580 Gut 1995; 37: 580-584

CASE REPORTS

Fetal mortality associated with cholestasis of Gut: first published as 10.1136/gut.37.4.580 on 1 October 1995. Downloaded from pregnancy and the potential benefit of therapy with ursodeoxycholic acid

M H Davies, R C M A da Silva, S R Jones, J B Weaver, E Elias

Abstract partum, but cholestasis of pregnancy is Cholestasis ofpregnancy is associated with associated with significant fetal morbidity increased fetal morbidity and mortality and mortality.'-9 Cholestasis of pregnancy and should be treated actively. The signifi- typically develops during the third trimester of cance attached to pruritus in pregnancy is pregnancy, but occasionally presents before often minimal, but it is a cardinal symp- 20 weeks. By definition, dermatological tom of cholestasis of pregnancy, which disease should be absent, if a diagnosis is may have no other clinical features. Eight made on clinical criteria alone,9 but this is women with previous cholestasis of not necessary if biochemical evidence of pregnancy were referred to The Liver cholestasis is obtained. Most patients are not Unit within a 12 month period for advice jaundiced and many have normal standard concerning future pregnancies. Thirteen liver function tests. Serum alanine trans- pregnancies had been affected by chole- aminase (ALT) is the most sensitive of stasis of pregnancy and 12 had been the conventional liver function tests,10-12 treated expectantly with resultant peri- although serum bile acids are invariably natal morbidity or mortality in 11 (one increased.0"11 13 Symptoms vary from mild normal delivery), including; eight still- pruritus to intractable pruritus, associated births, two premature deliveries with fetal with gastrointestinal upset and icterus.

distress (one died in perinatal period), and Symptoms almost invariably resolve within http://gut.bmj.com/ an emergency caesarean section for fetal one week of delivery. distress. The other pregnancy was treated Treatment of cholestasis of pregnancy varies actively and delivery was uncomplicated. widely. Despite evidence to the contrary, Subsequently, three of these cases with some obstetricians still perceive cholestasis of recurrent cholestasis of pregnancy were pregnancy as a benign condition and adopt an referred while pregnant. In each, chole- expectant policy. We report eight cases with a

stasis developed with severe pruritus, gross history of cholestasis of pregnancy whose preg- on October 1, 2021 by guest. Protected copyright. increase of serum bile acids, and deranged nancies had mostly been treated conservatively. liver tests. Each was treated with the Three of these cases were pregnant at the time choleretic agent ursodeoxycholic acid, with of referral and treated with the choleretic rapid clinical improvement and resolution ursodeoxycholic acid. of deranged biochemistry. In conclusion, Birmingham Liver cholestasis of pregnancy continues to be Unit, Queen Elizabeth Hospital, Edgbaston, treated expectantly despite its association Case reports and previous obstetric Birmingham with increased morbidity and mortality histories (Table) M H Davies and evidence suggesting improved progno- R C M A da Silva E Elias sis with active treatment and the potential Case 1: 34 year old white woman of reducing the associated perinatal First pregnancy, 1986 - pruritus from 28 Department of Clinical mortality. In an uncontrolled series of weeks gestation. She was reassured. Spon- Chemistry, Queen Elizabeth Hospital, three patients with cholestasis of preg- taneous onset of labour at 37/40. Stillborn Edgbaston, nancy, ursodeoxycholic acid seemed to female. Pruritus settled within two days. Birmingham provide safe and effective therapy. Second pregnancy 1988 - pruritus from. S R Jones (Gut 1995; 37: 580-584) 27/40. Induction oflabour at 38/40, because of Birmingham previous intra-uterine death. No meconium Maternity Hospital, Keywords: cholestasis of pregnancy, fetal mortality, staining. Male baby, alive and well. Pruritus Edgbaston, prognosis, treatment, ursodeoxycholic acid. settled within Birmingham four days. J B Weaver Third pregnancy - pruritus from 26 weeks, without jaundice. Fetal movements were normal Correspondence to: Dr M H Davies, Cholestasis of pregnancy is a disease of and she was reassured. Liver functions tests Birmingham Liver Unit, unknown aetiology, which may cause severe became abnormal, with increased serum aspar- Queen Elizabeth Hospital, Edgbaston, Birmingham. and intractable pruritus. The maternal prog- tate transaminase (AST) (135). Spontaneous Accepted for publication nosis is excellent, with symptoms and bio- onset of labour at 39/40, with stillbom female. 16 February 1995 chemical derangements resolving rapidly post Pruritus settled almost immediately. Fetal mortality associated with cholestasis ofpregnancy 581

