Cholestasis of pregnancy

– Where are we? Amanda Henry

Senior Lecturer in Obstetrics, School of Women’s and Children’s Health,

UNSW Sydney

Clinical Academic Obstetrician, St George Hospital, SESLHD

Senior Research Fellow, Global Women’s Health Program, The George

Institute for Global Health

Amanda.Henry@unsw.edu.auTwitter: Amanda_Henry_AK

DisclosuresI am not this cholestasis guru Or this one Or this one

Professor Catherine Williamson

Professor Catherine Nelson-Piercy

Professor Lucy Chappell

Further disclosures

• I have only ever performed one study focussing on cholestasis

• It was part of my PhD though

• I have no financial or non-financial COI to declare!

Overview- Who’s afraid of the big, bad itch?

- What are the actual complications associated with cholestasis?

- Who is at highest risk of complications, and what is the right cutoff?

- Should we be monitoring the fetus? If so, how?

- Is there any evidence-based therapy apart from induction?

- When should we induce, and on what evidence?

- Are we there yet? (NO) What trials are ongoing that might give us the answers we need?

Intrahepatic cholestasis of pregnancy (“cholestasis”)• Commonest primary liver disorder in

pregnant women: varies with ethnicity, Australian incidence about 1 in 150-200 (Marathe et al, EJOGRB 2017)

• Symptoms: Itch without rash (more rarely - if significant transaminitis -then nausea, abdominal pain)

• Signs: Excoriations (more rarely jaundice, pale stools, dark urine)

• Diagnosis: Clinical picture + serum bile acids (ideally fasting) ≥10µmol/L (note local reference range variations)

Source: Chappell et al BMJ 2018

Source: www.icpsupport.org

Why does it happen?• Bile acids = end products of cholesterol catabolism• Main ones cholic acid and chenodeoxycholic acid• Synthesis in liver à conjugation with glycine or taurine

à gallbladder for storage à released into intestines where they emulsify fats and fat-soluble vitamins – and are further modified by gut bacteria (microbiome!) in terminal ileum/colon à 95% reabsorbed in terminal ileum (enterohepatic circulation) à liver via portal vein

• Levels tightly regulated by various receptors e.g. FXR• Rise slightly in normal pregnancy: cholestatic effects

reproductive hormones through effects on BA transporter proteins and receptors

• Cholestasis: Though to be interaction of genetic susceptibility (FXR and transporter variants), oestrogen/progesterone, viral infections (e.g. HCV), environment ?low Vit D and selenium

Why do we care? A case study• TC, 36 year old G4P2 (2 X NVB, 1 first-trimester TOP), Russian background,

no major non-obstetric history

• Previous 2 children born in Russia 15 and 13 years ago, 37 and 38 weeks, second child rash/itch from 32 weeks, not told a diagnosis

• This pregnancy GIDDM (actrapid 12U tds, protophane 16U nocte), BSLs target range last 2 weeks

• Presents at 36+5 weeks to ANC visit with 2 week history of worsening itch: now can’t sleep, no rash although “scratch marks from all the itching”. Baby has “slowed down”

Examination• Observations NAD

• Fundal height 36cm, cephalic LOL, 3/5 palpable, not engaged, FHS 140bpm

• Excoriations on arms, legs, and abdomen, but no rash

• Spider naevi, no other stigmata liver disease

• Likely diagnosis? What to do next?

In Day Stay next day…• AST 257, ALT 217, other LFT normal

• Bile acids 167

• CTG normal

• Ultrasound EFW 3.3kg, AFI and UA Doppler normal

Unfortunately, it’s a Friday, patient hurries away and only gets seen by RMO, plan for IOL Monday….

• Comes in Sunday morning with 24 hour history of decreased fetal movement, midwife can’t auscultate fetal heart

Ultrasound confirms FDIU

Postpartum• IOL and NVB of stillborn girl, normal size

• Opts for full investigations including perinatal autopsy

• Comes back at 6 weeks and 6 months

• All investigations normal apart from the initial high bile acids and transaminitis. (including HbA1c normal and 2 months postpartum GTT normal).

• Gets pregnant again 9 months after stillbirth, low risk FTS, normal early GTT, what to say and do?

What are the actual risks?

