Australian and New Zealand Journal of Obstetrics and Gynaecology 2014; 54: 263–267
DOI: 10.1111/ajo.12178
Original Article
Intrahepatic cholestasis of pregnancy: diagnosis and management; a survey of Royal Australian and New Zealand College of Obstetrics and Gynaecology fellows Chris ARTHUR1 and Kassam MAHOMED2* 1
Redcliffe Hospital, Redcliffe, Queensland, Australia, and 2Ipswich Hospital, University of Queensland, Brisbane, Queensland, Australia
Background: Intrahepatic cholestasis of pregnancy (ICP) is an uncommon obstetric condition characterised by intense maternal pruritis and biochemical abnormality. There is a degree of contention regarding the diagnosis and management of ICP, and currently, there are no nationally accepted guidelines. Aims: To conduct a survey of Fellows and Members of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) regarding their diagnosis and management ICP. Methods: An online survey of currently practising RANZCOG Fellows and Members, utilising Survey Monkey. Results: Thirty percent of those sent the survey responded, comprising approximately 40% of practising obstetricians. Fasting bile acid and serum transaminase elevation in association with the characteristic itch define the disease process for the majority of respondents and also inform management decisions. There was no critical level of bile acid elevation that mandated treatment for the majority of respondents. Nearly 90% of respondents induce women with ICP at 37–38 completed weeks of pregnancy, due to concerns regarding possible fetal demise. About one-third of respondents refer to the Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline to advise their decision-making process, and a similar proportion use local or hospital-based guidelines. Conclusions: Elevated fasting bile acids and abnormal liver function tests define the diagnosis and inform management of ICP by Australian obstetricians. Routine induction of labour for patients with ICP at 37–38 completed weeks of pregnancy is widely practised in Australia. An evidence-based guideline would assist clinicians who manage such cases in Australia. Key words: cholestasis, diagnosis, disease management, health surveys, intrahepatic, pregnancy complications.
Introduction Intrahepatic cholestasis of pregnancy (ICP), or obstetric cholestasis, causes maternal pruritis which may occur anywhere on the body, but characteristically affects the palms of the hands and soles of the feet. ICP most commonly presents in the late second or third trimester.1–5 The itch may be intense and may lead to sleep deprivation and typically resolves after birth.1 Biochemical tests often reveal elevated fasting bile acids and/or deranged liver function tests.1–5 The risks to the fetus include preterm
Correspondence: Dr Chris Arthur, Department of Obstetrics and Gynaecology, Redcliffe Hospital, Anzac Ave, Redcliffe, Qld 4020, Australia. Emails: [email protected], [email protected] *Present address: Department of Obstetrics and Gynaecology, Ipswich Hospital, Chelmsford Ave, Ipswich, Queensland, 4305, Australia. Received 24 September 2013; accepted 16 December 2013.
birth, meconium staining of the amniotic fluid, fetal compromise and even sudden unexplained fetal death.1 The incidence of ICP varies according to ethnicity,2 and whilst the overall stillbirth rate for ICP approximates that for the general population3 (5.7/1000 births compared to 5.4/1000 births in a British population),4 in cases of severe ICP, it can be up to three times greater.5 The management of ICP principally focuses on the relief of maternal symptoms and avoidance of potential adverse fetal outcomes and often includes earlier delivery.1–8 Serial biochemical surveillance and regular assessment of fetal growth and well-being are often used to identify worsening condition and the at risk fetus, despite a lack of good evidence.5,6,7 Ursodeoxycholic acid is frequently prescribed to relieve maternal symptoms and decrease serum transaminases and bile acids, but is not currently licensed for this purpose in Australia.1,6,7 Many centres recommend delivery after 37 weeks, or earlier if there is deterioration of the maternal liver enzymes and/or worsening of clinical symptoms.1,6,7
© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
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Question 5 requested respondent’s rank commonly requested investigations in order of diagnostic merit (Table 1). Elevated fasting bile acids were ranked the most important investigative test by 56% of respondents and liver function tests as the number one investigation by 36%. As such, more than 90% of respondents rely on one, or both, of these tests in order to diagnose ICP. It was noted that cardiotocography (CTG) and ultrasound scan were considered the most useful diagnostic investigation by some of the respondents. Question 6 asked that clinicians rank investigations and clinical parameters in the order in which they most influence patient management (Table 2). An elevated fasting bile acid was ranked the investigation most likely to influence a clinician’s management of a patient with ICP (32% of respondents). Liver function tests and the maternal clinical state were the most important data for 22.4% and 19.8% of respondents, respectively. The clinical presentation was ranked as a more important determinant of management than either CTG (14.2%) or ultrasound determination of fetal well-being (9.9%). Two questions sought targeted information relating to the prevalence of the practice of planned induction of labour for patients with ICP, and the gestation at which this occurred. Nearly 90% of respondents would routinely induce labour in patients with ICP. When asked at what gestational age induction would be considered, 173 of the 342 (50.6%) respondents stated they would induce at 37 completed weeks, and 105 (30.7%) at 38 completed weeks. Twenty-three (6.8%) would wait longer, with 1.5% waiting until the due date. In response to questions regarding influences determining timing of birth, for 284 respondents (86%), the possibility of fetal death influenced their decision to expedite delivery. The rest did so because of concerns regarding maternal symptoms or fetal wellbeing excluding fetal demise. An ‘other’ option was available in this question for respondents to explain their rationale with respect to induction timing and indications. The overriding impression from answers provided is that the reasons are multifactorial in nature and vary between patients. Questions 11 and 12 sought opinion regarding specific levels of bile acid elevation that affected patient management. Two hundred and seventy-five respondents
As there is no good evidence to guide clinicians in the management of this complex and poorly understood disease process, we sought to ascertain how obstetricians in Australia diagnosed and managed ICP in their own clinical practice.
