Full
length
article
Incidence
of
toxoplasmosis
in
pregnancy
in
Campania:
A
population-based
study
on
screening,
treatment,
and
outcome
Vera
Donadono
a,
Gabriele
Saccone
a,
Giuseppe
Maria
Maruotti
a,
Vincenzo
Berghella
b,
Sonia
Migliorini
a,*
,
Giuseppina
Esposito
a,
Angelo
Sirico
a,
Salvatore
Tagliaferri
a,
Andrew
Ward
b,
Laura
Letizia
Mazzarelli
a,
Laura
Sarno
a,
Annalisa
Agangi
c,
Filomena
Quaglia
d,
Fulvio
Zullo
a,
Pasquale
Martinelli
aaDepartmentofNeuroscience,ReproductiveSciencesandDentistry,SchoolofMedicine,UniversityofNaplesFedericoII,Naples,Italy b
DivisionofMaternal-FetalMedicine,DepartmentofObstetricsandGynecology,SidneyKimmelMedicalCollegeofThomasJeffersonUniversity,Philadelphia, PA,USA
c
VillaBetaniaHospital,DepartmentofObstetricsandGynecology,Naples,Italy
d
G.RummoHospital,DepartmentofObstetricsandGynecology,Benevento,Italy
ARTICLE INFO
Articlehistory: Received10May2019
Receivedinrevisedform10July2019 Accepted24July2019 Availableonlinexxx Keywords: Toxoplasmosis Pregnancy Avidity Congenitaltoxoplasmosis Seroconversion ABSTRACT
Introduction:Theaimofthisstudywastoevaluatetheincidenceoftoxoplasmosisinfectionduring
pregnancyandtodescribethecharacteristicsoftheserological status,management,follow-upand
treatment.
Material and methods: This is a population-based cohort studyof women referred forsuspected
toxoplasmosisduringpregnancyfromJanuary,2001toDecember,2012.Suspectedtoxoplasmosiswas
defined aspositiveIgM antibodyduring pregnancy. Womenwith suspected toxoplasmosisduring
pregnancywereclassifiedintothreegroups:seroconversion,suspectedinfection,ornoinfectionin
pregnancy. Women in the first and second group were treated according to local protocol,and
amniocentesiswithtoxoplasmosisPCRdetectionandserialdetailedultrasoundscanswereoffered.
Neonateswereinvestigatedforcongenitaltoxoplasmosisatbirthandweremonitoredforatleastone
yearafterbirth.
Results:Duringthestudyperiod,therewere738,588deliveriesinCampania.Ofthem1159(0.2%)were
referredtoourInstitutionforsuspectedtoxoplasmosisduringpregnancy:183(15.8%)womenwere
classifiedasseroconversion,381(32.9%)weresuspectedinfection,and595(51.3%)werenotinfectedin
pregnancy.Neonataloutcomewasavailablefor476pregnancies,including479neonates(3twins,473
singletons),outofthe564pregnancieswithseroconversionorsuspectedinfection.384(80.2%)babies
werenotinfectedatbirthandatfollow-up,67(14.0%)hadcongenitaltoxoplasmosis,10(2.1%)were
voluntaryinducedterminationofpregnancy,15(3.1%)werespontaneousmiscarriage,and4(0.8%)were
stillbirth (of which one counted already in the infected cohort). Consideringcases of congenital
toxoplasmosis,thetransmissionrateinwomenwithseroconversionwas32.9%(52/158),andinwomen
withsuspectedinfectionwas4.7%(15/321).
Conclusions:Toxoplasmosisisuncommoninpregnancywithoverallincidenceofseroconversionand
suspectedinfectioninpregnancyof0.8per1000livebirthsandincidenceofcongenitaltoxoplasmosis0.1
per1000livebirthswhenapplyingastrictprotocolofscreening,follow-up,andtreatment.51.3%(595/
1159)ofwomenreferredtoourcenterforsuspectedinfectionwereactuallyconsiderednotinfected.
