups).
Dealing with missing data
For the included studies, we noted levels of attrition. We attempted to contact study authors to ask them to provide missing outcome data. Where this was not possible, we planned to explore the impact of including such studies in the overall assessment of results using a sensitivity analysis, but this was not required.
For all outcomes, we carried out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and all participants were analysed 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 is the number randomised minus any participants whose outcomes were known to be missing.
Assessment of heterogeneity
We assessed statistical heterogeneity in each meta‐analysis using the Tau2, I2 and Chi2 statistics. We regarded heterogeneity as substantial if an I2 was greater than 30% and either a Tau2 was greater than zero, or there was a low P value (< 0.10) in the Chi2 test for heterogeneity.
Assessment of reporting biases
Where there were 10 or more studies in a meta‐analysis we investigated reporting biases (such as publication bias) using funnel plots. We assessed funnel plot asymmetry visually.
Where we suspected reporting bias, (see ‘Selective reporting bias’ above), we attempted to contact study authors to ask them to provide missing outcome data. Where this was not possible, we planned to explore the impact of including such studies in the overall assessment of results using a sensitivity analysis, but this was not required.
Data synthesis
We carried out statistical analysis using the Review Manager 5 software (RevMan 2020). We used a fixed‐effect meta‐analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect, i.e. where trials examined the same intervention, and the trials’ populations and methods were judged sufficiently similar. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if we detected substantial statistical heterogeneity, we used a random‐effects meta‐analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. The random‐effects summary was treated as the average of the range of possible treatment effects, and we discuss the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials.
If we used random‐effects analyses, the results are presented as the average treatment effect with a 95% confidence interval, and the estimates of Tau2 and I2.
Subgroup analysis and investigation of heterogeneity
Where we identified substantial heterogeneity, we investigated it using subgroup analyses. We considered whether an overall summary was meaningful in the presence of heterogeneity, and if it was, we used a random‐effects analysis to produce it.
We had planned to carry out the following subgroup analyses.
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Drugs compatible with breastfeeding versus those that are not compatible with breastfeeding because they have adverse effects on the infant.
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Primiparous versus multiparous women.
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Women with perineal trauma versus women who gave birth over an intact perineum.
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Women who used prior pain relief versus women who did not use prior pain relief.
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Different time‐frames of when the dose was taken after the birth.
We were unable to carry out the planned subgroup analyses due to the absence of relevant data in the included studies.
We planned to use the following outcomes in subgroup analyses.
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Adequate pain relief as reported by the woman, or by determination of 50% or greater relief of pain (either as stated by the woman or as calculated using a formula).*
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Need for additional analgesia for relief of perineal pain.
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Maternal drug adverse effects, e.g. nausea, vomiting, sedation, constipation, diarrhoea, drowsiness, sleepiness, psychological impact.
* Assessment of 50% pain relief via TOTPAR and SPID scores (see 'Assessment of pain' section).
We assessed subgroup differences by interaction tests available within RevMan (RevMan 2020). We report the results of subgroup analyses quoting the Chi2 statistic and P value, and the interaction test I2 value.
We had also planned to use the outcome 'Neonatal drug adverse effects' in subgroup analyses, but this outcome was not measured in any of the included studies.
Sensitivity analysis
Where appropriate, we carried out planned sensitivity analysis to explore the effect of risks of bias for important outcomes in the review. We carried out sensitivity analysis for the primary outcomes, where appropriate, by excluding those studies judged to be at a high risk of bias for any of the following 'Risk of bias' domains: random sequence generation, allocation concealment, blinding of participants and personnel, and incomplete outcome data, reporting bias or other bias.
We also planned to conduct sensitivity analysis to explore the impact of including studies with high levels of missing data, but we did not have sufficient numbers of studies.
Summary of findings and assessment of the certainty of the evidence
We assessed the certainty of the evidence using the GRADE approach, as outlined in the GRADE handbook in order to assess the certainty of the body of evidence relating to the following outcomes for the main comparison (any NSAID versus placebo).
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Adequate pain relief as reported by the woman, or by determination of 50% or greater relief of pain.
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Need for additional analgesia for relief of perineal pain.
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Maternal drug adverse effects.
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Neonatal drug adverse effects.
We used GRADEpro Guideline Development Tool to import data from Review Manager 5 (RevMan 2020) in order to create a 'Summary of findings’ table. We produced a summary of the intervention effect and a measure of certainty for each of the above outcomes using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence for each outcome. The evidence can be downgraded from 'high certainty' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.
Results
Description of studies
Results of the search
See: Figure 1.
Study flow diagram.
We retrieved 221 records (3 CPC Register, 208 from ICTRP and ClnicalTrials.gov (none of these 208 were eligible), 10 from OpenSIGLE (none of these were eligible) and zero from Proquest). We added one report each to two previously included studies (De Vroey 1978; London 1983), and excluded one new trial report (Lataste 1981). Seven studies previously excluded have been included in this update.
Included studies
Design and setting
We include 35 studies (41 reports), of which two studies were reported in one publication (Laska 1981a; Laska 1981b). Twenty‐nine studies were multi‐arm studies; in such cases we only extracted the data for any non‐steroidal anti‐inflammatory drug (NSAIDs) compared with placebo, paracetamol or another NSAID. These studies are described in the Characteristics of included studies section. The effectiveness of paracetamol versus placebo has been examined in a previous Cochrane Review (Chou 2013) and the effectiveness of NSAIDs compared with other non‐NSAID drugs will be assessed in future reviews based on the generic protocol (Chou 2009).
Included studies were published between 1967 and 2013; one study was published in the 1960s, five in the 1970s, 22 in the 1980s and four in the 1990s. Only three studies were published since 2000; two in 2008 and one in 2013. Of the 35 included studies, 16 were conducted in the USA and eight in other high‐income countries (Canada, UK, Belgium, Spain, France, Italy). Six studies were conducted in Venezuela. The remaining five studies were conducted in other low‐ or middle‐income countries (India, Malaysia, Thailand, Iran).
Four studies reported the exact dates when the study had taken place (1965 ‐ 1966 Bloomfield 1967; 2006 Kamondetdecha 2008; 2005 Lim 2008; 2009 ‐ 2010 Suhrabi 2013). Similarly, reporting of declarations of interest was rare; only one study reported on this (Suhrabi 2013). Seven of the 35 studies had declared funding sources (public funding: Bloomfield 1967; Bloomfield 1974; funding from pharmaceutical industry: Hebertson 1986; Jain 1985; Melzack 1983; Olson 1997; Schachtel 1989). One study specifically stated that no funding or support was received (Suhrabi 2013).
Participants and sample sizes
A total of 5845 women were included in this review, of which 709 women received other drugs not included in this review and were subsequently excluded from the analysis. Of the 4837 women included in the analyses, 3145 received a NSAID and 1692 received placebo or paracetamol. Thirty‐four of the 35 studies examined the effectiveness of NSAIDs for relief of post‐episiotomy pain. One study (Lim 2008) only included women with any perineal trauma requiring repair but excluded third‐ or higher‐degree tears. All trials excluded women who were breastfeeding and none of the included trials reported neonatal adverse outcomes.