Materials and Methods The study survey and a covering letter were emailed to all Members and Fellows of the Royal Australian and New Zealand College of Obstetrics and Gynaecology (RANZCOG), with no prior discrimination with regard to area of practice or subspecialisation. Contact details had been obtained through the RANZCOG Professional Development Committee. Two further reminder emails were sent at fortnightly intervals, also with a link to the questionnaire. The survey was comprised of thirteen questions. The first four related to the demographics of respondents, and the other nine sought targeted information regarding diagnosis and management of ICP. In some questions, respondents were requested to rank the importance to them of specific investigations regarding the diagnosis and management of the condition. Options were provided within the body of the questionnaire for further comment or explanation regarding respondent’s answers. The study was approved by the Darling Downs West Moreton HREC.
Results Four hundred and fifteen (30%) out of the 1379 Members and Fellows responded but in only 396 of these were the data provided interpretable. Three hundred and forty-five responding Fellows were practising obstetricians, comprising 25% of all practitioners who received the initial email. One hundred and forty-nine (43%) of these obstetricians practised in public hospitals only, 82 (24%) practised privately only and 113 (33%) worked in both private and public facilities. Three quarters of responding obstetricians work in Metropolitan hospitals, with only a quarter working primarily in a rural or remote location. Three quarters of the respondents were from New South Wales, Queensland and Victoria.
Table 1 Investigations requested in rank order to establish the diagnosis of ICP Investigation ranking Number of responses (%) Investigation requested
1
Bile acids LFT US fetal growth and well-being CTG FBC RFT
195 123 3 10 10 1
2 (56.0) (35.9) (0.9) (2.9) (2.9) (0.3)
95 185 20 19 21 2
(27.8) (53.9) (5.8) (5.5) (6.1) (0.6)
3 15 22 93 92 77 33
(4.4) (6.4) (27.1) (26.8) (22.4) (9.6)
4 13 6 99 105 60 41
(3.8) (1.7) (28.9) (30.6) (17.5) (12.0)
5 6 2 60 54 95 78
(1.7) (0.6) (17.5) (15.7) (27.8) (22.7)
6 16 3 43 36 38 128
(4.7) (0.9) (12.5) (10.5) (11.1) (37.3)
n/a 3 2 24 27 42 60
(0.9) (0.6) (7.0) (7.9) (12.2) (17.5)
LFT, liver function tests; US, ultrasound; CTG, cardiotocograph; FBC, full blood count; RFT, renal function tests.
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© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
RANZCOG Fellows survey on intrahepatic cholestasis
Table 2 Rank order in which investigations or clinical presentation influence management Investigation ranking Number of responses (%) Investigation requested Bile acids LFT Clinical presentation US fetal growth and well-being CTG FBC RFT
1 110 77 68 34 49 4 1
(32.0) (22.4) (19.8) (9.9) (14.2) (1.1) (0.3)
2 85 118 39 47 43 8 3
(24.7) (34.3) (11.3) (13.7) (12.5) (2.3) (0.9)
3 47 71 80 51 66 17 9
(13.7) (20.6) (23.2) (14.8) (19.2) (4.9) (2.6)
4 30 47 45 90 68 41 15
(8.7) (13.7) (13.1) (26.2) (19.8) (11.9) (4.4)
5 34 24 47 60 66 60 27
(9.9) (7.0) (13.7) (17.4) (19.2) (17.4) (7.8)
6 16 2 13 25 28 128 80
(4.7) (0.6) (3.8) (7.3) (8.1) (37.2) (23.3)
7 15 2 43 21 5 37 152
(4.4) (0.6) (12.5) (6.1) (1.4) (10.8) (44.2)
n/a 7 2 9 16 19 49 57
(2.0) (0.6) (2.6) (4.7) (5.5) (14.2) (16.6)
LFT, liver function tests; US, ultrasound; CTG, cardiotocograph; FBC, full blood count; RFT, renal function tests.
(77%) stated that no specific level of bile acid elevation should instruct delivery of the fetus for either maternal or fetal well-being. Seventy-nine respondents have a defined bile acid elevation mandating delivery, and for 51 of these (66%), it is a level of >40 lmol/L, which instructs delivery. The final survey question invited respondents to list any guidelines that they use to inform management of patients with ICP. Eighty-one (38.9%) of the respondents used the Royal College of Obstetricians and Gynaecologists (RCOG) guideline, whereas 76 (36.5%) stated that they did not use any. The remaining few used local hospital- or state-based ones.
