DATE: 17 January 2011 CONTEXT AND POLICY ISSUES

TITLE: Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery: A Review of Clinical Effectiveness, Safety, and Clinical Practice Guidelines DATE: 17 January 2011 CONTEXT AND POLICY ISSUES Pain relief during labour and delivery is an important component of care and may influence the woman s satisfaction with labour and delivery. 1 Both pharmacologic and non-pharmacologic therapies have been shown to reduce maternal pain or improve coping with labour pain. 2 Intravenous (IV) or intramuscular opioids such meperidine, morphine, fentanyl and remifentanil have been used during labour. 3 Epidural administration of opioids and local anesthetics is also used for maternal pain relief. 1 Intravenous fentanyl has a rapid onset and a 30 to 60 minute duration of action. 4 It crosses the placental barrier and thus may cause adverse effects in the newborn. As with all opioids, it may cause sedation, nausea, vomiting, or respiratory depression. 4 This rapid review will evaluate the evidence on the safety, efficacy, and guidelines for use of IV fentanyl, and the fetal monitoring recommended for mothers who receive fentanyl during uncomplicated labour, to help inform a policy decision on the topic. RESEARCH QUESTIONS 1. What is the comparative safety and efficacy of IV fentanyl versus other analgesics used in uncomplicated labour and delivery? 2. What is the comparative safety and efficacy of continuous electronic fetal monitoring versus intermittent doppler monitoring for mothers receiving IV fentanyl during uncomplicated labour and delivery? 3. What are the clinical practice guidelines regarding the use of IV fentanyl in labour and delivery? Disclaimer: The Health Technology Inquiry Service (HTIS) is an information service for those involved in planning and providing health care in Canada. HTIS responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide a list of sources and a summary of the best evidence on the topic that CADTH could identify using all reasonable efforts within the time allowed. HTIS responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice, nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness particularly in the case of new and emerging health technologies, for which little information can be found, but which may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet. CADTH does not have control over the content of such sites. Use of third party sites is governed by the owners own terms and conditions.

KEY MESSAGE There is insufficient evidence to draw firm conclusions on the safety and efficacy of IV fentanyl versus other analgesics used on uncomplicated labour and delivery. There was no evidence on fetal monitoring during labour in women who received IV fentanyl, and evidence-based clinical practice guidelines on the use of IV fentanyl during uncomplicated labour were not found. METHODS A limited literature search was conducted on key health technology assessment resources, including PubMed, The Cochrane Library (Issue 12, 2010), University of York Centre for Reviews and Dissemination (CRD) databases, ECRI (Health Devices Gold), EuroScan, international health technology agencies, and a focused Internet search. The search was limited to English language articles published between January 1, 2000 and December 9, 2010. To address questions one and three, filters were applied to limit the retrieval to health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), nonrandomized studies and evidence-based clinical practice guidelines. To address question two, no filters were applied to limit the retrieval by study type. Reference lists of relevant articles were hand-searched. Rapid Report reports are organized so that the higher quality evidence is presented first. Therefore, systematic reviews are presented first, followed by RCTs, non-randomized studies, and evidence-based clinical practice guidelines. SUMMARY OF FINDINGS The literature search identified two systematic reviews 1,3 and three RCTs that evaluated the use of IV fentanyl compared to other analgesics for uncomplicated labour and delivery. 5-7 No relevant health technology assessments, meta-analyses or non-randomized studies were identified. No studies were identified that evaluated the comparative safety and efficacy of continuous electronic fetal monitoring versus intermittent doppler monitoring for mothers receiving IV fentanyl during uncomplicated labour and delivery. From the hand search of reference lists and the grey literature search, one Cochrane systematic review, and four guidelines were found that addressed fetal monitoring during labour. These reports were not specific to women receiving IV fentanyl and did not meet the inclusion criteria, thus they have been listed in Appendix B. No evidence based clinical practice guidelines were found regarding the use of IV fentanyl in labour and delivery. Four other guidelines were identified and have been listed in Appendix B. Systematic reviews and meta-analyses Two relevant Cochrane systematic reviews were identified in the literature search. 1,3 Ullman et al.2010 3 reviewed the use of parenteral opioids for pain relief during labour. They included RCTs that compared the effect intramuscular or IV opioids to placebo, a different dose of opioid or opioid combination, or another parenteral opioid, on maternal and neonatal outcomes. The authors searched the Cochrane and MEDLINE databases, hand searched journals, conference proceedings and BioMed Central alerts for relevant articles. Studies focusing on women in high-risk groups or premature labour were excluded. Two authors Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 2

