Factors associated with persistent pain after childbirth: a narrative review

British Journal of Anaesthesia, xxx (xxx): xxx (xxxx) doi: 10.1016/j.bja.2019.12.037 Advance Access Publication Date: xxx Review Article

REVIEW ARTICLE

Factors associated with persistent pain after childbirth: a narrative review Ryu Komatsu1,*, Kazuo Ando2 and Pamela D. Flood2 1

Department of Anaesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA and 2Department of

Anaesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA *Corresponding author. E-mail: [email protected]

Summary A systematic literature search was performed to identify studies that reported risk factors for persistent pain after childbirth. Many studies have sought to identify risk factors for post-delivery pain in different populations, using different methodologies and different outcome variables. Studies of several different but interrelated post-partum pain syndromes have been conducted. Factors strongly and specifically associated with persistent incisional scar pain after Caesarean delivery include a coexisting persistent pain problem in another part of the body and severe acute postoperative pain. For persistent vaginal and perineal pain, operative vaginal delivery and the magnitude of perineal trauma have been consistently linked. History of pregnancy-related and pre-pregnancy back pain and heavier body weight are robust risk factors for persistent back pain after pregnancy. Unfortunately, limitations, particularly small samples and lack of a priori sample size calculation designed to detect specific effect sizes for risk of persistent pain outcomes, preclude definitive conclusions about many other predictors and the strength of outcome associations. In future studies, assessments of specific phenotypes using a rigorous analysis with appropriate predetermined sample sizes and validated instruments are needed to allow elucidation of stronger and reliable associations. Interventional studies targeting the most robustly associated, modifiable risk factors, such as acute post-partum pain, may lead to solutions for the prevention and treatment of these common problems that impact a large population. Keywords: back pain; caesarean section; delivery; obstetric; opioid; pain; post-partum

Editor’s key points
The authors examined the evidence base for the risk factors relating to the important problem of persistent post-partum pain. They conducted a systematic literature search to identify studies reporting risk factors for several persistent post-partum pain syndromes.
Persistent Caesarean scar pain appears to be associated with coexisting persistent pain problems and severe, acute postoperative pain.
Persistent vaginal and perineal pain appears to be associated with operative vaginal delivery and the magnitude of perineal trauma.


A history of pregnancy-related and pre-pregnancy back pain and heavier body weight are associated with persistent post-partum back pain. Persistent pain in the large population of women after childbirth has attracted increasing attention from governments, medical societies, and the public over the past decade.1,2 One hundred and forty million births occur yearly worldwide.3,4 The reported incidence of persistent pain after childbirth varies depending on the method of delivery; study population; and, perhaps most importantly, study design. A meta-analysis published in 2016 that included prospective and retrospective observational studies and RCTs concluded that 11% of women undergoing Caesarean delivery have persistent pain at 12

Received: 23 November 2018; Accepted: 28 December 2019 © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]

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months.5 Thus far, some have attempted to use antepartum psychophysical testing to identify women who are at risk for persistent post-partum pain, and one study has identified catastrophising assessed by the Pain-Related Self-Statements Scale-Catastrophizing Subscale as a predictor for persistent perineal pain after vaginal delivery.6 Because of the size, youth, vulnerability, and therefore the societal importance of the population at risk, we undertook a narrative review of the underlying literature. Our objective was to provide a critical review of the current literature regarding predictive factors for persistent pain after childbirth, with the aim of improving the identification of individuals at risk. The elucidation of modifiable targets will point to interventions to be tested in treatment studies. The identification of non-modifiable targets will enhance screening effectiveness.

Methods MEDLINE database searches were conducted to identify studies focused on the identification of risk factors for persistent pain after childbirth using the following search string for matches in titles or abstracts: ‘pain [ti/ab] AND (childbirth [ti/ab] OR “Caesarean delivery” [ti/ab] OR “vaginal delivery” [ti/ab] OR delivery [ti/ab] OR postpartum [ti/ab])’, with restriction to human studies reported in English. Persistent pain was defined as pain that lasted at least 6 weeks after the delivery. Pain was considered at any location below the chest, except for isolated pelvic and pelvic girdle pain. A manual inspection was subsequently performed through the reference lists of identified studies independently by two authors (RK and KA) using a data form generated by the authors, which specifically documents the following: region of study origin, study design, method of patient recruitment used, inclusion criteria, sample size, reported pain outcome, incidence of persistent pain, predictors for persistent pain, and ratio of patients with Caesarean delivery amongst included patients. Collected data have been aggregated into Supplementary Appendix Table 1.1,6e25,26e59 Disagreement was adjudicated by author PDF. RCTs, prospective cohort studies, retrospective cohort studies, and cross-sectional studies that contain information about persistent pain lasting at least 6 weeks were considered for inclusion. Only articles in which pain was described as a dichotomous or continuous variable, in locations at or below the chest, and that included evaluation of risk factors with statistical inference, were included in this review. Case reports, case series, narrative reviews, systematic reviews, letters to the editor, and editorials were excluded.

