AISF position paper on liver transplantation and pregnancy: Women in Hepatology Group, Italian Association for the Study of the Liver (AISF)

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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

Position

Paper

AISF

position

paper

on

liver

transplantation

and

pregnancy

Women

in

Hepatology

Group,

Italian

Association

for

the

Study

of

the

Liver

(AISF)

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received18March2016 Accepted11April2016 Availableonline20May2016

Keywords: Fertility Immunosuppression Livertransplantation Pregnancy

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Aftertheﬁrstsuccessfulpregnancyinalivertransplantrecipientin1978,muchevidencehasaccumulated onthecourse,outcomesandmanagementstrategiesofpregnancyfollowinglivertransplantation. Gen-erally,livertransplantationrestoressexualfunctionandfertilityasearlyasafewmonthsaftertransplant. Consideringthatonethirdofalllivertransplantrecipientsarewomen,thatapproximatelyone-thirdof themareofreproductiveage(18–49years),andthat15%offemalelivertransplantrecipientsare pae-diatricpatientswhohavea>70%probabilityofreachingreproductiveage,theissueofpregnancyafter livertransplantationisratherrelevant,andobstetricians,paediatricians,andtransplanthepatologists evermorefrequentlyencountersuchpatients.Pregnancyoutcomesforboththemotherandinfantin livertransplantrecipientsaregenerallygood,butthereisanincreasedincidenceofpretermdelivery, hypertension/preeclampsia,foetalgrowthrestriction,andgestationaldiabetes,which,bydeﬁnition, ren-derpregnancyinlivertransplantrecipientsahigh-riskone.Incontrast,theriskofcongenitalanomalies andthelivebirthratearecomparabletothoseofthegeneralpopulation.Currentlytherearestillnorobust guidelinesonthemanagementofpregnanciesafterlivertransplantation.Theaimofthispositionpaper istoreviewtheavailableevidenceonpregnancyinlivertransplantrecipientsandtoprovidenational Italianrecommendationsforclinicianscaringforthesepatients.

1. Introduction

Mostoftheinformationregardingpregnancyinorgan trans-plantrecipients derives from kidney transplant recipients, and although several parallelisms can be drawn amongst different organrecipients,patientconditionsmaydifferconsiderablyeven intheabsenceof pregnancy.Theﬁrstsuccessfulpregnancy fol-lowing liver transplantation (LT) occurred in 1978 and led to excellentmaternalandfoetaloutcomes,despitelowbirthweight [1].Althoughnumerousstudieshavebeenpublishedreporting sin-glecases[1],caseseries[2–10],surveys[11,12],population-based studies[13],andregistries(e.g.theNationalTransplantation Preg-nancyRegistry[14–19]andtheUKTransplantPregnancyRegistry

WomeninHepatologyGroup:AnnaAlisi,ClaraBalsano,VeronicaBernabucci, AnnalisaBerzigotti,MauriziaBrunetto,ElisabettaBugianesi,PatriziaBurra, Vin-cenzaCalvaruso,ElisabettaCariani,BarbaraCoco,IsabelleColle,RosinaCritelli, EleonoraDeMartin,MariagraziaDelBuono,IsabelFabregat,FrancescaFaillaci, GiovannaFattovich,AnnarosaFloreani,GuadalupeGarcia-Tsao,ChantalHousset, AimiliaKarampatou,BarbaraLei,AlessandraMangia,MariaLuzMartinez-Chantar, FabiolaMilosa,FilomenaMorisco,PaolaNasta,TomrisOzben, TeresaPollicino, MariaLauraPonti,PatriziaPontisso,HelenReeves,MariaRendina,KryssiaIsabel Rodríguez-Castro,CaterinaSagnelli,GiadaSebastiani,AntonellaSmedile,Gloria Taliani,CarmenVandelli,EsterVanni,EricaVilla,RankaVukotic,AnnaLindaZignego,

ItalianAssociationfortheStudyoftheLiver(AISF):PatriziaBurra∗,Kryssia Rodríguez-Castro,MariaGuarino,FilomenaMorisco,EricaVilla,GiuseppeMazzella

∗ Correspondingauthor.

[20])onpregnancyinlivertransplantrecipients,norandomized controlledtrialshavebeencarriedout,andmuchoftheevidence regardingdrugsafetyduringpregnancycomesfromanimal stud-ies.Inaddition,reportingbiasinvoluntaryregistriesandselection biasinstudiesfromreferralcentreslimitthestrengthandqualityof scientiﬁcevidence.Thus,althougheffortshavebeenmadetowards thedevelopmentofevidence-basedmanagementstrategies[21], therearestillnorobustguidelinesonthemanagementof pregnan-ciesafterLT[3].Theaimofthispositionpaperistoreviewthe avail-ableevidenceonpregnancyinLTrecipientsandtoprovidenational Italianrecommendationsforclinicianscaring forthesepatients. Following the previous publication [22], the recommendations weredrawnusingthelevelofevidenceandstrengthof recommen-dationsgradedaccordingtotheAmericanCollegeofCardiologyand theAmericanHeartAssociationPracticeGuidelines[23].