independently screened articles, extracted data, and evaluated the risk of bias in the RCTs, according to the Cochrane methodology. 3 The review included a total of 54 RCTs. Of these studies, three included fentanyl IV (Rayburn 1989, Atkinson 1994, Morley-Forster 2000). 3 The study characteristics are summarized in Table 1, and the results in Table 2. The study by Atkinson 1994 was a double blind RCT that compared IV fentanyl to IV butorphanol in 100 healthy women in labour who requested an analgesic other than an epidural. The doses of fentanyl and butorphanol were considered equivalent by study authors (Table 1). 3 The study found that women who were randomized to fentanyl were statistically significantly more likely to request additional doses of pain medication compared to those who received butorphanol (Table 2). The likelihood of requiring an epidural was also increased (relative risk (RR) 2.0 [95% Confidence Interval (CI) 1.0 to 4.0]) but was on the cut point for statistical significance. No increased risk of Caesarean section was detected. More babies of mothers who received fentanyl required naloxone, ventilatory support or had an apgar score <7 at 5 minutes, compared to those who received butorphanol. However, the confidence intervals around these RR estimates were large and consistent with no increased risk. Six of 50 mothers who received fentanyl were drowsy (required tactile rousing) compared to 2/50 who received butorphanol (p=0.17). Visual analog pain (VAS) pain scores were recorded by study nurses but the review authors did not report this outcome. There were no statistically significant differences between groups on the babies neurobehavioural scores at 2 to 4 hours, or at 24 to 36 hours. 3 The Atkinson 1994 study may be limited by attrition bias. A total of 155 patients were enrolled, of which 24 requested an epidural and were excluded. Another 19 women who delivered within one hour and 12 who did not request an analgesic were excluded from analysis. The systematic review authors stated that it was not clear if randomization occurred before or after these patients were excluded. Data on 100 patients were presented. 3 One double blind RCT (Morley-Forster 2000) compared patient controlled IV analgesia (PCIA) with fentanyl to equivalent doses of alfentanil. 3 A total of 25 patients were randomized and 23 completed the study. Women included in the study had contraindications to epidural (no details provided) and were at >32 weeks of gestation. After delivery, 10 of 11 women who received fentanyl described pain relief as adequate or good compared to 7/12 who received alfentanil (RR 1.56 [95% CI 0.9 to 2.6]). The pain score (100 mm VAS) recorded at 4 to 6 cm of cervical dilation was lower in the fentanyl than alfentanil group however the difference was not statistically significant (mean difference -13 mm [95% CI -32 to 7] ). No statistically significant differences were detected between groups on the rate of Caesarean section, nausea, or need for naloxone (Table 2). 3 The study was limited by the small sample size. One unblinded RCT compared IV fentanyl to IV meperidine (Rayburn 1989). 3 A total of 105 healthy women were enrolled who were in early active labour and who reqested analgesia other than an epidural. The mean pain scores on a nurse recorded 10 point VAS scale were 5.9 in the IV fentanyl group and 6.1 in the meperidine group, when measured one hour after drug administration. These differences were statistically significant however the clinical importance is less clear. Women in the fentanyl group required statistically significantly more doses of analgesic than in the meperidine group (2.3 versus 1.9 doses, respectively; mean difference 0.4 doses [95% CI 0.14 to 0.66]). Maternal sedation occurred statistically significantly more frequently among those who received meperidine (11/56) than fentanyl (0/49). No statistically significant differences were detected between groups on other maternal and neonatal outcomes Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 3

(Caesarean section, nausea or vomiting, babies requiring resuscitation or naloxone, babies with apgar score <7 at 5 minutes, or neurobehavioural scores at two to 24 hours). 3 The Rayburn 1989 study was limited by lack of blinding and possibly selection bias. It was unclear if investigators and participants were aware of the next available treatment to be allocated. Studies with inadequate allocation concealment are more likely to report biased estimates of effect. 8 Blinding of participants to the treatment received is of particular importance for subjective outcomes such as pain. 8 With subjective outcomes the patient s or outcome assessor s expectations regarding a specific treatment may influence the outcomes reported. In this study it was not clear if the doses used were equivalent. The authors of the systematic review concluded that parenteral opioids provide some pain relief during labour but more research is needed to determine which regimen is most effective andprovides the greatest maternal satisfaction to women with the least incidence of adverse effects. 3 Table 1. Study characteristics of IV fentanyl RCTs included in Cochrane systematic reviews 1,3 Study, design, country, publication type, risk of bias Population Comparator treatment Fentanyl Parenteral opioid analgesia 3 Atkinson 1994 DB SC RCT USA (full text) Allocation concealment: adequate Women 37 weeks gestation with no medical or obstetric complications or evidence of fetal distress who were in early active labour and requested pain medication other than epidural IV butorphanol: 1 to 2 mg every 1 to 2 hours prn; max. 5 doses Continuous electronic fetal monitoring and intrauterine pressure catheters IV fentanyl: 50 to 100 µg every 1 to 2 hours prn; max. 5 doses Continuous electronic fetal monitoring and intrauterine pressure catheters Morley-Forster 2000 DB SC RCT Canada (full text) Allocation concealment: adequate Rayburn 1989 Unblinded SC RCT USA (full text) N=100 (age and parity not reported) Women >32 weeks gestation with contraindications to epidural analgesia and who requested pain relief during labour N=25 (83% primiparous, age not reported) Women 37 weeks gestation with no medical or obstetric complications or evidence of fetal distress who were in IV alfentanil (PCIA): 100 µg LD, 200 µg per hour infusion, 200 µg bolus prn PCIA stopped 15 minutes before delivery IV meperidine: 25 to 50 mg per hour infusion N=56 IV fentanyl (PCIA): 10 µg LD, 20 µg per hour infusion, 20 µg bolus prn PCIA stopped 15 minutes before delivery IV fentanyl: 50 to 100 µg per hour infusion N=49 Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 4