Case reports

UDCA A/N Otnset Mode of Mecomiiumti Cessationi Case Pregnancy Onset RX Ictenus clinlic labour Gestationi delivety AST stainizng Olutcolme (fpruritus 1 1st 28/40 No No Yes SPONT 37/40 Vaginal 243 Yes Stillbirth 2 Days 2nd 27/40 No No Yes Induced 38/40 Vaginal 129 No Normal 4 Days

3rd 26/40 No No Yes SPONT Term Vaginal 135 Yes Stillbirth 1 Day Gut: first published as 10.1136/gut.37.4.580 on 1 October 1995. Downloaded from 4th 25/40 Yes No Yes C/s 35/40 ELEC C/s 213 No Normal 2 Days 2 1st 35/40 No No Yes SPONT 38/40 EMERG C/s N/D Yes Fetal distress 3 Days 2nd 35/40 No No Yes SPONT Term Vaginal 82 Yes Stillbirth 1 Day 3rd 28/40 Yes No Yes C/s 35/40 ELEC C/s 42 No Normal 0 Days 3 1st 28/40 No No Yes SPONT 36/40 Vaginal N/D N/K Perinatal death 7 Days 2nd None No No Yes SPONT Term Vaginal N/D No Normal N/A 3rd 32/40 No No Yes SPONT 37/40 Vaginal N/D No Normal 7 Days 4th 30/40 Yes No Yes Induced 38/40 Vaginal 205 No Normal 2 Days 4 1 st None No N/A Yes SPONT Term Vaginal N/D No Normal N/A 2nd 30/40 No No Yes SPONT 36/40 Vaginal N/D ? Fetal distress 1 Week 3rd 31/40 No No Yes SPONT Term Vaginal N/D Yes Stillbirth 2 Days 5 1 st None No N/A Yes SPONT 35/40 Vaginal N/D Yes PREM+NIL N/A* 2nd None No N/A Yes SPONT Term Vaginal N/D No Normal N/A 3rd 25/40 No No Yes SPONT 32/40 Vaginal N/D Yes Stillbirth 1 Day 6 1st 31/40 No No Yes SPONT Term Vaginal N/D Yes Stillbirth 7 Days 7 1st 28/40 No No Yes SPONT 37/40 Vaginal N/D Yes Stillbirth 7 Days 8 1st 32/40 No No Yes SPONT 37/40 Vaginal 172 Yes Stillbirth 1 Day

A summary of details of all pregnancies of eight females referred subsequently to The Liver Unit. A total of 13 pregnancies were affected by cholestasis of pregnancy, resulting in two normal deliveries, two premature deliveries with fetal distress (1 perinatal death), one emergency caesarean section at 38 weeks for fetal distress, and eight stillbirths occurred. *First baby of case 5 was born premature, but with no other complications. UDCA RX=ursodeoxycholic acid therapy; N/D=liver function tests not done before delivery; A/N CLINIC=antenatal clinic; N/A=not applicable; N/K=not known; SPONT=spontancous; EMERG/ELEC C/s=emergency or elective caesarean section.

Case 2: 29 year old white woman Third pregnancy - pruritus from 25 weeks First pregnancy - pruritus from 35/40. gestation, without jaundice and liver function Spontaneous onset of labour, at 38+ weeks tests were not monitored. Fetal movements gestation. Emergency caesarean section for were normal and she was reassured. Onset of fetal distress. Baby discharged alive and well. labour was spontaneous at 32 weeks, with a Pruritus settled within three days. stillborn baby delivered vaginally. Pruritus Second pregnancy - pruritus from 35/40, settled within one day. without jaundice. Fetal movements were normal, she was reassured, and the pregnancy was treated routinely. Serum AST was Case 6: a 35 year old white woman increased at 82 lU/l. Spontaneous onset of First pregnancy - pruritus from 31 weeks, labour at term, with a stillborn baby delivered without jaundice. Fetal movements normal vaginally. Pruritus settled within one day. and the pregnancy was treated routinely.

