The purpose of this paper is to attempt to clarify some of the advice regarding pain relief.

Transcription

1 Scientific Impact Paper No. XX Peer Review Draft April 2017 Antenatal and Postnatal Analgesia 1. Purpose and scope Traditionally, codeine has been used extensively for antenatal and postnatal pain relief. However, in 2013 the Medicines and Healthcare Products Regulatory Authority (MHRA) 1 and European Medicines Agency (EMA) 2 issued advice on the use of codeine in pregnancy following the death of a breastfed infant in 2005 due to morphine toxicity following maternal use of codeine, 3 and three fatalities in children under 18 where codeine had been prescribed after tonsillectomy. 4,5 They have advised that codeine is contraindicated in women who are breastfeeding owing to the increased risks to the infant. 1,2 Correct management of pain during and after pregnancy is essential to minimise the risk of adverse outcomes to the mother and baby. Inadequate treatment of pain can lead to the development of anxiety and depression which can impact on a woman s physical and psychological wellbeing. 6 Reluctance to prescribe analgesia can also result in increased use of inappropriate over-the-counter medication or herbal remedies. The purpose of this paper is to attempt to clarify some of the advice regarding pain relief. 2. Analgesic mechanisms of action 2.1 Non-opioids Paracetamol The mechanism of action of paracetamol is not fully understood. It is generally considered to be a weak inhibitor of prostaglandin synthesis, although a report 7 has suggested that it appears to work as a selective cyclooxygenase (COX)-2 inhibitor. Paracetamol is widely used as a first line analgesic due to its excellent safety profile and few drug interactions. When taken orally, it can produce an analgesic effect within 40 minutes, but there are variations in bioavailablilty. When used in intravenous form, the variations in bioavailability are overcome and the onset of analgesic effect is only 5 minutes Nonsteroidal anti-inflammatory drugs (NSAIDS) Arachidonic acid is metabolised by the isoenzymes COX-1 and COX-2 to prostaglandins, which are mediators of pain and inflammation. NSAIDs relieve pain through peripheral inhibition of COX enzymes and, hence, inhibition of prostaglandin synthetase, and their clinical effects depend on their selectivity for these enzymes Opioids Codeine Codeine is a natural opioid with low affinity for opioid receptors and as such has poor analgesic properties in its natural form. 9 It relies on its conversion to active metabolites, primarily morphine. Scientific Impact Paper No. XX 1 of 11 Royal College of Obstetricians and Gynaecologists