2. Pregnancyafterlivertransplantation

Infertilewomen,successfulLTrestoresmenstrualfunctionin 97%offemalepatients,aswellaschildbearingpotential[23,24]. In general, LT leads to partial or complete normalization of bothlevelsofsex hormonesand sexualfunctionwithinseveral months,withnearly48%ofwomenintheirfertileage experienc-ingregularmenses,26%irregularbleeding,and26%amenorrhea [25,26], while more than 60% of peri-menopausal women http://dx.doi.org/10.1016/j.dld.2016.04.009

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reportedly experience a higher frequency of menstrual pattern disorders[23,27,28].Currently,womenconstituteone-thirdofall livertransplantrecipients,andapproximatelyone-thirdofthem areofreproductiveage(18–49years).IntheUnitedStatesonly, approximately14,000women of childbearingagearecurrently livertransplantrecipients,andanother500womenwillundergo LTeveryyear.Moreover,15%offemalelivertransplantrecipients arepaediatricpatientswhohave a>70%probabilityofreaching reproductiveage[8,29].Pregnancyoutcomesforboththemother andinfantinlivertransplantrecipientsaregenerallygood[30,31], but thereis anincreased incidenceofpreterm delivery, hyper-tension/preeclampsia, foetal growthrestriction, and gestational diabetes[4,7–10,12,14,16,32,33].

Background

Pregnancyinlivertransplantrecipientsisconsidereda high-riskpregnancy,withanincreasedriskofmaternalandfoetal complications,includingpre-eclampsia,gestationaldiabetes, spontaneous abortion,Caesarean delivery, pretermlabour, and intrauterine growth restriction; the risk of congenital anomalies,andlivebirthratearecomparabletothoseofthe generalpopulation.

Recommendations:

2.a.Pregnantlivertransplantrecipientsmustbemanagedby ateamincludinganobstetricianandatransplanthepatologist. (GradeIII)

2.b.Medicalandobstetricalfollowupaswellasdeliverymust becarriedoutinatertiarycentreand,preferably,inaliver transplantcentre.(GradeIII)

3. Pre-conceptioncounsellingandtimingofpregnancy

Together with menstruation, sexual function can return to normal and consequently women who have undergone suc-cessful LT may conceive as early as one month following LT [33,34]. In the presence of stable graft function, stable main-tenance immunosuppression, and absence of pre-conceptional hypertension,patientsare more likely tohave successful preg-nancy outcomes [19,35]. An inverse association between the intervalfromlivertransplantandabortionratehasbeenobserved [8,36],butnotconﬁrmedinallstudies[29].Ideally,preconception counsellingshouldbeginduringthepre-transplantationevaluation process[21].Livertransplantrecipientsshouldreceivecounselling regardingcontraceptionandtheyshouldbeprovidedwith appro-priatepre-conceptionmedicaladviceandeducationiftheywish tobecomepregnant.Patientsshouldreceivecounsellingregarding theincreasedriskofpotentialadversefoetaloutcomes,including stillbirth,prematurityandlowbirthweight,aswellasahigherrisk ofmaternalcomplicationssuchaspreeclampsia[11,37].

Althoughpregnancydoesnotincreasetheriskofmaternal mor-talityinlivertransplantrecipients,thesewomenshouldbeaware oftheirprognosisforlong-termsurvivalandabilitytocarefora child.Inaseriesof29transplantrecipientswhocompleteda preg-nancy,5diedbetween10and54monthspostpartum[8].However, thedecisionshouldrelyonthepatient,andduetotheacceptable risksofpregnancyafterLT,patientsshouldnotbeadvisedagainst pregnancy[11].Shouldthepatientmanifestherinformedintention tobecomepregnant,herhealthstatusregardingthegraft (avoid-anceofrecurrenceofdisease,establishmentofminimalrequired dosesofimmunosuppression,avoidanceofrejectionepisodes)and

generalhealth(renalfunction,diabetes,hypertension)shouldbe optimizedbeforeconception[35].

AccordingtoconsensusrecommendationsfromtheAmerican SocietyofTransplantation,pregnancycanbeconsideredifthere hasbeen(1)norejectionwithintheyearprevioustointended con-ception,(2)thereisadequateandstablegraftfunction,(3)noacute infectionsthatmayimpactfoetalgrowthandwell-being,and(4) maintenanceimmunosuppressionisatstabledosing[38].

Theoptimaltimingofconceptionisstillamatterofdebate,but waiting1–2yearsafterLTisgenerallyrecommended[19,21,38,39]. Afterthisinterval,theclinicalcourseisusuallystable,theriskof rejectionislower,immunosuppressiontherapyisusuallyat main-tenance levels,and therisk ofinfections is lower.The recently issued EASLguidelinesfor livertransplantation alsoadvocate a periodofatleast12–24monthsbetweenLTandconception[37].

Background

Inwomenofchildbearingage,fertilityisrestoredintheﬁrst several months after successful liver transplantation, and pregnancyis notonlypossible, butis generallyassociated withacceptable maternal and foetaloutcomes, and is not associatedwithincreasedriskofgraftrejectionperse.