Study, design, country, publication type, risk of bias Allocation concealment: unclear Population early active labour and requested pain medication other than epidural Comparator treatment Fentanyl Epidural analgesia 1 Nikkola 1997 Unblinded RCT Finland (full text) N=105 (~50% nulliparous, mean age 23 years) Healthy, primigravidas, age 20 to 36 years N=20 Epidural: 0.5% bupivacaine 6 ml LD, 4 ml top up during first stage labour IV fentanyl: 50 µg initially; 20 µg boluses (first stage only) Allocation concealment: unclear n=10 n=10 (4/10 women received epidural also) DB=double blinded; LD=loading dose; MC=multicenter; PCEA=patient controlled epidural analgesia; PCIA=patient controlled intravenous analgesia; prn=as needed for pain relief; SC=single center *IV fentanyl loading dose reported as 1 to 2 µg in the systematic review 1 however 100 µg is a more typical loading dose IV fentanyl doses reported as 20 mg and 50 mg 1 however this was interpreted to be 20 µg or 50 µg Table 2. Summary of results for RCTs comparing IV fentanyl to other parenteral opioids 3 Outcome Study, Comparator (RR [95% CI])* Atkinson 1994 Morley-Forster 2000 Rayburn 1989 IV butorphanol N=100 PCIA alfentanil N=23 IV meperidine N=105 Caesarean section 0.80 (0.23 to 2.81) 1.64 (0.33 to 8.03) 1.14 (0.24 to 5.40) Need for additional pain relief 1.39 (1.05 to 1.85) NR NR (2 or more additional doses) Epidural 2.0 (1.0 to 4.02) NR NR Nausea or vomiting NR 2.73 (0.66 to 11.3) 0.51 (0.17 to 1.55) Maternal sedation 3.0 (0.64 to 14.16) NR 0.05 (0 to 0.82) Babies requiring resuscitation/ 11.0 (0.62 to NR 1.03 (0.46 to 2.32) ventilator support 193.80) Apgar score <7 at 5 minutes 1.2 (0.39 to 3.68) NR 0.38 (0.02 to 9.12) Naloxone required 1.75 (0.81 to 3.80) 2.36 (0.53 to 10.55) (n=24) 0.16 (0.02 to 1.28) CI=confidence interval; IV=intravenous; n=number; NR=not reported; PCIA=patient controlled intravenous analgesia; RCT=randomized controlled trial; RR=relative risk) *RR <1 favors IV fentanyl A total of 25 patients were randomized in study. Two patients did not follow protocol and were not followed up. Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 5