Results of literature search The literature search using the MEDLINE database with the methods described previously, performed on September 23, 2018, resulted in 764 matches. Amongst the 764 matches, one duplication was found (one study published in two separate articles), reducing the records to 763. The reference lists of those records located 67 additional articles, which might have relevant information. After a review of titles and abstracts of a total of 830 records, we excluded 689 articles according to the aforementioned criteria and assessed the full text of 141 articles. After further exclusions according to the aforementioned criteria, 55 articles were retained and included in the current narrative review (Fig. 1). Information on study methodology,

location, and cohort details relevant for consideration of applicability and level of evidence is provided in Supplementary Appendix Table 1.1,6e25,26e59 Fourteen studies included in this narrative review did not find any significant association between candidate risk factors and persistent pain outcomes.31e37,49e51,56e59 Those consist of eight prospective cohort studies,31e33,35,37,50,56,57 five 34,49,51,58,59 RCTs, and a non-randomised trial.36 The types of pain investigated were low back pain,31,33e37 Caesarean scar pain,49e51 perineal pain,57e59 and combined pain.32,56

Nature of persistent post-partum pain There are several significant issues that make identifying persistent post-partum pain difficult. The definitions of persistent pain in the literature, and indeed the terms used for persistent pain, are inconsistent. Other terms used to describe persistent pain, including prolonged, protracted, and chronic, were found in the included literature. Herein, we use the term ‘persistent pain’. The relevant time frames that have been customarily used to define persistent pain are 2 months,60 3e6 months, or longer depending on the studies.61,62 We defined pain lasting 6 weeks or longer as persistent pain in this review. Post-partum women may have multiple different types of pain partially dependent on mode of delivery. Pregnancy itself is associated with a high prevalence of pain conditions that may continue into the post-partum period.63 For example, 20e90% of women suffer from low back pain during pregnancy depending on the cohort studied and the methodology used.64,65 As such, it is difficult to completely separate new onset of pain conditions that develop during or after the delivery from those that were pre-existing before pregnancy or delivery.

Persistent Caesarean scar pain The common horizontal suprapubic scar resulting from Caesarean delivery can entrap the ilioinguinal or iliohypogastric nerves initiating diffuse persistent neuropathic pain. In a study with a sample size of 81, Bollag and colleagues51 demonstrated that 56%, 50%, and 26% of women described wound pain with predominantly neuropathic descriptors of the Short-Form McGill Pain Questionnaire 2 at 3, 6, and 12 months after Caesarean delivery, respectively. Further, there have been multiple reports of pain relief after nerve block, neurotomy, re-implantation of the peripheral nerve into muscle, and radio-frequency treatment of affected nerves in patients with persistent pain after Caesarean delivery.66e69 Scar pain is the most commonly identified aetiology for persistent pain after Caesarean delivery. Amongst the studies that evaluated persistent Caesarean scar pain, the range of incidences reported has been large (Table 1). The reason underlying the wide range is likely multifactorial.38,40,43,45,46 The risk factors that have been evaluated for developing a painful scar after Caesarean delivery are summarised in Table 1. All studies that investigated Caesarean scar pain are prospective studies. The sample sizes are comparable between studies in which candidate risk factors predicted the pain outcome with statistical significance (positive studies; median: 297 [inter-quartile range: 236e599]), and those in which candidate risk factors failed to predict the pain outcome with statistical significance (negative studies; 469 [275e529]). Further, in one negative study, a power analysis was performed to detect an a priori determined effect size of a

Persistent pain after childbirth

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Fig 1. Flow diagram of the search for relevant references. Eight hundred and thirty-one records were initially identified. Removal of one duplication reduced the records to 830. Of the 830 studies, 55 studies met the inclusion criteria and were included in the narrative review.