3.a.Counsellingmustinitiatebeforelivertransplantation,and mustcontinueafterlivertransplantationandbefore concep-tion.(GradeIII)

3.b.Stablegraftfunctiononmaintenance immunosuppres-sion and good maternal health must be ensured before conception.(GradeIII)

4. Contraception

Periodicabstinenceandcoitusinterruptusareineffective meth-ods ofcontraceptionand cannot berecommended[40].Barrier methods represent a valid option due to the absence of drug interactions andlow cost,althoughfailure ratesrange between 15%and32%[41].Diaphragmsmightincreasetheriskofurinary infections,whichisalreadypresentintransplantrecipients[42]. Condomsrepresenttheonlyformofcontraceptionthatprevents mostsexuallytransmitteddiseasesandshouldberecommended forallpatientswithoutastablesexualpartner[41].Intrauterine devices, although veryeffective inthe generalpopulation, may increasetheriskofinfections[43]andapotentialreductionintheir effectiveness hasbeen reported in immunosuppressed patients [44,45]. Drug interactions are obviously only of minor impor-tance,andithasbeensuggestedthatintrauterinedevicesmight constitutethebestcontraceptiveoptionfortransplantrecipients [41,46].Regardingoralcontraceptivesortransdermal contracep-tives,thesamecontraindicationsasinthegeneralpopulationhave toberespected,includingpersonalhistoryofmyocardialinfarction, strokeordeepveinthrombosis,migrainewithfocalaura, uncon-trolledsystemichypertension,smokingovertheageof35,marked unexplainedlivertestabnormalitiesandhepaticadenoma.Being metabolizedbythehepaticcytochromeP4503A4system, drug-to-druginteractionsmaybeaconcern,especiallywithcyclosporine andtacrolimus,whicharebothmetabolizedbythisenzyme[47]. Oralcontraceptivesshouldbeusedcarefullyafterliver transplan-tation,withfrequentmonitoringofliverfunctiontests,andshould beusedonlyinrecipientswithstablegraftfunctionforatleast6–8 months and withoutother contraindications[48,49].Regarding surgicalsterilization,manylivertransplantrecipientschoosethis

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approach,whichavoidsdruginteractionsandisveryeffectiveat preventingunwantedconception[23,50].

Background

Although fertilityisrapidlyrestoredaftertransplantation,a shorterintervalbetweentransplantationsurgeryand initia-tionofpregnancyhasbeenassociatedwithworseoutcomes, makingcontraceptionparamount.

4.a.Anintervalofatleast12–24monthsaftersuccessfulliver transplantation is recommended before initiation of preg-nancy.(GradeIII)

4.b.Barriermethodsarerecommended,duetotheabsence ofdruginteractions,andcondomsshouldbeusedinpatients withoutastablesexualpartnertopreventmostsexually trans-mitteddiseases.(GradeIII)

4.c. Special attention is recommended with the use of intrauterinedevices, dueto ahigherriskof infectionsand reducedeffectivenesswhileonimmunosuppression.(Grade III)

4.d.Oralcontraceptivessharecommonmetabolicpathways withimmunosuppressivemedicationandmustbeusedwith caution.(GradeIII)

4.e.Surgicalsterilizationisrecommendedinpatientswhodo notdesireafuturepregnancy.(GradeIII)

5. Pre-gestationpregnancyrisksassociatedwithpost-liver transplantationstatus

Preconception hypertension (standardized prevalence ratio [SPR]=3.07, 95% conﬁdence interval [CI], 2.35–3.93), diabetes (SPR=5.99, 95% CI, 4.15–8.38), and chronic kidney disease ([SPR]=15.3±4.04) [51] are more frequent in liver transplant recipients,and these constitute majorrisk factorsfor obstetric complicationsincludingpreeclampsia[51–54],macrosomia[55], stillbirth[55], pre-term labour [56], and congenital malforma-tions[55]. The frequency of post-LT hypertension is especially higherinfemaletransplantrecipientsvstheirnon-transplanted counterpartsinthefertileagerange(<45years)[51].Moreover, hypertensionis statisticallymore frequent inpregnantpatients withapriorLT,withrespecttotheirpregnantnon-transplanted counterparts[13].

Diabetescomplicatesapproximately5.1%ofpregnanciesafter LT[39],and maybepresentprevioustoconception, whenit is mainlyassociatedtoimmunosuppressivemedicationafter trans-plantation,ormaydevelopasgestationaldiabetes,asaresultof thecombinationofbothdiabetogenicdrugsandpregnancyitself. Becauseallograftrecipientshaveanincreasedriskforgestational diabetes,theyshouldundergoa50-goralglucoseloadat16–18 weeksofgestation.Adequateglycemiccontrolduringpregnancyis mandatorytoreduceassociatedadversematernalandfoetal out-comes[55–57].

The presence of pre-conception end-organ damage such as nephropathy in diabetic patients, results in a higher risk for pregnancy-related adverse events including preeclampsia, pregnancy-inducedhypertension,pretermdelivery,Caesarean sec-tion,perinataldeath,andstillbirth[58–61].

5.1. Risksofpregnancyinlivertransplantrecipients

Generally, pregnancy does not have a negative impact on graft function, but is associated withsigniﬁcant obstetric risks

Background

Hypertensionanddiabetesmorefrequentlycomplicate preg-nancies in liver transplant recipients with respect to the generalpopulation,andmightexistpre-conceptionormay develop duringpregnancy.Thepresenceof pre-conception end-organ damage increases the risk of preeclampsia, pretermdelivery,Caesareansection,perinataldeath,and still-birth.