Interventions and comparisons
Sixteen different NSAIDs were examined in the studies included in this review. These were aspirin, ibuprofen, diclofenac, diflunisal, dipyrone, fenoprofen, fluproquazone, zomepirac, meclofenamate sodium, aceclofenac, ketoprofen, flurbiprofen, fendosal, piroxicam, tiaprofenic and celecoxib. Studies, or data from studies, reporting on indoprofen, zomepirac and fluproquazone were subsequently removed from the analyses, as these NSAIDs are currently withdrawn from the market due to causing the following adverse effects: fluproquazone for adverse effects on the liver (Kaplowitz 2013), indoprofen for reports of adverse reactions including reports of carcinogenicity in animal studies (Brayfield 2014), and zomepirac for being associated with fatal and near‐fatal anaphylactoid reactions (Brayfield 2014).
Doses of the intervention drugs varied across studies, with the different doses of individual drugs compared in subgroup analyses. Drugs deemed to have equivalent doses, i.e. aspirin 500 mg to 650 mg and ibuprofen 300 mg to 400 mg, were combined for purposes of analyses.
Outcomes
For 26 of the 35 included studies, some measure of adequate pain relief could be extracted four to six hours after drug administration. Seven studies provided data on adequate pain relief four hours after taking the medication, nine studies reported this outcome measure at six hours, and seven studies reported adequate pain relief at both four hours and six hours. In addition, three studies (two publications) reported adequate pain relief outcomes at five hours after drug administration (Jain 1985; Laska 1981a; Laska 1981b). We included these data in the six‐hours post‐administration outcomes for analysis purposes. Twenty studies reported summed pain intensity differences (SPIDs). Eleven of these studies also reported total pain relief (TOTPAR), and five studies also reported adequate pain relief as a good/excellent rating or the number of women reporting at least 50% pain relief. The remaining six studies only reported adequate pain relief as good/excellent or the number of women with at least 50% pain relief. In 20 of the 26 studies that reported SPID, we calculated the number of women with adequate pain relief using the SPID measure as per protocol. In four of the 11 studies that provided both SPID and TOTPAR (Gleason 1987; Hebertson 1986; Jain 1988; Schachtel 1989), the SPID and TOTPAR calculations of the number of women with adequate pain relief did not match and the raw data for pain intensity or pain relief were not available. In these cases, we used the SPID data to calculate the number of women with adequate pain relief. The reasons for the discrepancy in the number of women with adequate pain relief when calculated using SPID versus TOTPAR are not entirely clear, but they may be due to calculation errors in the reports or inaccurate time‐weighting. The formula to calculate %max TOTPAR contains the number of hours over which pain relief was measured. Some studies for example, measured pain relief at half‐hour and one‐hour post‐administration initially and then hourly thereafter up to six hours, providing a total of seven measurements of pain relief. To accurately apply these data to the formula, adjustments need to be made to account for the half‐hour periods, or the %maxTOTPAR would otherwise be overestimated. We noted this absence of adjustment in a study that additionally provided the raw data and we were able to check the calculations. Also, in one of the five studies that reported adequate pain relief as good/excellent, or as the number of women with at least 50% pain relief in addition to SPID, there was a significant unexplained discrepancy between these two measures of adequate pain relief (Hopkinson 1980).
Fifteen studies reported on the need for additional analgesia, and 18 studies reported on any maternal drug adverse effects. None of the secondary outcomes prespecified in the review were reported in any of the included studies. Furthermore, for seven studies that met the review's inclusion criteria, data were not available for analyses because the outcomes were reported beyond the review's maximum six‐hour time‐frame (e.g. at eight hours and 12 hours) (Bloomfield 1970; Melzack 1983), data for the unique medication groups were not provided (Gruber 1979), outcome data were presented in graphs or in a format that could not be accurately extracted (Jain 1978; Okun 1982), and the numbers randomised to the intervention and placebo groups were not reported (Sunshine 1987b; Trop 1983).
Excluded studies
Fifty‐eight of the 96 identified study reports did not meet the review's inclusion criteria and were excluded as follows: the intervention drug was not a NSAID or was administered by a route other than orally in 21 studies; two studies examined the effect of a NSAID in combination with another medication; the comparator was neither a placebo, paracetamol or an other NSAID in five studies; in 12 studies perineal pain was not reported separately for included women, but was reported collectively with other sources of pain or pain in other areas; 12 studies did not report on a single dose; and 4 studies were not RCTs. The remaining studies were excluded for the following reasons: one study (Cater 1985) was excluded because it only examined the NSAID zomepirac which was withdrawn voluntarily from the market by the manufacturer in 1983 because it was associated with fatal and near‐fatal anaphylactoid reactions; and one study (Pedronetto 1975) was excluded because it only examined the NSAID indoprofen, which was withdrawn from markets in the 1980s due to reports of adverse reactions including reports of carcinogenicity in animal studies.
Risk of bias in included studies
There was generally poor reporting in the studies included in this review, particularly around methods of randomisation sequence generation, allocation concealment, and blinding of the outcome assessor, with 21 studies receiving unclear judgements for all three of these 'Risk of bias' criteria (see Figure 2 and Figure 3).
'Risk of bias' graph: review authors' judgements on each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements on each risk of bias item for each included study.
Allocation
Only six of the 35 studies described their sequence generation process. Five described using a computer‐generated random sequence (Hebertson 1986; Jain 1988; Olson 1997; Schachtel 1989; Sunshine 1983a), and one described using random numbers but not the method (Melzack 1983).
Adequate allocation concealment was described in six studies (Bloomfield 1967; Bloomfield 1974; Daftary 1980; Gruber 1979; Lim 2008; Suhrabi 2013), but was unclear for all other included studies.
Blinding
Thirty‐two of the 35 included studies were described as double‐blind, defined as blinding of the participants as well as the personnel providing the treatment to the participants, reducing performance bias. Two studies were single‐blind, with only the participants blinded to the treatment they received (Olson 1999; Suhrabi 2013). However, all but two studies (Kamondetdecha 2008; Trop 1983) did not clearly report whether or not the outcome assessor was blinded, making the extent of potential detection bias unclear.
Incomplete outcome data
We assessed three studies to have a high risk of attrition bias (Laska 1981a; Laska 1981b; Melzack 1983); in Laska 1981aand Laska 1981b information on withdrawals due to the need for rescue medication was not provided and in Melzack 1983 there was differential attrition.
We assessed four studies as being at unclear risk of attrition bias (Gruber 1979; Hopkinson 1980; Jain 1978; Sunshine 1987b). In Hopkinson 1980 there appeared to be missing data (possibly due to dropouts or withdrawals) at two‐, three‐ and four‐hour assessments without a clear statement of reasons for this in the study publication. In the other three unclear studies there was insufficient information in the trial report to assess the extent of incomplete outcome data.
We assessed all other studies to have a low risk of attrition bias because there was either low or non‐differential attrition, or both.
Selective reporting
We rated the potential for reporting bias as low for most of the studies, but it is important to note that in the absence of trial protocols it is not truly possible to assess for reporting bias. We judged four studies (Hopkinson 1980; Jain 1978; Laska 1981a; Laska 1981b) as being at high risk of bias because they did not report one of the outcomes they had prespecified in the Methods sections of their papers.
