AISF position paper on liver disease and pregnancy.

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ContentslistsavailableatScienceDirect

Digestive

and

Liver

Disease

j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Special

Article

AISF

position

paper

on

liver

disease

and

pregnancy

The

Italian

Association

for

the

Study

of

the

Liver

(AISF)

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received15June2015 Accepted6November2015 Availableonline14November2015

Keywords: Liverdiseases Pregnancy

a

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Therelationshipbetweenliverdiseaseandpregnancyisofgreatclinicalimpact.Severeliverdiseasein pregnancyisrare;however,pregnancy-relatedliverdiseaseisthemostfrequentcauseofliver dysfunc-tionduringpregnancyandrepresentsaseverethreattofoetalandmaternalsurvival.Arapiddifferential diagnosisbetweenliverdiseaserelatedorunrelatedtopregnancyisrequiredinwomenwhopresent withliverdysfunctionduringpregnancy.Thisreportsummarizestherecommendationofanexpertpanel establishedbytheItalianAssociationfortheStudyoftheLiver(AISF)onthemanagementofliverdisease duringpregnancy.Thearticleprovidesanoverviewofliverdiseaseoccurringinpregnancy,anupdateon thekeymechanismsinvolvedinitspathogenesis,andanassessmentoftheavailabletreatmentoptions. Thereportcontainsinthreesections:(1)specificliverdiseasesofpregnancy;(2)liverdiseaseoccurring duringpregnancy;and(3)pregnancyinpatientswithpre-existingchronicliverdisease.Eachtopicis discussedconsideringthemostrelevantdataavailableinliterature;thefinalstatementsareformulated accordingtobothscientificevidenceandclinicalexpertiseoftheinvolvedphysicians,andtheAISFexpert panelrecommendationsarereported.

1. Introduction

Therelationshipbetweenliverdiseaseandpregnancyisapoorly studiedtopicandspeciﬁcsuggestionsforthemanagementofthese patientsarelacking.

ThepresentdocumentwasgeneratedbytheGenderCommittee oftheItalianAssociationfortheStudyoftheLiver(AISF)toprovide anofﬁcialpositionpaperinasettingcharacterizedbyuncertain clinicalbehaviourandlackofuniformapproach.

Forthisreason,twoExpertOpinionMeetingswereorganized withtheaimofﬁne-tuningrecommendationsforthemanagement ofliverdiseaseinpregnancy.ThetwomeetingswereheldinRome duringtheAISFAnnualMeetinginFebruary2014andinNaples duringtheAISFMonothematicConferenceinOctober2014.

Filomena Moriscoa,∗_, _Raffaele _Brunob_, _Elisabetta _Bugianesic_, _Patrizia _Burrad_,

VincenzaCalvarusoe_, _Alice_Cannonif_, _Nicola _Caporasoa_, _Gian _Paolo _Cavigliag_,

Alessia Cianciog_, _Silvia _Fargionh_, _Alessandro _Federicoi_, _Annarosa _Floreanij_,

Giovanni Battista Gaetak_, _Maria _Guarinoa_, _Pietro _Invernizzil_, _Anna _Licatae_,

CarmelaLoguercioi_,_Giuseppe_Mazzellam_,_Felice_Petragliaf_,_Massimo_Primignanin_,

KryssiaRodriguez-Castrod_,_Antonina_Smedileg_,_Luca_Valentih_,_Ester_Vannic_,_Silvia

Vannuccinif_,_Chiara_Voltolinif_,_Erica_Villao

a_{Gastroenterology}_Unit,_Department_of_Clinical_Medicine_and_Surgery,_University

ofNaples“FedericoII”,Naples,Italy

b-o_See_Appendix_B

∗ Correspondingauthorat:DepartmentofClinicalMedicineandSurgery, Gas-troenterologyUnitUniversityofNaples“FedericoII”,ViaSergioPansini,5,80131 Napoli,Italy.Tel.:+390817464746;fax:+390817464746.

E-mailaddress:ﬁlomena.morisco@unina.it(F.Morisco).

Primaryobjectiveofthis documentistoprovide recommen-dationsforclinicalpracticedeﬁningthebestmanagementofliver diseaseinrelationwithpregnancy.Theformatofrecommendations waschosentoofferadocumentedapproachtopregnantpatients withliverdisease.

Thereportisstructuredinthreeparts: 1.Speciﬁcliverdiseaseofpregnancy.

2.Occurrenceofliverdiseaseduringpregnancy. 3.Pregnancyinpatientswithchronicliverdisease.

Theissuesrelatedtolivertransplantationandpregnancywere notconsideredinthisreportduetospaceconstraints.Apublication bytheAISFexpertpanelonthistopicwillbeforthcoming.

Therecommendationsweredrawnusingthelevelofevidence andstrengthofrecommendationsgradedaccordingtothe Amer-icanCollege of Cardiologyand theAmerican Heart Association PracticeGuidelines,listedinSupplementaryTableS1.

2. Speciﬁcliverdiseasesofpregnancy

2.1. Physiologicalchangesinliverduringpregnancy

Inpregnancy,theliverisaffectedprimarilybycirculatoryand hormonalchanges.Pregnancyisassociatedwithahyperdynamic circulatorystatusin whichcardiacoutputincreases.Bloodﬂow to theliver remains unchanged, but the percentage of cardiac http://dx.doi.org/10.1016/j.dld.2015.11.004

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output tothe liver is reduced, which may impair clearance of substancesrequiringextensivehepaticmetabolism[1].The physi-ologicalchangesofnormalpregnancymimicabnormalitiesthatare associatedwithliverdiseaseinnon-pregnantindividuals (Supple-mentaryTableS2).Becauseofthehyperestrogenicstate,upto60% ofpregnantwomenmayexhibitspidernaeviorpalmarerythema. Gallbladdermotilityisalsodecreased[2].

2.2. Hyperemesisgravidarum

Hyperemesisgravidarum(HG)occursin0.1–2.0%ofall preg-nanciesandpresentswithptyalism,spitting,nauseaandvomiting leadingtodehydration,ketosisandweightlossof5%ormore.Itcan startasearlyasweek4andtypicallyresolvesbyweek18[3,4].

Risk factors include increased body mass index (BMI), psy-chiatricillness,molarpregnancy,pre-existingdiabetes,multiple pregnanciesandHGinapreviouspregnancy.Hyperthyroidismis observedinabout60%ofcaseslikelybecauseofincreased thyroid-stimulatingactivitybyhumanchorionicgonadotropin(HCG).

Thepathophysiologyappearstohaveacomplexmetabolic back-ground[5].HormonessuchasHCG,prolactinandoestradiolhave beenimplicated[6].

Persistentvomitingmayleadtoposturalhypotension, tachycar-dia,electrolytedisturbances,ketosis,musclewastingandweight loss[7,8].Jaundiceisuncommon,butindicatesliverinvolvement whenpresent.No singleconﬁrmatorytestexists,however clin-ical symptoms and biochemical abnormalities, includingraised serumureaandcreatinine,hypophosphataemia, hypomagnesiu-miaandhypokalaemia,aresuggestiveforHG[9].Abnormalliver functiontestsarefoundinabout50%ofpatientswithHG[4]:mild aminotransferaseelevation(upto200U/l)is themostcommon liverlaboratoryabnormality,whileelevationgreaterthan1600U/l hasbeenreportedrarely;alkalinephosphatasemayrisetotwice normalvalues;bothindirectanddirecthyperbilirubinemiaupto 4mg/dLmayalsooccur;serumamylaseandlipasemayriseupto5 timesnormalvalues.Interestingly,theseverityofnauseaand vomi-tinginpatientswithliverinvolvementcorrelateswiththedegree ofliverenzymeelevation[5].

Treatmentissupportiveandincludesintravenousrehydration, antiemetics,gradual reintroduction of oral intakeand vitamins supplementation(vitaminB1orthiamine,vitaminB6,vitaminB12, vitamin C).Earlyadministration ofhigh-dose thiamine(150mg daily orally or 100mg weekly intravenously) to prevent Wer-nicke’s encephalopathyis suggested [7,8].Among anti-emetics, dopamine agonists (metoclopramide 5–10mg every 6hours and domperidone 10–20mg every 6–8hours), phenothiazines (prochlorperazine 5–10mg every 8hours) and antihistamines (promethazine12.5–25mgevery4–6hours)haveallbeenshown tobesafe.H2 receptorantagonistshavebeenusedoccasionally withsomebeneﬁt[9].

Theuseofthe5-hydroxytryptamine(5-HT3)receptorblocker ondansetron(8mgevery12hours)hasbeenreportedtobesafein intractablehyperemesis.

Mostpatientsusuallyneed5–8daysofhospitaladmissionwith aself-limitingdiseasebutrelapseiscommon.Seriousmorbidity canresultonlyfrominadequateorinappropriatetreatment.AsHG resolvesby18weeks,lactationisnotcontraindicated.

AISFexpertpanelrecommendations:

• Intravenousrehydration(ClassI,LevelC),anti-emetics

(meto-clopramide5–10mgevery6hours,ordomperidone10–20mg

every6–8hours,orprochlorperazine5–10mgevery8hours,

orpromethazine12.5–25mgevery4–6hours),gradual

rein-troductionoforalintakeandvitamins(ClassI,LevelA)are

ﬁrstlinetreatmentsofHG.

• High-dose thiamine (150mg daily orallyor 100mg weekly

intravenously) should be given to prevent Wernicke’s

encephalopathyinwomenwithHG(ClassI,LevelA).