Liver function tests were not monitored. http://gut.bmj.com/ Spontaneous onset of labour at term, with a Case 3: 30 year old white woman stillborn baby delivered vaginally. Pruritus First pregnancy - pruritus from 28 weeks. settled within seven days. Spontaneous labour at 36/40, with fetal dis- tress. The baby was transferred to special care baby unit (SCBU). The baby was discharged Case 7: a 28 year old white woman

home, but readmitted with recurrent con- Firstpregnancy - pruritus from 28 weeks ges- on October 1, 2021 by guest. Protected copyright. vulsions and died in the perinatal period. tation, without jaundice. Liver function tests Second pregnancy - normal. were not monitored and pregnancy was treated Third pregnancy - pruritus from 32/40. routinely. Spontaneous onset of labour at Spontaneous onset of labour at 37/40, with 37/40, with a stillborn baby delivered vaginally. delivery of healthy baby. Pruritus settled within seven days.

Case 4: 30 year old white woman Case 8: a 27year old white woman First pregnancy - normal. First pregnancy - pruritus from 32 weeks, Second pregnancy - pruritus from 30 weeks without jaundice. Serum AST increased at 172 gestation. Early labour, at 36/40, with fetal dis- IU/l, but fetal movements were normal and she tress. Baby discharged alive and well. was reassured. Spontaneous labour at 37 Third pregnancy - pruritus from 31 weeks weeks gestation, with a stillborn baby delivered gestation, without jaundice. The pregnancy vaginally. Relief of pruritus occurred immedi- was treated routinely. Liver function tests were ately post partum. not monitored and she was reassured. Spontaneous onset of labour at term, with stillborn baby. Pruritus settled within two Cases treated with ursodeoxycholic acid days. Cases 1 to 3 were each referred during preg- nancy. The clinical course, effect of ursodeoxy- cholic acid (UDCA) therapy, and outcome of Case 5: 28 year old white woman these three pregnancies is described. Because First pregnancy - normal pregnancy. UDCA is not licensed for use in cholestasis of Spontaneous labour 35/40, meconium stained pregnancy fully informed patient consent was liquor, baby discharged fit and well. obtained before this treatment. In case 1, S- Second pregnancy - normal. adenosyl-L-methionine was started before the 582 Davies, da Silva, Jones, Weaver, Elias

Intravenous UDCA ('Ursofalk', Thames Laboratories, UK). Case S-ADENOSYL- 1 3 received 1000 mg daily. METHONNINE 350 - ORAL > 300 Progress 300 Pruritus score (0-4+) 0 0 1+ 3+ 3+ 4+ 4+ 3+ 1+ 0 250 Gut: first published as 10.1136/gut.37.4.580 on 1 October 1995. Downloaded from 250 Case 1 U') Figure 1 is a diagrammatic representation of .)_ 200 serum AST, pruritus score, and serum bile m 150 acids. The first trimester was normal. S-adenosyl- 100 L-methionine 1600 mg daily, was started 50 orally at 16 weeks as prophylaxis, even though liver function tests and serum bile acids were normal. Dyspepsia and diarrhoea developed, Gestation (weeks) so the dose was reduced to 1200 mg daily. Despite S-adenosyl-L-methionine, pruritus Figure 1: Clinical and biochemical parameters: case 1. developed at 25 weeks gestation. Liver func- tion tests remained normal, but serum bile onset of symptoms in an effort to prevent acid concentrations were increased. At 29 cholestasis developing. weeks, pruritus became increasingly severe All three patients were booked to antenatal and serum AST became abnormal. Intra- clinics at 10 weeks, while asymptomatic. venous S-adenosyl-L-methionine, 1200 mg Ultrasound scans at 16 weeks were normal in daily, was started, but AST continued to rise each. -213 IU/l (<30 IU/l) and pruritus became Each received standard antenatal care. more troublesome. She was admitted to When symptoms of cholestasis developed hospital for close monitoring. At 31 weeks, S- inpatient observation was offered. Cardio- adenosyl-L-methionine was stopped and tocography and Doppler ultrasound examina- UDCA was started at 750 mg daily, by mouth. tions of fetus and placenta were carried out Symptomatic improvement occurred within weekly. In cases 1 and 2, amniocentesis was days and serum AST and serum bile acids fell performed at 35 weeks gestation to examine to normal values within two weeks of starting the lecithin:sphingomyelin ratio, to determine treatment. Fetal monitoring by cardiotoco- evidence of fetal lung maturity, and proceed to graphy and Doppler ultrasound was satisfac- delivery by caesarean section, if appropriate. tory throughout this period. Labour was induced in case 3 at 38/40. Amniocentesis confirmed fetal lung matu-

Each patient kept her own record of rity at 35 weeks gestation. Delivery of a live- http://gut.bmj.com/ 'pruritus score' between 0 and 4+. 0 indicated born male (35/40 gestation) was performed by no pruritus; 1 + indicated occasional pruritus; caesarean section. The baby was nursed on 2 + indicated more prolonged episodes; 3 + SCBU for nine days. He required oxygen indicated pruritus present more than absent; therapy, but not mechanical ventilation. He 4 + represented almost constant pruritus, was discharged home at 18 days. present by day and night.