Other potential sources of bias
For two studies there was an imbalance in some baseline characteristics, so we judged them as unclear (Bloomfield 1970; Bloomfield 1974). Two studies (Honorato 1990; London 1983) did not provide a clear statement on whether baseline characteristics were balanced or not and we judged these at unclear risk of bias. We judged Sunshine 1987b as unclear on 'Other bias' as there was insufficient information to accurately assess this criterion, and we judged Bloomfield 1967 as unclear because there could have been potential carry‐over of effect of intrapartum analgesia.
One study that was stopped early due to administrative changes received a high risk of bias judgement (Olson 1999). Lastly, one study (Wisanto 1981) received a high risk of bias judgement for this criterion because the time‐lag between episiotomy and drug intake was significantly (P < 0.05) shorter in the placebo group (8.08 hours ± 0.81) compared to the intervention group (10.21 hours ± 0.70). We found no other potential sources of bias in any of the other included studies.
Effects of interventions
See: Summary of findings 1 NSAID compared with placebo for perineal pain in the early postpartum period; Summary of findings 2 NSAID (single administration, any dose) compared to paracetamol for perineal pain in the early postpartum period
1. Any NSAID versus placebo
Primary outcomes
Adequate pain relief
At four hours after drug administration, more women who receive a NSAID may experience adequate pain relief compared to women who receive placebo (risk ratio (RR) 1.91, 95% confidence interval (CI) 1.64 to 2.23; 10 studies, 1573 women; Analysis 1.1; low‐certainty evidence; summary of findings Table 1). Downgrading decisions were for risk of bias and possible publication bias (Figure 4).
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.1 Adequate pain relief (4 hours after administration).
At six hours after drug administration, more women may also experience adequate pain relief in the NSAID compared to the placebo group, although the certainty of evidence is very low (RR 1.92, 95% CI 1.69 to 2.17; 17 studies, 2079 women; Analysis 1.2; summary of findings Table 1). The number needed to treat for an additional outcome of have adequate pain relief is four (95% CI 3 to 4) at four hours after drug administration and four (95% CI 3 to 5) at six hours post‐administration. GRADE decisions for downgrading the certainty of the evidence for this outcome were based on risk of bias and possible publication bias (Figure 5).
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.2 Adequate pain relief (6 hours after administration).
Sensitivity analysis removing studies at high risk of bias did not substantially change the effect estimate at either four hours' follow‐up (RR 1.85, 95% CI 1.58 to 2.18) or at six hours (RR 1.74, 95% CI 1.53 to 1.97).
Additional analgesia
Women who received a NSAID are probably less likely to require additional analgesia at four hours (RR 0.39, 95% CI 0.26 to 0.58; 4 studies, 486 women; Analysis 1.3; moderate‐certainty evidence; summary of findings Table 1).
At six hours after initial administration women who received a NSAID may be less likely to require additional analgesia, although the evidence for this is very uncertain (RR 0.32, 95% CI 0.26 to 0.40; 10 studies, 1012 women; Analysis 1.4; very low‐certainty evidence; summary of findings Table 1). Downgrading was for risk of bias and possible publication bias (Figure 6).
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.4 Need for additional analgesia (6 hours after administration).
Sensitivity analysis removing studies at high risk of bias did not substantially change the effect estimate at either four hours' follow‐up (RR 0.39, 95% CI 0.24 to 0.62) or at six hours (RR 0.32, 95% CI 0.26 to 0.41).
Maternal adverse effects
We could not estimate the RR for maternal drug adverse effects at four hours post‐administration, as no adverse effects were observed in either the NSAID (60 women) or the placebo groups (30 women) in the one study (with two treatment arms) reporting at this follow‐up time (Sunshine 1983b).
We are uncertain if there is any difference between NSAID and placebo in overall adverse effects at six hours post‐administration because the certainty of the evidence is low and the 95% CI is consistent with both possible benefit and possible harm (RR 1.38, 95% CI 0.71 to 2.70; 13 studies, 1388 women; Analysis 1.5; summary of findings Table 1). A visual inspection of the funnel plot for this outcome (Figure 7) did not suggest evidence of publication bias.
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.5 Maternal drug adverse effects (6 hours after administration).
Sensitivity analysis removing studies at high risk of bias did not change the effect estimate at six hours' follow‐up, because the studies at high risk of bias did not contribute to the effect estimate, as they had no events in either arm.
At six hours after drug administration, six of the 17 comparisons (a NSAID versus placebo) across 13 studies reported adverse effects (Analysis 1.5). These were drowsiness (n = 5), abdominal discomfort (n = 2), weakness (n = 1), dizziness (n = 2), headache (n = 2), moderate epigastralgia (n = 1) for the NSAID groups, and drowsiness (n = 2), light‐headedness (n = 1), nausea (n = 1), backache (n = 1), dizziness (n = 1) and epigastric pain (n = 1) for the placebo group. In two studies that reported adverse effects (Bloomfield 1967; Daftary 1980), the specific adverse effects were not stated.
Neonatal adverse effects
Neonatal drug adverse effects were not reported in any of the included studies.
Secondary outcomes
None of the studies assessed any of the review's prespecified secondary outcomes.
2. Any NSAID versus paracetamol
Primary outcomes
Adequate pain relief
At four hours after drug administration more women who receive any NSAID may experience adequate pain relief than women who received paracetamol (RR 1.54, 95% CI 1.07 to 2.22; 3 studies, 342 women; Analysis 2.1; low‐certainty evidence; summary of findings Table 2). Only two studies (Movilia 1989; Yscla 1988) examined a NSAID (aceclofenac 100 mg) versus paracetamol six hours after administration. At six hours we are uncertain if there is a difference between NSAID and paracetamol in the number of women with adequate pain relief, because the certainty of evidence is very low (RR 1.82, 95% CI 0.61 to 5.47; 2 studies, 99 women; I2 = 59%; Analysis 2.2; summary of findings Table 2).
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Additional analgesia
One study (Schachtel 1989) assessed the need for additional analgesia four hours after NSAID (ibuprofen) administration compared with paracetamol (1000 mg). We are uncertain if there is any difference between the two drugs, because the certainty of evidence is very low (RR 0.55, 95% CI 0.27 to 1.13; 73 women; Analysis 2.3; summary of findings Table 2).
Another study (Behotas 1992) examined the need for additional analgesia six hours after NSAID (ibuprofen) administration compared with paracetamol (1000 mg). Women who receive NSAID may be less likely to need any additional analgesia compared with women who receive paracetamol (RR 0.28, 95% CI 0.12 to 0.67; 59 women; Analysis 2.4;, low‐certainty evidence; summary of findings Table 2).
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Maternal adverse effects
No maternal adverse drugs adverse effects were reported in the one study (Kamondetdecha 2008; 210 women) that reported this outcome at four hours after drug administration. Six hours post‐administration, two of three studies reported the following maternal drug adverse effects; pruritis (n = 1) for the NSAID group and sleepiness (n = 1) for the paracetamol group. We are uncertain if there is any difference in overall adverse effects between the groups (RR 0.74, 95% CI 0.27 to 2.08; 3 studies, 300 women; Analysis 2.5; very low‐certainty evidence; summary of findings Table 2).