Discussion This survey has confirmed the use of fasting bile acid elevation as the primary test used to diagnose of ICP for a majority of clinicians. However, it must be noted that the normal range for this test was derived from a nonpregnant population,8 and its use for pregnant women has been questioned.9 With regard to management, the lack of a clearly defined and utilised role for bile acids in monitoring the progress of ICP is evident. Although many respondents use fasting bile acid elevation to guide management, there was no consistent upper limit that would cause concern. The few whose management was influenced by a defined elevated bile acid result quoted 40 lmol/L as their action level. This is in keeping with the large cohort study of pregnant Swedish women10 that reported bile acid concentrations >40 lmol/L were associated with an increased likelihood of a poor pregnancy outcome. Geenes et al.,5 from their recent prospective case–controlled study, also noted a worsening obstetric outcome with increasing bile acid elevation. A level of >40 lmol/L was also considered significant in that study because of an increased risk of stillbirth, particularly if there were coexistent maternal obstetric or medical conditions.5 Ursodeoxycholic acid has long been shown to decrease serum transaminases and bile acids in patients with ICP.1,6,7,11 The recently published Cochrane review12 suggested that UDCA significantly improved pruritis and
recommended large trials to assess its effect on obstetric outcome. As the measure of improvement used in the contributing studies was unavoidably a subjective measure, its relevance with regard to the practical application of their findings may be variable. Some of our respondents stated that they have prescribed ursodeoxycholic acid for the relief of pruritis, and amongst all respondents, bile acids, liver function tests and maternal symptoms were the three quantitative entities most likely to influence management. It may be that given clinicians act on maternal symptoms and/or worsening biochemical profiles, as there are no proven methods for effective fetal monitoring, decreasing the lived and measured experience of the disease enables the clinician to feel more comfortable with delaying delivery. Geenes et al.5 have proposed that bile acid surveillance, regardless of fasting status, be used to identify the at risk fetus and to instruct delivery after 37 completed weeks, and point to an increased risk of stillbirth if the bile acids exceed 40 lmol/L. Dedicated, direct fetal monitoring during the antenatal period is practised by the majority of obstetric units in the UK in cases of ICP.13 Serial cardiotocography and ultrasound estimates of fetal growth, umbilical artery Doppler and amniotic fluid volume are recommended by a consensus of UK clinicians,13 but not the RCOG,4 for monitoring fetuses in women with ICP. Numerous tests have been proposed as markers for fetal well-being in ICP, but thus far none reliably predict fetal death.14 We did not ask whether Australian obstetricians routinely incorporate these fetal monitoring modalities in patients with ICP; however, given the risk-averse nature of medical specialties, it would be unlikely for many clinicians to deny their use. Of importance was the recognition by our respondents that influencing fetal markers of well-being (eg pathological CTG, abnormal umbilical artery Doppler studies) are less likely to be evident in women with ICP. Chronic uteroplacental insufficiency, which would be evident on ultrasound as growth changes, decreased amniotic fluid and/ or uterine Doppler abnormalities, is seldom identified in those fetal deaths associated with ICP.15 Obstetricians in Australia currently support and engage heavily in the induction of labour of patients with ICP at 37–38 weeks, similar to practices elsewhere.1,13 The lack
© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
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C. Arthur and K. Mahomed
of effective and appropriate tests for fetal well-being in mothers with ICP resounded as a driving influence behind the choice to induce. The majority of reported fetal deaths associated with ICP have occurred after 37-week gestation,16 and thus, the active management of the condition, incorporating planned earlier delivery, could account for the decrease in the observed mortality rate over time.14 One of the possible weaknesses of the study was the disappointingly low response rate of only 30%; however, many of the recipients of the survey were ineligible for inclusion as they no longer practise obstetrics. According to the 2003 Australian Medical Workforce Advisory Committee survey into the practices of Fellows,17 just over one-third of those qualified to work in obstetrics and gynaecology do not practise obstetrics. Extrapolating from this, it is estimated that 40% of RANZCOG Fellows currently practicing obstetrics in Australia provided a response to the survey. Poor response rates are not uncommon in surveys undertaken by obstetricians and gynaecologists using Survey Monkey. Results of internationally published surveys from 2011 and 2012 which used that particular modality and involved obstetric and gynaecological conditions reported return rates of 14–34%.18–21 Simplistic questionnaires regarding complex disease processes may also be viewed by potential respondents as untenable with the stated aims of the project, as they fail to enable the clinician to adequately explain their management processes, and are unable to account for differing clinical presentations. A survey similar in intent to ours undertaken in the United Kingdom13 had a higher response rate of 57%; however, only 118 individual obstetricians were surveyed, compared to our 345 individual responses. Our survey attempted to seek as many individual responses as possible, recognising that practices may differ not only between hospitals, but also within them. Other major differences between the studies comprised of the options provided in the closed questions regarding investigation and monitoring modalities. RANZCOG Fellows were most likely to turn to the RCOG Green-top Guidelines for advice with regard to management of this condition. Interestingly, they were nearly equally as likely to not utilise any guideline, preferring their own readings and education, as well as the opinions of their colleagues around them. There may be a role for a national guideline, the dissemination of which could lead to consistency of practice. In summary, intrahepatic cholestasis of pregnancy is a clinically suspected and serologically confirmed uncommon obstetric condition that can result in sudden and unexplained fetal death. Currently, there is no effective fetal monitoring that reduces the incidence of adverse fetal outcome. Active management of the condition incorporating relief of maternal symptoms and induction of labour at 37–38 weeks of gestation is currently widely practised within Australia. Inconsistencies between clinicians regarding the diagnosis and management of the 266
condition, as shown in this survey, indicate a need for a consensus guideline for obstetricians in Australia.