2 There are many genetic factors that influence the rate of metabolism of codeine to morphine. Polymorphisms occur in the cytochrome P450 isoenzyme CYP2D6, 10 which is one of the main pathways for codeine conversion to morphine. As this pathway is subject to genetic variation, the pharmokinetics of codeine in a given individual are unpredictable. Individuals can be classified as: poor; intermediate; extensive; or ultrarapid metabolisers. The proportion of Caucasians classified as poor metabolisers is 7 10%; defined as those who convert very little codeine into morphine and have little or no pain relief. 2 Some individuals are ultrarapid metabolisers and consequently extremely sensitive to the analgesic properties and adverse effects of codeine. The ultrarapid metaboliser phenotype is due to duplications of the CYP2D6 gene, and prevalence varies by ethnic origin: for example Ethiopian 29%, Spanish 10% and Caucasian 4%. 11 Ultrarapid metabolisers who take codeine have approximately 50% higher plasma concentrations of its active metabolite morphine than extensive metabolisers with the consequence that there is a risk of serious toxicity even at therapeutic doses of codeine in such individuals Dihydrocodeine (DHC) DHC has similar analgesic activity to codeine. However, unlike codeine, which is a pro-drug displaying no analgesic properties itself, the analgesic effect of DHC appears to be mainly due to the parent compound 7 and is largely unaffected by an individual s metabolising capacity. 12 DHC is metabolised to dihydromorphine (DHM) by CYP2D6, but only a small proportion of DHC becomes DHM. A study examining urinary metabolites showed that even in extensive metabolisers less than 10% of metabolites were derived from DHM. 13 Another study 14 examining 26 patients who died of self-harm considered the role of DHC metabolites in DHC-related deaths. From the levels measured, it was concluded that DHM and DHM-6-glucuronide have less influence on causing death than DHC itself, suggesting that the degree of adverse effects, such as respiratory depression, may not be influenced by genetic variation in metabolism Tramadol Tramadol is effective against mild to moderate pain, 2 and acts through both opioid and monoaminergic-mediated mechanisms. It is also metabolised by CYP2D6 to an active O-desmethyl metabolite. Tramadol has fewer typical opioid adverse effects, such as respiratory depression and constipation, but can cause psychiatric disturbances, which may be due to high plasma levels of the metabolite O-desmethyltramadol. However, it is important to note that more than 10% of the general population does not tolerate tramadol due to the adverse effects experienced. 15 In addition, tramadol was reclassified as a Schedule 3 Controlled Drug in June 2014, 16 which makes outpatient prescribing more complicated Morphine Morphine is used to treat moderate to severe pain. It is an opioid receptor agonist and is active in its parent form. Its main effect is binding to and activating the opioid receptors in the central nervous system. Its primary therapeutic actions are analgesia and sedation. Peak plasma levels are achieved in minutes of parenteral administration, and in minutes after oral administration. 17 It is subject to first pass metabolism by the cytochrome P450 pathway, and therefore an oral dose is approximately half as potent as an intramuscular dose. 3. Antenatal analgesia Scientific Impact Paper No. XX 2 of 11 Royal College of Obstetricians and Gynaecologists

3 Many women experience pain during pregnancy including headache, lower back and pelvic pain. Prior to giving advice regarding analgesic options pain should be investigated as appropriate to exclude serious causes. Non-pharmacological interventions should be considered first line; for example adequate rest, hot and cold compresses, massage, aromatherapy, acupuncture, physiotherapy, relaxation and exercise. Prior to administration in pregnant women all medicines should be assessed for risk versus benefit, and be used sparingly to try to reduce adverse effects on the developing fetus. 3.1 Before 30 weeks of gestation If possible, all teratogenic drugs should be avoided during the first trimester since the embryo is most vulnerable to teratogenic effects during organogenesis (4 10 weeks of gestation), although it is acknowledged that some will need to be continued to prevent maternal harm Paracetamol Paracetamol is widely used as a first choice analgesic for treatment of mild to moderate pain, and remains the analgesic of choice in pregnant and breastfeeding women. 6 It can be prescribed, but is also available as an over-the-counter medication. Some studies 18,19 have demonstrated associations between the use of paracetamol antenatally and adverse outcomes for the fetus. The US Food and Drug Adminstration (FDA) published a safety announcement in addressing the concerns raised by these studies, and stated that all of the studies reviewed had potential limitations in their design and contained conflicting results. Current advice 21 is that paracetamol remains safe for use during pregnancy and breastfeeding, and its use in any trimester does not appear to increase the risk of major birth defects. 16,22, NSAIDs There is conflicting evidence regarding the association between the use of NSAIDs and increased risk of first trimester miscarriage. To date, there are no studies demonstrating clear evidence of increased teratogenic effects following therapeutic doses of NSAIDs in the first trimester, such that the FDA has assigned NSAIDS to pregnancy category C prior to 30 weeks of gestation (see Appendix I for a glossary of FDA categories). Where possible, the use of NSAIDs should be avoided during pregnancy, but if their use is clinically indicated, the lowest effective dose for the shortest possible duration is advised Opioids Opioid analgesics can be used during pregnancy and breastfeeding for the short-term treatment of moderate to severe pain when paracetamol has not been effective. Studies evaluating the safety of opioid analgesics during pregnancy are limited and there are no prospective, comparative studies. UK Medicines Information (UKMi) concluded that the limited data available does not indicate an increased risk of fetal toxicity. 6 A statement from the FDA was issued following the publication of two case reports 27,28 linking first trimester use of opioids to increased neural tube defects. It concluded that opioid use may be linked to a small increase in neural tube defects, although evidence is limited and further research is needed. Opioid analgesics remain pregnancy category C drugs for all trimesters. Indiscriminate use should be avoided. Scientific Impact Paper No. XX 3 of 11 Royal College of Obstetricians and Gynaecologists