candidate risk factor.49 Therefore, the negative study has at least a comparable quality as that of positive studies. Both positive and negative studies combined, the risk factors studied in more than two studies are coexisting persistent pain problems in other parts of the body,1,43,47 and acute postoperative pain.1,47,50 All studies that assessed persistent pain problems in other parts of the body reported the effect sizes as odds ratios of 1.9e2.843,47 or a relative risk of 3.3.1 As the effect size is consistently in the same direction in all the studies, persistent pain problem in other parts of the body can be considered a robust risk factor. Acute postoperative pain has been assessed using different metrics between the studies.1,47,50 Sng and colleagues47 utilised a 0e10 numeric rating scale, and reported the effect size in adjusted odds ratio of 1.4 (odds of having persistent pain increases by 1.4 with every 1 point increase in numeric rating scale of acute postoperative pain), whereas Nikolajsen and colleagues1 reported

a relative risk of 1.5 in the patients who had recall of severe acute postoperative pain vs no recall of severe acute postoperative pain. Liu and colleagues50 reported a relative risk of 1.1 in those who experienced moderate-to-severe acute postoperative pain vs none-to-mild pain, which failed to attain statistical significance. Quantification of the magnitude of effect size of acute pain is difficult because of the use of different metrics in the studies. However, as the direction of the effect size is consistent in all studies, it is likely that the acute postoperative pain burden is associated with the development of persistent Caesarean scar pain. Potential interventions to decrease acute postoperative pain burden are aggressive use of labour epidural analgesia to decrease the need for general anaesthesia for urgent intrapartum Caesarean delivery, and increasing the dose of intrathecal local anaesthetics and other adjuvants for the cases in which intrathecal morphine is contraindicated.45

Time points after delivery 8 weeks

Wang and colleagues38 Jin and colleagues40 Moriyama and colleagues41

786

Niklasson and colleagues42 Richez and colleagues43

231

Ortner and colleagues44

335

Incidence Risk factors

de Brito Cancado and colleagues45

402

Incidence Risk factors

Shahin and Osman46 Sng and colleagues47

325

Incidence Risk factors Incidence

502 225

268

857

Incidence Risk factors Incidence Risk factors Incidence Risk factors

690

Incidence Risk factors

Nikolajsen and colleagues1

220

Incidence

Incidence Risk factors

8 months or greater

6.9%

1.9%

0.3%*

8.2%

3.7%

1.7%*

30.7% Lighter weight and omission of intrathecal morphine 22.4%

16.8%

5.5%*

y

28% Pain during current pregnancy, history of miscarriage, and lower mental component summary score of SF-36 11.0% Higher pain score at 24 h after operation

y

y

y

19% Postoperative complications and lower mental component summary score of SF-36 3.0%

11.4% Higher pain level at 12 h after operation and postoperative Day 2, lower intrathecal bupivacaine dose, and omission of perioperative NSAIDs

0.6%*

4.3%z y

Pain lasting more than 3 months: 9.2% Higher pain scores immediately after operation, pain present elsewhere, and non-private insurance status

Pain lasting more than 3 months: 18.6% General anaesthesia, pain problem elsewhere, and higher recall of severe postoperative pain

Risk factors

589

6 months

y

Incidence Risk factors Incidence Risk factors

Loos and colleagues48

3 months

y

Risk factors

Mackeen and colleagues49#

Komatsu et al.

Sample size

-

Study

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Table 1 Incidence and risk factors for Caesarean scar pain. *Pain at 12 months after delivery. yThe risk factors for combined pain of multiple body parts were reported, and the risk factors specific for Caesarean scar pain were not reported. zPain at 8 months after delivery. ¶Pain at 14.5 months after delivery. xPain at 26 months after delivery. jjPain at 10.1 months after delivery. #Studies in which evaluated risk factors for Caesarean scar pain failed to demonstrate statistical significance. CD, Caesarean delivery; SF-36, Short Form 36 Health Survey.

6.0%¶

32.3%x >2 previous Pfannenstiel incisions, presence of scar numbness, and emergency CD 12.3%jj

Skin closure with staples (vs suture) Continued

Persistent pain after childbirth

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Transversus abdominis plane block with placebo (vs bupivacaine vs bupivacaineþclonidine) Transversus abdominis plane block with placebo (vs bupivacaine vs bupivacaineþclonidine)

4.2%*

Transversus abdominis plane block with placebo (vs bupivacaine vs bupivacaineþclonidine) Incidence Risk factors

Incidence Risk factors

469

81

Liu and colleagues50#

Bollag and colleagues51#

14.6% Elective CD (vs emergency CD), repeat CD (vs primary CD), severe acute postoperative pain, general anaesthesia, and wound infection