The systematic review by Anim-Somuah et al 2005 1 assessed the effects of epidural analgesia on the mother and baby compared to non-epidural analgesia or no pain relief during labour. The authors searched the Cochrane and MEDLINE databases, BioMed Central and hand-searched relevant journals and conference proceedings. Two authors independently screened and evaluated articles for inclusion, performed the quality assessment and extracted the data. Study quality included assessment of allocation concealment, blinding and attrition bias, They included RCTs of women requesting pain relief during spontaneous and induced labour. Interventions were all forms of epidural analgesia compared to no pain relief or non-regional analgesia. A total of 50 maternal, infant and economic outcomes were evaluated and meta-analysis was performed when homogeneous data were available. The review included a total of 21 RCTs and of these, two compared epidural analgesia to IV fentanyl (Muir 2000, Nikkola 1997). The 1997 study characteristics by Nikkola are summarized in Table 1. Muir 2000 was available as an abstract only and appears to be interim results of the Halpern 2004 6 report. This study is discussed in the RCT section of this report. The second RCT (Nikkola 1997) compared intermittent epidural analgesia to PCIA fentanyl in 20 healthy primigravidas women. None of the patients in the study required a Caesarean section, however 4/10 in the epidural group required an instrumental vaginal delivery compared to 0/10 in the IV fentanyl group [RR 9.0 (95% CI 0.6 to 148)]. No babies had an apgar score <7 at 5 minutes and none required naloxone. All ten patients in the epidural group were satisfied with their pain relief compared to 8/10 in the IV fentanyl group. Nausea and vomiting was reported in 10% versus 50% of patients, shivering in 20% versus 0%, and drowsiness in 60% versus 0%, in the epidural versus IV fentanyl groups respectively. The study was limited by the lack of blinding and small sample size (n=20). The authors of the systematic review did not report findings separately for different comparator analgesic regimens thus their conclusions represent pooled findings for all control treatments, (active and no treatment comparators). Overall, the authors concluded that epidural analgesia provides better pain control than non-epidural forms of pain relief but increases the risk of instrumental vaginal delivery. 1 Randomized controlled trials Three relevant RCTs were identified in the literature search. 5-7 The study by Douma 2010 was a double blind randomized study that evaluated the efficacy and safety of PCIA during labour. 5 The study randomized a total of 180 healthy women who were full term and in active labour to either IV remifentanil, meperidine or fentanyl (see Table 3 for further details). Twenty one women who delivered within one hour of starting analgesia were excluded from the analysis. Patient characteristics were similar between groups at baseline. Investigators found that women who received meperidine were more likely to crossover to epidural analgesia than those who received remifentanil or fentanyl (34% versus 13% or 15% respectively, p<0.05) (Appendix A Table 4). The proportion of women who required instrumental delivery or Caesarean section was not statistically significantly different between groups. Spontaneous vaginal delivery occurred in 85% of those who received fentanyl compared to 69% or 62% who received meperidine or remifentanil (p<0.05). It should be noted that patients who crossed over to epidural analgesia were not included in the analysis of mode of delivery. An intention to treat analysis, therefore, was not conducted. 5 Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 6

Patient assessment of pain was scored hourly using a 0 to 10 cm VAS. 5 The within-group analysis showed that pain scores were statistically significantly lower versus baseline for all groups at one hour and for the fentanyl and remifentanil groups at two hours. After two hours, the pain scores were similar to baseline values. In the between-group analysis there were no statistically significant differences between groups on the pain scores at baseline, or the change in pain scores one hour and three hours after initiating analgesia. At two hours, the remifentanil group showed a greater reduction in pain scores than the fentanyl (-3.2 cm versus -1.4 cm, p<0.01) or meperidine (-0.8 cm, p<0.001) groups. There was no statistical difference between fentanyl and meperidine on the mean change in pain score from baseline to two hours. 5 A blinded observer assessed patient sedation using a 5 point scale (1= awake, 5=unrousable). 5 Sedation scores increased from baseline for all groups (p<0.05). The remifentanil groups showed the greatest increase in sedation which was statistically significantly different than the fentanyl or meperidine groups at one or two hours after starting therapy. Sedation scores were similar in the fentanyl and meperidine groups after one, two or three hours of analgesia. 5 Duration of the first and second stage of labour, the use of oxytocin, or incidence of nausea or vomiting was not statistically significantly different between groups. 5 Statistically significantly more patients who received remifentanil reported itching compared to those who received meperidine or fentanyl. More mothers who received remifentanil had an oxygen saturation <95% (74%) compared to meperidine (33%, p<0.0001) or fentanyl (56%, p=not significant). Neonatal apgar scores, cord blood ph or Neurologic and Adaptive Capacity Score (NACS) were not statistically significantly different between groups. Maternal overall satisfaction was higher in the remifentanil than the meperidine group (p<0.05) and not statistically significantly different between other groups. 5 The study was limited by use of a per-protocol analysis rather than the intention to treat method, which could potentially bias the findings. Allocation concealment was unclear. Data reported was incomplete for some outcomes (e.g., apgar scores for 11 newborns were not reported). The authors concluded that remifentanil PCIA provided more effective pain relief than meperidine or fentanyl in the first two hours after initiation, but with more maternal sedation, itching and periods of oxygen desaturation. 5 One RCT was conducted in Canada (Halpern 2004 6 ). This study appears to be the full report of the Muir 2000 abstract discussed in the Cochrane review. 1 In this study, 242 healthy nulliparas women, >37 weeks gestation, who requested analgesia for labour pain, were randomized to either fentanyl PCIA or fentanyl + bupivacaine patient controlled epidural analgesia (PCEA) (Table 3). Maternal and neonatal characteristics were similar between groups. 6 Most maternal outcomes were similar between groups (Appendix A Table 5). 6 Of the 118 patients who received IV fentanyl, 51 requested and 12 received an epidural to assist delivery during the second stage of labour. Three patients in the epidural group had inadequate analgesia. Maternal satisfaction with analgesia was higher and pain scores were lower in the epidural group versus the IV fentanyl group (both outcomes were statistically significant). The incidence of Caesarean section, instrumental vaginal delivery or spontaneous vaginal delivery was not statistically significantly different between the two groups. Seventeen percent of women in the IV fentanyl group required antiemetic therapy compared to 6% in the epidural group (p=0.01). Maternal sedation was also higher in the IV fentanyl than the epidural group (39% versus 5%, respectively, p<0.001). One patient in the IV fentanyl group experienced respiratory Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 7