Acknowledgements The authors wish to acknowledge the RANZCOG CPD for providing the email addresses for Members and Fellows of the College, and also those Members and Fellows who kindly and graciously completed the survey.
References 1 Mays JK. The active management of intrahepatic cholestasis of pregnancy. Curr Opin Obstet Gyn 2010; 22: 100–103. 2 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15: 2049–2066. 3 Wikstr€ om Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 2013; 120: 717–723. 4 Royal College of Obstetricians and Gynaecologists (UK). Obstetric Cholestasis (Internet). Green-top Guideline No. 43. London (UK):RCOG;2006 Jan [Updated April 2011; Accessed 16 August 2013] Available from URL: http://www. rcog.org.uk/womens-health/clinical-guidance/obstetric-cholestas is-green-top-43 5 Geenes V, Chappell LC, Seed PT et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: A prospective population-based case-control study. Hepatology 2014; 59: 1482–1491. 6 King Edward Memorial Hospital Clinical Guidelines (AU). Cholestasis in Pregnancy (Internet). Perth, WA (Australia): King Edward Memorial Hospital (AU). 2000 Feb [Updated 2010 Nov; Accessed 16 August 2013] Available from URL: http://www.kemh.health.wa.gov.au/development/manuals/O&G_ guidelines/sectionb/2/8859.pdf 7 SA Maternal and Neonatal Clinic Network (AU). Obstetric Cholestasis (Internet). Adelaide, SA (Australia): Department of Health, Government of South Australia; 2004 May 4 [updated 2007 Nov 18; Accessed 16 August 2013] Available from URL: http://www.health.sa.gov.au/ppg/Default.aspx? PageContentMode=1&tabid=104 8 Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006; 26: 527–532. 9 Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol Clin N Am 2010; 37: 269–282. 10 Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40: 467–474. 11 Palma J, Reyes H, Ribalta J et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992; 15: 1043–1047. 12 Gurung V, Middleton P, Milan SJ et al. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013 Jun 24;6: CD000493. doi: 10.1002/14651858. CD000493.pub2. 13 Saleh MM, Abdo KR. Consensus on the management of obstetric cholestasis: National UK survey. BJOG 2007; 114: 99–103.
© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
RANZCOG Fellows survey on intrahepatic cholestasis
14 Roncaglia N, Arreghini A, Locatelli A et al. Obstetric cholestasis: outcome with active management. Eur J Obstet Gynecol Reprod Biol 2002; 100: 167–170. 15 Fisk NM, Bye WB, Storey GN. Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital. Aust NZ J Obstet Gynaecol 1988; 28: 172–176. 16 Williamson C, Hems LM, Goulis DG et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004; 111: 676–681. 17 AMWAC Report 2004.2 (AU). The Specialist Obstetrics and Gynaecology Workforce – An Update 2003-2013 (Internet). Sydney, NSW (Australia): Australian Medical Workforce Advisory Committee; 2004 April [Accessed 16 August 2013] Available from URL: http://www.ahwo.gov.au/documen ts/Publications/2004/Specialist%20obstetrics%20and%20gynaec ology%20workforces%20in%20Australia.pdf
18 Ramondetta L, Brown A, Richardson G et al. Religious and spiritual beliefs of gynecologic oncologists may influence medical decision making. Int J Gynecol Cancer 2011; 21: 573– 581. 19 Grant E, Joshi GP. Glycemic control during labor and delivery: a survey of academic centers in the United States. Arch Gynecol Obstet 2012; 285: 305–310. 20 Hilton P, Bryant A, Howel D et al. Assessing professional equipoise and views about a future clinical trial of invasive urodynamics prior to surgery for stress urinary incontinence in women: a survey within a mixed methods feasibility study. Neurourol Urodyn 2012; 31: 1223–1230. 21 Pauls RN, Fellner AN, Davila GW. Vaginal laxity: a poorly understood quality of life problem; a survey of physician members of the International Urogynecological Association (IUGA). Int Urogynecol J 2012; 23: 1435–1448.