5.a.Screeningforgestationaldiabeteswitha50-goral glu-coseloadshouldbeperformedat16–18weeksofgestation. (GradeIII)

5.b. Maintenance of adequate pharmacological control of bloodpressureandglycemiaduringtheentirecourseof preg-nancyismandatory.(GradeIII)

[17,19,39,61,62].Pregnancyin livertransplant recipientsshould beconsideredahigh-riskpregnancybecauseoftheincreasedrisk for bothmaternal andfoetalcomplications [39], andshouldbe managedbyamultidisciplinaryteamincludingahigh-risk obstetri-cianandatransplanthepatologist[63,64].Medicalandobstetrical followupaswellasdeliveryshouldbemanagedinatertiarycentre and,preferably,inalivertransplantcentre.

Maternaldeathsandmostadversepregnancyoutcomesdonot differsigniﬁcantlybetweentransplantrecipientsandthegeneral population[13].However,foetaldeaths,antepartumadmissions, and maternal and foetal complications overall are 2- to 3-fold greaterinliverallograftrecipients[13].

5.2. Foetalcomplications

Mostfoetalcomplications[13]includingspontaneousabortion (5%),pretermbirth(27.4%),intrauterinegrowthrestriction(4.8%), andfoetaldistress(10.3%)arestatisticallymorefrequentin trans-plantrecipientscomparedtothegeneralpopulation[65],butthe incidenceofcongenitalanomaliesisapparentlycomparabletothat ofthenon-transplantpopulation(1.4%)[36].Althoughsomehave suggestedthatthehigherriskofpretermbirthmightbedueinpart toepisodesofgraftrejectionandearlyonsetpreeclampsia,thishas notbeenconﬁrmed[8].

5.3. Maternalcomplicationsassociatedtopregnancy

The frequency of maternal complications in liver transplant recipientsincludingdeath,antepartumhaemorrhage,and peripar-tuminfections,issimilartothatofthegeneralpopulation,whereas post-partumhaemorrhage,bloodtransfusions,and hypertensive disordersofpregnancy(preeclampsia,butnoteclampsia)aremore frequentinliverallograftrecipientswithrespecttothegeneral population[13,63].Ameta-analysison450pregnanciesin306LT recipientsshowedthatalthoughtheratesofpre-eclampsia(21.9%), caesareansectiondelivery(44.6%),andpretermdelivery(39.4%) werehigherthantheratesfortheUSgeneralpopulation(3.8%, 31.9%,and12.5%,respectively),thepost-LTlivebirthrate(76.9%) washigherthanthelivebirthratefortheUSgeneralpopulation (66.7%),andthepost-LTmiscarriagerate(15.6%)waslowerthan themiscarriagerateforthegeneralpopulation(17.1%)[53].

Hypertension(presentinasmanyas39%ofpregnanciesafterLT) andpreeclampsia(presentinasmanyas18%ofpregnanciesafter LT)probablyconstitutemajorfactorscontributingtotheincreased prevalenceof pretermdeliveryand foetalgrowthrestrictionin transplantrecipients[19].Pregnancy-inducedhypertension and

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preeclampsiamayberelatedtoimmunosuppressivetherapyand anincreasedincidenceofbaselinerenaldysfunctioninliver trans-plantrecipients.Theincidenceofhypertensionaccordingtothe type ofimmunosuppressionis between22% and29% with cor-ticosteroids [14], 68%and 73%with cyclosporine, and 47% and 54%withtacrolimus[17].Itisunclearifthesteroidcomponentof immunosuppressionisthedeterminantofthegreaterfrequencyof pregnancy-inducedhypertensioninthesepatients[8]. Tacrolimus-based immunosuppressive regimenshave been associated with lowerratesofhypertension[6,8,66].Overall,thesmallnumberof patientsevaluatedandthesuboptimalqualityofevidencedonot allowforunivocalconclusions.

5.4. Maternalcomplicationsregardingtransplantrecipientstatus The reported incidence of rejection (with a mean age at conception of 26.8_±3.4 years) is highly variable (from 0% to 20%) [4,6–10,14,30,67–69], whereas rejection rates in the non-pregnantpopulationafterlivertransplantationareapproximately 2–3%[69,70].Voluntarysuspensionofimmunosuppressionbythe motherhasbeenreportedasthecauseofahigherrateofrejection, andepisodesaregenerallyreversiblewithsteroidbolusesand re-establishmentofadequateimmunosuppressivetherapy[71].Ina recentlypublishedstudyonKing’sCollege’sexperienceanalyzing 117conceptionsin79patients,acutecellularrejectionwas signiﬁ-cantlymorecommoninwomenwhoconceivedwithin12months ofLT(P=0.001)[63].

Although there have been reports of worsening renal func-tionduring pregnancyafter LT[3], manyother serieshave not reportedsuchfinding,and pregnancy doesnot seemto trigger humoralrejectioninvolvinganti-HLAclassIandIIantibodies[72]. Atpresent,thereisnotsufficientevidencetoconsiderrenal func-tiondeteriorationafrequentfindinginthisgroupofpatients.

5.5. Generalobstetricoutcomes

Regardingobstetricoutcomesinlivertransplantrecipients,the followingfrequencieshavebeenreported:spontaneousabortion 11–19%[3,7,8,20,35],Caesareandelivery20–63%[3–5,7–10,20,36], pretermlabour(<37weeksgestation) 14–53%[3–5,8–10,20,36], graftrejection5–17%[4,7–10,20,36,37],andhypertensivedisorders ofpregnancy(preeclampsia/eclampsia)5–33%[3–5,7–10,36].