depression. In the epidural group approximately 68% of patients had minimal or no motor block. 6 Among the neonates, 28% in the IV fentanyl group and 17% in the epidural group had a one minute apgar score <7 (p=0.04). 6 Apgar scores at 5 minutes, umbilical artery blood gasses, and the incidence of neonatal fever were not statistically significantly different between groups. Active resuscitation was required in 52% and 31% of babies, and naloxone was required in 17% and 3% of babies in the IV fentanyl and epidural groups respectively (p 0.001 for both outcomes). The study s authors reported that resuscitation with oxygen and bag and mask was short-lived (length of time was not specified). They stated that the need for naloxone may be related to the amount of IV fentanyl required to achieve adequate pain relief, or bias on the part of physicians who were unblinded to the method of analgesia. 6 The lack of blinding was a study limitation. The study was also underpowered to detect a difference in the primary outcome of Caesarean section incidence. The authors were unable to achieve their targeted sample size since a number of women had induced labour and, subsequently, were excluded from the study. The authors concluded that PCIA with bupivacaine and fentanyl does not increase the incidence of Caesarean section or instrumental vaginal delivery compared to fentanyl PCIA in healthy nulliparous women in spontaneous labour. Maternal satisfaction with analgesia was higher, and neonatal depression was less likely in women receiving epidural analgesia than IV fentanyl. 6 In the study by Nikkola 2000 7 a total of 12 healthy women in labour were enrolled in the open label RCT. Patients were randomized to receive either a paracervical block using bupivacaine or PCIA with fentanyl (Table 3). The study was terminated early, before the planned 20 patients had been enrolled, due to an adverse event in one neonate in the fentanyl group. This neonate had an oxygen desaturation event (Sp O2 59%) requiring naloxone three hours after birth. The authors did not report the patient characteristics for each group. 7 Maternal pain was measured using a 100 mm VAS and pain relief was reported to be similar in the short- and long-term analyses. 7 No details were provided and it was unclear if the patient or a proxy determined pain scores. In the fentanyl group, 4 of 5 women had sedation, three had dizziness, and two reported nausea. In the block group one patient reported nausea. Duration of labour was similar between groups. One patient in the block group required vacuum extraction due to threatened fetal asphyxia. All other mothers had spontaneous vaginal deliveries. 7 The mean neonatal blood pressure, temperature or respiratory frequency values were not statistically significantly different between groups. 7 None of the babies had an apgar score <8, nor did they have central cyanosis or require oxygen. Neonates whose mother s had received fentanyl experienced more episodes of oxygen saturation between 81% and 90% (p=0.02). The authors concluded that there were differences on a number of maternal and neonatal ouctomes between fentanyl and paracervical block and that post-delivery monitoring of neonates is important born to mothers who received opioids during labour. 7 The study was limited by the lack of blinding and the sample size (n=12). The authors failed to report the characteristics of patients enrolled, and the methods used to randomize patients or conceal allocation. The findings should be considered exploratory. Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 8