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DOI: 10.1111/ajo.12178
Original Article
Intrahepatic cholestasis of pregnancy: diagnosis and management; a survey of Royal Australian and New Zealand College of Obstetrics and Gynaecology fellows Chris ARTHUR1 and Kassam MAHOMED2* 1
Redcliffe Hospital, Redcliffe, Queensland, Australia, and 2Ipswich Hospital, University of Queensland, Brisbane, Queensland, Australia
Background: Intrahepatic cholestasis of pregnancy (ICP) is an uncommon obstetric condition characterised by intense maternal pruritis and biochemical abnormality. There is a degree of contention regarding the diagnosis and management of ICP, and currently, there are no nationally accepted guidelines. Aims: To conduct a survey of Fellows and Members of the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) regarding their diagnosis and management ICP. Methods: An online survey of currently practising RANZCOG Fellows and Members, utilising Survey Monkey. Results: Thirty percent of those sent the survey responded, comprising approximately 40% of practising obstetricians. Fasting bile acid and serum transaminase elevation in association with the characteristic itch define the disease process for the majority of respondents and also inform management decisions. There was no critical level of bile acid elevation that mandated treatment for the majority of respondents. Nearly 90% of respondents induce women with ICP at 37–38 completed weeks of pregnancy, due to concerns regarding possible fetal demise. About one-third of respondents refer to the Royal College of Obstetricians and Gynaecologists (RCOG) Green-top Guideline to advise their decision-making process, and a similar proportion use local or hospital-based guidelines. Conclusions: Elevated fasting bile acids and abnormal liver function tests define the diagnosis and inform management of ICP by Australian obstetricians. Routine induction of labour for patients with ICP at 37–38 completed weeks of pregnancy is widely practised in Australia. An evidence-based guideline would assist clinicians who manage such cases in Australia. Key words: cholestasis, diagnosis, disease management, health surveys, intrahepatic, pregnancy complications.
Introduction Intrahepatic cholestasis of pregnancy (ICP), or obstetric cholestasis, causes maternal pruritis which may occur anywhere on the body, but characteristically affects the palms of the hands and soles of the feet. ICP most commonly presents in the late second or third trimester.1–5 The itch may be intense and may lead to sleep deprivation and typically resolves after birth.1 Biochemical tests often reveal elevated fasting bile acids and/or deranged liver function tests.1–5 The risks to the fetus include preterm
Correspondence: Dr Chris Arthur, Department of Obstetrics and Gynaecology, Redcliffe Hospital, Anzac Ave, Redcliffe, Qld 4020, Australia. Emails: [email protected], [email protected] *Present address: Department of Obstetrics and Gynaecology, Ipswich Hospital, Chelmsford Ave, Ipswich, Queensland, 4305, Australia. Received 24 September 2013; accepted 16 December 2013.
birth, meconium staining of the amniotic fluid, fetal compromise and even sudden unexplained fetal death.1 The incidence of ICP varies according to ethnicity,2 and whilst the overall stillbirth rate for ICP approximates that for the general population3 (5.7/1000 births compared to 5.4/1000 births in a British population),4 in cases of severe ICP, it can be up to three times greater.5 The management of ICP principally focuses on the relief of maternal symptoms and avoidance of potential adverse fetal outcomes and often includes earlier delivery.1–8 Serial biochemical surveillance and regular assessment of fetal growth and well-being are often used to identify worsening condition and the at risk fetus, despite a lack of good evidence.5,6,7 Ursodeoxycholic acid is frequently prescribed to relieve maternal symptoms and decrease serum transaminases and bile acids, but is not currently licensed for this purpose in Australia.1,6,7 Many centres recommend delivery after 37 weeks, or earlier if there is deterioration of the maternal liver enzymes and/or worsening of clinical symptoms.1,6,7
© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists The Australian and New Zealand Journal of Obstetrics and Gynaecology
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C. Arthur and K. Mahomed
Question 5 requested respondent’s rank commonly requested investigations in order of diagnostic merit (Table 1). Elevated fasting bile acids were ranked the most important investigative test by 56% of respondents and liver function tests as the number one investigation by 36%. As such, more than 90% of respondents rely on one, or both, of these tests in order to diagnose ICP. It was noted that cardiotocography (CTG) and ultrasound scan were considered the most useful diagnostic investigation by some of the respondents. Question 6 asked that clinicians rank investigations and clinical parameters in the order in which they most influence patient management (Table 2). An elevated fasting bile acid was ranked the investigation most likely to influence a clinician’s management of a patient with ICP (32% of respondents). Liver function tests and the maternal clinical state were the most important data for 22.4% and 19.8% of respondents, respectively. The clinical presentation was ranked as a more important determinant of management than either CTG (14.2%) or ultrasound determination of fetal well-being (9.9%). Two questions sought targeted information relating to the prevalence of the practice of planned induction of labour for patients with ICP, and the gestation at which this occurred. Nearly 90% of respondents would routinely induce labour in patients with ICP. When asked at what gestational age induction would be considered, 173 of the 342 (50.6%) respondents stated they would induce at 37 completed weeks, and 105 (30.7%) at 38 completed weeks. Twenty-three (6.8%) would wait longer, with 1.5% waiting until the due date. In response to questions regarding influences determining timing of birth, for 284 respondents (86%), the possibility of fetal death influenced their decision to expedite delivery. The rest did so because of concerns regarding maternal symptoms or fetal wellbeing excluding fetal demise. An ‘other’ option was available in this question for respondents to explain their rationale with respect to induction timing and indications. The overriding impression from answers provided is that the reasons are multifactorial in nature and vary between patients. Questions 11 and 12 sought opinion regarding specific levels of bile acid elevation that affected patient management. Two hundred and seventy-five respondents
As there is no good evidence to guide clinicians in the management of this complex and poorly understood disease process, we sought to ascertain how obstetricians in Australia diagnosed and managed ICP in their own clinical practice.