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Neonatal adverse effects
Neonatal drug adverse effects were not reported in any of the included studies.
Secondary outcomes
None of the studies assessed any of the review's prespecified secondary outcomes.
3. NSAID versus another NSAID
Primary outcomes
Adequate pain relief
It is unclear if there is any difference in effectiveness between different NSAIDs in providing adequate pain relief at four hours after administration (Analysis 3.1) or six hours after administration (Analysis 3.2).
Even though comparisons between different NSAIDs did not show differences in benefit, the direction of effect was in favour of aspirin when compared to diflunisal, in favour of diclofenac when compared to aspirin, in favour of etodolac when compared to aspirin, in favour of dipyrone when compared to aspirin, in favour of ibuprofen when compared to aspirin at four hours but not at six hours, and in favour of flurbiprofen when compared to aspirin except at a lower dose (25 mg) (Analysis 3.1; Analysis 3.2).
Suhrabi 2013 was not included in the meta‐analysis, as it did not report any of the review's prespecified outcome measures, but only reported pain intensity scores four hours post‐administration on a 10‐cm visual analogue scale. Using this measure of pain, no difference between celecoxib 100 mg (mean 2.57, standard deviation (SD) 1.4) and ibuprofen 400 mg (mean 2.7, SD 1.4) was found.
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Additional analgesia
It is unclear if there is any difference in the need for additional analgesia between the different NSAID groups at four hours after administration (Analysis 3.3) or at six at hours after administration (Analysis 3.4).
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Maternal adverse effects
There were no reports of maternal adverse effects at four hours after administration in either of the NSAID groups (aspirin: 62 women; other NSAID:103 women) (De Vroey 1978; Sunshine 1983b).
It is unclear if there is any difference between the different NSAID groups in the risk of maternal adverse effects at six hours after administration (Analysis 3.5).
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Neonatal adverse effects
Neonatal drug adverse effects were not reported in any of the included studies.
Secondary outcomes
None of the studies assessed any of the review's prespecified secondary outcomes.
4. NSAID versus a different dose of the same NSAID
Primary outcomes
Adequate pain relief
It is unclear if there is any difference between different doses of the same NSAID for achieving adequate pain relief at four hours after administration (Analysis 4.1) or at six hours after administration (Analysis 4.2). The different doses of the same NSAID that were investigated were equally effective, with the exception of fenoprofen 50 mg providing adequate pain relief to more women than fenoprofen 100 mg six hours after administration (Laska 1981a). All but one comparison showed little or no difference, but the direction of effect in the included studies was in favour of a lower dose of diflunisal (125 mg) compared to a higher dose (250 mg or 500 mg), in favour of a higher dose of diclofenac (50 mg or 100 mg) versus a lower dose (25 mg), in favour of flurbiprofen 50 mg or 100 mg versus 25 mg, in favour of aceclofenac 150 mg versus 50 mg or 100 mg, in favour of etodolac 100 mg versus 25 mg, in favour of a higher dose of fenoprofen (25 mg, 50 mg, 100 mg, 200 mg, 300 mg) versus a lower dose of fenoprofen (12.5 mg, 25 mg, 50 mg). In contrast, there was no or minimal direction of effect between ibuprofen 300 mg to 400 mg and ibuprofen 800 mg, meclofenamate sodium 100 mg and 200 mg, aceclofenac 50 mg and 100 mg, ketoprofen 25 mg and 50 mg, flurbiprofen 50 mg and 100 mg, fenoprofen 25 mg and 50 mg, and between fenoprofen 100 mg, 200 mg and 300 mg (Analysis 4.1; Analysis 4.2).
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Additional analgesia
It is unclear if there is any difference in the need for additional analgesia between groups examining different doses of the same NSAID at fours after administration (Analysis 4.3) or at six hours after administration Analysis 4.4).
We did not conduct a sensitivity analysis, since there were no studies at high risk of bias included in this comparison.
Maternal adverse effects
There were no reports of maternal adverse effects at four hours after administration in either of the NSAID groups (Hopkinson 1980; De Vroey 1978). It is unclear if there is any difference between the different doses of NSAID in the risk of maternal adverse effects at six hours after administration (Analysis 4.5).
Discussion
Summary of main results
This review involved 5136 women with perineal pain in the early postpartum period, mostly following episiotomy, of whom 3145 received non‐steroidal anti‐inflammatory drugs (NSAIDs) and 1692 were given paracetamol or placebo. Aspirin 500 mg to 650 mg was the most studied NSAID/dose in the included studies (nine studies), followed by ibuprofen (six studies), while many other NSAIDs were only examined in a single study.
For women who sustained perineal trauma during childbirth, any NSAID may be more effective at providing adequate pain relief than placebo at four hours (low‐certainty evidence) but we are less certain about the effects at six hours (very low‐certainty evidence; summary of findings Table 1). Women who received a NSAID are probably less likely to need additional analgesia at four‐hour follow‐up compared with placebo (moderate‐certainty evidence), and may be less likely to need additional analgesia at six hours, although we are uncertain about this evidence (very low‐certainty evidence; summary of findings Table 1).
NSAIDs may be more effective than paracetamol four hours after administration (low‐certainty evidence; summary of findings Table 2), but we are uncertain about their relative effectiveness at six hours post‐administration (very low‐certainty evidence; summary of findings Table 2). It may be that fewer women need additional analgesia at six hours after receiving a NSAID compared with paracetamol (low‐certainty evidence; summary of findings Table 2).
Maternal adverse effects were rare in both the NSAID group and the placebo or paracetamol groups. We are uncertain if there is any difference between NSAID and placebo (summary of findings Table 1) or between NSAID and paracetamol (summary of findings Table 2) in overall adverse effects at six hours post‐administration.
In the studies that reported adverse effects, more than one adverse effect was reported in the aspirin, ibuprofen and dipyrone groups. Fewer adverse effects were reported for ibuprofen compared to aspirin. An equal number of adverse effects was reported at a lower dose of ibuprofen (300 mg to 400 mg) and a higher dose (800 mg), but their effectiveness in providing pain relief was also equivalent. Information on adverse effects of diclofenac, another commonly‐used NSAID, was not reported in the included studies, but more women in the diclofenac group reported adequate pain relief than women in the aspirin group.
It is unclear if there is any difference in effectiveness between the different NSAIDS or the different doses of the same NSAID examined in the included studies. For example, ibuprofen 300 mg to 400 mg was equally as effective in relieving perineal pain in the early postpartum period as ibuprofen 800 mg to 900 mg at four and at six hours after drug administration.
Overall completeness and applicability of evidence
Only three of the 14 prespecified outcomes were examined in the included studies. The studies in this review did not examine the compatibility of NSAIDs with breastfeeding and did not report on neonatal adverse effects. In general, NSAIDs should be used with caution when breastfeeding, with paracetamol as the preferred choice of analgesic for breastfeeding women (BNF 2014). If a NSAID is required, of the NSAIDs that were examined in the studies included in this review, ibuprofen, fenoprofen, diclofenac sodium would be preferred when breastfeeding, while diflunisal, aceclofenac, aspirin, celecoxib, etodolac, flurbiprofen, ketoprofen, dipyrone, meclofenamate sodium should be avoided (BNF 2014; LacMed 2015). Although NSAIDs seem to provide better pain relief than placebo at four and six hours postpartum, there is no evidence available to evaluate the effect of NSAIDs on neonatal outcomes, since the studies in this review only included non‐breastfeeding mothers. In addition, there are no data on outcomes such as disability and depression, that can be related to experiencing pain. Other prespecified outcomes that are important for women and service providers, including prolonged hospitalisation and rehospitalisation due to perineal pain, were also not examined in the included studies.