3 months 8 weeks

Sample size Study

Table 1 Continued

Time points after delivery

6 months

8 months or greater

Persistent vaginal and perineal pain The nature of persistent vaginal and perineal pain is less well characterised. As it has been speculated that tissue damage and inflammation are potential mechanisms for vaginal and perineal pain, it is considered predominantly nociceptive pain.70 Neuropathic pain attributable to obstetric trauma, such as pudendal neuropathy, is also a possible contributor. Perineal and vaginal pain after vaginal delivery has been associated with tissue trauma related to operative vaginal delivery, perineal laceration, and use of episiotomy,15,16,18e20,22,26,53e55 although some studies also report its occurrence after Caesarean delivery with and without labour.20,22,26,52 Incidences of vaginal and perineal pain at different time points after the delivery and the risk factors are summarised in Table 2. Both studies, in which candidate risk factors predicted the pain outcome with statistical significance (positive studies) and those in which candidate risk factors failed to predict the pain outcome with statistical significance (negative studies), are mostly prospective studies, and sample sizes are comparable between positive studies (median: 501 [inter-quartile range: 445e821]) and negative studies (444 [227e1684]). As none of the studies performed a priori sample size calculation aiming for the detection of a specific effect size of candidate risk factors, it is possible that potential risk factors with clinically relevant effect size might have been missed in the negative studies because of lack of power. For positive and negative studies, the risk factors assessed in more than two studies are the mode of delivery22,26,52,57 and magnitude of perineal trauma.6,19,54e56,58,59 Operative vaginal delivery (vs spontaneous vaginal delivery) was consistently reported as a risk factor, and in the studies where effect sizes were reported in the form of odds ratio, the magnitude ranges from 1.6 to 3.6.22 Even in the negative study, pain level assessed on 0e10 visual analogue scale tended to be higher with operative vaginal delivery.57 As the effect is in the same direction in all studies, operative vaginal delivery is likely to be a robust predictor for persistent perineal pain. Studies of the magnitude of perineal trauma vary in comparison groups. Some compared episiotomy vs no episiotomy,19,56 others compared perineal trauma vs no perineal trauma,6,55,58,59 or multilevel comparisons between episiotomy and different degrees of perineal laceration.54 This makes assessment of effect size on the effect of perineal trauma on persistent pain difficult. However, even in the negative studies, reported pain intensity of perineal pain tended to be higher in women with episiotomy than those without episiotomy,56 with a trend of increased incidence of persistent pain with increased tissue trauma burden (doseeresponse relation).59 It is likely that perineal trauma burden has some effect on the development of persistent perineal pain, and the mechanism has face validity. A potential intervention that may address to decrease perineal trauma burden is the judicious use of episiotomy.

Other persistent pain syndromes after vaginal and Caesarean delivery Aside from pain in specific body locations, many studies have evaluated risk factors for persistent general back pain,10,13,21,23e25,27e30 persistent diffuse pain, or any pain after childbirth.7,9,11,12,17,20,28,39,40,42,44,45 Persistent back pain has been extensively studied. Many potential risk factors have been evaluated. Our literature

Time points after delivery 6e8 weeks

Glowacka and colleagues15

150

Incidence Risk factors

Woolhouse and colleagues16 Paterson and colleagues18

1431

Incidence Risk factors Incidence Risk factors

Thompson and colleagues22

1193

Eisenach and colleagues20 Glazener and colleagues26

114

939 438

Declercq and colleagues19

1573

Risk factors

Primiparity and operative vaginal delivery (vs spontaneous vaginal delivery)

Incidence Risk factors Incidence

1.3%z

Risk factors Klein and colleagues55 Sartore and colleagues54 Williams and colleagues52

697 519 482

55

12e18 months

6.4%

2.2%,* 1.8%y

4.2% for 17e24 weeks Primiparity and operative vaginal delivery (vs spontaneous vaginal delivery)

¶

10% between 2 and 18 months Primiparity and operative vaginal delivery (vs spontaneous vaginal delivery) 2% for vaginal deliveryx Mode of delivery and primiparity

Mode of delivery and episiotomy

Incidence Risk factors Incidence Risk factors Incidence

Incidence Risk factors

6.5% for 9e16 weeks Primiparity and operative vaginal delivery (vs spontaneous vaginal delivery)

22% between discharge home and 8 weeks Primiparity and operative vaginal delivery (vs spontaneous vaginal delivery) 48% for vaginal deliveryzx

55.7% Degree of perineal trauma 4.4% Episiotomy

Risk factors Soares and colleagues6

6 months

30.2% Previous diagnosis of nongenital chronic pain 22.1% for 0e8 weeks

Incidence

4 months

27.3% Non-genitopelvic pain prior to pregnancy 29.1%

Incidence

Risk factors

3 months

14.5%z Catastrophising assessed by Pain-Related SelfStatements Scale during admission of delivery, and perineal trauma

Caesarean delivery: 0%; normal vaginal delivery: 30.0%; operative vaginal delivery: 36.4%*jj Asian race (vs Caucasian) and forceps delivery

Continued

Komatsu et al.