Areviewof285pregnanciesafterLTfoundanon-signiﬁcant higher frequency of abortions in patients transplanted for autoimmune hepatitis [36]. At present, there is not enough evidencethattheriskofrejectionisdependentupontheindication forLT.

Caesarean sections are statistically more frequent in liver transplantrecipientsvstheircounterpartswithnoprevious trans-plantation[13],whereas thefrequencyofprematureruptureof membranes,placentaprevia,andplacentalabruptionaresimilarin transplantedpregnantpatientscomparedtothegeneralpopulation [13].

5.6. Managementofpregnancyinalivertransplantrecipient 5.6.1. Metaboliccomplications

Gestationaldiabetesislikelyprovokedbychronicprednisone administration, thus these patients may beneﬁt from diabetes screeningbetween16and18weeksofgestation.

Hypertension must be adequately controlled, avoiding angiotensinreceptorblockersandangiotensin-convertingenzyme inhibitors,whicharecontraindicatedduringpregnancy;according to the American College of Obstetricians and Gynaecologists

(ACOG), methyldopa constitutes an appropriate ﬁrst-line agent [73,74].

5.6.2. Infectiouscomplications

Infections frequently affect transplant recipients [75], and althoughurinaryinfectionsandpyelonephritisaremorefrequent andsevereinrenaltransplantrecipients[76],surveillance,prompt diagnosisandtherapyofpossibleinfectionsiswarrantedinLTas well[21].

Thetransplantedgraftisasourceofcytomegalovirus(CMV),and patientstypicallyreceiveprophylaxisagainstCMVfor1–3months postoperatively,whentheriskofinfectionishighest.Thegreatest riskofcongenitalinfectioninthefoetusisrepresentedbyprimary CMVinfectionduringpregnancy,butrecurrentCMVinfectioninthe immunosuppressedfemalepatienthasalsobeenreportedtocause congenitalCMVintheinfant[77].MonitoringfordenovoCMV infection,or,morefrequently,reactivationinducedby immunosup-pression,isparamount,asitcancauseseriousfoetalmalformations ifleftuntreated[78,79].

CMVinfection,transmittedtothefoetusthroughthe transpla-centalrouteaswellasduringdeliveryorbreastfeeding,cancause seriouscomplicationsinthefoetus,includinghydropsfetalis, still-birth, mental retardation,visual, andhearingloss, and preterm birthwithneonataldeathsinoffspringoflivertransplantrecipients [80,81].Thepresenceofmaternalimmunitydoesnotabsolutely protectthefoetus,althoughitdoesreducethelikelihoodof trans-mission[82,83].However,antiviralprophylaxishasnotgenerally beenrecommendedduringpregnancy[84].

Otherinfectionsthatmayposeadditionalrisksinthe immuno-suppressedmotherincludetoxoplasmosis,primaryherpessimplex infection,primaryvaricellainfection,HIVinfection,andinfection witheitherhepatitisBorCvirus[85,86].Prenatalscreeningcan detecteachoftheseinfections,althoughinmanycasesthemother presentsjustbeforeprenatalscreeningwhenmaternalprophylaxis cannolongerbeconsidered.

5.6.3. Generalmanagement

The followingconstitute generalmanagement guidelinesfor pregnancyafterLT[87].

-As in case of all high risk pregnancies, monthly evaluation includingclinicalexamination,assessmentofgraftfunctionand maternalhealthbymonitoringbloodpressure,routinelaboratory testsincludingurinarycultureiswarranted[21].

-Moreover,viralserologyforhepatitisBandC,Toxoplasma, rou-tinebloodtestsforhepaticandrenalfunctions,andCMVaswellas microbiologicalculturesofvaginalsmearsforB-hemolytic Strep-tococcus, Chlamydiatrachomatis, Mycoplasma spp., Ureaplasma urealyticum,Candidaspp.,andEscherichiacolishouldberepeated monthly.

-Aﬁrsttrimesterultrasonographyshouldbeperformedto deter-minegestationalage,andthis examshouldberepeatedat20 weeksforassessmentoffoetalmorphology.Thereafter,beginning at24to26weeksofgestation,serialultrasonographyshouldbe performedevery4weekstoevaluatefoetalgrowth[21]. -Foetalheartrateshouldbeassessedweeklyfromweek28until

delivery[36].

-Ifintra-uterinegrowthretardationisdocumented,foetalhealth should be strictly monitored by serial ultrasound biometry, Dopplerassessment,andelectronicfoetalheartratemonitoring [88].

-Supported by recent evidence, the mode of delivery is inde-pendentfromthetransplantrecipientstatus;thefrequencyof Caesareansectionsisatpresentnotdifferentbetweentransplant recipients and their non-transplanted counterparts [13]. Cae-sareansectionshouldbereservedforobstetricalcomplications,

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Table1

Pregnancycategoryofimmunosuppressivedrugscommonlyusedafterlivertransplantation.