©2019PublishedbyElsevierB.V.
Introduction
Toxoplasmosis is one of the commonworldwide parasitic zoonosis caused by the intracellular protozoon Toxoplasma gondii. Maternal primary infection may cause congenital toxoplasmosis when acquired during pregnancy, because of thetransplacentalpassageoftheparasite[1].Theinfectionin
Abbreviation:VTP,voluntaryterminationofpregnancy. *Correspondingauthor.
E-mailaddress:[email protected](S.Migliorini).
https://doi.org/10.1016/j.ejogrb.2019.07.033
0301-2115/©2019PublishedbyElsevierB.V.
ContentslistsavailableatScienceDirect
European
Journal
of
Obstetrics
&
Gynecology
and
Reproductive
Biology
thefetuscancausemiscarriage,stillbirth,intrauterinegrowth restriction, ocular and central nervous system abnormalities withauditory andvisualdisorders, andmentalretardationin theinfant[1,2].Verticaltransmissionincreaseswithgestational age, while the severity of the symptoms in the fetus are inverselyrelated[3].
Diagnosis of maternal infectionalmost completely relies on serologicalfindingsincludingIgM,IgG,andIgGAvidity. Serocon-versionisdemonstratedwhenIgMandIgGfromnegativebecome positivewithbothsamplestakenafterconception[4].
Theseroprevalenceoftheinfectioninwomeninchildbearing ageinItalyisconsideredtohavedeceasedoverthelast30years.It wasestimated48.5%inthe1991[5],21.5%inthe2005[6]and, recently, 22.3% in the2011 [7]. On theother hand the risk of congenitaltoxoplasmosisincaseofmaternalinfectioncanbeas highas70%inthethirdtrimester[3],thereforetheeffectivenessof apolicyofuniversalscreeningfortoxoplasmosisinfectionduring pregnancyisstillsubjectofdebate[8].
Objective
The aim of this study was to evaluate the incidence of toxoplasmosisinfectionduringpregnancyinapopulation-based cohortstudy,andtodescribethecharacteristicsoftheserological status,management,follow-upandtreatment.
Materialandmethods Studydesign
Thisisapopulation-basedcohortstudyofwomencounselled forsuspectedtoxoplasmosisinfectionduringpregnancybetween January,2001andDecember,2012inCampania,Italy.
In Italy,allpregnant womenare screenedfor toxoplasmosis duringpregnancywithIgGandIgMantibodyatthefirstvisitand,if bothnegative,everymonthuntildelivery.InCampania,Italy,all womenwhowerefoundtohavepositiveIgMantibodyarereferred for counselling and further evaluation at University of Naples FedericoII,Naples,Italy.
Atthefirstcounsellingvisit,womenundergosamplesforIgG andIgMantibodiesandIgGavidityatourreferencelaboratoryat Universityof NaplesFederico II, analyzedby enzyme immuno-assays(EIAS).Theresultswereexpressedininternationalunitsper ml(IU/ml).IgMantibodieswereconsiderateasnegativeif<0.55, borderlineifincludedbetween0.55and0.65,andpositiveif>0.65. IgG antibodieswere consideredas negativeif <4,borderline if includedbetween 4 and 8, and positive if >8. IgG avidity was consideredaslow if<0.200, intermediateifbetween0.200and 0.300,andhighif>0.300.
Womenwerethereforeclassifiedintothreegroupsaccordingto antibodystatus:
1Group1:Seroconversion.
OneormoresamplestakenwithIgG-/IgM-followedbyanother samplewithIgG+/IgM+.Thetimeofseroconversion(first,second, orthirdtrimester)wascalculatedasthemidpointbetweenthelast IgG-/IgM-, and first IgM+/IgG+test or 14 days before the first IgM+ifIgG-test[3].