Sample size

-

Study

6

Table 2 Incidence and risk factors for perineal pain and vaginal pain. *Pain at 12 months after delivery. yPain at 18 months after delivery. zPain at 8 weeks after delivery. ¶The risk factors for combined pain of multiple body parts were reported, and the risk factors specific for perineal and vaginal pain were not reported. xBoth vaginal and Caesarean deliveries were included in the study, but only incidences for vaginal delivery were reported. jjThe incidences for the entire study population were not reported, and only the incidence for each delivery type was reported. #Pain at 6 weeks after delivery. **Studies in which evaluated risk factors for vaginal and perineal pain failed to demonstrate statistical significance.

5404

Incidence Risk factors Incidence Risk factors Leeman and colleagues58** Albers and colleagues59**

179

444

7.1%# Primiparity Incidence Risk factors Incidence Risk factors 447

Macarthur and Macarthur53 Fodstad and colleagues57**

6e8 weeks

Sample size Study

Table 2 Continued

Time points after delivery

3 months

24.6% Episiotomy type (midline vs mediolateral vs lateral vs non-classifiable), episiotomy length, and spontaneous vaginal delivery (vs operative vaginal delivery) 9.7% Degree of perineal trauma 6.8% Degree of perineal trauma

4 months

6 months

12e18 months

Persistent pain after childbirth

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search identified the following risk factors for persistent back pain: history of back pain prior to pregnancy,23e25,27,29,30 back pain during index or previous pregnancy,21,25,27 earlier onset, longer duration,21 more severe and disabling back pain during pregnancy,21,23 sick leave attributable to back pain,29 pain in other body locations during pregnancy,28 unmarried status,28 heavier weight,13,27 larger weight gain during the postpartum period,21 heavy physical work,29 Caesarean delivery (vs vaginal delivery),10,16 use of epidural labour analgesia,28 induced labour as opposed to spontaneous labour,13 no use or short-term use of oral contraceptives (vs long-term use),23 and urinary tract infection and renal calculi.10 Older age10,21,24,27 and primiparity22,24 have been reported both as protective and risk factors. Candidate variables from negative studies include the use of epidural for labour analgesia,37 Caesarean delivery (vs nulliparity), vaginal delivery (vs nulliparity),33 Caesarean delivery (vs vaginal delivery),35 operative vaginal delivery (vs spontaneous vaginal delivery),35 postsurgical complication (such as diastasis recti abdominis),31 a physical therapy programme developed by the authors,34 and a home exercise programme developed by the authors.36 Both studies, in which candidate risk factors predicted the pain outcome with statistical significance (positive studies) and those in which candidate risk factors failed to predict the pain outcome with statistical significance (negative studies), are largely prospective studies, and sample sizes are comparable between positive studies (median: 916 [inter-quartile range: 385e1253]) and negative studies (185 [95e6921]). Because none of the studies included an a priori sample size calculation aiming for the detection of a specific effect size of candidate risk factors, it is possible that potential risk factors with clinically relevant effect sizes might have been missed in the negative studies because of lack of power. For positive and negative studies, the risk factors studied in more than two studies are obesity and pregnancy-related weight gain,13,21,27 pregnancy-related back pain,21,25,27,29,30 history of nonpregnant back pain,21,23e25,29 Caesarean delivery (vs vaginal delivery),10,16,35 and age.10,21,24,27,28 As the reported effect size is consistently in the same direction13,21,27 and there is a mechanistic rationale, obesity and pregnancy-related weight gain are likely to be associated with the development of persistent back pain. The effect size is not readily interpretable in many of these studies as an odds ratio or relative risk is not reported. For the studies of pregnancy-related back pain, in which effect sizes were reported in interpretable form, the magnitude odds ratios range from 1.7 to 5.9.21,25,27 Odds ratios for history of pre-pregnancy back pain range from 4.4 to 7.5.21,23,25 Given the large effect size that is consistently in the same direction, both pregnant and non-pregnant back pain are robust risk factors for persistent back pain. In contrast, the effect size for age has been rarely reported.10 The association between Caesarean delivery (vs vaginal delivery) and the development of persistent back pain was reported to be small (odds ratios and relative risks between 0.9 and 1.4).10,16,35

Pregnancy-related hormonal changes and persistent pain After surgical (Caesarean) delivery, a lower incidence of persistent pain has been reported in comparison with that after some general surgical procedures in similar locations in women.71 Because of this observation, it has been speculated that the high oestrogen and progesterone concentrations found during pregnancy may result in pregnancy-induced

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analgesia. Animal models of central and peripheral nerve injury have demonstrated neuroprotective effects for oestrogen and progesterone via multiple mechanisms. In human experimental models, results have been mixed related to the modality of pain.72e75 Preclinical studies that have demonstrated an anti-nociceptive effect from oxytocin are robust.76,77 At this time, the results of human clinical trials are sparse.