2.3. Intrahepaticcholestasisofpregnancy

Intrahepaticcholestasisofpregnancy(ICP)usuallyoccurs dur-ingthelasttrimesterandhasarapidpost-natalresolution[10]. Itischaracterizedbyseverepruritus,associatedwithincreasein serumbile acidand aminotransferases.The symptomsand bio-chemicalabnormalitiesresolverapidlyafterdeliverybutmayrecur insubsequentpregnanciesandwiththeuseofhormonal contra-ception[11].Interestingly,serumautotaxin,alysophospholipase D essential for angiogenesis and neuronal developmentduring embryogenesis, wasfoundtobeahighlysensitive, speciﬁcand robust diagnosticmarkerdistinguishingICP fromotherpruritic disordersofpregnancyandpregnancy-relatedliverdisease[12]. TheincidenceofICPrangesbetween0.5%and1.8%of pregnan-ciesinEurope,butthehighestpeakofincidencehasbeenreported inChile(upto28%in theAraucanicpopulation)andin Scandi-navia[13]. Geneticdefectsin atleast4canaliculartransporters canbefoundinICP(SupplementaryTableS3).Geneticvariations mayimplicateheterozygousorhomozygousmutationslocatedin differentpositionsofthegenes.Alltheassociationstudieswith thesecandidategenesstressthecomplexvariabilityofgenotypes, thedifferentpenetrance,andtheinﬂuenceofseveral environmen-talfactors.Arecentstudyutilizingmicro-arraytechnologyin12 women withICP andin 12healthy controls,foundthat twenty geneswerepotentiallycorrelatedtoICP[14].Amongthese,an up-regulationofGABRA2receptorgene(thatcodesforasubunitofthe gamma-aminobutyricacidtypeAreceptor)mayindicatethatGABA mayplayaroleinthepathogenesisofpruritusinthiscondition.

SevereICP(withserumbileacids>40␮mol/L)isassociatedwith adversepregnancyoutcome[15].

ThecurrentmedicaltreatmentforICPisursodeoxycholicacid (UDCA),whichactsasseveralmechanismsofaction:protection ofhepatocytesandcholangiocytesbyreplacingendogenous, cyto-toxicbilesalts,inductionofexpressionoffunctionaltransportersat transcriptionalandpost-transcriptionallevel,andenhancingbile ﬂow[16].Arecentmeta-analysisincluding9published random-izedcontrolledtrials(3doubleblind)thatcomparedtheeffectof UDCAtootherdrugs,placebo,ornospeciﬁctreatmentinpatients withICP,demonstratedthatUDCAiseffectiveinreducingpruritus andimprovinglivertestsinpatientswithICP[17].

• ManagementofICPshouldbeperformedbyadedicatedteam;

monitoring of serumbile acids is recommended,although

thereisnogeneralconsensusonacorrelationbetweensevere

complicationsandhighserumbileacidlevels(ClassIII,Level

A).

• Ursodeoxycholicacidatadosageof15mg/kgofbodyweight

issafeandeffectiveinthemanagementofsymptomsofICP

(ClassIIa,LevelA).

2.4. Eclampsiaandpreeclampsia

Pre-eclampsiaoccursafter20weeksofpregnancyand/orwithin 24–48hoursafterdelivery.Itaffects5–10%ofallpregnanciesand caninvolvethekidney,theliver,thecentralnervousand haema-tologicalsystem.Pre-eclampsiaischaracterizedbyhypertension andproteinuria(greaterthan300mgin24h).Presenceofseizures differentiateseclampsiafrompre-eclampsia[18].

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Riskfactorsincludeextremematernalage(<16yearsand>45 years),primiparity,pre-existinghypertension,familyhistoryand occurrenceinapreviouspregnancy[18].

Thepathophysiologyinvolvessuboptimalutero-placental per-fusion associated with systemic inﬂammatory response and vascular endothelial dysfunction. Genetic predisposition and imbalanceofprostacyclinandthromboxanehavealsobeen impli-cated[19].

Clinicalfeaturesincluderightupperquadrantpain,headache, nauseaandvomiting.Abnormallivertests,secondaryto vasocon-strictionofthehepaticvascularbed,occurin20–30%ofpatients andinclude10-to-20-foldelevationinaminotransferases, eleva-tionsinalkalinephosphataseandbilirubinincrease oflessthan 5mg/dL[20].

Pre-eclampsiaandeclampsiaareassociatedwith3-to-25-fold increasedriskofpulmonaryoedema,abruption,aspiration pneu-monia, renal failure, hepatic failure, disseminatedintravascular coagulation(DIC), and stroke.Haemorrhagic strokeis themost commoncauseofdeath,vasculardisease,renal,andneurological sequelae.Mostcasesresolveswithin12weekspostpartum[21,22]. Maternalmortalityis15–20%whilefoetalmortalityis1–2%of livebirths[23,24].

Closemonitoringofblood pressureandproteinuriais neces-sary during pregnancy. First lineof hypertension treatment in pregnantwomenwithpre-eclampsiaislabetolol,methyldopaor nifedipine.Treatmentisaimedtokeepthesystolicbloodpressure below150mmHg andthediastolicbetween80and100mmHg. Magnesiumsulphateremainsthedrugofchoiceforseizure pro-phylaxis in severepreeclampsia and for controllingseizures in eclampsia.Treatmentconsistsinearlydeliverywheneverpossible [23,24].Breast-feedingisnotcontraindicatedinwomenon anti-hypertensivetherapypost-partum:nifedipine,labetalol,atenolol, methyldopa,captoprilandenalaprilhavebeenshowntobesafe [25].Magnesiumsulphateisexcretedinbreastmilkbutissafefor breastfedinfants.

• Labetolol,methyldopaornifedipineareﬁrst-linetreatments

forpre-eclampsia(ClassI,LevelA).

• Magnesium sulphate should be given for seizure

prophy-laxisinseverepre-eclampsiaandforcontrollingseizuresin

eclampsia(ClassI,LevelA).

• Inpre-eclampsia,earlydeliveryshouldbeperformedwhen

gestationalageisover37weeksormaternal-foetalconditions

aredeteriorating(ClassI,LevelA).

• Breast-feedingisnotcontraindicatedinpre-eclampticwomen

onantihypertensivetherapy:nifedipine,labetalol,atenolol,

methyldopa,captopril,andenalaprilcanbeusedsafely(Class

III,LevelB).

2.5. HELLPsyndrome

The haemolysis, elevated liver enzymes, and low platelets (HELLP)syndromeisassociatedwithendothelialcellinjury and microangiopathicplateletactivationandconsumption.Itoccursin 4–20%ofpre-eclampsia[25].

Thedisorder can bediagnosed antepartum (in70% of cases between27and30weeks)orpostpartum.Riskfactorsareadvanced maternalage,multiparityandCaucasianethnicity.

Thepathophysiologyremains unknown: activation endothe-lialcellsmayleadtoreleaseofVonWillebrandfactormultimers whicharehighlyreactivewithplatelets.Thesyndromeseemstobe theﬁnalmanifestationofsomeinsultthatleadstomicrovascular endothelialdamageandintravascularplateletactivation[26,27].

Patientsmaypresentwithrightupperquadrantandepigastric pain,nausea,vomiting,and malaise.Hypertensionand protein-uriaareevidentinupto85%ofcases.Becauseofthehaemolysis, highserumunconjugatedbilirubinandlactatedehydrogenaseare frequent[28,29],aswellasamoderateriseinliverenzymes.In later stages,DIC maybepresent withincreasedlevelsof ﬁbrin degradationproductsand d-dimer,and thrombin–antithrombin complexes.TworecognizedclassiﬁcationsofHELLP(knownasthe TennesseeandtheMississippisystems)areavailable[30].

ComplicationsincludeDIC,pulmonaryoedemaand placental abruption.Perinatalmortalityrateis6–70%,whilematernal mor-talityis1%[31].

OnceHELLPdevelops,theonlydeﬁnitivetreatmentisdelivery offoetus.Ifthegestationalageisbetween24and34weeks, cortico-steroidsareusuallygiventopromotefoetallungmaturity.Delivery shouldbeconsidered24hoursafteradministration.Afterdelivery, closemonitoringofthemothershouldcontinue,assomewomen mayhaveworseningthrombocytopeniaandincreasingLDHlevels upto48hourspostpartum[27,31].Asinpre-eclampsia, breast-feedingisnotcontraindicatedinHELLPsyndromeandforwomen receivingantihypertensivetherapy;nifedipine,labetalol,atenolol, methyldopa,captoprilandenalaprilhavebeenshowntobesafe [32].

• Deliveryofthe foetusis ﬁrst-linetreatment ofHELLP

syn-dromebefore24orafter32weeksgestationandinpresence

ofmaternal-foetalcomplications(ClassI,LevelB).

• InHELLPsyndromebetween24and34weeks’gestation,

cor-ticosteroidsshouldbegiventopromotefoetallungmaturity

(ClassI,LevelA)anddeliveryshouldbeconsidered24hours

aftercorticosteroidsadministration(ClassI,LevelA).

• Breast-feedingisnotcontraindicatedinwomenwithHELLP

syndromeonantihypertensivetherapy:nifedipine,labetalol,

atenolol,methyldopa, captopril,andenalapril can be used

safely(ClassIII,LevelB).

2.6. Acutefattyliverofpregnancy

Acutefattyliverofpregnancy(AFLP)isamicrovescicularfatty inﬁltrationofhepatocytesandacommoncauseofliverfailurein pregnancy.Itisalate-gestationalcomplication,oftenoccurringat week28–40.Itisararedisorderaffectingfrom1:7000to1:16,000 pregnancies,butitisamedicalandobstetricsemergency[33].Risk factorsarenulliparity,preeclampsia,multiplegestation, pregnan-cieswithamalefoetus,lowBMI[33].

Theaetiologyisunknown.Defectsinintra-mitochondrialfatty acidbeta-oxidation(enzymaticmutations),inparticulara homozy-gousfoetaldeﬁciencyoftheenzymelong-chain3-hydroxyacyl-CoA dehydrogenase (LCHAD) in a mother carrying a heterozygous LCHADdeﬁciencycanbefound[34].Hepatotoxicmetabolites pro-ducedbythefoetusand/orplacentamaycauseliverdiseaseinthe heterozygousmotherwhencombinedwiththemetabolicstressof thethirdtrimester[34,35].However,AFLPmayoccurintheabsence ofknowngeneticmutations[36].