Materials and Methods The study survey and a covering letter were emailed to all Members and Fellows of the Royal Australian and New Zealand College of Obstetrics and Gynaecology (RANZCOG), with no prior discrimination with regard to area of practice or subspecialisation. Contact details had been obtained through the RANZCOG Professional Development Committee. Two further reminder emails were sent at fortnightly intervals, also with a link to the questionnaire. The survey was comprised of thirteen questions. The first four related to the demographics of respondents, and the other nine sought targeted information regarding diagnosis and management of ICP. In some questions, respondents were requested to rank the importance to them of specific investigations regarding the diagnosis and management of the condition. Options were provided within the body of the questionnaire for further comment or explanation regarding respondent’s answers. The study was approved by the Darling Downs West Moreton HREC.
Results Four hundred and fifteen (30%) out of the 1379 Members and Fellows responded but in only 396 of these were the data provided interpretable. Three hundred and forty-five responding Fellows were practising obstetricians, comprising 25% of all practitioners who received the initial email. One hundred and forty-nine (43%) of these obstetricians practised in public hospitals only, 82 (24%) practised privately only and 113 (33%) worked in both private and public facilities. Three quarters of responding obstetricians work in Metropolitan hospitals, with only a quarter working primarily in a rural or remote location. Three quarters of the respondents were from New South Wales, Queensland and Victoria.
Table 1 Investigations requested in rank order to establish the diagnosis of ICP Investigation ranking Number of responses (%) Investigation requested
1
Bile acids LFT US fetal growth and well-being CTG FBC RFT
195 123 3 10 10 1
2 (56.0) (35.9) (0.9) (2.9) (2.9) (0.3)
95 185 20 19 21 2
(27.8) (53.9) (5.8) (5.5) (6.1) (0.6)
3 15 22 93 92 77 33
(4.4) (6.4) (27.1) (26.8) (22.4) (9.6)
4 13 6 99 105 60 41
(3.8) (1.7) (28.9) (30.6) (17.5) (12.0)
5 6 2 60 54 95 78
(1.7) (0.6) (17.5) (15.7) (27.8) (22.7)
6 16 3 43 36 38 128
(4.7) (0.9) (12.5) (10.5) (11.1) (37.3)
n/a 3 2 24 27 42 60
(0.9) (0.6) (7.0) (7.9) (12.2) (17.5)
LFT, liver function tests; US, ultrasound; CTG, cardiotocograph; FBC, full blood count; RFT, renal function tests.
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© 2014 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists
RANZCOG Fellows survey on intrahepatic cholestasis
Table 2 Rank order in which investigations or clinical presentation influence management Investigation ranking Number of responses (%) Investigation requested Bile acids LFT Clinical presentation US fetal growth and well-being CTG FBC RFT
1 110 77 68 34 49 4 1
(32.0) (22.4) (19.8) (9.9) (14.2) (1.1) (0.3)
2 85 118 39 47 43 8 3
(24.7) (34.3) (11.3) (13.7) (12.5) (2.3) (0.9)
3 47 71 80 51 66 17 9
(13.7) (20.6) (23.2) (14.8) (19.2) (4.9) (2.6)
4 30 47 45 90 68 41 15
(8.7) (13.7) (13.1) (26.2) (19.8) (11.9) (4.4)
5 34 24 47 60 66 60 27
(9.9) (7.0) (13.7) (17.4) (19.2) (17.4) (7.8)
6 16 2 13 25 28 128 80
(4.7) (0.6) (3.8) (7.3) (8.1) (37.2) (23.3)
7 15 2 43 21 5 37 152
(4.4) (0.6) (12.5) (6.1) (1.4) (10.8) (44.2)
n/a 7 2 9 16 19 49 57
(2.0) (0.6) (2.6) (4.7) (5.5) (14.2) (16.6)
LFT, liver function tests; US, ultrasound; CTG, cardiotocograph; FBC, full blood count; RFT, renal function tests.
(77%) stated that no specific level of bile acid elevation should instruct delivery of the fetus for either maternal or fetal well-being. Seventy-nine respondents have a defined bile acid elevation mandating delivery, and for 51 of these (66%), it is a level of >40 lmol/L, which instructs delivery. The final survey question invited respondents to list any guidelines that they use to inform management of patients with ICP. Eighty-one (38.9%) of the respondents used the Royal College of Obstetricians and Gynaecologists (RCOG) guideline, whereas 76 (36.5%) stated that they did not use any. The remaining few used local hospital- or state-based ones.