Genetic factors and pain related to childbirth The physiology that underlies pain perception is multifactorial, complex, and also beyond the purview of this review.78 Briefly discussed next, genetic factors have been considered as potential contributing factors in the setting of acute pain,79 persistent pain,80 and in some studies of acute post-partum pain.81e83 Although few studies have evaluated the effects of gene polymorphisms specifically on persistent post-partum pain, a few selected gene polymorphisms that have been widely implicated in other pain phenotypes have been evaluated for association with acute post-partum pain. As acute post-partum pain is a risk factor for persistent post-partum pain, these associations may be relevant. The m-opioid receptor gene (OPRM-1) encodes the m-opioid receptor, a primary site of opioid action. A common singlenucleotide substitution at position 118 of the OPRM-1 gene, adenine by guanine (A118G), is associated with changes in receptor glycosylation, decreased binding affinity for exogenous and endogenous opioids, and increased pressure pain threshold in humans.84 Whilst this variant is strongly associated with higher opioid requirements in the perioperative setting, the effect size is relatively small.85 With regard to acute post-partum pain, several studies have evaluated the effect of OPRM-1 A118G polymorphism on systemic opioid requirements after Caesarean delivery performed under spinal anaesthesia.81e83 Results have been mixed according to the population studied and perhaps the relative frequency of the polymorphism. In a study of a North American cohort, systemic opioid requirements during 3 post-partum days were not different between parturients who carry the G118 allele and those with AA118 homozygosity.83 In Chinese Singaporean patients, post-partum 24 h i.v. patient-controlled opioid analgesia consumption was higher in women carrying G118 allele than those with AA118 homozygosity.81 The same group showed an association between higher 24 h i.v. morphine requirements and the G118 allele in a separate cohort of mixed ethnicities.82 As higher opioid dose requirements are likely associated with higher acute post-partum pain burden, a predictor for persistent pain,17,20 it is possible that OPRM-1 A118G polymorphism might have some effects on developing persistent pain after the delivery, and may be worth further investigation. The catechol-O-methyltransferase (COMT) enzyme breaks down catecholamines and regulates oestrogen metabolism. A single-nucleotide polymorphism in the COMT gene at position 472 (p. 472 G/A) results in amino acid substitution Val158Met, which is associated with lower COMT enzyme activity and higher baseline pain sensitivity.86,87 In an experimental setting, subjects homozygous for the Met158 allele demonstrate increased pain sensitivity88 and greater opioid-induced hyperalgesia.89 This polymorphism has been put forward as a risk factor for the development of persistent pain90 and severity of acute pain.91 In non-pregnant surgical patients, Met158 allele has been associated with higher numerical

rating scores to various acute noxious stimuli,91 and i.v. fentanyl was less effective for the treatment of early-stage labour pain in women homozygous for Met at COMT158.92 Thus far, one Chinese study has evaluated the effect of COMT Val158Met polymorphism on systemic analgesic requirements during the acute period after Caesarean delivery and incidence of persistent pain at 3 months; this found that the polymorphism is not associated with either outcome.93 However, an a priori sample size calculation to detect a specific effect size of the polymorphism on the incidence of persistent pain was not performed in that study.93