Theinitialmanifestations of AFLPinclude headache, fatigue, nauseaandvomiting.Clinicalpresentationmayvaryfrom abdom-inal pain, jaundice, signs of preeclampsia (50%), hypoglycemia, hepaticencephalopathy,coagulopathy(DIC).Biochemicalﬁndings include elevated aminotransferases levels (from mild elevation to 1000IU/L, usually 300–500), elevated bilirubin (frequently >5mg/dL),leukocytosis,anaemia,thrombocytopeniaand hypoal-buminemia, increased uric acid, renal impairment, metabolic acidosis,hyperammonemia,biochemicalpancreatitis.Differential diagnosisiswithHELLPsyndrome(Table1)[37,13].Thediagnosis

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Table1

Differential diagnosis between haemolysis, elevated liver enzymes, and low plateletssyndromeandacutefattyliverofpregnancy.

HELLP AFLP

Prevalence(%) 0.2–0.6 0.005–0.01 Onset Thirdtrimesteror

post-partum

Thirdtrimesteror post-partum Familyhistory No Occasionally Onsetofpreeclampsia(%) 70–80 50 Clinicalfeatures Haemolysis

(anaemia) Thrombocytopenia (50,000platelets) Liverfailure, coagulopathy, encephalopathy hypoglycemia,DIC Aminotransferases Mildincrease(may

beupto10–20fold)

300–500UI/Ltypically Bilirubin <5mg/dLunless

massivenecrosis

>5mg/dL Liverimaging Hepaticinfarcts,

hematomas,rupture Fattyinﬁltration Histology Patchy/extensive, necrosis,periportal haemorrhage,ﬁbrin deposits Microvescicular steatosisinzone3 Maternalmortality(%) 1–25 7–18 Foetal/perinatalmortality (%) 11 9–23 Recurrenceinsubsequent pregnancy(%)

4–19 25(fattyacidoxidation defects)

HELLP,haemolysis,elevatedliverenzymes,andlowplatelets;AFLP,acutefattyliver ofpregnancy;DIC,disseminatedintravascularcoagulation

isbasedonclinicalandlaboratoryﬁndings.Liverbiopsyisthegold

standardalthoughrarelynecessary[38].

Complicationsincludeencephalopathy,thrombocytopenia,DIC and renal failure. Promptdiagnosis and adequate management improveclinicalconditionsin1to4weekspostpartum.Maternal mortalityrangesfrom7%to18%andfoetalmortalityfrom9%to 23%[13,37,38].

Themanagement of AFLPrequires:(i) earlyrecognitionand diagnosis,asthebestmaternalsurvivalrateiswhentheinterval fromoccurrenceofAFLPtodeliveryisoneweek;(ii)aggressive maternalstabilizationinintensivecaresetting,adequate support-ivetherapy(dietlowinfatandproteinandhighincarbohydrates, bloodcomponents,plasma exchangeand haemodialysis, broad-spectrum antibiotics, correctionof dehydration, electrolyte and acid-base balance,treatmentstoprotect theliver,reduce jaun-dice,anddiminishliverenzymes);(iii)rapiddelivery:ifvaginal deliverycannotbeachievedquickly,caesareansectionisthe pre-ferredmethod[37,38].Breast-feeding is not contraindicatedby AFLPitself,howeverthisshouldbeevaluatedonthebasisofthe supportivetherapyneededformaternalstabilizationinthe inten-sivecaresetting.

• IntervalfromAFLPonsettodeliveryshouldnotexceedone

week(ClassIIa,LevelB),thereforepromptdiagnosisiscrucial.

• InwomenwithAFLP,maternalstabilizationshouldbe

per-formedinanintensivecaresettingwithpromptsupportive

therapy(ClassIIa,LevelB).

• Whenvaginaldelivery cannotbe achievedquicklyinAFLP,

caesareansectionshouldbeperformed(ClassIIa,LevelB).

3. Liverdiseaseoccurringduringpregnancy

3.1. Acuteviralhepatitis

Themostcommoncauseofjaundiceinpregnancyisacuteviral hepatitis.Theincidenceof hepatitisin pregnancyvariesgreatly

throughouttheworldaccordingtohygiene,sanitationand socio-economicconditions[39].

HepatitisAvirus(HAV)isthemostcommoncauseofacuteviral hepatitisinthegeneralpopulationbutitsoccurrenceduring preg-nancyhasbeenscarcelyreported.HepatitisAisnotassociatedwith asevereoutcomeduringpregnancyandverticaltransmissionis veryrare.InarecentstudyoftheKoreaUniversity,16,944pregnant womenwerereviewedretrospectivelyand12casesofacuteHAV infectionwereidentiﬁed (0.07%).Amongthem,4patients(30%) developedmaternalcomplications,includingcholestatichepatitis andpretermcontraction.Inonly1caseitwasreportedfoetalascites andintra-abdominalcalciﬁcations[40].

HAVvaccinationshouldbeconsideredparticularlyforwomen livinginareasofhighendemicityandpoorsocioeconomic condi-tions,toavoidmaternalandfoetalcomplicationsassociatedwith HAVinfectionin pregnancy. Sincethere is noevidenceof HAV verticaltransmissionwithlactation,breast-feedingappearstobe safe.

AcutehepatitisBvirus(HBV)infectionisnotassociatedwithan increasedmortalityorcongenitalmalformations,althoughitcan causespontaneousabortionintheﬁrstweeksofpregnancy[41].A recentstudyinvolving22pregnantpatientsand87matched non-pregnantcontrolsinvestigatedtheclinicalfeaturesandoutcomeof acutehepatitisBinpregnancy[42].Nodifferenceinmortalityor occurrenceoffulminanthepatitiswasfoundbetweenthe2groups. Clinical recovery was also similar betweenpregnant and non-pregnantwomen.However,signiﬁcantlyhigherlevelsofhepatitis Bsurfaceantigen(HBsAg)andlowerant-HBsseroconversionrates werefoundinpregnantpatientsthaninnon-pregnantpatients, indicatingthatpregnancycouldbeariskfactorforchronicity fol-lowingacuteHBVinfection.AcuteHBVinfectioninpregnancyhas ahigherrateofverticaltransmissionthanthatusuallyoccurring duringdelivery,duetonewbornexposuretocervicalsecretions andmaternalblood[43].HBVvaccinationandhepatitisBimmune globulinadministrationtonewbornsofHBsAg-positivemothers representthemainstrategytopreventHBVverticaltransmission [44].

AcutehepatitisCvirus(HCV)infectionhasbeenrarelyreported during pregnancy and is limited to high-risk groups, such as intravenous drug users. Frequency of acute hepatitis C during pregnancyis estimatedbetween0.4% and6%[45].Severalcase reports can be found in literature and none of them reported relevantadverseclinicaloutcomeinpregnancy[46].HCV infec-tioncanbeverticallytransmitted(riskfrom3%to5%),butthere isnoevidenceofincreasedtransmissionthroughbreast-feeding [47]. Howeverantiviraltreatmentis contraindicateddue tothe teratogeniceffectofdrugsavailableuntilrecently[48]whileno data are available for thenew interferon-free regimens in this setting.

HepatitisDvirus(HDV)canbeacquiredbyco-infectionwith HBVorbysuper-infectionofa HBVcarrier[49].Dataregarding acutehepatitisDandpregnancyarescant.Krajdenetal.describeda caseina18-year-oldpregnantwoman(intravenousdruguser)who developedfatalfulminanthepatitiswithmassivehepaticnecrosis duetoHBVandHDVco-infection[50].Consideringtheavailability ofHBVvaccinationandthechangeinHDVepidemiology,acute hepatitisDinpregnancyappearstobeonlysporadic.

HepatitisEvirus(HEV)isresponsibleformajoroutbreaksof acute hepatitis in developing countries. HEVis enterally trans-mitted andclinicalmanifestationsare similartootherformsof viral hepatitis, except in pregnant women that are at greater riskofdevelopingfulminanthepatitis(25%mortalityrate)[51].A recentstudycomparedmaternalandfoetaloutcomesinpregnant womenwithacuteviralhepatitiscausedbyHEVandother hepati-tisviruses.Authorsfoundthatfulminanthepaticfailurewasmore common(relativerisk,2.7[95%CI,1.7–4.2];p=0.001)andmaternal

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Table2

Clinicalfeaturesofacuteviralhepatitisinpregnancy.

Maternalcomplications Foetalcomplications Verticaltransmission Preventionandtreatment HAV Mildgestationalcomplications Rare Probableinperinatalperiod Vaccination

HBV Sameasgeneralpopulation Rare,pretermdelivery 50–70%inIIItrimester Vaccinationandprophylaxis

HCV No No 3–5% Peg-IFN+RBVcontraindicated

HDV Sameasgeneralpopulation n.a. n.a. HBVvaccination

HEV Lethal(upto25%) Pretermlabourandstillbirth ∼50% NoFDA-approvedvaccine HAV,hepatitisAvirus;HBV,hepatitisBvirus;HCV,hepatitisCvirus;HDV,hepatitisDvirus;HEV,hepatitisEvirus;n.a.,notavailable;Peg-IFN,pegylatedinterferon;RBV, ribavirin.

mortalitywasgreater(relativerisk,6.0[95%CI,2.7–13.3];p<0.001)

inHEV-infectedwomenthaninnon-HEV-infectedwomen.

More-over,womenwithHEVinfectionhadahigherriskofintrauterine

foetaldeath[52].Verticaltransmissionratesarereportedbetween

33.3%and 78.9%[53,54].ThereiscurrentlynoevidenceofHEV transmissionthroughbreast-milk.Table2summarizestheclinical featuresofacuteviralhepatitisandpregnancy.