4 Morphine has been used extensively in pregnancy and in the postnatal period, and is licensed for use. It is readily absorbed through all routes of administration. 3.2 After 30 weeks of gestation Paracetamol Paracetamol is considered safe for use throughout pregnancy. 16,22, NSAIDs The FDA has assigned NSAIDs, for example ibuprofen and diclofenac, to pregnancy category D after 30 weeks of gestation, since they can lead to neonatal pulmonary hypertension and premature closure of the ductus arteriosus. 28 NSAIDs also reduce fetal renal blood flow and thus urine production leading to a reduced amniotic fluid volume. The use of NSAIDs should, therefore, be avoided at more than 30 weeks of gestation Opioids The FDA has assigned all opioids to pregnancy category C. Opioid use, especially around the time of delivery, may lead to neonatal respiratory depression. Long-term use of opioid analgesia can lead to neonatal withdrawal symptoms and the lowest effective dose should therefore be used, for the shortest possible time. Opioids can exacerbate constipation, nausea and vomiting, which may already be a problem for women who are pregnant. The risk and severity of adverse effects should be weighed against the amount of pain the woman is experiencing. When women are admitted acutely to the antenatal ward with severe pain and require additional analgesia, oral morphine solution or intramuscular morphine may be considered. If a woman is admitted in early labour, intramuscular pethidine or diamorphine may be given. 4. Postnatal analgesia Inadequate treatment of postnatal pain has serious implications and regular postnatal analgesia is therefore importantas. Inadequately controlled pain can mean women are less mobile, which increases their risk of venous thromboembolism, and more prone to shallow breathing, which puts them at risk of developing pneumonia. 29 It may also impact negatively on the woman's ability to breastfeed or care for her new infant and may contribute to depression or mental exhaustion. 30 Postnatal analgesia should not be based on whether a woman is breastfeeding. Units should adopt a uniform policy in line with the MHRA guidance. A single policy for breastfeeding and nonbreastfeeding women is safer in order to avoid confusion among clinicians when prescribing, especially as some women switch between bottle and breastfeeding their baby. Paracetamol with the addition of NSAIDs (unless there are contraindications) should be the mainstay of analgesia in all women. In addition to analgesic drugs, women should be offered advice regarding nonpharmacological methods of pain relief, including hot and cold compresses, and on comfortable positions for sitting and lying Paracetamol Scientific Impact Paper No. XX 4 of 11 Royal College of Obstetricians and Gynaecologists