Fetal

1), 2) and 3) StillbirthAlso:

• Meconium-stained liquor• Preterm birth: iatrogenic [RR 3-10]

• Preterm birth: spontaneous [RR1.5-3]

• Low birth weight but LGA Geenes et al, TOG 2016; 18: 273-81

What are the actual risks?Maternal

• Distress/discomfort of intense itch

• Increased obstetric intervention

• Co-morbidities: Higher rates

- HBV/HCV (although NB recent Chappell et al study)

- GDM (RR 1.5-3)

- Preeclampsia (RR 1.5-3)

- Gallstones (will be present in 10-15%)

Which pregnancies are at increased risk?1) Of getting cholestasis

• Past history (recurrence risk 40-90%)• Family history/genetics (about 15% have a first degree

relative Hx)• Certain ethnicities e.g. Chilean• History of pruritis on OCP• Pre-existing liver disease especially gallstones, chronic

hepatitis• Multiple pregnancy (RR 5)

Which pregnancies are at increased risk?2) Of having a poor outcome (specifically, stillbirth)• High bile acids/ “severe” cholestasis (NB Only about 1 in 5 cases, 4 in

5 have “mild” disease)- Glantz et al 2004: 1-2% increase in risk of MSL, “asphyxia” events and spont

PTB for every µmol/L above 40- Geenes et al 2014: Stillbirth risk singletons SBA≥40 µmol/L 1.5% versus

controls from UKOSS database 0.5%- Chappell et al 2018 (presented): IPD meta-analysis of 4163 cholestasis

cases stillbirth risk 0.83% versus controls 0.32%, however risk only significantly increased if bile acids ≥100 µmol/L (stillbirth rate 3.1%, HR 17) NB HR 1.5 for 40-100 range, but NS

- • Multiple pregnancy

DiagnosisIn the patients where you have a level of suspicion i.e. onset of itch without rash, perform- LFTs- Serum bile acids (fasting is ideal, however as most pathology runs only done once

or twice a week, non-fasting fine first – if the result definitive no need to do fasting as well)

• Diagnosis = SBA ≥ 10µmol/LCaveats: 1) Local reference ranges vary (e.g. NSW Health Pathology 7.5µmol/L)2) If non-fasting then up to 15µmol/L ideally repeat it fasting (particularly if LFT

normal/not convincing clinically)3) Bile acid values sometimes “lag” the clinical symptoms, so if persistent itch with no

rash then repeat within 1 week if >34 weeks (particularly if abnormal AST/ALT) and within 1-2 weeks if <34 weeks

What about for this?

My patient has cholestasis – any other tests?“Typical” cholestasis: usual symptoms, SBA<40µmol/L, LFT N or only mild transaminitis, no Hx or Ex to suggest other cause

High-risk or atypical cholestasis: Hx to suggest potential other liver Dx, abnormal Ex (including high BP, jaundice, RUQ tenderness), SBA≥40µmol/L, AST/ALT>100-200

Obstetric growth and wellbeing ultrasound (usually normal)

Obstetric growth and wellbeing ultrasound (usually normal)

And potentially:

Coagulation studies

Preeclampsia screen

Hep A/B/C, autoantibody screen

Liver ultrasound

Should we be monitoring the fetus? If so, how?

• Reminder why cholestasis is scary: Sudden fetal death in a well-grown baby, where CTG may have been entirely normal 6 hours before

• Happens as mechanism of death is likely direct toxic effect of bile acids on cardiac conducting system and cardiomyocytes

• Reasonable to perform growth/wellbeing ultrasound at diagnosis

• Cardiac measures such as PR interval and MPI tantalising but unproven

• ?Weekly CTG (because reviewing weekly for bile acids/LFTs/symptoms anyway)

(a) (b) (c)

Figure

Myocardial performance index

PR interval

Medications (i.e. non-IOL therapy!)Medication Dose Evidence? Considerations

Ursodeoxycholicacid (UDCA): upregulates bile acid export pathways in liver

Commence 250mg bd or tds, titrate up, max 2g/day (UK up to 3g/day)

-Reduces pruritis(modestly) and bile acids-Uncertain re stillbirth risk

Not on PBS for obscholestasis: dispense through hospital

Rifampicin (2nd

line/add-on): ?enhances bile acid detoxification, bilirubin conjugation and excretion

Commence 150mg bd, max 1200mg/day

-Small cohort: bile acids decreased in about 50% when added-on to UDCA

Alters urine colour and tears (orange)May worsen hepatic impairment

Cholestyramine(2nd/3rd line): bind bile acids

4-16g/day -No good evidence efficacy (now rarely used)

Depletes Vitamin K so need for Vit K if taking

Antihistamines: may help with sedation/sleep

Depends on antihistamine

-Probably only via sedative effect

Use at night

Chappell et al BMJ 2018; Geenes et al 2015 EJOGRB

When to induce, and on what evidence?General considerations:• Balance of neurodevelopmental risks of “early term” birth and risk of stillbirth• NO reliance able to be placed on reassuring ultrasound or CTG• No convincing ­ stillbirth with bile acids <40µmol/L (possible exception:

multiple pregnancy), and maybe not until 100µmol/LMy take in 2018:• 40+µmol/L birth at 37 weeks, acknowledging that the absolute risk is still

small here (and 40 may be too aggressive a threshold)• Under 40µmol/L not later than 39-40 weeks (maternal symptoms!!!):

acknowledging that many women and clinicians will decide to go earlier.• If waiting for “term term”, need to keep regularly reviewing bile acids.