Drug Pregnancycategory Risks/observedassociations

Corticosteroids(prednisone, prednisolone,and methylprednisolone)

B Intrauterinegrowthretardation,maternalhypertension,gestational diabetes,foetaladrenalinsufﬁciency

Calcineurininhibitors C Intrauterinegrowthretardation,maternalhypertension,gestational diabetes,renaldysfunction,foetalperinatalhyperkalemia

Mycophenolatemofetil D Spontaneousabortion,malformationsincludingmicrotia,hypoplastic nailsandshortenedﬁfthﬁngers,cleftlipandpalate,absenceof auditorycanals,neonataldeathwithmultiplemalformations

mTORinhibitors C Animalstudieshaveshowndecreasedfoetalweight,delayed

ossiﬁcationofskeletalstructures,butnoteratogenicity.Theriskin humanscannotberuledout.

Azathioprine D Intrauterinegrowthretardation,foetalanaemia,thrombocytopenia,

leucopenia,decreasedfoetalimmunoglobulinlevels,neonatal infectionandsepsis,pretermdelivery,lowbirthweight

mTOR(mammaliantargetofrapamycin).AccordingtotheFoodandDrugAdministrationoftheUnitedStates,thefollowingarethedrugsafetycategoriesduringpregnancy. CategoryA:Adequateandwell-controlledstudieshavefailedtodemonstratearisktothefoetusinthefirsttrimesterofpregnancy(andthereisnoevidenceofriskin latertrimesters).CategoryB:Animalreproductionstudieshavefailedtodemonstratearisktothefoetusandtherearenoadequateandwell-controlledstudiesinpregnant women.CategoryC:Animalreproductionstudieshaveshownanadverseeffectonthefoetusandtherearenoadequateandwell-controlledstudiesinhumans,butpotential benefitsmaywarrantuseofthedruginpregnantwomendespitepotentialrisks.CategoryD:Thereispositiveevidenceofhumanfoetalriskbasedonadversereaction datafrominvestigationalormarketingexperienceorstudiesinhumans,butpotentialbenefitsmaywarrantuseofthedruginpregnantwomendespitepotentialrisks. CategoryX:Studiesinanimalsorhumanshavedemonstratedfoetalabnormalitiesand/orthereispositiveevidenceofhumanfoetalriskbasedonadversereactiondatafrom investigationalormarketingexperience,andtherisksinvolvedinuseofthedruginpregnantwomenclearlyoutweighpotentialbenefitsFDAimmunosuppressivedrugs recommendedduringpregnancyandlactation.

andthereisnoparticularcontraindicationtovaginaldeliveryin

relationtothetransplantstatus[66].

6. Immunosuppressionduringpregnancy

Thebeneﬁtsofimmunosuppressivetherapyintransplant recip-ients generally outweigh theslightly increased risk of adverse pregnancyoutcomeandmostwomentakingthesedrugswillhave normal,healthy babies[18], withoutevidenceof increasedrisk ofneurologicalimpairmentwhen followedintochildhood years [89].Thelowestpossibledoseneededtopreventrejectionshould beused, in order toavoid potential adverse effects on mother andfoetus [18,19,21]. Maintenanceof pre-conception immuno-suppressionisrecommended,withtheexceptionofmycophenolic acidproducts and azathioprine, which should be discontinued beforeconceptionandreplacedwithanalternativemedication[21] (Table1).

Althoughstudieshaveshown relativelystableplasmatic val-uesofimmunosuppressantsduringpregnancy[36],otherstudies havedemonstratedavariabledemandfortacrolimus,with high-est tacrolimus demand coinciding with the lowest values of hematocritphysiologicallyobservedduringpregnancy[71].Plasma levelsofimmunosuppressivedrugsshouldbemonitored,and dos-ingadjustedinrelationtothephysiologicalchangesofpregnancy andgraftfunction[21] toavoidunderoroverdosingrelatedto physiologicalchangesofpregnancy.

6.1. Calcineurininhibitors

Calcineurininhibitors(includingcyclosporineandtacrolimus) have notbeen definitively associatedwith teratogenicity; rates of major foetalmalformation in exposed infants are similarto thoseofthenon-exposedpopulation,andnospecificpatternof malformationhasbeenreported[5].Initialreportsofcalcineurin inhibitor-induced intrauterine growth restriction, spontaneous abortions,andprematurebirthswereassociatedwithelevated lev-els(tacrolimuslevels8.5–9.9ng/mL)[90,91],andhavenotbeen confirmedbysubsequentstudies[5,6,90].

For patients taking either cyclosporine or tacrolimus, fre-quentmonitoringofrenalfunctionanddruglevelsiswarranted, especiallysince duringpregnancythehepaticcytochromeP450

enzymesmay beinhibited, which canlead to increasedserum level of tacrolimus.The dosemay thereforehave to be signiﬁ-cantlyreducedtopreventtoxicity(sometimesbyasmuchas60%) [38,39,78].Increasedmonitoringofbloodlevelsofcyclosporineis alsowarranted,duetoincreasedhepaticclearanceduring preg-nancy[92,93].

6.2. Steroids

The shorter-acting agents prednisone, prednisolone, and methylprednisolone, which are metabolized by placental 11-hydroxygenase,cancrosstheplacenta,butmaternal–tocord– bloodratiosareapproximately10:1andresultinfoetalexposure thatcorrespondstoapproximately10%ofthematernaldose[94]. Asidefromtheiruseasimmunosuppressantsaftertransplantation, thesearealsoemployedroutinelyforthetreatmentofmaternal disordersandalsoforinducingfoetalpulmonarymaturationwhen pre-termbirthisforeseen[95].