Table 3. Randomized Controlled Trial Characteristics Study, design, Population Interventions country, publication type, risk of bias Douma 2010 5 Healthy, term parturients in active labour requesting analgesia DB RCT Netherlands (full text) Allocation concealment: unclear Halpern 2004 6 Unblinded MC RCT Canadian (full text) Allocation concealment: adequate Nikkola 2000 7 Unblinded SC RCT Finland (full text) Allocation concealment: unclear Enrolled: N=180 Completed: n=159 Mean age: 33 years Primiparous: 64% Mean gestation: 40 weeks Healthy, nulliparous women, 37 to 42 weeks gestation in spontaneous labour, requesting analgesia Enrolled N= 242 Completed N=242 Mean age: 28 years Mean gestation: PCIA 39 weeks, PCEA 40 weeks Healthy multiparous mothers in active labour requesting analgesia; >37 weeks gestation; age 20 to 36 years Enrolled: N=12 Completed: N=12 Patient characteristics not reported IV remifentanil (PCIA): 40 µg LD, 40 µg every 2 minutes prn; max 1200 µg/h IV meperidine (PCIA): 49.5 mg LD, 5 mg every 10 minutes prn; max 200 mg. IV fentanyl (PCIA): 50 µg LD, 20 µg every 5 minutes prn, max 240 µg/h Epidural (PCEA): 15 to 25 ml 0.1% bupivacaine + 100 µg fentanyl LD, then 5 ml 0.08% bupivacaine + 1.6 µg/ml fentanyl, every 10 minutes prn IV fentanyl (PCIA): 100 to 150 µg LD, 25 to 50 µg every 10 minutes prn Paracervical block: 10 ml of 0.25% bupivacaine injected in 4 locations at cervix IV fentanyl (PCIA): 50 µg every 5 minutes prn DB=double blinded; LD=loading dose; MC=multicenter; PCEA=patient controlled epidural analgesia; PCIA=patient controlled intravenous analgesia; prn=as needed for pain relief; RCT=randomized controlled trial; SC=single center Limitations This rapid review is limited by the number and quality of the RCTs identified. We found eight reports of seven RCTs that evaluated the safety and efficacy of IV fentanyl. No studies or guidelines were found to address research questions two or three. For the RCTs described in the systematic reviews, 1,3 we have reported the data available in the review and were not able to verify the accuracy and completeness of these data. The Rayburn 1989 3 study and the RCTs 1,6,7 that compared IV fentanyl to epidural or paracervical block may potentially be biased by the lack of blinding. The Morley-Forster 2000, 3 Nikkola 1997 1 and Nikkola 2000 7 studies were limited by sample size (<25 patients). The RCTs included may have Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 9

limited power to detect differences between groups on less common outcomes, such as adverse events. Allocation concealment was unclear for four studies (Rayburn 1989, 3 Nikkola 1997, 1 Douma 2010 5 and Nikkola 2000 7 ) and it is possible that the selection of patients was biased if the next available treatment was known to the investigator when patients were enrolled in the trial. It was assumed that the mothers, rather than a proxy, were asked to rate pain level using the VAS, however this was not clearly stated for most studies. In two studies published before 1995 nurses recorded the VAS pain scores. 3 Some studies reported a statistically significant difference between IV fentanyl and comparators on pain levels using a VAS. When interpreting these findings, it is important to consider the smallest change in pain that patients would consider important. This minimal clinically important difference (MCID) may be larger than some of the statistically significant differences detected. We were unable to find the MCID for labour pain but for patients with acute low back pain, the MCID is 35 mm on a 0 to 100mm VAS. 9 In patients presenting to the emergency department with acute pain a mean reduction in the VAS of 30 mm represents a clinically important difference to patients. 10 CONCLUSIONS AND IMPLICATIONS FOR DECISION OR POLICY MAKING: The literature search identified two systematic reviews and three RCTs that addressed the safety and efficacy of IV fentanyl for pain relief during uncomplicated labour. From these reports IV fentanyl was compared to another opioid in four RCTs, to epidural analgesia in two RCTs and to paracervical block in 1 RCT. When comparing pain scores among women who received IV fentanyl to those who received other parenteral opioids, no clear clinically important differences were noted in the RCTs. The rates of other maternal and neonatal outcomes appear to be similar however conclusions should be drawn cautiously due to the small number of RCTs, and the limited sample size. One study suggested that maternal sedation and nausea and vomiting, and the need for neonatal resuscitation were more common in mothers who received IV fentanyl than epidural analgesia during labour. In this study maternal satisfaction with analgesia was higher in women who received epidural analgesia. Due to the lack of studies, no conclusions can be drawn on fetal monitoring during labour in women who received IV fentanyl. No evidence based clinical practice guidelines were found on the use of IV fentanyl during uncomplicated labour. PREPARED BY: Canadian Agency for Drugs and Technologies in Health Tel: 1-866-898-8439 www.cadth.ca Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 10