Quality of the evidence
Most of the included studies did not report details on how they generated the random sequence, whether allocation was concealed, and whether the outcome assessment was blinded. Only three studies were published after the year 2000, with most included studies conducted in the 1980s or earlier. Trial registries were only introduced in the past two decades; for example, ClinicalTrials.gov was launched in the year 2000. Moreover, the first CONSORT (Consolidated Standards of Reporting Trials) statement to improve reporting in clinical trials was only published in 1996 (Begg 1996). This may explain the lack of reporting of key methodological aspects in the studies included in this review.
We assessed the GRADE certainty of evidence for the main comparisons (NSAID versus placebo and NSAID versus paracetamol) for all primary outcomes at four‐ and six‐hour follow‐ups. The certainty of the evidence was downgraded for risks of bias, imprecision (due to low numbers of women and few events), and publication bias.
Asymmetry in the funnel plots (for the outcome of adequate pain relief) suggests that additional smaller studies comparing the use of a NSAID versus placebo may not have been published, which may lead to an overestimation of the intervention effect (Page 2020). In addition, one trial registration report identified in the search strategy included a letter from the authors confirming that their study would not be published (McCallum 1991). The funnel plots for additional analgesia and adverse effects at six hours post‐administration were more symmetrical, but still did not show an equal spread across the triangle.
Potential biases in the review process
We reduced bias in the review process as far as possible by conducting a comprehensive literature search with no language or publication‐status restrictions. We contacted study authors for missing data or to clarify information. Two review authors independently conducted study selection, data extraction and GRADE rating.
Agreements and disagreements with other studies or reviews
The results of this review are in agreement with a Cochrane Review assessing analgesia for relief of pain due to uterine cramping/involution after birth (Deussen 2020). This review found that NSAIDs were more effective than placebo in improving pain relief based on eleven studies including 946 women, but adverse effects reported were similar in the placebo and control groups.
'Risk of bias' graph: review authors' judgements on each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements on each risk of bias item for each included study.
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.1 Adequate pain relief (4 hours after administration).
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.2 Adequate pain relief (6 hours after administration).
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.4 Need for additional analgesia (6 hours after administration).
Funnel plot of comparison: 1 NSAID (single administration, any dose) versus placebo, outcome: 1.5 Maternal drug adverse effects (6 hours after administration).
Comparison 1: NSAID (single administration, any dose) versus placebo, Outcome 1: Adequate pain relief (4 hours after administration)
Comparison 1: NSAID (single administration, any dose) versus placebo, Outcome 2: Adequate pain relief (6 hours after administration)
Comparison 1: NSAID (single administration, any dose) versus placebo, Outcome 3: Need for additional analgesia (4 hours after administration)
Comparison 1: NSAID (single administration, any dose) versus placebo, Outcome 4: Need for additional analgesia (6 hours after administration)
Comparison 1: NSAID (single administration, any dose) versus placebo, Outcome 5: Maternal drug adverse effects (6 hours after administration)
Comparison 2: NSAID (single administration, any dose) versus paracetamol, Outcome 1: Adequate pain relief (4 hours after administration)
Comparison 2: NSAID (single administration, any dose) versus paracetamol, Outcome 2: Adequate pain relief (6 hours after administration)
Comparison 2: NSAID (single administration, any dose) versus paracetamol, Outcome 3: Need for additional analgesia (4 hours after administration)
Comparison 2: NSAID (single administration, any dose) versus paracetamol, Outcome 4: Need for additional analgesia (6 hours after administration)
Comparison 2: NSAID (single administration, any dose) versus paracetamol, Outcome 5: Maternal drug adverse effects (6 hours after administration)
Comparison 3: NSAID versus a different NSAID, Outcome 1: Adequate pain relief (4 hours after administration)
Comparison 3: NSAID versus a different NSAID, Outcome 2: Adequate pain relief (6 hours after administration)
Comparison 3: NSAID versus a different NSAID, Outcome 3: Need for additional analgesia (4 hours after administration)
Comparison 3: NSAID versus a different NSAID, Outcome 4: Need for additional analgesia (6 hours after administration)
Comparison 3: NSAID versus a different NSAID, Outcome 5: Maternal drug adverse effects (6 hours after administration)
Comparison 4: NSAID versus a different dose of the same NSAID, Outcome 1: Adequate pain relief (4 hours after administration)
Comparison 4: NSAID versus a different dose of the same NSAID, Outcome 2: Adequate pain relief (6 hours after administration)
Comparison 4: NSAID versus a different dose of the same NSAID, Outcome 3: Need for additional analgesia (4 hours after administration)
Comparison 4: NSAID versus a different dose of the same NSAID, Outcome 4: Need for additional analgesia (6 hours after administration)
Comparison 4: NSAID versus a different dose of the same NSAID, Outcome 5: Maternal drug adverse effects (6 hours after administration)
| NSAID compared with placebo for perineal pain in the early postpartum period | ||||||
| Patient or population: women with perineal pain in the early postpartum period | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Placebo | NSAID | |||||
| Adequate pain relief | 284 per 1000 | 543 per 1000 | RR 1.91 | 1573 | ⊕⊕⊝⊝ | ‐ |
| Adequate pain relief | 321 per 1000 | 615 per 1000 | RR 1.92 | 2079 | ⊕⊝⊝⊝ | ‐ |
| Need for additional analgesia | 305 per 1000 | 119 per 1000 | RR 0.39 | 486 | ⊕⊕⊕⊝ | ‐ |
| Need for additional analgesia (6 hours after administration) | 438 per 1000 | 140 per 1000 | RR 0.32 | 1012 | ⊕⊝⊝⊝ | ‐ |
| Maternal drug adverse effects | See comment | Not estimable | 90 (1 RCT) | One small study (90 women) reported no maternal drug adverse events in either the intervention or control group | ||
| Maternal drug adverse effects | 22 per 1000 | 31 per 1000 | RR 1.38 | 1388 | ⊕⊕⊝⊝ | ‐ |
| Neonatal drug adverse effects | Not reported | |||||
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level for serious risk of bias: two studies included in this outcome had instances of high risk of bias. The remaining studies had a mix of low and unclear risk of bias. eDowngraded one level for imprecision (few events); 95% CI around the pooled estimate includes no effect. | ||||||
| NSAID (single administration, any dose) compared to paracetamol for perineal pain in the early postpartum period | ||||||
| Patient or population: women with perineal pain in the early postpartum period | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with paracetamol | Risk with NSAID (single administration, any dose) | |||||
| Adequate pain relief (4 hours after administration) | Study population | RR 1.54 | 342 | ⊕⊕⊝⊝ | ‐ | |
| 205 per 1000 | 315 per 1000 | |||||
| Adequate pain relief (6 hours after administration) | Study population | RR 1.82 | 99 | ⊕⊝⊝⊝ | ‐ | |
| 200 per 1000 | 364 per 1000 | |||||
| Need for additional analgesia (4 hours after administration) | Study population | RR 0.55 | 73 | ⊕⊝⊝⊝ | ‐ | |
| 405 per 1000 | 223 per 1000 | |||||