Discussion This survey has confirmed the use of fasting bile acid elevation as the primary test used to diagnose of ICP for a majority of clinicians. However, it must be noted that the normal range for this test was derived from a nonpregnant population,8 and its use for pregnant women has been questioned.9 With regard to management, the lack of a clearly defined and utilised role for bile acids in monitoring the progress of ICP is evident. Although many respondents use fasting bile acid elevation to guide management, there was no consistent upper limit that would cause concern. The few whose management was influenced by a defined elevated bile acid result quoted 40 lmol/L as their action level. This is in keeping with the large cohort study of pregnant Swedish women10 that reported bile acid concentrations >40 lmol/L were associated with an increased likelihood of a poor pregnancy outcome. Geenes et al.,5 from their recent prospective case–controlled study, also noted a worsening obstetric outcome with increasing bile acid elevation. A level of >40 lmol/L was also considered significant in that study because of an increased risk of stillbirth, particularly if there were coexistent maternal obstetric or medical conditions.5 Ursodeoxycholic acid has long been shown to decrease serum transaminases and bile acids in patients with ICP.1,6,7,11 The recently published Cochrane review12 suggested that UDCA significantly improved pruritis and
recommended large trials to assess its effect on obstetric outcome. As the measure of improvement used in the contributing studies was unavoidably a subjective measure, its relevance with regard to the practical application of their findings may be variable. Some of our respondents stated that they have prescribed ursodeoxycholic acid for the relief of pruritis, and amongst all respondents, bile acids, liver function tests and maternal symptoms were the three quantitative entities most likely to influence management. It may be that given clinicians act on maternal symptoms and/or worsening biochemical profiles, as there are no proven methods for effective fetal monitoring, decreasing the lived and measured experience of the disease enables the clinician to feel more comfortable with delaying delivery. Geenes et al.5 have proposed that bile acid surveillance, regardless of fasting status, be used to identify the at risk fetus and to instruct delivery after 37 completed weeks, and point to an increased risk of stillbirth if the bile acids exceed 40 lmol/L. Dedicated, direct fetal monitoring during the antenatal period is practised by the majority of obstetric units in the UK in cases of ICP.13 Serial cardiotocography and ultrasound estimates of fetal growth, umbilical artery Doppler and amniotic fluid volume are recommended by a consensus of UK clinicians,13 but not the RCOG,4 for monitoring fetuses in women with ICP. Numerous tests have been proposed as markers for fetal well-being in ICP, but thus far none reliably predict fetal death.14 We did not ask whether Australian obstetricians routinely incorporate these fetal monitoring modalities in patients with ICP; however, given the risk-averse nature of medical specialties, it would be unlikely for many clinicians to deny their use. Of importance was the recognition by our respondents that influencing fetal markers of well-being (eg pathological CTG, abnormal umbilical artery Doppler studies) are less likely to be evident in women with ICP. Chronic uteroplacental insufficiency, which would be evident on ultrasound as growth changes, decreased amniotic fluid and/ or uterine Doppler abnormalities, is seldom identified in those fetal deaths associated with ICP.15 Obstetricians in Australia currently support and engage heavily in the induction of labour of patients with ICP at 37–38 weeks, similar to practices elsewhere.1,13 The lack
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of effective and appropriate tests for fetal well-being in mothers with ICP resounded as a driving influence behind the choice to induce. The majority of reported fetal deaths associated with ICP have occurred after 37-week gestation,16 and thus, the active management of the condition, incorporating planned earlier delivery, could account for the decrease in the observed mortality rate over time.14 One of the possible weaknesses of the study was the disappointingly low response rate of only 30%; however, many of the recipients of the survey were ineligible for inclusion as they no longer practise obstetrics. According to the 2003 Australian Medical Workforce Advisory Committee survey into the practices of Fellows,17 just over one-third of those qualified to work in obstetrics and gynaecology do not practise obstetrics. Extrapolating from this, it is estimated that 40% of RANZCOG Fellows currently practicing obstetrics in Australia provided a response to the survey. Poor response rates are not uncommon in surveys undertaken by obstetricians and gynaecologists using Survey Monkey. Results of internationally published surveys from 2011 and 2012 which used that particular modality and involved obstetric and gynaecological conditions reported return rates of 14–34%.18–21 Simplistic questionnaires regarding complex disease processes may also be viewed by potential respondents as untenable with the stated aims of the project, as they fail to enable the clinician to adequately explain their management processes, and are unable to account for differing clinical presentations. A survey similar in intent to ours undertaken in the United Kingdom13 had a higher response rate of 57%; however, only 118 individual obstetricians were surveyed, compared to our 345 individual responses. Our survey attempted to seek as many individual responses as possible, recognising that practices may differ not only between hospitals, but also within them. Other major differences between the studies comprised of the options provided in the closed questions regarding investigation and monitoring modalities. RANZCOG Fellows were most likely to turn to the RCOG Green-top Guidelines for advice with regard to management of this condition. Interestingly, they were nearly equally as likely to not utilise any guideline, preferring their own readings and education, as well as the opinions of their colleagues around them. There may be a role for a national guideline, the dissemination of which could lead to consistency of practice. In summary, intrahepatic cholestasis of pregnancy is a clinically suspected and serologically confirmed uncommon obstetric condition that can result in sudden and unexplained fetal death. Currently, there is no effective fetal monitoring that reduces the incidence of adverse fetal outcome. Active management of the condition incorporating relief of maternal symptoms and induction of labour at 37–38 weeks of gestation is currently widely practised within Australia. Inconsistencies between clinicians regarding the diagnosis and management of the 266
condition, as shown in this survey, indicate a need for a consensus guideline for obstetricians in Australia.