2Group2:Suspectedinfection:
IgG+/IgM+at firstsampletakenin pregnancy.Thissubsetof womenwasfurtherclassifiedaccordingtotheIgGavidityresults (low,intermediate,andhighavidity).WomenwithIgG+/IgM+at firstsampletakeninpregnancybutwithhighaviditybefore12
weeks were excluded from this group and were classified in Group3.
3Group3:Noinfectioninpregnancy: Susceptible:
IgG-/IgM-Past infection: IgG+/IgM- and/or maternal preconception seropositivesample
PersistentIgMantibodies:IgM+withoutappearanceofIgG IgG+/IgM+atfirstsampletakeninpregnancywithhighavidity before12weeks
Maternalmanagementandfollow-up
Womeningroup3weredischargedfromfollow-up.
Womeninthefirstandsecondgroupweretreatedaccordingto a local protocol.Amniocentesisfor thepresenceof Toxoplasma DNAbypolymerasechainreaction(PCR)wasofferedstartingfrom 200/7weeksanduntil236/7weeksofgestation,atleastafter6 weeksfollowingseroconversionincaseofgroup1woman,andin selectedcasesincaseofgroup2.Womenwerealsooffereddetailed ultrasoundscanevery4weeksafterroutineanatomyscan,inorder tolookforultrasoundsignssuggestiveoffetalinfection(i.e.fetal abnormalitiesincludingventriculomegaly,brainorhepatic calci-fications,cataract,hepatosplenomegaly,ascites,severeIUGR)[9].
Localprotocolincluded:
-Amniocentesispositive regardlessofthegroup:pyrimethamine (50mgevery12hfor2days,then50mgdaily)withsulfadiazine (75mg/kgfollowedby50mg/kgevery12h,respectingamaximum of4g/day),andfolinicacid(10–20mgdaily)until38weeks. -Amniocentesis negative regardless of the group: Spiramycin
3000IUevery8huntildelivery.
-Amniocentesis not performed:Spiramycin 3000IU every8h untildeliveryincaseofgroup2women;pyrimethamine(50mg every 12h for 2 days, then 50mg daily) with sulfadiazine (75mg/kg followed by 50mg/kg every 12h, respecting a maximum of4g/day),and folinicacid(10–20mgdaily)from 22weeksuntil38weeks,incaseofgroup1women.
-Ultrasound signs of infection regardless of the group and regardlessoftheamniocentesisresult:pyrimethamine(50mg every 12h for 2 days, then 50mg daily) with sulfadiazine (75mg/kg followed by 50mg/kg every 12h, respecting a maximum of4g/day),and folinicacid(10–20mg daily)until 38weeks.
Neonatalmanagementandfollow-up
Allbabiesbornfromwomeningroup1and2werefollowedby a team of selectedpediatricians. Theprotocolfor neonatal and children surveillance offered in our center has already been described in a previous report [10]. In summary, babies were consideredinfectedincaseofpresenceofIgGantibodiesbeyond age12monthswithoutspecifictreatment.
Statisticalanalysis
StatisticalanalysiswasperformedusingStatisticalPackagefor SocialSciences(SPSS)v.19.0(IBMInc.,Armonk,NY,USA).
Data are shown as means, or as number (percentage). Univariate comparisons of dichotomous data were performed with theuse of the chi-square test with continuitycorrection. Comparisonsbetweengroupswereperformedwiththeuseofthe t-test to test group means by assuming equal within-group variances.Oddsratio(OR)with95%confidenceinterval(CI)was
calculated. A 2-sided P value less than 0.05 was considered significant.
Positive and negative likelihood ratio and sensibility and specificityofultrasoundandamniocentesiswerealsocalculated
This study was reported following the Strengthening The ReportingofObservationalstudiesinEpidemiologyguidelines[11]. Results
Populationcharacteristics
During the study period, there were 738,588 deliveries in Campania. Of them 1159 (0.2%) were referred to University of Naplesforsuspectedtoxoplasmosisduringpregnancy,definedas positiveIgMantibodyduringpregnancy.Afterconfirmedsamplein ourreferencelaboratory,183(15.8%)women wereclassifiedas seroconversions,381(32.9%) were suspectedinfection and 595 (51.3%)werenotinfectedinpregnancy(Fig.1).