REFERENCES: 1. Anim-Somuah M, Smyth RMD, Howell CJ. Epidural versus non-epidural or no analgesia in labour. Cochrane Database of Syst Rev [Internet]. 2005 [cited 2010 Dec 9];(4). Art. No.: CD000331. Available from: http://www.thecochranelibrary.com/view/0/index.html Subscription Required. 2. National Collaborating Centre for Women's and Children's Health. Intrapartum care: care of healthy women and their babies during childbirth [Internet]. London: Royal College of Obstetricians and Gynaecologists; 2007 Sep. 332 p. [cited 2010 Dec 9]. Available from: http://www.nice.org.uk/nicemedia/live/11837/36275/36275.pdf 3. Ullman R, Smith LA, Burns E, Mori R, Dowswell T. Parenteral opioids for maternal pain relief in labour. Cochrane Database of Syst Rev [Internet]. 2010 [cited 2010 Dec 9];(9). Art. No.: CD007396. Available from: http://www.thecochranelibrary.com/view/0/index.html Subscription required. 4. Opioids (CPhA monograph). 2010 Dec [cited 2010 Dec 9]. In: e-cps [Internet]. Ottawa (ON): Canadian Pharmacists Association; c. 2009 -. Available from: https://www.etherapeutics.ca Subscription required. 5. Douma MR, Verwey RA, Kam-Endtz CE, van der Linden PD, Stienstra R. Obstetric analgesia: a comparison of patient-controlled meperidine, remifentanil, and fentanyl in labour. Br J Anaesth. 2010 Feb;104(2):209-15. 6. Halpern SH, Muir H, Breen TW, Campbell DC, Barrett J, Liston R, et al. A multicenter randomized controlled trial comparing patient-controlled epidural with intravenous analgesia for pain relief in labor. Anesth Analg [Internet]. 2004 Nov [cited 2010 Dec 9];99(5):1532-8. Available from: http://www.anesthesiaanalgesia.org/content/99/5/1532.long 7. Nikkola EM, Jahnukainen TJ, Ekblad UU, Kero PO, Salonen MA. Neonatal monitoring after maternal fentanyl analgesia in labor. J Clin Monit Comput. 2000;16(8):597-608. 8. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA. 1995 Feb 1;273(5):408-12. 9. Mannion AF, Balague F, Pellise F, Cedraschi C. Pain measurement in patients with low back pain. Nat Clin Pract Rheumatol. 2007 Nov;3(11):610-8. 10. Lee JS, Hobden E, Stiell IG, Wells GA. Clinically important change in the visual analogue scale after adequate pain control. Acad Emerg Med [Internet]. 2003 Oct [cited 2010 Dec 9];10(10):1128-30. Available from: http://onlinelibrary.wiley.com/doi/10.1197/s1069-6563(03)00372-5/pdf Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 11

APPENDICES: Appendix A: Results from included RCTs Table 4. Summary of Results from Douma 2010 5 Outcome Remifentanil Meperidine Fentanyl P value N=52 N=53 N=54 n/n (%) n/n (%) n/n (%) Oxytocin used 33/47 (70) 26/37 (70) 36/51 (71) NS Spontaneous delivery 28/45 (62) 24/35 (69) 39/46 (85) <0.05 Instrumental delivery 10/45 (22) 8/35 (23) 6/46 (13) NS Caesarean section 7/45 (16) 3/35 (9) 1/46 (2) NS Crossover to epidural 7/52 (13) 18/53 (34) 8/54 (15) <0.05 Itching 8/51 (16) 3/51 (6) 1/50 (2) <0.05 Nausea or vomiting 20/51 (39) 23/51 (45) 20/51 (39) NS Maternal oxygen saturation <95% 37/50 (74) 16/58 (33) 30/54 (56) R vs M, <0.0001 R vs F, NS Maternal oxygen supplementation Maternal satisfaction (using 1-10 scale) Pain score at baseline (10 cm VAS) Change in pain score: baseline to 1 hour M vs F <0.05 6/51 (12) 5/52 (8) 1/52 (2) NS Mean (SD) Mean (SD) Mean (SD) 8.1 (1.1) 7.0 (1.5) 7.3 (1.2) R vs M, <0.05 R vs F, NS M vs F, NS 7.8 (1.6) 7.41 (1.5) 7.4 (1.6) NS -3.2 (2.9) -0.8 (2.2) -1.4 (2.4) R vs M, <0.001 R vs F, <0.01 M vs F, NS -2.0 (3.1) -0.5 (2.8) -0.9 (2.6) NS Change in pain score: baseline to 2 hours Maternal sedation 1.1 (0.3) 1.12 (0.3) 1.13 (0.3) NS score at baseline Change in maternal 0.75 (0.8) 0.34 (0.6) 0.26 (0.6) R vs M, <0.05 sedation score: R vs F, <0.01 baseline to 1 hour M vs F, NS Apgar score 1 min 8.9 (0.7) n=38 8.6 (0.9) n=32 8.5 (1.3) n=45 NS Apgar score 5 min 9.9 (0.3) 9.7 (0.6) 9.6 (0.8) NS F=fentanyl; M=meperidine; min=minutes; R=remifentanil; SD=standard deviation; VAS=visual analogue scale Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 12