5 Paracetamol should be considered the analgesic of choice for breastfeeding women as the risk to a breastfed infant is low since the quantity of drug that passes into milk is very small; representing only a small proportion of a normal therapeutic infant dose NSAIDs There is very limited information on the use of NSAIDs and breastfeeding. However, as ibuprofen and diclofenac have been used extensively for breastfeeding women, these are the preferred choices. Of the two, ibuprofen is the favoured NSAID due to the concerns raised over long term diclofenac use and increased cardiovascular risk. 32 Ibuprofen is considered safe for the breastfed infant as only very small quantities appear to be excreted into breast milk after maternal ingestion. 17 A one-off dose of rectal diclofenac can be offered to women following delivery. NSAIDs affect renal function, platelet function, and can exacerbate asthma (in approximately 10% of patients 33 ). In addition they may cause gastric irritation/ulcers. 5 Diclofenac and ibuprofen are contraindicated in those with a known hypersensitivity and should be avoided in the following circumstances: If there has been significant haemorrhage, the women is hypovolaemic, and/or there is a risk of ongoing haemorrhage. In women with impaired renal function or moderate/severe pre-eclampsia. In women with severe asthma. In women with asthma known to be exacerbated by NSAIDs, including aspirin. In women with a history of gastric ulceration. 4.3 Opioids If women experience more severe pain and in need of additional analgesia, then opioid analgesics should be used. In general, women who have had a caesarean section are more likely to experience severe pain for a longer duration than those who have delivered vaginally, although those who have undergone a rotational forceps delivery may need additional analgesia Codeine Until recently, codeine was considered the preferred opioid for use in breastfeeding mothers. However, a fatal case of morphine toxicity in a breastfed infant following maternal use of codeine led the MHRA and EMA to contraindicate its use in breastfeeding women. 1,2 The mother in the fatal infant case report 3 was an ultrarapid metaboliser, which led to ultrarapid production of morphine. This is a very rare complication of codeine use and genetic testing is currently impractical as the assays are complex and expensive. 34 There have been several reports of adverse effects in breastfed infants following maternal use of codeine. These include bradycardia, respiratory depression, lethargy, drowsiness, poor feeding, cyanosis and infant death The overall recommendations from UKMi 38 regarding DHC and tramadol are: As it is not practical to genotype all breastfeeding mothers and infants, weak opioids, specifically DHC or tramadol, can be considered for a breastfeeding mother instead of codeine. The lowest effective dose should be administered for the shortest duration, and regular use of any opioid beyond 3 days should be under close medical supervision. If significant opioid adverse effects develop in the mother, this may suggest the possibility that she is an ultrarapid metaboliser and that the risk of adverse effects in the infant may be increased. Scientific Impact Paper No. XX 5 of 11 Royal College of Obstetricians and Gynaecologists

6 All breastfeeding mothers, regardless of ethnicity, should be informed of potential problems and advised to stop breastfeeding if symptoms develop and to seek medical advice DHC The advice from UKMi 38 is that DHC in the breastfeeding mother should be at the lowest effective dose for the shortest duration. All breastfed infants should be monitored for opioid adverse effects regardless of the maternal dose. If significant opioid adverse effects develop in the mother, there is the possibility she is an ultrarapid metaboliser and that the risk of adverse effects in the infant may be increased Tramadol The manufacturer's product information on tramadol provides very limited data on the transfer of tramadol and its active O-desmethyl metabolite into breast milk, and the British National Formulary breastfeeding advice states that amount is probably too small to be harmful, but manufacturer advises avoid. A study 39 has demonstrated that tramadol and its metabolites are found in breast milk, even after a single dose. Another study 40 examining milk samples from 75 mothers who were 2 4 days postpartum demonstrated that an exclusively breastfed infant would receive maternal weightadjusted dosages of 2.24% of tramadol and 0.64% of its metabolite. No adverse behavioural effects were observed in the breastfed infants. Likewise comparing poor and extensive metabolisers, 41 it was shown that the relative and combined infant dose remained below the suggested 10% threshold for drugs in breast milk, irrespective of the metabolising capacity of the mother Morphine In hospital, oral morphine solution can be prescribed as required (e.g mg 2-hourly). Intramuscular morphine may be prescribed alongside the oral solution if necessary, for example if a woman is vomiting. The documentation should be clear that morphine should not be given simultaneously by two different routes. For women who are intolerant of morphine tramadol, orally or intramuscularly, should be considered as required, or DHC orally as required. 4.4 Recommendations for analgesia on discharge from hospital The majority of women requiring analgesia on discharge should receive paracetamol and ibuprofen (unless there are contraindications to NSAIDs). If additional analgesia is required, for example if a woman is discharged 1 2 days post lower segment caesarean section as part of an enhanced recovery programme, and is still requiring oral morphine solution in hospital or cannot take NSAIDs, she should be discharged with a limited supply of DHC to take as required (maximum four doses per day). Tramadol may be considered if a woman is known to be intolerant to DHC. As tramadol is classified as a Schedule 3 Controlled Drug, its additional requirements must be checked when prescribing (see 5. Opinion Codeine is a prodrug relying on conversion to active metabolites, and many different genetic factors cause variation in the rate of codeine metabolism via the P450 isoenzyme CYP2D6 pathway, with the consequence that the pharmokinetics of codeine in an individual are unpredictable. Although there is very limited evidence, ultrarapid metabolisers are at higher risk of codeine toxicity leading to fatalities, Scientific Impact Paper No. XX 6 of 11 Royal College of Obstetricians and Gynaecologists