• Vaccinationisthemosteffectivestrategyforpreventionof

HAVandHBVtransmission(ClassI,LevelA).Inaddition,

hep-atitisBimmuneglobulinmustbeadministeredtonewborns

fromHBsAg-positivemotherstopreventHBVvertical

trans-mission(ClassI,LevelA).

• Currently,thereisnoFDA-approvedvaccinetopreventHEV

infection.ConsideringtheseverecourseofhepatitisEin

preg-nancy,particularlyincountries withpoorsanitation, early

deliveryofthefoetusshouldbeconsideredtoavoidmaternal

complications(ClassI,LevelC).

• Breast-feeding isnot contra-indicated in case of maternal acuteviralhepatitis(ClassI,LevelB).

3.2. Gallstonedisease

Gallstones are common during pregnancy. The prevalence rangesbetween 2.5%and 11% of cases [45]. During pregnancy, female sex hormones are endogenously increased, and biliary sludge(composedofcholesterol,calciumbilirubinateandmucin) appears in 5–30% of women [55]. In the post-partum period sludgeresolutiondevelopsintwo-thirdofcases,smallgallstones (microlithiasis) disappear in one-third, but deﬁnite gallstones becomeestablishedinapproximately5%ofcases[56,57]. Addi-tionalriskfactorsincludeobesity,reducedhigh-densitylipoprotein cholesteroland metabolicsyndrome[55].Anotheroften under-diagnosed condition may be the low-phospholipid-associated cholelithiasis,whichisassociatedtoageneticdefectintheABCB4 genewithlossofcanalicularMDR3proteinand/orlossofprotein function[58].Mostwomenwiththisgeneticvariantdevelop intra-hepaticcholestasisofpregnancyandeventuallycholelithiasis.

Acutebiliarycolicoruncomplicatedcholecystitiscanbetreated conservativelywithbedrest,intravenousfluids,andantibiotics. Conservativetreatmentofcholelithiasisanditscomplications dur-ingpregnancyisassociatedwithrecurrentbiliarysymptomsand frequentemergencydepartmentvisits;thusERCPandlaparoscopic cholecystectomyshouldbeconsidered[59].Theuseofdrugssuch asUDCAandthelipid-loweringcompoundezetimibecouldalso beconsidered[60]. ERCPcan beperformedsafely during preg-nancyandremainsthefirst-linemodalityforthemanagementof choledocolithiasisanditsassociatedcomplications.Whilenewer techniquesfocusonavoidingtheuseoffluoroscopy,their bene-fitsovertraditionaltechniquesemployingminimalfluoroscopyare unclear[61].Cholecystectomyduringpregnancyisnotentirelysafe becauseoftheabortionriskwithanaesthesia.Inaretrospective

study,however,surgicalmanagementofsymptomatic cholelithi-asis in pregnancy was found tobe safe and more useful than conservativemanagementinreducingtherateoflabourinduction andpretermdeliveries[62].Laparoscopiccholecystectomy,when indicated,shouldbeperformedinthesecondtrimestertoavoid seriouscomplications.

• Biliarycolicandacutecholecystitisduringpregnancyshould

betreatedconservatively.ERCPshouldbeconsideredincase

ofcholedocolithiasisanditscomplications(ClassIII,LevelA).

• Laparoscopic cholecystectomy should be considered in

selectedcasesassecond-linemanagementincaseoffailureof

conservativemanagement;whenindicated,itshouldbe

per-formedinthesecondtrimestertoavoidseriouscomplications

(ClassIII,LevelA).

3.3. Vascularliverdiseases

Inpregnancy,thelevelsofcoagulationfactorsVIIandVIII,von Willebrandfactorandﬁbrinogenareincreased,whilefreeprotein Slevelsarereduced.Moreover,increasedplasminogenactivator inhibitor-1and2(thelattersynthesizedbytheplacenta)decrease ﬁbrinolyticactivity.Such changesshiftthehaemostaticbalance towardshypercoagulability, which persistsup to8 weeksafter delivery[63].Therefore,itisnotsurprisingthatthevascularliver diseases,inwhichthrombophiliaoftenplaysamajorrole,canoccur orworsenduringpregnancy.

3.3.1. Budd–Chiarisyndrome

Budd–Chiarisyndrome(BCS)isa rare diseasecausedbythe obstructionofthehepaticvenousoutﬂow,duetothrombosisof thehepaticveinsorofthesuprahepaticportionoftheinferiorvena cava,leadingtosinusoidalcongestion,ischaemicliverdamageand portalhypertension[64,65].

Oneormoreriskfactorsforvenousthromboembolismare usu-allypresentinBCSpatients.Pregnancy,aswellasoralcontraception oroestrogen-replacementtherapy,mayprecipitateBCS[66–70].

BCSoccurringinpregnancyaccountsforabout15%ofallwomen withBCS[71].Symptomsincludefever,abdominalpain,ascites, lowerlimboedema,jaundice,gastrointestinalbleedingandhepatic encephalopathy. In pregnancy, the clinical presentation is fre-quentlyfulminant,withahighmortality.

Ultrasoundis theimaging technique of choicein pregnancy asthereisnoionizingradiationexposureassociatedwithit[72]. Computedtomography(CT)scaniscontraindicated.Thesafetyof gadolinium-basedcontrastagentsiscontroversial;therefore mag-neticresonanceimaging(MRI)shouldbeusedifthediagnosisof BCScannotbeotherwiseexcluded(ClassIIb,LevelC).

Besidesfewreports ofBCSinpregnancy[66,68,73],a recent study[74] investigatedthe maternal and foetaloutcome of 43 womenwithBCS,sevenofthemwiththediseasepresentingin pregnancy.Inthese7womentherewere3miscarriages,1early

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pretermdelivery,and3healthynewborns.Twowomenreceived tranjugularporto-systemicshunt(TIPS)andoneunderwent ortho-topiclivertransplantation(OLT)withintwomonthspostpartum. Allwerealiveafter57±46monthsfromdelivery.

ThemanagementofBCSoccurringinpregnancydiffersfromthat innon-pregnantwomenasvitaminKantagonists(VKA)are con-traindicatedduetoriskoffoetalhaemorrhageandteratogenicity [72].Astepwisetreatment,startingwithatwice-dailylow molecu-larweightheparin(LMWH),followedbyTIPSinfailuresorrelapses, isrecommended(ClassIIa,LevelC).Livertransplantationispossible [75].Anticoagulation,withLMWHorVKA,canberestarted12hours afterdelivery(or24hoursaftercaesareansection).Breast-feeding iscontraindicatedinwomentakingLMWH,butnotinthosetaking VKA,whichareexcretedinactiveinmaternalmilk(ClassI,LevelC).

• PregnancymayprecipitateBCS.Theclinicalpresentationis

oftenfulminant.ThetreatmentofBCSduringpregnancyisthe

sameasinnon-pregnantwomenexceptforthe

contraindica-tionofVKA(ClassI,LevelC).

• ManagementofwomenwithBCSduringpregnancyrequires

amultidisciplinaryteamintertiaryreferralcentres(ClassI,

LevelC). Maternal outcome maybe good provideda

step-wisetreatmentisadopted(ClassIIa,LevelC).Foetaloutcome,

althoughamatterofconcern,canbegood(ClassII,LevelC).

Duetotherarityofthedisease,thereisnodatatosupport

furtherrecommendations.

• Breast-feedingiscontraindicatedinwomentakingLMWHand

allowedinwomentakingVKA(ClassI,LevelC).

3.3.2. Acuteextrahepaticportalveinobstruction

Acute extra hepatic portal vein obstruction (EHPVO) is the sudden,usuallythrombotic,occlusionoftheportalvein,variably involvingitsintrahepaticbranchesortributaries,mesentericand splenicveins.Thrombophiliaandabdominalprecipitatingfactors oftencoexist.However,andincontrasttoBCS,pregnancyrarely triggersEHPVO.Indeed,inthreeEuropeanseries,pregnantwomen accountedforonly0–2%ofpatients[76–78].

AcuteEHPVOoftenpresentswithabdominalpain,ascites or fever. However, symptoms vary from almost asymptomatic to intestinalinfarction,dependingontheextensionofthe involve-mentofthespleno-portalaxis,particularlyoftheproximalrootsof thesuperiormesentericvein.

AsforBCS,Doppler ultrasoundistheprocedureofchoicein pregnancy.

Nodataonmaternalandfoetalmorbidityandprognosisinacute EHPVOareavailable.InacuteEHPVOnotoccurringinpregnancy, ifearlyrecognizedandtreated,a75%rateofcompleteorpartial recanalizationisexpected[79].

Asinnon-pregnantwomen,thetreatmentisbasedon anticoag-ulationwithLMWH.Anticoagulationcanberestarted12hoursafter delivery(or24hoursaftercaesareansection)withVKAif breast-feedingisdesired(ClassI,LevelC).

• Pregnancyrarelytriggers EHPVO.The treatmentof EHPVO

occurring in pregnancy, is the same as in non-pregnant

women,exceptforthecontraindicationofVKA(ClassI,Level

C).Duetotherarityofthedisease,thereisnodatatosupport

furtherrecommendations.

• Breast-feedingiscontraindicated inwomen takingLMWH,

andallowedinwomentakingVKA,(ClassI,LevelC).

4. Pregnancyinpatientswithpre-existingchronicliver

disease

4.1. ChronichepatitisB

InwomenwithchronicHBVinfection,immunologicalchanges typicalof pregnancymaycause anincrease in HBVDNA levels whilealanineaminotransferase(ALT)remainnormalornear nor-mal.Mildexacerbationsmayoccurafterdelivery[80,81].Inclinical practice,womenwhoareHBV-positivecarriersshouldbe coun-selledregardingpregnancybothonandofftreatment.