Acknowledgements The authors wish to acknowledge the RANZCOG CPD for providing the email addresses for Members and Fellows of the College, and also those Members and Fellows who kindly and graciously completed the survey.
References 1 Mays JK. The active management of intrahepatic cholestasis of pregnancy. Curr Opin Obstet Gyn 2010; 22: 100–103. 2 Geenes V, Williamson C. Intrahepatic cholestasis of pregnancy. World J Gastroenterol 2009; 15: 2049–2066. 3 Wikstr€ om Shemer E, Marschall HU, Ludvigsson JF, Stephansson O. Intrahepatic cholestasis of pregnancy and associated adverse pregnancy and fetal outcomes: a 12-year population-based cohort study. BJOG 2013; 120: 717–723. 4 Royal College of Obstetricians and Gynaecologists (UK). Obstetric Cholestasis (Internet). Green-top Guideline No. 43. London (UK):RCOG;2006 Jan [Updated April 2011; Accessed 16 August 2013] Available from URL: http://www. rcog.org.uk/womens-health/clinical-guidance/obstetric-cholestas is-green-top-43 5 Geenes V, Chappell LC, Seed PT et al. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: A prospective population-based case-control study. Hepatology 2014; 59: 1482–1491. 6 King Edward Memorial Hospital Clinical Guidelines (AU). Cholestasis in Pregnancy (Internet). Perth, WA (Australia): King Edward Memorial Hospital (AU). 2000 Feb [Updated 2010 Nov; Accessed 16 August 2013] Available from URL: http://www.kemh.health.wa.gov.au/development/manuals/O&G_ guidelines/sectionb/2/8859.pdf 7 SA Maternal and Neonatal Clinic Network (AU). Obstetric Cholestasis (Internet). Adelaide, SA (Australia): Department of Health, Government of South Australia; 2004 May 4 [updated 2007 Nov 18; Accessed 16 August 2013] Available from URL: http://www.health.sa.gov.au/ppg/Default.aspx? PageContentMode=1&tabid=104 8 Lee RH, Goodwin TM, Greenspoon J, Incerpi M. The prevalence of intrahepatic cholestasis of pregnancy in a primarily Latina Los Angeles population. J Perinatol 2006; 26: 527–532. 9 Pathak B, Sheibani L, Lee RH. Cholestasis of pregnancy. Obstet Gynecol Clin N Am 2010; 37: 269–282. 10 Glantz A, Marschall HU, Mattsson LA. Intrahepatic cholestasis of pregnancy: Relationships between bile acid levels and fetal complication rates. Hepatology 2004; 40: 467–474. 11 Palma J, Reyes H, Ribalta J et al. Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy. Hepatology 1992; 15: 1043–1047. 12 Gurung V, Middleton P, Milan SJ et al. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013 Jun 24;6: CD000493. doi: 10.1002/14651858. CD000493.pub2. 13 Saleh MM, Abdo KR. Consensus on the management of obstetric cholestasis: National UK survey. BJOG 2007; 114: 99–103.
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RANZCOG Fellows survey on intrahepatic cholestasis
14 Roncaglia N, Arreghini A, Locatelli A et al. Obstetric cholestasis: outcome with active management. Eur J Obstet Gynecol Reprod Biol 2002; 100: 167–170. 15 Fisk NM, Bye WB, Storey GN. Maternal features of obstetric cholestasis: 20 years experience at King George V Hospital. Aust NZ J Obstet Gynaecol 1988; 28: 172–176. 16 Williamson C, Hems LM, Goulis DG et al. Clinical outcome in a series of cases of obstetric cholestasis identified via a patient support group. BJOG 2004; 111: 676–681. 17 AMWAC Report 2004.2 (AU). The Specialist Obstetrics and Gynaecology Workforce – An Update 2003-2013 (Internet). Sydney, NSW (Australia): Australian Medical Workforce Advisory Committee; 2004 April [Accessed 16 August 2013] Available from URL: http://www.ahwo.gov.au/documen ts/Publications/2004/Specialist%20obstetrics%20and%20gynaec ology%20workforces%20in%20Australia.pdf
18 Ramondetta L, Brown A, Richardson G et al. Religious and spiritual beliefs of gynecologic oncologists may influence medical decision making. Int J Gynecol Cancer 2011; 21: 573– 581. 19 Grant E, Joshi GP. Glycemic control during labor and delivery: a survey of academic centers in the United States. Arch Gynecol Obstet 2012; 285: 305–310. 20 Hilton P, Bryant A, Howel D et al. Assessing professional equipoise and views about a future clinical trial of invasive urodynamics prior to surgery for stress urinary incontinence in women: a survey within a mixed methods feasibility study. Neurourol Urodyn 2012; 31: 1223–1230. 21 Pauls RN, Fellner AN, Davila GW. Vaginal laxity: a poorly understood quality of life problem; a survey of physician members of the International Urogynecological Association (IUGA). Int Urogynecol J 2012; 23: 1435–1448.
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