Although an association between corticosteroid use during pregnancyand cleft lipand/or palatein animal models [96,97] aswellas inhumans [98–100]wasinitiallyreported,this data wasbasedonoldstudiesinwhichhighdosesofsteroids(mean dose27±29mg/day)wereused,andteratogenicityderivingfrom maternalunderlyingdiseaseand/ortheconcomitantuseof estab-lishedteratogenssuchascarbamazepinecannotnotberuledout. Newerandlargerstudieshavedemonstratednosuchassociation, andhaveestablishedthesafetyofcorticosteroiduseinpregnancy [101–103].Therefore,accordingtotheUnitedStatesFoodandDrug Administration,atpresentthereisnoevidencethateither pred-nisoneormethylprednisoloneisteratogenicinhumans(Foodand DrugAdministration[FDA]riskcategoryB).

Aside from steroid-associated complications that can be observed in all non-pregnant patients such as immunosup-pression, avascular necrosis of bone, osteopenia, hypertension, hyperglycemia,cataracts,andstriae,maternalpregnancy-speciﬁc complicationssuchasdevelopmentorworsening ofgestational diabetesandhypertensionmaycomplicatethecourseofpregnancy [104,105].

TheroutineuseoforalcalciumandvitaminDsupplementsis warrantedtopreventosteoporosis,especiallyinpatientstreated withsteroids[105,106].

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Patients who have been treated withcorticosteroids during pregnancyshouldbegiven“stressdoses”ofhydrocortisoneforany emergencysurgery, Caesareansection,or prolongedlabourand delivery.Neonates shouldbemonitoredforevidenceofadrenal insufﬁciencyandinfection.Womenwhochoosetobreastfeedwhile takinghighdosesofglucocorticoidscouldwait4hafteringesting adosetoresumebreastfeeding,astrategythatwilldecreasethe amountofglucocorticoidinmilk[107,108].

6.3. Azathioprine

Azathioprineis apparently not teratogenicin humans [109], althoughitsoncogenicriskraisesconcernsaboutitsusein preg-nancyandbreastfeeding[6,8].Azathioprinecrossestheplacenta, butthelackoffoetalenzymaticactivitycapableofconverting aza-thioprinetoitsactivemetabolitesseeminglyprotectsthefoetus fromanyteratogeniceffects of azathioprine earlyin pregnancy [105].Althoughthisdrughasbeenassociatedwithanincreased riskofgrowthretardation[110,111],theunderlyingcondition(e.g. hypertensioninrenaltransplantrecipients)mayhaveactuallybeen themajorcontributorinreportedcases.Ontheotherhand,there havebeenreportsofnormalpregnanciesandneonatesinpatients treatedwithazathioprineandprednisone[86,112,113].

Infantsexposedtoazathioprineinearlypregnancy(including pregnancies in organ transplant recipients) may be at a mod-erately increased risk of congenital malformations, speciﬁcally ventricular/atrialseptaldefects.Thereisalsoanincreasedriskof growthrestrictionandpretermdelivery,butitisnotclearisthese complicationscouldbepartlyduetotheseverityofmaternal ill-ness[114].Azathioprinehasbeenassociatedwithadose-related myelosuppressioninthefoetus,butleukopenia isnotusually a problemintheneonateifthematernalwhitebloodcountis main-tained at values higher than 7500mm−3 [115]. Because of the potentialforcarcinogenesisandtheunknownlong-termeffects offoetalimmunosuppression,useofazathioprineshouldbe with-heldifpossible;reductionoftheazathioprinedoseat32weeks’ gestationmay preventseriousneonatalleukopenia and throm-bocytopenia,whilecloseprenatalfoetalgrowthmonitoringand long-term post-natalevaluation of the offspring are warranted [115].

6.4. Mycophenolatemofetil

Mycophenolatemofetil(MMF),whichblocks denovopurine synthesis in T and B lymphocytes, has been associated with teratogenic risks including developmental toxicity, intrauterine death,andmalformationsatdoseswhichappearedtobewithin recommended clinicaldoses based onbody surface area [116]. Exposuretomycophenolatemofetilduring earlypregnancy has beenassociatedwithahigherincidenceofstructural malforma-tions.InthestudybySifontisandcollaborators[117],amongst33 pregnancieswithearlyexposuretoMMF(withTAC)indifferent organtransplantrecipients(includingpregnanciesin26kidney, 1kidney/pancreas,3liver,and3hearttransplantrecipients),15 resulted in spontaneousabortion, and malformations including hypoplasticnailsandshortenedfifthfingers,microtiawithcleft lipandpalate,isolatedmicrotia,andneonataldeathwith multi-plemalformationswerereportedin4/15livebirthsfromkidney transplantrecipients.Asaresultofthissignificantteratogenicrisk, theUnitedStatesFoodandDrugAdministrationhasissuedaboxed warningconcerningtheriskoffirsttrimesterfoetallossand con-genitalmalformations[118];thisdrugisnowclassifiedasUSFDA categoryDmedicationandshouldnotbeusedduringpregnancy [21,38].