Inallcases,indicationtotreatmentaccordingtocurrent recom-mendationsshouldbeconsideredanddiscussedwiththepatient [82].Whenﬁbrosisismildorabsent,treatmentcanbedelayed; stoppingantiviraldrugsmaybeconsideredinwomen currently receivingtreatment.Pegylatedinterferon(PEG-IFN)is contraindi-catedduringpregnancy.Whentreatmentis indicated,tenofovir isthedrugofchoice(seebelow);womenwhobecomepregnant whilereceivingentecavir,adefovirorPEG-IFN,shouldbeswitched totenofovir,iftreatmentisindicated.

VerticaltransmissionofHBVinfectionispreventedbyvaccine andanti-HBsimmunoglobulinadministrationtonewbornswithin 12hours afterdelivery [83]. Thisstrategy is cost-effective [84]. However,newbornstoHBeAg-positivemothersretaina6–10%risk ofacquiringHBVinfection,despiteprophylaxis[83].Thereis gen-eralagreementthatriskofimmunoprophylaxisfailureincreases withincreasingmaternalviralload.Moststudiessettherisk thresh-oldataHBVDNAlevelof107_IU/mL,_although_there_is_no_consensus

onthispoint[85].

Administration of antiviral nucleos(t)ide analogues (NUCs) activeagainstHBVtomotherswithhighviralloadhasbeen exam-inedinsomestudies,inordertoestablishthesafetyandefﬁcacyin preventingverticaltransmission.

4.1.1. SafetyofNUCsinpregnancy

TheFoodandDrugAdministration(FDA)recentlyreleasedrules thatreplacethecurrentproductlettercategories–A,B,C,DandX –toindicatethepotentialofadrugtocausebirthdefectsifused duringpregnancy[86].Thenewlabellingsystementailstheuse ofthreesubsectionsinthelabelling,titled“Pregnancy”, “Breast-feeding”and“FemalesandMalesofReproductivePotential”that provideasummaryoftherisksofusingadrugduringpregnancy andbreast-feedingandadiscussionofthesupportingdata.

Lamivudine,tenofovirandtelbivudinehavebeenadministered inpregnancy.LamivudinewaspreviouslylistedinclassC; how-ever,itwasusedextensivelyin humanimmunodeﬁciencyvirus (HIV)-positivemothers aspartoftheirantiretroviral treatment, withnoexcessinreportedbirthdefectrates[87];tenofovirand telbivudine were listed in class B. In 6 studies of HIV type 1 and/orHBV-infectedwomenreceivingtenofovirduringpregnancy, adverseeventsweremildtomoderate;nonewereconsideredto betenofovir-related.Fivestudiesthatfollowedinutero tenofovir-exposed infants showed no increased risk of growth or bone abnormalities[88].Along-termfollow-upofbabiesbornto moth-erstreatedwithtelbivudineconﬁrmedsafety[89].

4.1.2. NUCsinpreventingmother-to-childtransmissionfrom highlyviremicwomen

Lamivudinegivenfromweek32ofpregnancytomotherswith serumHBVDNA ≥109_IU/mL_reduced _the_incidence_of_newborn

infectioninaplacebo-controlledtrial[90];howevernotall new-bornsreceivedcompleteprophylaxis.Afurthermeta-analysisof sixstudiesconﬁrmedtheefﬁcacyoflamivudine[91].Onestudy showedarapidemergenceofresistantvariants[92].

Telbivudinewasadministeredto135HBeAg-positivewomen startingfromweek20toweek32ofgestation;94womenserved

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as control. Allnewborns receivedactive and passive immuno-prophylaxis.The incidenceof perinataltransmission was0% in thetreatmentgroupvs. 8%incontrols(p=0.002)[93]. No seri-ousadverseeventswerereported.Ameta-analysisofsixstudies conﬁrmedtheefﬁcacyoftelbivudineinthiscontext;however,the qualityofthestudieswaspoor[94].Afurtherstudyin648 moth-ersreceivingtelbivudineorlamivudineornodrug(n=252/51/345) fromweek28ofpregnancyshowedthatbothregimensweresafe andsuperiortonodrug[95].

Tenofovirwasevaluatedinthreenon-randomized,small-sized studies,both showingefﬁcacyin preventingnewborninfection [96–98].Ina non-randomizedstudytenofovirgivenfor 58±19 daysbeforedeliverywasmorepotentthanlamivudine[99].

Ofnote,thelabelsofNUCsrecommendagainsttheiruseduring breast-feeding.Arecentpaperreviewedthedataonlamivudine andtenofovirandfoundthattheexposuretothedrugsislower duringbreast-feedingthaninutero[100].

Amniocentesis performed on HBsAg-positive mothers with serumHBVDNA≥107_copies/mL_{signiﬁcantly}_increased_the

fre-quencyofverticaltransmission[101].

• AllpregnantwomenmustbetestedforHBsAg(ClassI,LevelA)

andifpositivetestedforHBeAg/antiHBeandHBV-DNA(Class

I,LevelB).Earlytestingmayallowabettermanagementof

HBsAg-positivewomen(ClassI,LevelC).Earlyantiviral

treat-mentmustbeconsideredinthepresenceofadvancedliver

ﬁbrosis(F3-F4);tenofoviristhepreferreddrugduetoitshigh

geneticbarrier,safetyandpotency;treatmentmustbe

con-tinuedafterdelivery(ClassI,LevelA).

• Pregnantwomen with serumHBV DNA≥107_IU/mL _should

receiveantiviraltreatmentwithaNUCtominimizetheriskof

verticaltransmission(ClassII,LevelB).Tenofoviror

telbivu-dinearethedrugsofchoiceandshouldbestartednolater

thanweek32ofgestation(ClassI,LevelB);lamivudineisalso

allowed(ClassII,LevelB);treatmentisstoppedatweek0–4

afterdelivery.Duringbreast-feeding,thesafetyofcontinuing

treatmentisuncertain(ClassII,LevelC).

• All newborns from HBsAg-positive mothers must receive

standardprophylaxiswithvaccineagainstHBVandantiHBs

immunoglobulinswithin12hoursafterdelivery(ClassI,Level

A).

4.2. ChronichepatitisC

HepatitisCisamajorpublichealthproblem:worldwidemore than 200million people are infected with HCV, withan over-allprevalence of 3.3%. The epidemiology of HCV varies among countriesand its prevalence in pregnantwomen hasnot been extensivelystudied.Theprevalenceofanti-HCVpositivityamong pregnantwomeninEuropeisestimatedbetween1.7%and2.5% [45,102,103],butincreasesto8%insomedevelopingcountries.

Thenatural history of liverdiseasein pregnant women and theiroffspringisnotfullyunderstood.Pregnancydoesnotseem tomodifythenaturalcourseofHCVdisease:pregnantwomenare generallyasymptomaticandduringpregnancyasigniﬁcant reduc-tioninALTlevelshasbeenreported,withareboundduringthe postpartumperiod,accompaniedbyHCVRNAincreasetowardsthe endofpregnancyinthemajorityofHCV-infectedpregnantwomen. However, in different studies, which monitored viral load by monthlytesting,HCVRNAwasstableduringpregnancyinchronic HCVcarrierswithoutbiochemicalactivity,whereasviremicﬂares occurredinpregnantwomenwithbiochemicalactivity[46,104].

FewdataareavailableabouttheimpactofHCVinfectionon fertility or pregnancy. Preliminary data suggest no increase in

spontaneousmiscarriagerateorinobstetriccomplicationsin HCV-infected women compared to controls. However, somestudies reporteda decreaseinnewbornweight,anincreasein congeni-talabnormalitiesandinpretermdeliveryrate[105,106].Moreover, retrospectivedatasuggestsasigniﬁcantlyhigherincidenceof intra-hepaticcholestasisofpregnancyinHCV-infectedpregnantwomen comparedwithcontrols.

Chronichepatitis CcanleadtoverticaltransmissionofHCV, whileitonlymarginallyinﬂuencesthecourseofpregnancyand seldominducesspontaneousabortion.Theglobalrateofvertical transmission of HCV is relatively low; it has been estimated between3%and5%[107],ininfantsbornfromHCV-positive moth-ers.Somestudiessuggestthatperinataltransmissionislimitedto viremicwomen,particularlyifmaternalviralloadishigherthan 100,000UI/mLduringdelivery.Besidesviralload,theriskof ver-tical transmissionincreases in women co-infectedwithHIV, in thoseabusingalcoholordrugsandafterinvasiveproceduressuch as amniocentesis,instrumented vaginal delivery and prolonged ruptures of membranes (>6hours). Delivery modalities do not inﬂuencetransmission,andcaesareansectiondoesnotdecrease perinatal HCV transmission. Breast-feeding should not be dis-couraged,astransmissionofHCVbybreast-feedinghasnotbeen demonstrated[108].

HCV-infectedpregnantwomendonotneedspeciﬁc monitor-ing;antiviraltherapyforHCViscontraindicatedduringpregnancy duetothepotentialteratogeniceffectsofribavirinandtheside effectsofPEG-IFN.Nodataareavailableregardingnew interferon-freeregimens(Table3).Treatmentoptionsshouldbeofferedbefore pregnancy[109,110].

• Pregnancy doesnot seem to modify thenatural course of

HCVdiseaseandchronichepatitisConlyrarelyinﬂuencesthe

courseofpregnancy(ClassI,levelB).

• Theriskofverticaltransmissionincreasesinhighlyviremic

HCV-infected women, in those co-infected with HIV, or

abusingalcoholordrugs,orafterinvasiveprocedures

(amnio-centesis,instrumentedvaginaldelivery,prolongedruptures

ofmembranes)(ClassII,levelA).

• AntiviraltherapyforHCViscontraindicatedduringpregnancy

duetothepotentialteratogeniceffectsofribavirinandthe

sideeffectsofPEG-IFN(ClassI,levelA).Nodataareavailable

aboutinterferon-freeregimens.