What about the preterm “difficult case”?• No easy answers, and given lack of a specific monitoring

trigger to justify preterm birth likely to always be case by case

My suggestions:• Make sure you have looked for underlying issues that might

be contributing/correctable• Spread the love and involve obstetric physicians• Try at least UDCA and rifampicin before pulling out• Steroid cover, neonatal consultation• Shared decision making with the woman, acknowledging

uncertainty of stillbirth risk with certain risks of preterm birth

Postpartum management• Cease UDCA and other medication after delivery• Pruritis will usually settle rapidly, LFTs (if they were abnormal) should start

improving within a week• If abnormal LFTs prior to birth, needs GP follow-up after discharge to check

returning to normal. Usually no need for repeat bile acids.• If LFTs have not returned to normal by six weeks postpartum:- Arrange serological screen for other causes (hepatitis, autoimmune)- Upper abdominal/liver ultrasound- Specialist referral• Ensure woman is aware of risk of recurrence, and overall association with

gallstones and hepatobiliary disease• Long-term: some evidence of increased hepatobiliary cancer (however NB as

these cancers are rare, absolute risk still very low)

What trials are ongoing that might get us “there”?

• PITCHES (Chappell and Williamson group): Phase III trial in IntrahepaTicCholestasis of pregnancy (ICP) to Evaluate urSodeoxycholic acid (UDCA) in improving perinatal outcomes; ISRCTN91918806). Comparing UDCA with placebo in 580 women with mild and severe intrahepatic cholestasis of pregnancy. Primary outcome composite perinatal death/preterm birth/admission to NICU 4+ hours

• TURRIFIC (Bill Hague and colleagues): RCT UDCA versus rifampicin ACTRN12618000332224. Enrolling women with SBA>40 at <34 weeks. Primary outcome pruritus score. 110 women.

• Bile Acid Effects in Fetal Arrhythmia Study (BEATS): 400 women (case-control), effect of bile acid levels on fetal ECGs

Back to TC• Almost certainly a cholestasis-related stillbirth: GIDDM associated but

probably not contributory given normal size baby, BSLs on target, normal HbA1c and postpartum GTT

• Yes, high recurrence risk of cholestasis• In this case, baseline LFTs and bile acids now (i.e. 12 weeks in the next

pregnancy) probably reasonable: would not be standard for most prior cholestasis cases (i.e. those with normal or only very mildly raised transaminases, where SBA <40, and no major medical co-morbidities)

• Probably also reasonable to do again at 28 and 32 weeks (again, not for the non-severe prior cases: in those cases, await symptoms)

• Ensure appropriate psychological supports are available• Obstetric discussion re timing of birth (if no recurrence of cholestasis by

34-36 weeks)

Further resources and reading

Guidelines• South Australian 2016 guidelines(type obstetric cholestasis SA Health into your browser)• RCOG green-top guidelines (2011

so a bit outdated) – link from RANZCOG https://www.ranzcog.edu.au/Statements-Guidelines/Obstetrics/Obstetric-Cholestasis

http://www.icpsupport.org/

ReferencesGeenes V, Chappell LC, Seed PT, Steer PJ, Knight M, Williamson C. Association of severe intrahepatic cholestasis of pregnancy with adverse pregnancy outcomes: a prospective population-based case-control study. Hepatology. 2014; 59(4):1482-91.Glantz A, Marschall HU, Mattsson LÅ. Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates. Hepatology. 2004;40(2):467-74.Chappell LC, Gurung V, Seed PT, Chambers J, Williamson C, Thornton JG. Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. BMJ. 2012;344:e3799.Geenes V, Chambers J, Khurana R, Shemer EW, Sia W, Mandair D, Elias E, Marschall HU, Hague W, Williamson C. Rifampicin in the treatment of severe intrahepatic cholestasis of pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2015;189:59-63.Geenes V, Williamson C, Chappell LC. Intrahepatic cholestasis of pregnancy. The Obstetrician & Gynaecologist. 2016;18(4):273-81.Williamson C, Geenes V. Intrahepatic cholestasis of pregnancy. Obstetrics & Gynecology. 2014;124(1):120-33.Chappell LC, Chambers J, Williamson C. Does ursodeoxycholic acid improve perinatal outcomes in women with intrahepatic cholestasis of pregnancy?. BMJ. 2018;360(k104):1-5.Marathe JA, Lim WH, Metz MP, Scheil W, Dekker GA, Hague WM. A retrospective cohort review of intrahepatic cholestasis of pregnancy in a South Australian population. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2017 ;218:33-8.