7 as detailed in the case reports published. 3 5 It was on the basis of these reports that the MHRA and EMA issued their guidance. 1,2 Prior to this guidance many obstetric units used codeine extensively for many years without apparent problems. Consequently, despite the controversy surrounding the MHRA and EMA statements it is necessary to review prescribing practices, 42 especially with regard to postnatal analgesia. References 1. Medicines and Healthcare products Regulatory Agency [ 2. European Medicines Agency. Restrictions on use of codeine for pain relief in children CMDh endorses PRAC recommendation. London: EMA; 2013 [ 851.pdf]. 3. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet 2006;368: Ciszkowski C, Madadi P, Phillips MS, Lauwers AE, Koren G. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med 2009;361: Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN, et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012;129:e UK Medicines Information. Can opioids be used for pain relief during pregnancy? [London]: London Medicines Information Service; 2014 [ nancy%22]. 7. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology 2013;21: Vane JR, Botting RM. Mechanism of action of nonsteroidal anti-inflammatory drugs. Am J Med 1998;104:2S 8S discussion 21S 22S. 9. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician 2008;11 Suppl 2:S133 S Pattinson KTS. Opioids and the control of respiration. Br J Anaesth 2008;100: Bernard S, Neville KA, Nguyen AT, Flockhart DA. Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications. Oncologist 2006;11: (2006). 12. Wilder-Smith CH, Hufschmid E, Thormann W. The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolizers. Br J Clin Pharmacol 1998;45: Fromm MF, Hofmann U, Griese EU, Mikus G. Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther 1995;58: Al-Asmari AI, Anderson RA. The role of dihydrocodeine (DHC) metabolites in dihydrocodeinerelated deaths. J Anal Toxicol 2010;34: Jarernsiripornkul N, Krska J, Richards RM, Capps PA. Patient reporting of adverse drug reactions: useful information for pain management? Eur J Pain 2003;7: Servey J, Chang J. Over-the-Counter Medications in Pregnancy. Am Fam Physician 2014;90: Glare PA, Walsh TD. Clinical pharmacokinetics of morphine. Ther Drug Monit 1991;13: Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevelopment: a sibling-controlled cohort study. Int J Epidemiol 2013;42: Eyers S, Weatherall M, Jefferies S, Beasley R. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clin Exp Allergy 2011;41: Scientific Impact Paper No. XX 7 of 11 Royal College of Obstetricians and Gynaecologists