| Need for additional analgesia (6 hours after administration) | Study population | RR 0.28 | 59 | ⊕⊕⊝⊝ | ‐ | |
| 571 per 1000 | 160 per 1000 | |||||
| Maternal drug adverse effects (4 hours after administration) | See comment | not estimable | 210 | 1 study (210 women) reported no maternal drug adverse events in either the intervention or control group | ||
| Maternal drug adverse effects (6 hours after administration) | Study population | RR 0.74 | 300 | ⊕⊝⊝⊝ | ‐ | |
| 53 per 1000 | 39 per 1000 | |||||
| Neonatal drug adverse effects ‐ not reported | ‐ | ‐ | ‐ | ‐ | ‐‐ | ‐ |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level for serious risk of bias: unclear risk of selection bias. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Adequate pain relief (4 hours after administration) Show forest plot | 10 | 1573 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.91 [1.64, 2.23] |
| 1.1.1 Aspirin 500 mg to 650 mg | 4 | 183 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.69 [1.41, 5.10] |
| 1.1.2 Ibuprofen 300 mg to 400 mg | 3 | 240 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.64 [1.62, 4.30] |
| 1.1.3 Ibuprofen 800 mg | 1 | 121 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.83 [0.87, 3.87] |
| 1.1.4 Diclofenac 25 mg | 1 | 65 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.00 [0.86, 4.65] |
| 1.1.5 Diclofenac 50 mg | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.21 [0.96, 5.11] |
| 1.1.6 Diclofenac 100 mg | 1 | 64 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.36 [1.03, 5.42] |
| 1.1.7 Ketoprofen 25 mg | 1 | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.33 [1.19, 9.34] |
| 1.1.8 Diflunisal 125 mg | 1 | 41 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.91 [0.44, 19.22] |
| 1.1.9 Meclofenamate sodium 100 mg | 3 | 260 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [1.10, 1.82] |
| 1.1.10 Meclofenamate sodium 200 mg | 3 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.42 [1.10, 1.83] |
| 1.1.11 Ketoprofen 50 mg | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.23 [1.15, 9.10] |
| 1.1.12 Diflunisal 250 mg | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.40 [0.35, 16.26] |
| 1.1.13 Diflunisal 500 mg | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.73 [0.57, 24.29] |
| 1.1.14 Flurbiprofen 25 mg | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.75 [0.41, 18.29] |
| 1.1.15 Flurbiprofen 50 mg | 1 | 37 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.14 [0.64, 26.76] |
| 1.1.16 Flurbiprofen 100 mg | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.87 [0.60, 25.09] |
| 1.2 Adequate pain relief (6 hours after administration) Show forest plot | 17 | 2079 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.92 [1.69, 2.17] |
| 1.2.1 Aspirin 500 mg to 650 mg | 7 | 416 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [1.37, 2.24] |
| 1.2.2 Aspirin 900 mg | 1 | 27 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.15 [0.97, 10.26] |
| 1.2.3 Ibuprofen 300 mg to 400 mg | 2 | 124 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.08 [1.30, 3.32] |
| 1.2.4 Ibuprofen 900 mg | 1 | 27 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.98 [0.91, 9.74] |
| 1.2.5 Ketoprofen 25 mg | 1 | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [1.06, 8.49] |
| 1.2.6 Ketoprofen 50 mg | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.05 [1.08, 8.64] |
| 1.2.7 Meclofenamate sodium 100 mg | 3 | 260 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.36 [1.05, 1.76] |
| 1.2.8 Meclofenamate sodium 200 mg | 3 | 262 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [1.07, 1.83] |
| 1.2.9 Diflunisal 125 mg | 1 | 41 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.15 [0.48, 20.69] |
| 1.2.10 Diflunisal 250 mg | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.67 [0.40, 17.86] |
| 1.2.11 Diflunisal 500 mg | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.27 [0.66, 27.51] |
| 1.2.12 Dipyrone 500 mg | 1 | 133 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.21 [1.44, 3.39] |
| 1.2.13 Aceclofenac 50 mg | 1 | 22 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [0.57, 4.27] |
| 1.2.14 Aceclofenac 100 mg | 1 | 28 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.62, 4.51] |
| 1.2.15 Aceclofenac 150 mg | 1 | 25 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.81 [0.67, 4.87] |
| 1.2.16 Etodolac 25 mg | 1 | 53 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.34, 2.33] |
| 1.2.17 Etodolac 100 mg | 1 | 53 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.22 [0.49, 3.02] |
| 1.2.18 Antrafenine 300 mg | 1 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | 5.33 [1.74, 16.36] |
| 1.2.19 Flurbiprofen 25 mg | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.25 [0.50, 21.31] |
| 1.2.20 Flurbiprofen 50 mg | 1 | 37 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.97 [0.78, 31.75] |
| 1.2.21 Flurbiprofen 100 mg | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.90 [0.77, 31.33] |
| 1.2.22 Fenoprofen 12.5 mg | 1 | 29 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.08 [0.34, 12.80] |
| 1.2.23 Fenoprofen 25 mg | 1 | 28 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.39 [0.39, 14.53] |
| 1.2.24 Fenoprofen 50 mg | 2 | 62 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.38 [0.93, 12.26] |
| 1.2.25 Fenoprofen 100 mg | 2 | 62 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.95 [1.10, 14.19] |
| 1.2.26 Fenoprofen 200 mg | 2 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.95 [1.10, 14.19] |
| 1.2.27 Fenoprofen 300 mg | 1 | 34 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.93 [0.79, 30.74] |
| 1.3 Need for additional analgesia (4 hours after administration) Show forest plot | 4 | 486 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.39 [0.26, 0.58] |
| 1.3.1 Aspirin 500 mg to 650 mg | 2 | 125 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.23, 0.93] |
| 1.3.2 Ibuprofen 300 mg to 400 mg | 3 | 240 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.18, 0.56] |
| 1.3.3 Ibuprofen 800 mg | 1 | 121 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.51 [0.19, 1.36] |
| 1.4 Need for additional analgesia (6 hours after administration) Show forest plot | 10 | 1012 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.32 [0.26, 0.40] |
| 1.4.1 Aspirin 500 mg to 650 mg | 3 | 157 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.37 [0.22, 0.62] |
| 1.4.2 Aspirin 900 mg | 1 | 27 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.13 [0.01, 2.81] |
| 1.4.3 Ibuprofen 300 mg to 400 mg | 3 | 186 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.33 [0.20, 0.54] |
| 1.4.4 Ibuprofen 900 mg | 1 | 27 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.13 [0.01, 2.81] |
| 1.4.5 Meclofenamate sodium 100 mg | 3 | 299 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.34 [0.21, 0.53] |
| 1.4.6 Meclofenamate sodium 200 mg | 2 | 142 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.45 [0.29, 0.70] |
| 1.4.7 Antrafenine 300 mg | 1 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.31 [0.13, 0.74] |
| 1.4.8 Flurbiprofen 25 mg | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.06 [0.01, 0.49] |
| 1.4.9 Flurbiprofen 50 mg | 1 | 37 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.03 [0.00, 0.56] |
| 1.4.10 Flurbiprofen 100 mg | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.03 [0.00, 0.53] |
| 1.5 Maternal drug adverse effects (6 hours after administration) Show forest plot | 13 | 1388 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.38 [0.71, 2.70] |
| 1.5.1 Aspirin 500 mg to 650 mg | 6 | 365 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.31 [0.38, 4.60] |
| 1.5.2 Aspirin 900 mg | 1 | 27 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [0.24, 12.51] |