Outofthe183womenwithseroconversion,79(43.2%) were first-trimesterseroconversion,88(48.1%)second-trimester,and16
(8.7%) third-trimester. Out of the 381women classified in the Group2:220(57.7%)hadlowavidity,161(42.3%)hadintermediate avidityorhighavidityafter12weeks.
Finally,outofthe595womenclassifiedingroup3:18(3.0%) weresusceptible,120(20.2%)werepastinfection,27(4.5%)were persistentIgM,and430(72.3%)werehighaviditybefore12weeks. 51.3%(595/1159)ofwomen(Group3)referredtoourcenterfor suspectedinfectionwerethereforeconsideredasnotinfectedin pregnancyafteranalysisofserologyinpreviouspregnancies,when available,andconfirmedsampleinourreferencelaboratory,and werethereforedischargedwithnofurtherfollow-up.
In the remaining 564 women (Group 1 and Group 2), amniocentesis was performed in 256 (45.4%) cases. 47 (18.4%) caseswerepositive.
Managementandfollow-up
All women in group 1 and 2 received treatment during pregnancy. 75% (423/564) of the women received prophylaxis with spiramycin, 3.5% (20/564) received treatment with
pyrimethamine and sulfadiazine, 21.3% (120/564) received first spiramycinfollowedbypyrimethamineandsulfadiazine,andone patientrefusedthetreatmentatallbecauseintendedtoterminate thepregnancy.
Ultrasoundfollow-upwasperformedinall183womenofgroup 1andthose381ofgroup2(Fig.1).Themostcommonultrasound signsuggestiveofcongenitaltoxoplasmosiswasventriculomegaly, presentin4(2.2%)fetusesofgroup1andin3(0.8%)ofgroup2. Neonataloutcomes
Neonataloutcomewasavailablefor476pregnancies,including 479neonates(3twins,473singletons),outofthe564pregnancies withseroconversion or suspectedinfection. 384(80.2%) babies were not infected at birth and at follow-up, 67 (14.0%) had congenital toxoplasmosis, 10 (2.1%) were voluntary induced terminationofpregnancy,15(3.1%)werespontaneousmiscarriage, and4(0.8%)werestillbirth(ofwhichonecountedalreadyinthe infectedcohort).
Pregnancieswithadverseoutcome
Characteristics of pregnancies ended withadverse outcome, includingvoluntaryterminationofpregnancy,miscarriageandstill birth are shown in Table 1. Ultrasound signs suggestive of congenital toxoplasmosis in infected and not infected fetuses areshowninTable2.
10.4%of thefetuses withof congenitaltoxoplasmosis hadat leastoneultrasoundsignsuggestiveofinfectioncomparedwith 1.6%notinfected fetuses(p value0.001,OR7.4,CI 2.4 to22.6). Fetuseswithcongenitaltoxoplasmosishadstatisticallysignificant higher risk of having brain calcification, ventriculomegaly, hepatosplenomegaly, hepatic calcification compared to not infectedfetuses(Table2).
Sensitivityandspecificityofultrasoundandofamniocentesis Overall positive and negative likelihood ratio of ultrasound wererespectively5.7(95%CI1.9to17.2)and0.9(95%CI0.9to1), sensitivitywas9%andspecificitywas98.4%.Furthermore,positive andnegativelikelihoodratioofamniocentesiswererespectively 11.9(95%CI7to10.1)and0.2(95%CI0.1to1.4),sensitivitywas 86.2%andspecificitywas92.8%.