Liver function tests were measured by the on October 1, 2021 by guest. Protected copyright. hospital clinical chemistry department. Case 2 Samples for serum bile acids were stored at Figure 2 is a diagrammatic representation of -20°C and analysed using a commercial total liver function tests, pruritus score, and serum serum bile acid kit, assaying 3ot-hydroxy bile bile acids. acids (Sigma, UK). - Liver function tests were initially normal. Case 1 received S-adenosyl-L-methionine Pruritus developed at 28 weeks gestation and (Ademetionine), provided in oral and intra- became severe. She was referred as an out- venous formulations by Knoll Ltd (BASF patient to The Liver Unit at 33 weeks gesta- group). tion. Liver function tests were only mildly Cases 1 and 2 received UDCA 750 mg daily deranged, but serum bile acids were greatly increased. UDCA was started orally at 750 mg daily. Pruritus completely resolved within five 350 r days of starting treatment, with return of 300 UDCA l serum bile acids to normal concentrations. Pruritus score (0-4+) Amniocentesis was performed at 35 weeks 250 U) 1+ 2+ 3+ 4+ 4+ 1+ 0 0 to assess fetal lung maturity. The following day C.) 200 a liveborn female was delivered by caesarean m section. She was nursed on SCBU for five 1150- Bile days, requiring oxygen therapy, but not requir- acids Parturition - 100 _ ing assisted ventilation. She was discharged home at 10 days. 50- AST 50 U- 0 a , , O -A ^ 27 28 29 30 32 33 34 35 Case 3 Gestation (weeks) Figure 3 is a diagrammatic representation of Figure 2: Clinical and biochemical parameters: case 2. ALT, pruritus score, and serum bile acids. Fetal mortality associated with cholestasis ofpregnancy 583

A study of 18 patients from Vancouver1 350 - UDCA 300 recorded fetal distress in and meconium Pruritus score (0-4+) 33/3% 300 staining in 58%. These authors,1 and others3 19 1+1+2+ 3+ 4+ 4+ 4+ 4+ 4+ 3+ 2+ 1+ 250 250 recommended delivery when evidence of lung U) 200 maturity has been established, although early

ALT Gut: first published as 10.1136/gut.37.4.580 on 1 October 1995. Downloaded from CoC.)_ 200 _ delivery is not without morbidity. Shaw reported cc 150 59% morbidity in their intervention group.1 mO 150 Parturition Some report fetal prognosis to 100 authors 100 _ correlate with disease severity.2 820 In a pro- Bile acidsI\ - 50 spective study of 1 17 patients with cholestasis of 50 pregnancy, Laatikainen8 reported concentra- O L A tions of serum bile acids to be a more sensitive 283 29 30 33 32 34 35 36 37 37.2 37.5 38 39 predictor of fetal distress than standard liver Gestation (weeks) function tests, so that women with highest Figure 3: Clinical and biochemical parameters: case 3. serum bile acid concentrations should be sub- jected to more intensive monitoring. Even in The first and second trimesters were normal. mild or moderate cases, however, fetal risk was Pruritus developed at 30 weeks gestation. She still noted.8 Biochemical markers of fetoplacen- was referred as an outpatient to The Liver Unit tal function, oestriol, and human placental when liver function tests and serum bile acids lactogen, have proved ineffective at predicting were noted to be abnormal at 37 weeks. fetal distress.21 22 Treatment with UDCA was started orally at Development of the optimal treatment 1000 mg daily. Serum ALT rapidly returned to policy in cholestasis of pregnancy is hindered normal from a peak of 205 IU/1 (<30 IU/1). by difficulty predicting fetal outcome. The Serum bile acids rapidly declined from a peak stillborn babies in the cases we report showed of 102 U/l (<8.1 U/1) and pruritus, which had no evidence of dysmaturity, suggesting that been intractable for several weeks had almost chronic nutritional deficiency was not present disappeared by the time she was induced at and all but one of the fetal deaths occurred at, 38/40. Serum bile acids responded rapidly. or beyond, 37 weeks gestation. These findings A healthy female baby was delivered are in accordance with previous reports, in vaginally. which most stillbirths occurred late in preg- nancy.2 6 22-24 This provides a rationale for early delivery in cholestasis of pregnancy. Discussion Invasive means of monitoring may assist prog- Treatment of cholestasis of pregnancy varies nostication.3 Non-invasive measures should widely. Despite evidence to the contrary,2-9 12 include regular cardiotocographs, yet these