Table 5. Summary of Results from Halpern 2004 6 Outcome PCEA bupivacaine PCIA Difference P value + fentanyl N=124 fentanyl N=118 (95% CI) Caesarean section, n (%) 12 (10.2) 12 (9.7) 0.5% (-7% to 8%) 0.9 Instrumental vaginal delivery, n (%) 36 (29) 25 (21) -7% (-18% to 3%) 0.16 Spontaneous vaginal delivery 76 (61) 81 (69) 7% (-4% to 19%) 0.23 Addition of oxytocin (after analgesia) 61 (49) 62 (53) 3% (-9% to 16%) 0.60 Maternal fever, n (%) 19 (15) 10 (9) 7% (-15% to 1%) 0.10 Antiemetic therapy, n (%) 8 (6) 20 (17) 10% (2% to 18%) 0.01 Maternal sedation (sleeping between 6/110 (5) 46/117 (39) 34% (24% to 44%) <0.001 or during contractions), n/n (%) Maternal satisfaction with analgesia, 7.7 (2.8) 6.8 (2.7) -0.9 (-1.6 to 0.14) 0.02 mean (SD) Neonatal active resuscitation, n (%) 38 (31) 61 (52) 21% (9% to 33%) 0.001 Apgar <7 at 1 min, n (%)* 21 (17) 33 (28) 11% (0.4% to 21%) 0.04 Apgar <7 at 5 min, n (%)* 4 (3) 5 (4) 1% (-4% to 6%) 0.68 Use of naloxone in neonate, n (%) 4 (3) 20 (17) 14% (6% to 21%) <0.001 Neonatal fever, n (%) 4 (3) 3 (3) 0.7% (-5% to 4%) 0.75 Umbilical artery ph, mean (SD) 7.24 (0.10) 7.23 (0.07) 0.07 (-0.03 to 0.01) 0.50 CI=confidence interval; Min=minutes; N=number; PCIA=patient controlled intravenous analgesia; PCEA = patient controlled epidural analgesia; SD=standard deviation no details on the VAS scale used to assess maternal satisfaction were provided in the report; *number in the PCEA group=123 Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 13

Appendix B: Additional References Systematic Review on Fetal Monitoring Alfirevic Z, Devane D, Gyte GML. Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. Cochrane Database of Syst Rev [Internet]. 2006 [cited 2010 Dec 9],(3). Art. No.: CD006066. Available from: http://www.thecochranelibrary.com/view/0/index.html Subscription required. Guidelines on Fetal Monitoring During Labour National Collaborating Centre for Women's and Children's Health. Intrapartum care: care of healthy women and their babies during childbirth [Internet]. London: Royal College of Obstetricians and Gynaecologists; 2007. 332 p. [cited 2010 Dec 9]. Available from: http://www.nice.org.uk/nicemedia/live/11837/36275/36275.pdf Liston R, Sawchuck D, Young D. Fetal health surveillance: antepartum and intrapartum consensus guideline [Internet]. SOGC. 2007 [cited 2010 Dec 9];29(9):suppl.4. Available from: http://sogc.org/guidelines/documents/gui197cpg0709.pdf American College of Obstetricians and Gynecologists (ACOG). Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. Washington (DC): American College of Obstetricians and Gynecologists (ACOG); 2009 Jul. (ACOG practice bulletin; no.106). Summary available from: http://www.guideline.gov/content.aspx?id=14885&search=fetal+monitor+and+electronic+and+c ontinuous Wallace E, Dowd J, Ellwood D, Hornbuckle J, Kirker P, Merkur H, et al. Intrapartum fetal surveillance: clinical guidelines [Internet]. 2 nd edition. East Melbourne (Australia): The Royal Australian and New Zealand College of Obstetricians and Gynaecologists; 2006. [cited 2010 Dec 9]. Available from: http://www.ranzcog.edu.au/publications/pdfs/clinicalguidelines-ifsseced.pdf Other Guidelines on Use of IV Fentanyl During Labour Guideline for the administration of fentanyl for pain relief in labour [Internet]. Halifax (NS): Reproductive Care Program of Nova Scotia; 2006. [cited 2010 Dec 9]. Available from: http://rcp.nshealth.ca/sites/default/files/clinical-practice-guidelines/fentanyl.pdf Labour Analgesia: Guidelines for Obstetrical Practice. Reproductive Care Program of Nova Scotia; 2005. http://as01.ucis.dal.ca/wag/template/uploads/rcp/labour_analgesia.pdf Obstetric guideline 4: pain management options during labour [Internet]. Vancouver (BC): British Columbia Perinatal Health Program; 2007 Oct. [cited 2010 Dec 9]. Available from: http://www.perinatalservicesbc.ca/sites/bcrcp/files/guidelines/obstetrics/ob4painmanagement. pdf Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 14

OGCCU Anaesthetics Team. Clinical guidelines section B: obstetrics and midwifery guidelines: 4.7 administration of intramuscular/intravenous opioid analgesia [Internet]. Perth (Australia): King Edward Memorial Hospital; 2010 Jul. [cited 2010 Dec 9]. Available from: http://www.wnhs.health.wa.gov.au/development/manuals/o&g_guidelines/sectionb/4/b4.7.3.pdf Use of Fentanyl and Continuous Electronic Fetal Monitoring in Labour and Delivery 15