Prevalenceoftoxoplasmosis
Considering cases of congenital toxoplasmosis, 52 children werebornfromwomeningroup1resultinginatransmissionrate of32.9%;17.6%(12/68)ofchildrenhadcongenitaltoxoplasmosisin caseofseroconversioninthefirsttrimester,40.5%(32/79)inthe second trimester and 53.3% (8/15) in the third trimester. The remaining15childrenwerebornfromwomeningroup2witha transmissionrateof4.7%.
Considering the738,588deliveriesinCampaniafromJanuary 2001toDecember2012,theoverallincidenceofseroconversionand suspectedinfectioninpregnancywas0.8per1000livebirthsand incidenceofcongenitaltoxoplasmosiswas0.1per1000livebirths. Discussion
Mainfindings
Ourstudyshowedthat51.3%(595/1159)ofwomenreferredfor suspectedtoxoplasmosis duringpregnancywereconsiderednot infected afteranalysis ofserologyin previouspregnancies, and confirmatorytestatreferencelaboratory.Thesedatahighlighted theimportancetostandardizetechniquesandtestsfor toxoplas-mosisinthelaboratories,andalsotheneedtoreferthesecasesto centralizedcentreswheretherearetraineddoctorsinthisspecific fieldforfurtherevaluationandcounselling.Thereasonforthisis
Table1
Characteristicsofpregnanciesendedwithadverseoutcomeincludingvoluntaryterminationofpregnancy(VTP),miscarriage,andstillbirth.
Total Group Amniopositive/
totamnio
Ultrasoundsignpresent/totultrasound
VTP 10 3(30) 7(70) Group1 Group2 3seroconversionItrim 0 0/11 Miscarriage 15 2 (13.3) 13 (86.7) Group1 Group2 2seroconversionItrim 1/2(50%) 0/16
Stillbirth 4 3(75) Group1 1seroconversionItrim,1seroconversionIItrim,1 seroconversionIIItrim
1/2(50%) 1/4(25%)brainandhepaticcalcifications, hepatosplenomegaly,ventriculomegaly 1(25) Group2
Table2
Ultrasoundsignssuggestiveofcongenitaltoxoplasmosisininfectedandnotinfectedfetuses.
Infected Notinfected Tot Pvalue OR(CI)
67(16.5) 384(83.5) 451
AtleastoneUSsign 7(10.4) 6(1.6) 13 0.001 7.4(2.4to22.6)
Braincalcification 3(4.5) 0(0) 3(0.7) 0.003 Ventriculomegaly 4(6) 3(0.8) 7(1.6) 0.011 8.1(1.8to38.9) Cataract 0 1(0.3) 1(0.2) 0.851 hepatosplenomegaly 2(3) 0 2(0.4) 0.022 Ascites 1(1.5) 0 1(0.2) 0.149 Hepaticcalcification 2(3) 0 2(0.4) 0.022 IUGR 2(3) 2(0.5) 4(0.9) 0.107 5.1(0.8to42.5)
IUGR,intrauterinegrowthrestriction;US,ultrasound;OR,oddsratio;CI,confidenceinterval. Datapresentedasnumber(percentage).
thatincasesotherthanseroconversion,wherethediagnosisof maternalinfectioninpregnancyisuncertain,isdifficulttoquantify theriskoffetaladverseoutcome.Thismayleadtounnecessary tests,andcouple anxietyassociated withuncertaintyonbaby’s prognosisthat can induce unnecessary interventions including terminationofpregnancy[12,13].
Nowadays the ability to identify toxoplasmosis infection is primarilybasedonserologicalassay(detectionofIgM,IgG,andIgG avidity).ConsistentlypresenceofIgMantibodiesarea transient markerofrecentacuteinfection,howevertheymaypersistfora longerperiodoftime[14].Ontheotherhandthehighaviditytest canhelpconfirmchronicinfections,butloworintermediatelevels donotconfirma recentinfectionbecausetheycanpersistfora longertime[14–17].