8 US Food and Drug Administration. FDA Drug Safety Communication: FDA has reviewed possible risks of pain medicine use during pregnancy. FDA; 2015 [ Davanzo R, Bua J, Paloni G, Facchina G. Breastfeeding and migraine drugs. Eur J Clin Pharmacol 2014;70: Rebordosa C, Kogevinas M, Horváth-Puhó E, Nørgård B, Morales M, Czeizel AE, et al. Acetaminophen use during pregnancy: effects on risk for congenital abnormalities. Am J Obstet Gynecol 2008;198:178.e Feldkamp ML, Meyer RE, Krikov S, Botto LD. Acetaminophen use in pregnancy and risk of birth defects: findings from the National Birth Defects Prevention Study. Obstet Gynecol 2010;115: Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ 2003;327: Daniel S, Koren G, Lunenfeld E, Bilenko N, Ratzon R, Levy A. Fetal exposure to nonsteroidal antiinflammatory drugs and spontaneous abortions. CMAJ 2014;186:E Schiavetti B, Clavenna A, Campi R, Bonati M. NSAIDs during pregnancy and risk of miscarriage: true risks or only suspicions? BMJ 2004;328:108; author reply Antonucci R, Zaffanello M, Puxeddu E, Porcella A, Cuzzolin L, Pilloni MD, et al. Use of non-steroidal anti-inflammatory drugs in pregnancy: impact on the fetus and newborn. Curr Drug Metab 2012;13: Janssen NM, Genta MS. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation. Arch Intern Med 2000;160: Mkontwana N; Novikova N. Oral analgesia for relieving post-caesarean pain. Cochrane Database Syst Rev 2015;(3):CD East CE, Sherburn M, Nagle C, Said J, Forster D. Perineal pain following childbirth: prevalence, effects on postnatal recovery and analgesia usage. Midwifery 2012;28: Eshkevari L, Trout KK, Damore J. Management of postpartum pain. J Midwifery Womens Health 2013;58: Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, et al.; Coxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal antiinflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013;382: Gryglewski RJ. Aspirin-induced asthma and cyclooxygenases. In: Vane JR, Botting J, editors. Selective COX-2 inhibitors: Pharmacology, Clinical Effects and Therapeutic Potential. Dordrecht: Springer Science+Business Media; p Personal communication. Professor Ann K Daly. Pharmacogenetics Group. School of Clinical and Laboratory Sciences. University of Newcastle Medical School. December Smith JW. Codeine-induced bradycardia in a breast-fed infant. Clin Res 1982;30:259A. 36. Madadi P, Shirazi F, Walter FG, Koren G. Establishing causality of CNS depression in breastfed infants following maternal codeine use. Paediatr Drugs 2008;10: Naumburg EG, Meny RG. Unexplained neonatal apnea, bradycardia, cyanosis: an association with opioids in breast milk. Clin Res 1987;35:79A. 38. UK Medicines Information. Codeine and breastfeeding: Is it safe and what are the alternatives? Leicester: Trent Medicines Information Service; 2013 [ hat+are+the+alternatives%3f%22]. 39. Kmetec V, Roskar R. HPLC determination of tramadol in human breast milk. J Pharm Biomed Anal 2003;32: Ilett KF, Paech MJ, Page-Sharp M, Sy SK, Kristensen JH, Goy R, et al. Use of a sparse sampling study design to assess transfer of tramadol and its O-desmethyl metabolite into transitional breast milk. Br J Clin Pharmacol 2008;65: Scientific Impact Paper No. XX 8 of 11 Royal College of Obstetricians and Gynaecologists

9 Salman S, Sy SKB, Ilett KF, Page-Sharp M, Paech MJ. Population pharmacokinetic modeling of tramadol and its O-desmethyl metabolite in plasma and breast milk. Eur J Clin Pharmacol 2011;67: Halder S, Russell R, Quinlan J. Codeine and breast-feeding mothers. Int J Obstet Anesth 2015;24:5 7. Scientific Impact Paper No. XX 9 of 11 Royal College of Obstetricians and Gynaecologists

10 Appendix I: Food and Drug Administration (FDA) classifications 31 The FDA has established five categories of drugs used during pregnancy. The categories are based on the drug s potential teratogenic effect on the fetus and the risk to benefit ratio. They do not take into account the effect of excretion of the drug into breast milk. Category A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Category B Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. Category C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits. Scientific Impact Paper No. XX 10 of 11 Royal College of Obstetricians and Gynaecologists

11 This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by: Dr DL Bisson FRCOG, Bristol; Dr SD Newell MRCOG, Bristol; and Dr C Laxton, North Bristol NHS Trust and peer-reviewed by: XXX. The Scientific Advisory Committee lead reviewers were: Professor T Bourne FRCOG, London; and Dr A Horne MRCOG, Edinburgh, Scotland. The chair of the Scientific Advisory Committee was: Dr S Ghaem-Maghami MRCOG, London. All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any conflicts of interest for this Scientific Impact Paper is available from: The final version is the responsibility of the Scientific Advisory Committee of the RCOG. The review process will commence in 20XX, unless otherwise indicated. DISCLAIMER The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available. 481 This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient s case notes at the time the relevant decision is taken. Scientific Impact Paper No. XX 11 of 11 Royal College of Obstetricians and Gynaecologists