some obstetricians still perceive cholestasis of may remain normal until a very late stage, even http://gut.bmj.com/ pregnancy as a benign condition and adopt an in cases of stillbirth.8 expectant treatment policy. We have reported Despite uncertainty as to the mechanism of eight cases who had experienced at least one cholestasis, treatment with choleretic agents previous episode ofcholestasis of pregnancy and has been shown to be of benefit in uncon- were referred to The Liver Unit within a 12 trolled and controlled trials, including S- month period. All pregnancies, except one, had adenosyl-L-methionine, which has been used

been treated conservatively receiving standard with variable benefit,25-28 although a double on October 1, 2021 by guest. Protected copyright. antenatal care, without additional fetal or mater- blind placebo controlled study showed no nal monitoring. All women were reassured that benefit.29 Other agents used with apparent pruritus occurs within the spectrum of normal benefit include epomediol,30 dexametha- pregnancy and is 'nothing to worry about'. Each sone,31 and UDCA.19 32 had experienced a stillbirth or perinatal death in We have presented the progress of three association with cholestasis of pregnancy. One women treated with UDCA, all of whom had patient had suffered a second stillbirth and two previous stillbirths or perinatal deaths associated had pregnancies complicated by fetal distress with cholestasis ofpregnancy. Our cases suggest requiring immediate delivery. These were all UDCA provides well tolerated and effective associated with cholestasis of pregnancy. treatment. In each case there was rapid sympto- When cholestasis of pregnancy was recog- matic relief and biochemical improvement. The nised as a clinical entity, it was considered mechanism ofaction ofUDCA is unknown, but benign.'4-18 Subsequent reports showed a con- its effects probably result from modification of sistent pattern of increased fetal morbidity and the bile acid pool, choleresis, and a reduction of mortality.2-9 12 Fifty six cases from Sydney had serum bile acids. While there are concerns over a perinatal death rate of 11%, spontaneous prescribing novel drugs during pregnancy, the premature labour in 36%, and heavily start of treatment is usually delayed until the meconium stained liquor in 27%.2 A later third trimester, which minimises the risk of study from the same centre showed improved teratogenicity. There are no reports of adverse results,3 after an elective policy was instituted. effects upon the fetus as yet. Despite careful fetal monitoring, the authors Because the mechanism of fetal toxicity is were unable to predict a poor outcome in those unknown, it cannot be assumed that resolution babies who died. All stillbirths were associated of clinical and biochemical derangements with meconium staining. Amniocentesis for associated with cholestasis of pregnancy will the presence/absence of meconium was the necessarily reduce fetal morbidity, though this most sensitive predictor of fetal well being.3 seems a likely further benefit. 584 Davies, da Silva, Jones, Weaver, Elias

9 Berg B, Helm G, Petersohn L, Tryding N. Cholestasis of UDCA has been of benefit in the treatment pregnancy. Clinical and laboratory studies. Acta Obstet Gynecol Scand 1986; 65: 107-13. of cholestasis of pregnancy in other small 10 Heikkinen J, Maentausta 0, Ylostalo P, Janne 0. Changes series,19 32 but to date there are no results from in serum bile acid concentrations during normal controlled trials. Palma19 reported improve- pregnancy, in patients with intrahepatic cholestasis of pregnancy and in pregnant women with itching. Br _7