Possible preventive interventions Intraoperative management that limits acute postoperative pain has been put forward as being potentially preventative for persistent pain. This seems reasonable because of the association between the severity of acute postoperative pain and persistent pain.1,47 Neuraxial analgesia is the most common anaesthetic technique used for elective Caesarean delivery in the USA and in Europe,94,95 often using a combination of local anaesthetic with lipophilic opioids, such as fentanyl, and more hydrophilic, longer-lasting opioids, such as morphine. Neuraxial analgesia is increasingly supplemented with a multimodal postoperative analgesic regimen consisting of non-steroidal anti-inflammatory agents, acetaminophen, and oral opioids.94 In an attempt to reduce postoperative pain burden and opioid utilisation, multiple analgesic adjuncts have been evaluated and found effective in reducing acute pain. The efficacy for the prevention of persistent pain after surgical delivery has been studied less commonly and with mixed results. Clonidine is a prototypical a2-adrenergic agonist. Neuraxially administered clonidine mediates its analgesic effect by activating a2-receptors located in the dorsal horn of the spinal cord and postsynaptic activation of descending inhibitory neurones. The efficacy of neuraxial clonidine for postCaesarean pain and opioid requirement has been evaluated.96e99 A meta-analysis published in 2018 showed that clonidine prolongs neuraxial anaesthesia and reduces opioid consumption more than 24 h after Caesarean delivery.100 Only a few studies have evaluated the effect of clonidine on more persistent pain.51,97 Lavand’homme and colleagues97 demonstrated that high-dose (150 mg) intrathecal clonidine decreased the incidence and area of peri-incisional hyperalgesia at 48 h after operation, which has been shown to be a marker of central sensitisation and a predictor of persistent pain in a non-pregnant surgical population.101 Bollag and colleagues51 studied clonidine’s activity in the peripheral nervous system. Clonidine 150 mg, administered into the transversus abdominal plane combined with a local anaesthetic (bupivacaine), did not have a significant effect on the incidence or area of periincisional hyperalgesia at 24 and 48 h after Caesarean delivery.51 Neither study found a decreased incidence of persistent pain at 6 months,97 or decrease in persistent pain descriptors evaluated using the Short-Form McGill Pain Questionnaire at 3e12 months in clonidine-treated patients.51 However, those studies may have been underpowered to detect a beneficial effect of clonidine on chronic pain after Caesarean delivery likely because of a floor effect. At this time, the efficacy, optimal dose, route of administration, and target population have yet to be confirmed for a2-agonists. Gabapentin and pregabalin are anticonvulsants widely used for the treatment of neuropathic pain conditions. They

Persistent pain after childbirth

decrease excitatory neurotransmitter activity by binding to voltage-gated calcium channels,102 thereby attenuating afferent nociceptive signalling. Several placebo-controlled trials have evaluated the efficacy of perioperative gabapentin on acute post-partum pain after Caesarean delivery with spinal anaesthesia.103e108 The incidence of persistent pain at 3 months post-partum was evaluated in two studies.103,104 The study by Moore and colleagues103 used a single dose of gabapentin at 600 mg, whereas the study by Short and colleagues104 used a single dose of gabapentin at 300 or 600 mg, 1 h before operation. Those studies failed to show a statistically significant difference in the incidence of persistent pain between gabapentin and placebo. However, those studies similarly suffered from a floor effect with a few patients in the placebo group suffering from severe or persistent pain. Gabapentin may require a larger dose, longer duration, or an enriched population to demonstrate a clinically meaningful effect for the prevention of persistent pain after Caesarean delivery. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, which has analgesic properties at a subanaesthetic dose, and has been used for the prevention and treatment of acute and persistent pain. It prevents hyperalgesia and central sensitisation caused by noxious stimuli via NMDA inhibition,109,110 and may also prevent acute opioid tolerance.111 A meta-analysis, published in 2015, aggregated the results of 12 RCTs, in which i.v. ketamine administered during surgery (0.15e1 mg kg1), placebo, or other interventions were compared with respect to the incidence of post-Caesarean pain.112 The analyses demonstrated that time to first analgesic request was significantly longer, and the visual analogue scale pain sores at rest 2 h after surgery performed under spinal anaesthesia were significantly lower in ketamine-treated women. No such effects were observed in the studies, in which general anaesthesia was used.112 Very few studies have investigated the effect of ketamine on persistent pain after Caesarean delivery.113 One RCT failed to show the efficacy of ketamine on persistent pain at 1, 6, and 12 months (0.25e1 mg kg1 in conjunction with general anaesthesia).113 Another RCT, in which S-ketamine 0.5 mg kg1 was given intramuscularly, followed by i.v. infusion at 2 mg kg1 min1 for 12 h in conjunction with spinal anaesthesia found no effect on persistent pain at 3 yr after operation.114 In contrast, a study, in which ketamine 10 mg was given after Caesarean delivery performed with spinal anaesthesia, lower pain scores were reported in women who received ketamine 2 weeks post-partum despite no measurable analgesic benefit of ketamine was observed during 24 post-partum hours.115 S-ketamine did attenuate hyperalgesia at the dermatomes corresponding to Caesarean incision at 12 and 24 h after operation,114 which suggests the potential of ketamine for the prevention of persistent neuropathic pain. In the majority of the studies of the efficacy of clonidine,51,97e99 gabapentin,103e105,107 and ketamine described previously,113e115 multimodal analgesia was used for post-Caesarean analgesia. One study of clonidine96 and two studies of gabapentin106,108 did not document whether other agents were used in their studies and were therefore of lower quality. Currently, there are few studies with mixed findings on the efficacy of perioperative analgesics on persistent pain after Caesarean delivery, and even less information regarding preventive measures of persistent pain after vaginal delivery.