In our cohort we identified 183 women with documented seroconversion in pregnancy and 381 women with suspected infectioninpregnancyduetopresenceofbothIgMandIgGandlow orintermediateavidityorhighavidityafter12weeks.
Ultrasoundfollowupwas extensivelyperformedinallthese pregnancies,butsignsofinfectionwereuncommon.Only7(10.4%) fetuseswithcongenitaltoxoplasmosishadatleastoneultrasound signsuggestiveofinfection.Manderlbrotetal.documentedsimilar result,theyreportedonlycerebralultrasound signsofinfection whichwerepresentin4.2%offetuseswithcongenital toxoplas-mosis[18].Inourcohortwhenultrasoundsignsofinfectionwere detected, 57.1% of women were undergoing treatment with spiramycinand42.9%withpyrimethamineandsulfadiazine.
256amniocentesiswereperformed,withsensitivityof86.2% andspecificityof 92.8%.In otherstudieswasreporteda higher sensitivityandspecificitycloseto100%[19,20].Thisdiscordancein theresultcouldbeexplainedbyworstqualitycontrolinlaboratory performance, a reduction of parasite load due to maternal treatmentordelayedintransmission.
Therateoftransmissionwasoverall32.9%(52/158)inwomen with documented seroconversion in pregnancy. The rate of congenitaltoxoplasmosisincreased comparing thetrimesterof seroconversion,accordingtoliterature[3],subdividedas:17.6% (12/68) of children had congenital toxoplasmosis in case of seroconversioninthefirsttrimester,40.5%(32/79)inthesecond trimesterand53.3%(8/15)inthethird.Theremaining15children werebornfromwomenwithsuspectedinfectioninpregnancy withatransmissionrateof4.7%.Rateofcongenitaltoxoplasmosis in women with suspected infection has been recently docu-mentedtobeashighas56%byAvelinoetat.[21],andmuchlower as0.8–4.8%inotherstudiesinwomenwithIgM+/IgG+andlow avidity [22,23]. This wide difference in rate of congenital toxoplasmosiscould beexplained bypoor antenatalscreening withdelayin first trimesterscreening inthe studyby Avelino etal. Thisdifference in rateof congenitaltoxoplasmosiswhen comparing women with seroconversion with women with suspectedinfectionin pregnancy highlights theimportance of propercounsellingoftheparentsandstrategyofmanagementof thepregnancyaccordingtotherisk.Todate,manystudiesarenot clearaboutcasedefinitionandtenttoevaluateseroconversion togetherwithcaseswithsuspectedinfectioninpregnancy[23– 30]. A direct comparison between studies is rather difficult, because of different screening programs for toxoplasmosis, differenttreatmentschemesandriskgroupsanalyzed.
Themostimportantlimitationofourstudyistheretrospective approach. We do acknowledge that several biases may be highlightedduetothestudydesign.Womenpositiveto toxoplas-mosisinpregnancycouldbenotreferredtoourinstitution.Women couldbenotscreenedduringpregnancy.Onlyonefetusamongthose withinducedterminationofpregnancy,miscarriageandstillbirth caseswastestedfortoxoplasmosisinfection.Pregnancyoutcomes wereavailableforonly476pregnancies.
Conclusion
Inconclusion,50%ofwomenreferredforsuspected toxoplas-mosis during pregnancy were considered not infected in pregnancyafter appropriate analysisof serology.The incidence ofcongenitaltoxoplasmosiswasaslowas0.1per1000livebirths. The incidence of congenital toxoplasmosis was statistically significant higher in women with seroconversioncompared to those withsuspected infection,respectively32.9%(52/158)and 4.7%(15/321).Thesefindingsshouldquestionaboutbenefitsand cost-effectivenessofuniversalscreeningpolicyfortoxoplasmosis inpregnancy.
Funding
Nofinancialsupportwasreceivedforthisstudy. DeclarationofCompetingInterest
Theauthorsreportnoconflictofinterest. References
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