| 1.5.3 Ibuprofen 300 mg to 400 mg | 3 | 186 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.27, 3.85] |
| 1.5.4 Ibuprofen 900 mg | 1 | 27 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.05 [0.13, 8.52] |
| 1.5.5 Ketoprofen 25 mg | 1 | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.6 Ketoprofen 50 mg | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.7 Aceclofenac 50 mg | 1 | 22 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.79 [0.04, 16.59] |
| 1.5.8 Aceclofenac 100 mg | 1 | 28 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.9 Aceclofenac 150 mg | 1 | 25 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.10 Diflunisal 125 mg | 1 | 41 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.11 Diflunisal 250 mg | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.12 Diflunisal 500 mg | 1 | 38 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.13 Dipyrone 500 mg | 2 | 335 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [0.49, 12.46] |
| 1.5.14 Antrafenine 300 mg | 1 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.15 Flurbiprofen 25 mg | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.16 Flurbiprofen 50 mg | 1 | 37 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 1.5.17 Flurbiprofen 100 mg | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Adequate pain relief (4 hours after administration) Show forest plot | 3 | 342 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.54 [1.07, 2.22] |
| 2.1.1 Ibuprofen 300 mg to 400 mg versus paracetamol 1000 mg | 1 | 73 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.68 [0.93, 3.04] |
| 2.1.2 Ibuprofen 300 mg to 400 mg versus paracetamol 500 mg | 1 | 210 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [0.86, 2.28] |
| 2.1.3 Aceclofenac 100 mg versus paracetamol 650 mg | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.07 [0.57, 7.50] |
| 2.2 Adequate pain relief (6 hours after administration) Show forest plot | 2 | 99 | Risk Ratio (M‐H, Random, 95% CI) | 1.82 [0.61, 5.47] |
| 2.2.1 Aceclofenac 100 mg versus paracetamol 650 mg | 2 | 99 | Risk Ratio (M‐H, Random, 95% CI) | 1.82 [0.61, 5.47] |
| 2.3 Need for additional analgesia (4 hours after administration) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.3.1 Ibuprofen 300 mg to 400 mg versus paracetamol 1000 mg | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.4 Need for additional analgesia (6 hours after administration) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.4.1 Ibuprofen 300 mg to 400 mg versus paracetamol 1000 mg | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.5 Maternal drug adverse effects (6 hours after administration) Show forest plot | 3 | 300 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.27, 2.08] |
| 2.5.1 Dipyrone 500 mg versus paracetamol 500 mg | 1 | 201 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.23, 2.15] |
| 2.5.2 Aceclofenac 100 mg versus paracetamol 650 mg | 2 | 99 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.07, 14.90] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Adequate pain relief (4 hours after administration) Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.1 Aspirin 500 mg to 650 mg (A) versus Diflunisal 125 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.2 Aspirin 500 mg to 650 mg (A) versus Diflunisal 250 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.3 Aspirin 500 mg to 650 mg (A) versus Diflunisal 500 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.4 Aspirin 500 mg to 650 mg (A) versus Ibuprofen 300 mg to 400 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.5 Aspirin 500 mg to 650 mg (A) versus Diclofenac 25 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.6 Aspirin 500 mg to 650 mg (A) versus Diclofenac 50 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.7 Aspirin 500 mg to 650 mg (A) versus Diclofenac 100 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.8 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 25 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.9 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 50 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1.10 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 100 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2 Adequate pain relief (6 hours after administration) Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.1 Aspirin 900 mg (A) versus Ibuprofen 300 mg to 400 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.2 Aspirin 900 mg (A) versus Ibuprofen 900 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.3 Aspirin 500 mg to 650 mg (A) versus Diflunisal 125 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.4 Aspirin 500 mg to 650 mg (A) versus Diflunisal 250 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.5 Aspirin 500 mg to 650 mg (A) versus Diflunisal 500 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.6 Aspirin 500 mg to 650 mg (A) versus Etodolac 25 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.7 Aspirin 500 mg to 650 mg (A) versus Etodolac 100 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.8 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 25 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.9 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 50 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.10 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 100 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.2.11 Aspirin 500 mg to 650 mg (A) versus Dipyrone 500 mg (B) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.3 Need for additional analgesia (4 hours after administration) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.3.1 Aspirin 500 mg to 650 mg (A) versus Ibuprofen 300 mg to 400 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 11.00 [0.64, 190.53] |
| 3.4 Need for additional analgesia (6 hours after administration) Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.4.1 Aspirin 900 mg (A) versus Ibuprofen 300 mg to 400 mg (B) | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.13, 69.52] |
| 3.4.2 Aspirin 900 mg (A) versus Ibuprofen 900 mg (B) | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.4.3 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 25 mg (B) | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.10 [0.07, 16.85] |
| 3.4.4 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 50 mg (B) | 1 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.13, 70.74] |
| 3.4.5 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.20 [0.14, 75.55] |
| 3.5 Maternal drug adverse effects (6 hours after administration) Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 3.5.1 Aspirin 900 mg (A) versus Ibuprofen 300 mg to 400 mg (B) | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.46, 6.06] |
| 3.5.2 Aspirin 900 mg (A) versus Ibuprofen 900 mg (B) | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.67 [0.46, 6.06] |
| 3.5.3 Aspirin 500 mg to 650 mg (A) versus Dipyrone 500 mg (B) | 1 | 178 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.5.4 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 25 mg (B) | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.5.5 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 50 mg (B) | 1 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.5.6 Aspirin 500 mg to 650 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.5.7 Aspirin 500 mg to 650 mg (A) versus Diflunisal 125 mg (B) | 1 | 65 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.5.8 Aspirin 500 mg to 650 mg (A) versus Diflunisal 250 mg (B) | 1 | 62 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 3.5.9 Aspirin 500 mg to 650 mg (A) versus Diflunisal 500 mg (B) | 1 | 62 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 4.1 Adequate pain relief (4 hours after administration) Show forest plot | 9 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1.1 Ibuprofen 300 mg to 400 mg (A) versus Ibuprofen 800 mg (B) | 1 | 160 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.63, 1.58] |