ment of serum bile acid concentrations and Obstet Gynaecol 1981; 88: 240-5. Gut: first published as 10.1136/gut.37.4.580 on 1 October 1995. Downloaded from 11 Laatikainen T, Ikonen E. Serum bile acids in cholestasis of pruritus in response to 1000 mg UDCA daily pregnancy. Obstet Gynaecol 1977; 50: 313-8. in eight patients. In three of eight patients, 12 Fisk NM, Bye WB, Storey GNB. Maternal features of obstetric cholestasis: 20 years experience at King George withdrawal of treatment was associated with V Hospital. Aust NZJ Obstet Gynaecol 1988; 28: 172-6. relapse of symptoms and biochemical derange- 13 Lunzer M, Barnes P, Byth K, O'Halloran M. Serum bile acid concentrations during pregnancy and their relation- ment, which settled when UDCA was reinsti- ship to obstetric cholestasis. Gastroenterology 1986; 91: tuted. UDCA also reduces biochemical 825-9. 14 Sherlock S. In: Diseases ofthe liver and biliary system. Oxford: parameters of cholestasis in other cholestatic Blackwell Scientific, 1968: 296. liver diseases.33 34 15 Bames CG. In: Medical disorders in obstetric practice. Oxford: We have on women with Blackwell Scientific, 1973: 160. reported eight 16 Davidson CS. Hepatic disease and pregnancy. _7 Reprod Med cholestasis of pregnancy associated with eight 1973; 10: 107-10. two 17 Orellana JM, Gonzalez AR, Rodrigues Y. Benign jaundice stillbirths, a perinatal death, and potential of pregnancy. Rev Med Chile 1961; 89: 676-9. 'near misses'. We suggest there is a causal 18 Roszkowski I, Miedzinska DP. Jaundice in pregnancy II. cholestasis of pregnancy and Clinical course ofpregnancy and delivery and condition of relation between the neonate. AmJ Obstet Gynecol 1968; 101: 500-3. the stillbirths, although this cannot be proved. 19 Palma J, Reyes H, Ribalta J, Iglesias J, Gonzalez MC, Hernandez I, et al. Effects of ursodeoxycholic acid in Cholestasis of pregnancy causes distressing patients with intrahepatic cholestasis of pregnancy. symptoms and is associated with significant Hepatology 1992; 15: 1043-7. 20 Laatikainen T, Ikonen E. Fetal prognosis in obstetric increases in fetal morbidity and mortality. The hepatosis. Ann Chir Gynecol 1975; 64: 155-64. aim of this report is to highlight the condition, 21 Garoff L. Prediction of fetal outcome by urinary estriol, maternal serum placental lactogen and alpha-fetoprotein which we consider to be commonly under in diabetes and hepatosis of pregnancy. Obstet Gynecol recognised and inappropriately treated. 1976; 48: 659-66. 22 Laatikainen TJ, Ikonen E. Serum bile acids in cholestasis of Its recognition is essential if early diagnosis pregnancy. Ann Chir Gynaecol Fenn 1975; 64: 63. is to permit timely fetal surveillance and inter- 23 Friedlaender P, Osler M. Icterus and pregnancy. A?n _7 Obstet Gynecol 1967; 97: 894-900. vention. Most stillbirths occur at or just before 24 Ikonen E. Jaundice in late pregnancy. Acta Obstet Gynecol term. Elective delivery when fetal lung Scand 1964; 43 (suppl 5). 25 Stramentinoli G, Di Padova C, Gualano M, Rovagnati P, maturity is established could prevent the vast Galli-Kienle M. Ethinylestradiol-induced impairment of majority of such fetal loss. Appropriate obstet- bile secretion in the rat: protective effect of S-adenosyl-L- methionine and its implication in estrogen metabolism. ric treatment in cholestasis of pregnancy there- Gastroenterology 1981; 80: 154-8. fore represents a potential means by which 26 Boelsterli UA, Rakhit G, Balazs T. Modulation by S-adeno- syl-L-methionine of hepatic Na+K+ATPase, membrane perinatal mortality can be reduced. fluidity, and bile flow in rats with ethinyl estradiol- UDCA, in a small, uncontrolled series induced cholestasis. Hepatology 1983; 3: 12-7. effective at biochemical 27 Frezza M, Pozzato G, Chiesa L, Stramentinoli G, Di seems improving Padova C. Reversal of intrahepatic cholestasis of preg- http://gut.bmj.com/ abnormalities and symptoms. Whether this nancy in women after high dose S-adenosyl-L-methionine administration. Hepatology 1984; 4: 274-8. would influence morbidity and mortality 28 Bonfirraro G, Chieffi 0, Quinti R, Tedesco R, LeGrazie C. associated with the condition is unknown. S-adenosyl-L-methionine (SAMe)-induced amelioration of intrahepatic cholestasis of pregnancy: results of an open These biochemical and clinical end points study. Drug Investigation 1990; 2: 125-8. should be measured in controlled trials. 29 Ribalta J, Reyes H, Gonzalez MC, Iglesias J, Arrese M, Poniachik J. S-adenosyl-L-methionine in the treatment of patients with intrahepatic cholestasis of pregnancy: a 1 Shaw D, Frohlich J, Wittmann BAK, Willms M. A prospec-

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