4.3. Autoimmunehepatitis

Autoimmunehepatitis(AIH)usually affectswomenin fertile age,thuspregnancyisrathercommoninthosepatients.Ina ret-rospectiveGermanstudytheoutcomeofpregnancywasassayed byaquestionnaireobtainedby22AIHpatientswith42 pregnan-cies[111].Sevenpregnancies(17%)weredeliveredpre-termbefore week36ofgestation,andtherateofadversepregnancyoutcome was26%.Ofthe35livebirths,30childrenshowedacompletely normaldevelopmentoveramedianobservationof56months.One childwasbornwithSmith-Lemli-Opitzsyndrome,arareautosomal recessivedisorderofcholesterolmetabolism,andanother devel-oped tetraparesisafterpre-term delivery. The causeof adverse pregnancyoutcomecouldbeelucidatedin4of11cases:oneseptic abortionoccurredintheweek19ofgestation.Anotherpregnancy lossoccurredintheweek18ofgestation,duetomaternalfulminant hepaticfailure.Onechildwasdeliveredbyemergencycaesarean sectionatweek32anddiedforcongenitalheartblock.Thesame mother delivereda second babyat week24 and the babyhad Edward’ssyndrome(trisomy18)anddiedshortlythereafter[111].

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Table3

PharmacotherapyforhepatitisCvirusinfectionduringpregnancyandbreast-feeding.

Drug FDAclass Pregnancy Breast-feeding

Peg-Interferon␣ C Therearenoadequateandwell-controlledstudiesofPEG-IFN inpregnantwomen.PEG-IFNistobeusedduringpregnancy onlyifthepotentialbeneﬁtjustiﬁesthepotentialrisktothe foetus.

Nodataavailable.

Becauseofthepotentialforadversereactionsinnursing infants,adecisionmustbemadewhethertodiscontinue nursingordiscontinuePEG-IFNtreatment.

Ribavirin X Therearenocontrolleddatainhumanpregnancies.

Ribavirin-containingregimensarecontraindicatedinpregnant womenandinmalepartnersofwomenwhoarepregnant. Effectivecontraception(atleast2reliableforms)isrequired duringribavirintherapyandforatleast6monthsafter therapy.

Nodataavailable.

Becauseofthepotentialforadversereactionsfromthedrugs innursinginfants,adecisionmustbemadewhetherto discontinuenursingordiscontinueRibavirintreatment.

Telaprevir X Telaprevircombinationtherapyiscontraindicatedinwomen whoareormaybecomepregnantandinthemalepartnersof womenwhoarepregnant.

Nursingshouldbediscontinuedbeforestartingtherapy.

Boceprevir X Boceprevircombinationtherapyiscontraindicatedinwomen whoareormaybecomepregnantandinthemalepartnersof womenwhoarepregnant.

Nursingshouldbediscontinuedbeforestartingtherapy.

Sofosbuvir Ba _Use_should_be_avoided. _Use_should_be_avoided.

Simeprevir X Useshouldbeavoided. Useshouldbeavoided. Daclatasvir X Useshouldbeavoided.Therearenodatafromtheuseof

daclatasvirinpregnantwomenthereforedaclatasvirisnot recommendedduringpregnancy.

Useshouldbeavoided.Itisnotknownwhetherdaclatasviris excretedinhumanmilk.Mothersshouldbeinstructednotto breastfeediftheyaretakingdaclatasvir.

Ledipasvir Ba _Use_should_be_avoided._This_drug_should_be_used_during

pregnancyonlyifthebeneﬁtoutweighstherisktothefoetus. Effective

Useshouldbeavoided.Itisnotknownwhetherledipasviris excretedinhumanmilk.Developmentalandhealthbeneﬁtsof breast-feedingshouldbeconsideredaswellasthemother’s clinicalneedforthedrug;potentialsideeffectsinthe breastfedchildduetothedrugorthemother’sunderlying conditionshouldbeconsidered.

ViekiraPackb _Ba _Not_recommended_for_use_during_pregnancy. _Use_should_be_avoided._It_is_not_known_whether_Viekira_Pack

drugsareexcretedinhumanmilk.Mothersshouldbe instructednottobreastfeediftheyaretakingdasabuvir. PEG-IFN,peginterferon.

a_In_association_with_ribavirin,_to_be_considered_FDA_class_X. b_Ombitasvir,_{paritaprevir,}_and_ritonavir_plus_dasabuvir.

An Englishstudy reported the outcome of pregnancy in 53 womenwith81pregnancies[112].Sixpregnancieswereconceived byinvitrofertilization;20%ofpregnanciesweredelivered pre-term.Thelivebirth ratewas73%(59/81). Ofthe remaining22 conceptions,therewere8spontaneousmiscarriages(10%),12 ter-minationsofpregnancy,1stillbirthand1foetaldeathduetoan unexpectedmaternal death. Twoof the livebirth children had abnormalities:one had cerebralpalsyand theother developed Perthes’ diseaseof the hip. The presence of maternal cirrhosis impactedonfoetaloutcome,andthelivebirthratewaslowerin motherswithlivercirrhosisatthetimeofconception(p=0.002).

ABrazilianstudyreportedaretrospectiveanalysisof54 preg-nanciesin 39 AIH patients[113].The rateofpre-term delivery was11.8%andthefoetallossratewas29.4%.Onewoman expe-riencedatubal ectopicpregnancy.Onetwinpregnancyandone full-termpregnancyweredeliveredviaemergencycaesarean sec-tionbecauseofacutefoetaldistresswithoutneonataldeath.One pregnancyresultedinastillbirthsecondarytoananencephalic foe-tus;anotherwomendeliveredababywithuretralstenosis.

Thematernalcourseis highlyvariable.In case ofpregnancy occurringatpresentationofAIHwith“acute”onset,liverdisease mayhaveafulminantcourseandthefoetushasalowchanceof sur-vival[114].Ingeneral,womenwhoreachdiseaseremissionanddo nothavecirrhosiswithportalhypertension,haveahighchance ofafavourablepregnancyoutcome[115].Ingeneral,pregnancy confersabeneﬁcialeffectonimmunosuppressionwithareduction inmaintenancetherapy.Thisisduetoseveralfactors,including thephysiologicalincreaseofserumcortisol[116,117].Inclinical practicethedosageofsteroidstomaintainremissionshouldbe reducedincaseofpregnancy.However,pregnancy-relatedﬂares mayoccurinupto21%ofcases(SupplementarytableS4),whereas theprobabilityoffaresishighestafterdeliverywithanincidence

ashighas40%[118].Table4reportstherecommendationsof phar-macotherapyforAIHduringpregnancyandbreast-feeding.

• Treatmentoptionsshouldbediscussedbeforepregnancyin

patientswithAIH.Ifthepatientisreceivingsteroid

monother-apythedosageneededtomaintainremissionwilllikelybe

lower.Aspregnancy-relatedﬂaremayoccur,areasonable

rec-ommendationistoincreasethesteroiddoseshortlybefore

theexpecteddateofdelivery,andtomonitorliverenzymes

andIgGcloselyintheweeksfollowingdelivery (ClassII-III,

LevelA).

• In case of combined treatment withsteroids and

azathio-prine,azathioprinecanbediscontinuedalthoughtheriskof

stillbirthand/orfoetalmalformationisnegligible.Incaseof

azathioprinemonotherapythereisariskofﬂareafter

ther-apywithdrawal;thusmaintenancetherapywithazathioprine

shouldbecontinuedstrictlymonitoringliverenzymes(Class

III,LevelA).

• Duringthebreast-feedingperiodonly steroidscanbeused (ClassIII,LevelA).

4.4. Primarybiliarycholangitis

Primary biliary cholangitis (PBC) generally develops near menopausalage,withabroadrange thatincludesboththe fer-tileandthegeriatricages.Pregnanciesareratheruncommonafter PBChasbeendiagnosed,andtherearelimitedreportsinthe lit-eraturespeciﬁcallyfocusingontheoutcomeofpregnancyinPBC patients,aswellasontheeffectofpregnancyonPBCcourse.There isonlyonereportdealingontheonsetofPBCduringpregnancy

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Table4

Pharmacotherapyforautoimmunehepatitisduringpregnancyandbreast-feeding.

Drug FDAclass Pregnancy Breast-feeding

PrednisoneorPrednisolone C Shouldbeusedmonitoringthedosage Excretedintothebreastmilkbutinsuchlowdoses thatnoeffecttothechildcanbeexpected Budesonide C Clinicalexperienceisscant,shouldonlybeusedunder

strictindication

Nodataavailable Azathioprine D Shouldbeusedunderstrictindicationandmonitoring

thedosage

Useshouldbeavoided Tacrolimus Shouldnotbeusedwithoutspecialriskevaluation,

littleclinicalexperience

Useshouldbeavoided Cyclosporine C Clinicalexperienceisscant,butanimalstudiesindicate

thatissafe,couldbeusediftheadvantagetothe motherisgreaterthantherisktotheoffspring

Excretedintobreastmilk,riskofadverseeffectsonthe newborncannotbeexcluded

MycophenolateMofetil C Useshouldbeavoided Useshouldbeavoided

Metothrexate X Useshouldbeavoided Useshouldbeavoided

[119],ina47year-oldJapanesewomanwhodevelopedjaundice atthe24thweekofpregnancy.InformationonPBCandpregnancy intheliteraturehavebeenobtainedbyaquestionnaire method-ology.Inparticular,theNationalHealthandNutritionintheUSA administeredastandardizedquestionnaireto182PBCpatientsand 225age-andsex-matchedcontrols[120].Theresultsofthisstudy showedthatthereweresignificantlymorepregnanciesamongthe PBCcasesthanamong controls.Thisstudy,however, presented severallimitations:therewasnoconfirmationoftheself-reported data,norinformationonthetimingofpregnancies,andbiasinthe selectionofthecontrolgroup.Arecentretrospectivestudy iden-tified32women (50pregnancies)whoeither becamepregnant afterPBCdiagnosisorinwhompregnancyledtodiagnosis[121]. Liverbiochemistryremainedstablein70%ofpatientsthroughout pregnancy,noadversematernaleventswereobservedduring preg-nancyorpost-partum,andonly6%developedprogressivedisease followingdelivery[121].Finally,theoutcomeofpregnancy and theinfluenceofpregnancyonthecourseofPBCwereanalyzedin acase–controlstudyincluding186consecutivepatientswithPBC whohadatleastoneconceptionanda1:2controlgroupof367 healthywomen[122].Thetwogroups’historywassimilarinterms ofmiscarriages,voluntaryinterruptionofpregnancy,andtermand pre-termdeliveries.Pruritusduringpregnancywasrecordedin15 pregnanciesinvolving13PBCpatients(3%)andin noneof con-trols.Perinatalandpostnataldeathsandcomplicationsatchildbirth wereonlyrecordedinthePBCpatients,involving11babies(2.7%, p<0.05).EightpregnanciesoccurredafterPBCwasdiagnosedin 6patients,allofwhomhadafavourablecourseatterm,withno complicationsatchildbirth.