| 4.1.2 Diflunisal 125 mg (A) versus Diflunisal 250 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.21 [0.60, 2.46] |
| 4.1.3 Diflunisal 125 mg (A) versus Diflunisal 500 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.78 [0.43, 1.41] |
| 4.1.4 Diflunisal 250 mg (A) versus Diflunisal 500 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.33, 1.25] |
| 4.1.5 Meclofenamate sodium 100 mg (A) versus Meclofenamate sodium 200 mg (B) | 3 | 348 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.85, 1.17] |
| 4.1.6 Diclofenac 25 mg (A) versus Diclofenac 50 mg (B) | 1 | 102 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.90 [0.68, 1.21] |
| 4.1.7 Diclofenac 25 mg (A) versus Diclofenac 100 mg (B) | 1 | 103 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.65, 1.11] |
| 4.1.8 Ketoprofen 25 mg (A) versus Ketoprofen 50 mg (B) | 1 | 54 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.03 [0.73, 1.46] |
| 4.1.9 Aceclofenac 50 mg (A) versus Aceclofenac 100 mg (B) | 1 | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.65, 1.54] |
| 4.1.10 Aceclofenac 50 mg (A) versus Aceclofenac 150 mg (B) | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.56, 1.21] |
| 4.1.11 Aceclofenac 100 mg (A) versus Aceclofenac 150 mg (B) | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.82 [0.58, 1.17] |
| 4.1.12 Flurbiprofen 25 mg (A) versus Flurbiprofen 50 mg (B) | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.37, 1.20] |
| 4.1.13 Flurbiprofen 25 mg (A) versus Flurbiprofen 50 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.71 [0.39, 1.30] |
| 4.1.14 Flurbiprofen 50 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.07 [0.64, 1.77] |
| 4.2 Adequate pain relief (6 hours after administration) Show forest plot | 11 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.2.1 Ibuprofen 300 mg to 400 mg (A) versus Ibuprofen 900 mg (B) | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.77, 1.30] |
| 4.2.2 Diflunisal 125 mg (A) versus Diflunisal 250 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.18 [0.61, 2.29] |
| 4.2.3 Diflunisal 125 mg (A) versus Diflunisal 500 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.43, 1.27] |
| 4.2.4 Diflunisal 250 mg (A) versus Diflunisal 500 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.62 [0.34, 1.15] |
| 4.2.5 Meclofenamate sodium 100 mg (A) versus Meclofenamate sodium 200 mg (B) | 3 | 348 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.84, 1.18] |
| 4.2.6 Ketoprofen 25 mg (A) versus Ketoprofen 50 mg (B) | 1 | 54 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.98 [0.66, 1.46] |
| 4.2.7 Aceclofenac 50 mg (A) versus Aceclofenac 100 mg (B) | 1 | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.93 [0.69, 1.27] |
| 4.2.8 Aceclofenac 50 mg (A) versus Aceclofenac 150 mg (B) | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.65, 1.14] |
| 4.2.9 Aceclofenac 100 mg (A) versus Aceclofenac 150 mg (B) | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.92 [0.73, 1.16] |
| 4.2.10 Etodolac 25 mg (A) versus Etodolac 100 mg (B) | 1 | 80 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.39, 1.39] |
| 4.2.11 Flurbiprofen 25 mg (A) versus Flurbiprofen 50 mg (B) | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.65 [0.39, 1.09] |
| 4.2.12 Flurbiprofen 25 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.40, 1.10] |
| 4.2.13 Flurbiprofen 50 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.68, 1.51] |
| 4.2.14 Fenoprofen 50 mg (A) versus Fenoprofen 100 mg (B) | 2 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.62, 1.16] |
| 4.2.15 Fenoprofen 50 mg (A) versus Fenoprofen 200 mg (B) | 2 | 99 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.62, 1.17] |
| 4.2.16 Fenoprofen 50 mg (A) versus Fenoprofen 300 mg (B) | 1 | 54 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.61, 1.31] |
| 4.2.17 Fenoprofen 100 mg (A) versus Fenoprofen 200 mg (B) | 2 | 99 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.76, 1.34] |
| 4.2.18 Fenoprofen 100 mg (A) versus Fenoprofen 300 mg (B) | 1 | 53 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.74, 1.46] |
| 4.2.19 Fenoprofen 200 mg (A) versus Fenoprofen 300 mg (B) | 1 | 53 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.74, 1.46] |
| 4.2.20 Fenoprofen 12.5 mg (A) versus Fenoprofen 25 mg (B) | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.46, 1.65] |
| 4.2.21 Fenoprofen 12.5 mg (A) versus Fenoprofen 50 mg (B) | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.87 [0.46, 1.65] |
| 4.2.22 Fenoprofen 12.5 mg (A) versus Fenoprofen 100 mg (B) | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.64 [0.37, 1.12] |
| 4.2.23 Fenoprofen 12.5 mg (A) versus Fenoprofen 200 mg (B) | 1 | 47 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.74 [0.41, 1.33] |
| 4.2.24 Fenoprofen 25 mg (A) versus Fenoprofen 50 mg (B) | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.55, 1.83] |
| 4.2.25 Fenoprofen 25 mg (A) versus Fenoprofen 100 mg (B) | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.73 [0.44, 1.23] |
| 4.2.26 Fenoprofen 25 mg (A) versus Fenoprofen 200 mg (B) | 1 | 46 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.85 [0.48, 1.48] |
| 4.3 Need for additional analgesia (4 hours after administration) Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.3.1 Ibuprofen 300 mg to 400 mg (A) versus Ibuprofen 800 mg (B) | 1 | 160 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.57 [0.17, 1.88] |
| 4.4 Need for additional analgesia (6 hours after administration) Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.4.1 Ibuprofen 300 mg to 400 mg (A) versus Ibuprofen 900 mg (B) | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.00 [0.13, 69.52] |
| 4.4.2 Meclofenamate sodium 100 mg (A) versus Meclofenamate sodium 200 mg (B) | 2 | 191 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.91 [0.55, 1.50] |
| 4.4.3 Flurbiprofen 25 mg (A) versus Flurbiprofen 50 mg (B) | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.73 [0.12, 64.42] |
| 4.4.4 Flurbiprofen 25 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.91 [0.12, 68.81] |
| 4.4.5 Flurbiprofen 50 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5 Maternal drug adverse effects (6 hours after administration) Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.5.1 Ibuprofen 300 mg (A) versus Ibuprofen 900 mg (B) | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.00 [0.23, 4.37] |
| 4.5.2 Diflunisal 125 mg (A) versus Diflunisal 250 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5.3 Diflunisal 125 mg (A) versus Diflunisal 500 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5.4 Diflunisal 250 mg (A) versus Diflunisal 500 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5.5 Ketoprofen 25 mg (A) versus Ketoprofen 50 mg (B) | 1 | 54 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5.6 Aceclofenac 50 mg (A) versus Aceclofenac 100 mg (B) | 1 | 42 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.95 [0.17, 91.61] |
| 4.5.7 Aceclofenac 50 mg (A) versus Aceclofenac 150 mg (B) | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.47 [0.15, 80.35] |
| 4.5.8 Aceclofenac 100 mg (A) versus Aceclofenac 150 mg (B) | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5.9 Flurbiprofen 25 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 61 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5.10 Flurbiprofen 25 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 63 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
| 4.5.11 Flurbiprofen 50 mg (A) versus Flurbiprofen 100 mg (B) | 1 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | Not estimable |