6.5. Mammaliantargetofrapamycin(mTOR)inhibitors

Evidence is still scarce regarding the use of sirolimus and everolimusduringpregnancyafterLTandtheyarecontraindicated inpregnancy.Theyshouldalsobediscontinuedatleast12weeks prior toattemptedconception [119], switchingtoa calcineurin inhibitorforthedurationofpregnancy.Whenweighingtherisks forthefoetus,thereisstillagreatdealofambiguityaboutwhether sirolimusisintrinsicallyteratogenic,anditistherefore contraindi-catedforpregnancy(FDACategoryC).Actualevidenceofadverse effectsislacking,andtherehavebeennumerousreportsof suc-cessfulmaternalandfoetaloutcomesduringpregnanciesinwhich sirolimusoreverolimuswereused[19,118,120–123].

Although revision according to stricter evidence is ongoing [123],andconsideringthatintransplantrecipientsmanyfactors otherthanadirectteratogeniceffectarepresent,suchasvascular issues,directeffectsofmaternalconditionsandalsotheinteraction withotherpotentialpharmacologicalagents[124],currently,the followingistheofﬁcialPregnancyCategoryofimmunosuppressive drugs.(Datafrom[125])

Background

Thebeneﬁtsofimmunosuppressioninmaintainingadequate graft function outweigh thepossible risks associatedwith foetal exposure,and the goal is to use the minimal dose requiredtoavoidrejectionwhileminimizingfoetalexposure. Pregnancymayalterpharmacokineticsand pharmacodynam-ics of immunosuppressive drugs, and may determine the needfordoseadjustments.

6.a.Maintenance immunosuppressionwith corticosteroids and/orcalcineurininhibitorsmustbecontinued.(GradeII-2)

6.b.Mycophenolatemofetilandazathioprineare contraindi-catedduringpregnancyandmustbesuspendedatleast12 weeks before planned conception, substituting them with Pregnancy category B or C immunosuppressive agents. (GradeII-2)

6.c.Frequentmonitoringofplasmaticlevelsof immunosup-pressivemedicationsisrecommended.(GradeIII)

6.d.mTORinhibitorsshouldbewithhelduntilstrongerand unequivocalevidenceofsafetyisavailable.(GradeIII)

7. Post-partumandbreastfeeding

Maternal drug toxicity is more likely postpartum, as physi-ological changes of pregnancyregarding hematocrit, total body watercontentanddistributionreturntothepre-gestationalstage and foetal hepatic metabolism is no longer a contributor to pharmacodynamics and pharmacokinetics. Careful attention to immunosuppressive druglevels,cyclosporine and tacrolimusin particular, is warranted as maternal intravascular volume and glomerularhyperﬁltrationreturntonormal[19,38].

Breastfeeding is generally discouraged because of the pas-sageofimmunosuppressivedrugs,particularlycyclosporineand tacrolimus,tothebaby;however,theconsensusopinionof the AmericanSociety of Transplantation(AST)is thatbreastfeeding neednotbeviewedasabsolutelycontraindicated[38],and evi-dence is accumulating supporting safety of this practice [17], providedmonitoringofdruglevelsisperformedintheinfant.A reportonakidneytransplantrecipientoncyclosporine immuno-suppression demonstrated a breast milk cyclosporine 2-hour

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post-dose concentration of 49␮g/L and blood concentration in the infant shortly after breastfeeding which was undetectable (<10␮g/L) [126]. Anotherstudy of kidney and kidney/pancreas recipientstreatedwithcyclosporineshowedbreastmilk concen-trationsrangingfrom50to227ng/mLandwasbelowthedetection limitof30ng/mLinallbreastfedinfants,withnoadverseevents observed[127].Incontrast,measurablelevelsintheinfantmaybe asubstantialreasontodiscontinuebreastfeeding[128].The docu-mentedbeneﬁtsofbreastfeedingmayoutweighthepotentialrisks ofinfantimmunosuppressiveexposure[17,78].

Smallamountsofglucocorticoidscanbepresentinthebreast milkofwomen onsteroidtherapy;however,noadverseeffects have been reported,and theAmerican Academy of Paediatrics hasdeclared prednisone and prednisolonesafe and compatible withbreast-feeding[107].Specialattentionshouldbedevotedto diagnosing and treating postpartum depression, which may be exaggeratedbychronicsteroiduse[129,130].

Lowconcentrations ofazathioprinearefoundinbreastmilk, andnursingisnotrecommendedduetothelong-termpotentialof immunosuppressionandcarcinogenesis[107].Therearenodataon thesafetyofMMFandmTORinhibitorsregardingtheiruseduring breastfeeding.

Background

Althoughbreastfeedingisgenerallydiscouragedduetothe passageof immunosuppressivedrugsto theneonate, this practicemaybeconsideredinmothersreceiving corticoste-roids and/orcalcineurin inhibitors, upon demonstration of negligibleamountsofthedruginbreastmilk.

7.a.Breastfeedingisnotrecommended.(GradeIII)

7.b.BreastfeedingduringtherapywithmTORinhibitors, aza-thioprine,ormycophenolatemofetiliscontraindicated.(GIII)

Finalrecommendation:

ThecreationofanItalianNationalTransplantationPregnancy Registry, which fosters active, complete, and continuous centrereportingoncourseofpregnancies,useof immuno-suppressive therapies, and outcomes in liver transplant recipientsishighlyencouraged.(GradeIII)

Conﬂictofinterest

Nonedeclared.

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