UDCAissafeandwelltoleratedduringpregnancy.Areportfrom aFrenchgroupdescribed6patientswithPBChaving9 pregnan-cies:theirUDCAtreatmentwaswithdrawnintheﬁrsttrimester andrestoredduringthesecondandthird [123].Allthewomen remainedasymptomaticandtheirliverfunctiontestsfellwithin normalrangeforanormal pregnancy,and therewereno deliv-eryissuesorchildbirthcomplications[123].UDCAtreatmentwith increasingdoses up to 25mg/kg/day during breast-feeding has beenshowntobesafe,andnoadverseeffectswereobservedin eitherinfantsormothers[124].

• Pregnancy in PBC patients in the pre-cirrhotic stage

(his-tologicalstageI-III)hasafavourableoutcomeandthereis

no contraindication for pregnancy continuation (Class III,

LevelA).

• InpatientswithPBCinthecirrhoticstagepregnancyand

deliv-erymustbemonitoredforthepotentiallyhigherthannormal

riskof complicationsboth due to portalhypertensionand

childbirthcomplications(ClassIII,LevelA).

• UDCAshouldbecontinuedatstandarddosageduring

preg-nancyandbreast-feeding(ClassIII,LevelA).

4.5. Primarysclerosingcholangitis

Primarysclerosing cholangitis(PSC)hasanincidencearound 0.9–1.3per100,000peryearandaprevalencearound8.5–14.2per 100,000inNorthernEuropeandintheUnitedStates[125].Upto 80%ofPSCpatientshaveconcurrentinﬂammatoryboweldisease (IBD)[125].Fertilitydoesnotseemtobereducedinpatientswith PSC,andinyoungfemalepatientspregnancyispossible.

Nostrongassociationhasbeenfoundbetweenthedevelopment ofPSCandpreviousperinataleventsincludingbirthlength, breast-feedingandthemajorityofmaternalmedicalcomplications[126]. Thirteenpregnanciesin10patientswithPSCwereobservedin Sweden[127].SevenpatientshadPSCbeforepregnancy,2 devel-oped PSC during pregnancy, and one patient developed PSC 2 monthsafteranormalpregnancywithanormaldelivery.Nofoetal lossoccurred,theoutcomeofallneonateswasnormalandliver testsdidnotchangeduringpregnancy.However,thesymptoms relatedtoPSC,andinparticularpruritusandabdominalpain, wors-enedinseveralaffectedwomen,andinonecasethisbroughtto pretermbirth[127].

Acase reportdescribed a36-year-oldwomanwithPSCwho became pregnant after developing dominant stricture [128]. A healthybabyboywasdeliveredat33.5weeks.Themotherrequired cholangiographyandstentplacementimmediatelyafterdelivery, butherpost-partumcoursewasotherwiseunremarkable.

Anothercasereportshowedanimprovementinliverfunction duringpregnancyanddeteriorationafterpregnancy,suggestiveof autoimmuneaetiology[129].

Thelargestseriesofpatients(n=17)withPSChavingatleast onepregnancywasreportedinGermany[130].Despiteafrequent riseinserumlivertests,noseriousmaternalcomplicationswere observed.Twopregnanciesweredeliveredpre-termand4foetal lossesoccurredearlyinpregnancy.Continuationoftreatmentwith UDCAorazathioprinehadnonegativeeffectsonpregnancy out-come.

TheexacerbationofIBDduringpregnanciescomplicatedbyPSC isdescribedin25–30%ofcases[127].PSCalsocarriesariskof bil-iarysludgeandstones;nevertheless,theriskofbiliarycolicand/or complicationsofgallstonesisverylow.

• PregnancyisnotcontraindicatedinpatientswithPSC;therisk

ofunfavourablecourse,iscorrelatedwiththedegreeofportal

hypertension.Theincreasedriskofpretermbirthandfoetal

demiseassociatedwithhighfoetalbileacidlevelssuggeststhe

(10)

• UDCAshouldbecontinued atastandarddoseduring

preg-nancy,steroidscanbeusedformanagementofbothPSCand

IBD,ifpresent(ClassII,LevelA).UDCAshouldalsobe

contin-uedduringbreast-feeding(ClassII,LevelA).

• Possibly avoid azathioprine, althoughthe risk of stillbirth

and/orfoetalmalformationisnegligible(ClassIII,LevelA).

4.6. Geneticdisorders

4.6.1. Hereditaryhemochromatosis

Hereditaryhemochromatosis(HH)isarecessivedisease (preva-lence2–5/1000)dueinmostofthecasestohomozygosityforthe C282YmutationofHFEgene,whichconfersagenetic predisposi-tiontoprogressivebodyironoverload.Host-relatedandacquired factorsareneededforthephenotypicexpressionofthedisease.

Fertilityisimpairedonlyifdiagnosisandtreatmentarelate, when women have developed gonadal dysfunction. Given the recessivepatternofinheritance,thereisnoneedforprenatal diag-nosisforpregnantwomenwithHH[131].

Anormalpregnancyusuallymobilizesabout1gofironfrom themother’sbody toallowexpansionoftheblood volumeand provideirontothefoetus,thusmildanaemiaisfrequentin preg-nancy, and iron supplementationis frequentlyprescribed. Iron shouldnotbeprescribedroutinelytopregnantwomenwithHH unless clearly iron deﬁcient, and ferritin should be frequently checked.

Inthepresenceofironoverload,irondepletionbyphlebotomy orchelatorsshouldbedelayedtotheend of pregnancy,unless evidentcardiacinvolvementispresent.

Gestationaldiabetesseemsto bemorefrequent inpregnant womenheterozygousfortheC282Ymutation[132].

• No special care for pregnant women with hereditary

hemochromatosis is needed, except for cases of juvenile

hemochromatosis or in women who developed cirrhosis.

Phlebotomiesinpregnantwomenwithhereditary

hemochro-matosisshouldbedelayedtotheendofpregnancy(ClassIII,

LevelA).

4.6.2. Wilson’sdisease

Wilson’sdiseaseis arecessive disease(prevalence1/30,000) characterizedbydefectivebiliaryexcretionofcopperand conse-quentaccumulationinliverandbrain,duetoraremutationsof ATP7Bgene,whichencodesacoppertransportingprotein.Clinical presentation,whichcanoccuratanyage,maybeverydifferent includingacuteandchronicliverdisease,cirrhosis, neuropsychi-atricdisorders,andacutehaemolysis.

Womenarefrequentlynonovulatory,buttreatmentcanrestore fertilitywhenstartedinanearlystageofthedisease.Successful treatmentallowspregnancybutcopperstatusshouldbeoptimized beforepregnancy.Likelihoodofdeliveringahomozygote,without knowledgeofthepaternalstatus,is0.05%[133].

Maintaining therapy during pregnancy is essential because interrupting the drugs has been associated with haemolytic episodes, hepatic insufﬁciency and maternal death. d-Penicillamineissafe,althoughthedrugisteratogenicinanimal studies,andtherearereportsofneonateswithcutaneous abnor-malities.InpatientsonD-penicillaminetherapy,thedoseshould bereducedby25–50%ofthepre-pregnancydosetoreducefoetal risks.Theidealregimenis750mgto1gofeitherD-penicillamine or trientine during the ﬁrst two trimesters and 0.5g in the last trimester.There isnoevidence thatzinc sulfate or acetate increases the risk of foetal abnormalities. Therefore, therapy shouldbe continuedat regulardoses. Allpatientswith Wilson

disease should be offered genetic counselling when consider-ingpregnancy and offspringshouldalwaysbe screenedfor the disease[133–135].

• All patients withWilson disease shouldbe offered genetic

counselling when considering pregnancy and offspring

should always be screened for the disease. Copper status

shouldbeoptimizedbeforepregnancy.Maintainingtherapy

duringpregnancyisessentialwithreduceddosesofchelators

comparedtothepre-pregnancyperiod(ClassII-III,LevelB).

4.6.3. Porphyrias

Porphyriascanpresentasacuteorchronicdisease.The inheri-tancepatternisusuallyautosomaldominant,withlowpenetrance, andtriggerfactorsareneededforthediseasetobecome appar-ent.Prevalencerangesfrom0.5to10/100,000foracuteporphyrias (acuteintermittentporphyria,variegateporphyriaandhereditary coproporphyria),withpolymorphousclinicalpresentationthatcan belife-threatening.Aprevalenceof1/25,000isknownforporphyria cutanea tarda. This is themost frequent of chronic porphyrias andusuallypresentswithcutaneoussymptoms,whileporphyria variegataand hereditarycoproporphyriamayalsopresent neu-ropsychiatricsymptoms.