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Opioid use after childbirth Despite the fact that childbirth is a common entry point for opioid use amongst a large number of young women, the issue had not gathered attention until two large population-based studies evaluated persistent opioid use after Caesarean delivery in 2016.2,116 Those studies identified younger age, cocaine and other illicit substance, tobacco, antidepressant, benzodiazepine use, and persistent pain history (back pain and migraine) as risk factors for persistent opioid use.2,116 Several other studies have evaluated the extent of opioid use during the acute phase after Caesarean117,118 and vaginal delivery in the USA.119,120 Most women (estimated 83% in one study117) in the USA used opioids after discharge from a hospital after Caesarean delivery. The median duration of opioid use after discharge amongst all women included in this one study was 8 days.117 The investigators found that smoking during pregnancy, public insurance, and higher opioid dose requirement during post-partum hospital stay were associated with greater opioid use after discharge.117 They subsequently performed an RCT comparing the standard prescription of 30 oxycodone 5 mg tablets at hospital discharge with an individualised discharge opioid prescription based on inpatient opioid requirement for each patient. The group that received an opioid prescription based on their in-hospital use had a 50% reduction in post-partum outpatient opioid dose without compromising the quality of pain control.121 Similarly, Bateman and colleagues118 found that 85% of women filled an opioid prescription after Caesarean delivery, and used a median 20 tablets of oxycodone or hydrocodone 5 mg. Women who were prescribed a larger amount of opioid also used more medication, whilst pain reports and patient satisfaction were not different according to opioid prescription.118 This suggests that the amount of opioids the patients take after Caesarean delivery is influenced by the number of pills/ doses prescribed at discharge from the hospital. In the setting of vaginal delivery, single-institution data showed that only a minority of women required opioids after discharge.122 Twenty per cent of American women who delivered vaginally filled an opioid prescription within 5 days of delivery.119 The risk factors for filling opioid prescription were tobacco use and mental health condition.119 In another study of vaginal delivery, multiparous women used more opioids than primiparous women.120

Limitations The sample sizes of many studies included in this narrative review did not have a priori statistical plan and were not powered to detect a priori determined effect size of candidate risk factors for persistent pain. In small studies with inadequate power, there is a significant risk of a Type 2 error. Further statistical adjustments for confounding variables for persistent pain were often not performed. Pain present during pregnancy and new pain developed after the delivery were often not differentiated in the included studies. Therefore, the risk of bias could be substantial, and caution is warranted for interpretation of the results of many individual studies included in this narrative review.

Future directions The reported incidence of persistent pain after childbirth is quite variable depending on the location and type of pain

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syndrome, duration studied, and study methodology. The good news is that most women have an uneventful childbirth and require analgesic medication for a short duration, and do not suffer from persistent pain. Most studies evaluated demographic, obstetrical, surgical, anaesthetic, and some psychological attributes as candidate predictors for persistent pain. Few included a thorough evaluation of genetic or psychological factors using current, validated instruments. Studies involving larger populations with pre-specified analysis plans and sample size calculations will help to identify robust generalisable predictoreoutcome relationships. In future prospective studies, clear pre-pain phenotypes and documentation of the timing of onset of pain are essential. To improve comparability between studies, and to develop normative data specific to parturients, assessment using validated instruments, such as the ones recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials, will be needed.123 Furthermore, bidirectional predictoreoutcome relationships for some phenotypes, such as depression, are likely where the interaction between predictor and outcome happens over time.40,124 As such, acquisition of longitudinal data for both predictor and outcome is warranted to allow for identification of specific type and timing of preventive interventions to be tested. Further, studies focused on functional outcome in relation to pain40 and those focused on women with vaginal delivery are important, as the incidence and severity of persistent pain after vaginal delivery are not as different from Caesarean delivery as one might suspect,20 and information about functional outcome and the differences in persistent pain outcomes between Caesarean and vaginal delivery is presently scarce. Amongst the consistently reported risk factors for persistent pain, acute post-partum pain is unique in that it is easily recognisable and is potentially modifiable. Strategies most effective for women at risk are only now developing and require rigorous evaluation and testing. Further multidisciplinary interventional studies designed to evaluate the efficacy and effectiveness of interventions in women at risk for persistent post-partum pain are warranted.

Authors’ contributions Study design: all authors Data collection: RK, KA Data interpretation: all authors Drafting/final approval of article: all authors

Declaration of interest The authors declare that they have no conflicts of interest.

Funding Department of Anaesthesiology and Pain Medicine, University of Washington.

Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2019.12.037.

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