Acute porphyrias usually manifest after puberty, more fre-quentlyinwomenwithapeakinthethirddecade[136].Attacks occurparticularlyduringperiodsofhormonalchange(e.g.,luteal phaseofthemenstrualcycle,andduringoralcontraceptiveuse). Pregnancyisnotcontraindicated,althoughattacksaremore fre-quentduringearlyweeksofgestation,potentiallycausingmaternal and foetalproblems, and in theimmediate postpartum period. Recurrentattacksmayoccurduringpregnancy inpatientswith acuteintermittentporphyria,variegateporphyria,or hereditary coproporphyria.Porphyriacutaneatardamaypresentfortheﬁrst timeduringpregnancy.

Inapopulation-basedstudy,pregnantwomenwiththe herita-bleformofporphyriacutaneatardaorwithactiveacuteporphyria hadasigniﬁcantexcessriskofprenataldeath,low birthweight andprematuredelivery[136].Mostcommonlynospeciﬁctherapy foracuteporphyriasisrequiredduringpregnancy.Incaseofacute attacks,standard therapywithglucoseinfusion(200–500g/day) andhemearginate(4mg/kg/day)isrecommendedfor3–4days. Thelistofpotentiallysafeandunsafedrugsisreportedat:www. drugs-porphyria.org.

• Inwomenwithacuteporphyriaspregnancyisnot

contraindi-catedalthoughattacksmayexacerbateinperiodsofhormonal

changes,Pregnantpatientswithacuteporphyriasshouldbe

referredtoaporphyriareferenceCentreforfollowup(Class

III,LevelA).

4.6.4. Glycogenstoragediseases

Glycogenstoragediseases(GSD)areveryrareinherited reces-sivemetabolicdiseases(prevalence3–6/100,000)causedbydefects ofenzymesinvolvedinglycogenstorageanddisposal.Alleast15 typeshavebeenidentiﬁedwithsomeinvolvingprimarilytheliver andotherstheskeletalmuscle.Initiallyconsideredanalmost uni-versallyfataldisease,nowadaysGSDareconditions,whichallow womentogrowintoadulthoodandpotentiallybecomepregnant.

Presentationisstronglydependentonthetypeofdisease,and is characterized by severe hypoglicemia, and/or muscle symp-toms.Long-termcomplications(hepaticadenomaoftencorrelated topolycysticovaries,nephropathy,andcardiomyopathy)canbe delayedorpreventedwithoptimalmetaboliccontrol.

(11)

Despitehighprevalenceofirregularmenstrualcyclesand poly-cysticovaries,nofertilityimpairmentwasdetectedinwomenwith GSDtypeIa/Ib,andIIIa/IIIb,thetwomoreprevalentGSD,which involvetheliver.Hepaticadenomasandnephropathy(inparticular inwomenwithalbuminuria)arethemainrisksofpregnancy.

Good metaboliccontrol prior to conception and maintained throughoutgestationdirectlycorrelateswithsuccessfuloutcome inwomenwithGSD[137,138].

• Inwomenwithglycogenstoragediseasesgoodmetabolic

con-trolpriortoconceptionandthroughoutgestationisessential

sincedirectlycorrelateswithsuccessful outcome(Class III,

LevelB).

4.7. Metabolicdisorders 4.7.1. Alcoholicliverdisease

Pregnancyinalcoholicliverdisease(ALD)presentstwomain problems:liverdamageandalcoholintake,includingtheeffectsof alcoholonotherorgansandalcoholdependence,itself[139].

ALDcomprises a largespectrumof alcohol-relatedliver dis-eases,ranging from fatty liver or simple steatosis to alcoholic hepatitis,chronichepatitiswithhepaticﬁbrosisorcirrhosis.

PregnancydataarescarceinwomenwithALD,aswomenwith ALDareofteninfertile.ALDleadstoanovulationandamenorrhea duetomanyfactorsincludingdisturbedoestrogenandendocrine metabolism [140]. Whenpregnancy is successful in a cirrhotic woman,spontaneousabortionrate,riskofprematurity,and peri-nataldeathrateareallincreased[141].

Alcoholiccirrhoticpatientshaveahighriskofliver decompen-sationbecauseofworseningsyntheticliverfunction,development ofascites,andhepaticencephalopathywithhighmaternal mortal-ity[141,142].Maternalprognosisdependsonthedegreeofhepatic dysfunctionduring pregnancy rather than its cause[143]. Por-talhypertensionworsensduringpregnancybecauseofincreased bloodvolumeandﬂow.Portalpressurescanalsoincreasebecause ofanincreasedvascularresistanceduetoexternalcompressionof theinferiorvenacavabythegraviduterus.Upto25%ofpatients withvariceshaveableedingepisodeduringpregnancy[45].The greatestriskisinthesecondtrimester,whenportalpressurespeak [142].Allpatientswithcirrhosisshouldundergovaricealscreening. Bandingbeforepregnancy,althoughnotproven,isappropriatefor high-riskvarices(moderateevidence;weaklypositive recommen-dation).Finally,althoughtherearenogoodstudiesevaluatingthe impactofvaginaldeliveryontheriskofvaricealbleeding,itis rec-ommendedthatpatientshavecaesareansectiontoavoidincreased straining[144].Caesareansectionismorecommoninwomenwith ALD,butonecannotruleoutthattheliverdiseasecontributedto thechoice(verylowevidence;weaklynegativerecommendation). Concerningtheeffectsofalcoholonotherorgans,isimportant tomarkthatduringpregnancymaternalheartrateandcardiac out-putincrease,whilebloodpressureandsystemicvascularresistance decrease.Thesealterationsmimicphysiologicalchangesinpatients withdecompensatedchronicliverdisease.Bloodvolumeincreases byabout50%,peakinginthesecondtrimester.However,bloodﬂow totheliverremainsconstantduringpregnancy.

Alcoholconsumptionduringpregnancyhasbeenlinkedto poor-birthoutcomesandlong-termcognitiveandbehaviouraldeﬁcits [145].Abusiveandheavydrinkingareassociatedwithfoetal alco-holsyndrome(FAS),which includesgrowthretardation,central nervoussystem damage, neurodevelopmentaldelays and facial malformations[146].Epilepsyisoftenreportedinchildrenwith FAS[147].EvenintheabsenceofFAS,heavyalcoholconsumption duringpregnancyiscorrelatedwithadverseoutcomes,including

miscarriage,stillbirth,pretermdeliveryandsmall-for-gestational age(SGA)birth[148].

Dataondiseasefrequenciesinchildrenborntomotherswith ALDdo notexist, althoughprenatalalcohol exposuremay neg-ativelyaffectthefoetus[147].However,convincingevidenceof adverseeffectsrelatedtolowtomoderateprenatalexposureto alcoholis lacking[149].Studyingamountand timingofalcohol intakeduringpregnancyiscomplicatedbyrecallbiasandby socio-economicandlife-styleconfoundingsuchascigarettesmokingand underreportingofdrinkingduringpregnancy.

Women hospitalized with ALD have an increased risk of adversepregnancyoutcomes,includingpretermandSGAbirth.The increasedriskofpretermbirthcouldbeattributedtoalcoholintake duringpregnancy,butalsotochronicliverdiseaseperse.Chronic liverdiseaseisassociatedwithincreasedlevelsofinﬂammatory cytokines,whichmayincreasetheriskofpretermbirth[150].A Danishstudyfoundthatalcoholconsumptionbelowfourdrinks perweekdidnotincreasetheriskofpretermbirth.Womeninthat study,whoconsumed2–3.5drinksperweek,hada20%reductionin risk[151].Severalrecentstudiesfoundthatalcoholisariskfactor forpretermbirth[152,153](moderateevidence;weaklypositive recommendation).

Thereisanearly40%increaseinrisk ofstillbirthforwomen withALDdiagnosedbeforepregnancy.However,thenumbersof stillbirthwerefewanddidnotreachstatisticalsigniﬁcanceinthe adjustedmodels.Datashouldthereforebeinterpretedwithcaution (verylowevidence;weaklynegativerecommendation).

Severalstudieshave been conductedtoinvestigate whether alcoholintakeduringbreast-feedingcancausedamagetothebaby. Infact,therewasnodifferenceinthescoresofcognitive devel-opment,whileasmallbutsigniﬁcantdifference,wasdetectedin motordevelopmentofchildren[154](lowevidence;weakly posi-tiverecommendation).

Benzodiazepines seem the most recommendable option for managingalcoholwithdrawal,andpsychosocialinterventions suc-ceedinreducingalcoholconsumptionorinmaintainingabstinence inalcohol-dependentpregnantwomen[155](moderateevidence; weaklypositiverecommendation).

• ALDwasassociatedwithadversepregnancyoutcomes,

espe-ciallyamongwomendiagnosedbeforedelivery(ClassIII,Level

A).

• Screening for alcohol use in antenatal care could identify

high-riskwomenandtherebypreventpregnancyandbirth

complications(ClassIII,LevelA).

• Alcoholconsumption duringpregnancyis contraindicated;

breast-feedinginwomenwithorwithoutpre-existingliver

diseaseiscontraindicated(ClassIII,LevelB).

4.7.2. Non-alcoholicliverdisease

Non-alcoholicfattyliverdisease(NAFLD)isthemostcommon chronicliverdiseaseworldwide.Itisthehepaticexpressionofthe metabolicsyndrome(MS)andsharestherisksassociatedwithits components.However,veryfewstudieshaveaddressedthe con-cernsrelatedtopregnancyinNAFLD.Itisdifﬁculttoascertainfrom availabledatawhetherpregnancymayplayaroleinpresentation ordeteriorationofpre-existingNAFLD.InasmallseriesfromUK [156],pregnantwomenwithchronic(atleast29weeks)abnormal liverfunctiontestsduringpregnancywerescreenedforpotential hepaticdisorders,bothrelatedandunrelatedtopregnancy.In5 womenallknownaetiologieswereexcluded;furtherevaluation byliver ultrasoundshoweda variable degreeoffatty liverand conﬁrmedthediagnosisofNAFLD,associatedwithincreasedBMI. Noneofthemhadpre-eclampsianorgestationaldiabetes(GDM)