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1 This publiction ws rscdd by Ntionl Hlth Mdicl Rsrch Council on 9/9/2005 is vilbl on th ntrnt ONLY for hisricl purposs. mportnt Notic This notic is not b rsd must b cludd on ny prtd vrsion this publiction. This publiction ws rscdd by th Ntionl Hlth Mdicl Rsrch Council on 9/9/2005. Th Ntionl Hlth Mdicl Rsrch Council hs md this publiction vilbl on its ntrnt Archivs sit s srvic th public for hisricl rsrch purposs ONLY. Rscdd publictions r publictions tht no longr rprsnt th Council s position on th mttrs contd thr. This mns tht th Council no longr ndorss, supports or pprovs ths rscdd publictions. Th Ntionl Hlth Mdicl Rsrch Council givs no ssurnc s th ccurcy or rlvnc ny th formtion contd this rscdd publiction. Th Ntionl Hlth Mdicl Rsrch Council ssums no lgl libility or rsponsibility for rrors or omissions contd with this rscdd publiction for ny loss or dmg currd s rsult rlinc on this publiction. Evry usr this rscdd publiction cknowldgs tht th formtion contd it my not b ccurt, complt or rlvnc th usr s purposs. Th usr undrtks th rsponsibility for ssssg th ccurcy, compltnss rlvnc th contnts this rscdd publiction, cludg skg dpndnt vrifiction formtion sought b rlid upon for th usr s purposs. Evry usr this rscdd publiction is rsponsibl for nsurg tht ch prtd vrsion conts this disclimr notic, cludg th dt rcision th dt downlodg th rchivd ntrnt vrsion.

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3 Guidls on th prophylctic us Rh D immunoglobul (Anti-D) obsttrics Endorsd 22 Mrch 1999 i

4 Commonwlth Austrli 1999 SBN This work is copyright. Aprt from ny us s prmittd undr th Copyright Act 1968, no prt my b rproducd by ny procss without prmission from Ausnfo. Rqusts nquiris concrng rproduction rights should b ddrssd th Mngr, Lgisltiv Srvics, Ausnfo, GPO Box 1920, Cnbrr ACT Th strtgic tnt th Ntionl Hlth Mdicl Rsrch Council (NHMRC) is work with othrs for th hlth ll Austrlins, by promotg formd dbt on thics policy, providg knowldg-bsd dvic, fostrg high qulity trntionlly rcognisd rsrch bs, pplyg rsrch rigour hlth issus. Th documnt is sold through Ausnfo t pric which covrs th cost prtg distribution only. NHMRC documnts r prprd by pnls xprts drwn from pproprit Austrlin cdmic, prssionl, community govrnmnt orgnistions. NHMRC is grtful ths popl for th xcllnt work thy do on its bhlf. This work is usully prformd on n honorry bsis ddition thir usul work commitmnts. ii

5 CONTENTS EXECUTVE SUMMARY... 1 SUMMARY OF GUDELNES... 4 NTRODUCTON... 7 Chptr 1 BACKGROUND Purpos nti-d obsttrics ncidnc Rh D comptibility Th Rh Projct Austrli Rsons for th currnt shortg nti-d Chptr 2 CURRENT AVALABLTY AND USE OF ANT-D N AUSTRALA Currnt vilbility Currnt dm Currnt prctic Chptr 3 BEST PRACTCE FOR THE USE OF ANT-D N OBSTETRCS Postprtum us nti-d Anti-D for ntntl snsitisg vnts Rout ntntl us nti-d Chptr 4 COSTS AND COST EFFECTVENESS OF ANT-D USE Dt Rsults Conclusions Chptr 5 RATONALE FOR GUDELNE RECOMMENDATONS Chptr 6 STRATEGES TO MANTAN AND NCREASE ANT-D SUPPLES Promotg ffict us nti-d Scurg futur supply nti-d iii

6 CONTENTS APPENDCES 1 Mmbrship trms rfrnc th Workg Prty Th guidl dvlopmnt procss Communiction strtgy Evlution monirg strtgy Litrtur rviw srch strtgy tbls rsults Cost-ffctivnss nlysis ACRONYMS AND ABBREVATONS GLOSSARY BBLOGRAPHY iv

7 EXECUTVE SUMMARY Bckground Th discovry, troduction utilistion Rh D immunoglobul (nti-d) for prophylxis gst hmolytic diss th nwborn hs bn on th mjor mdicl chivmnts th pst hlf cntury. This condition is cusd by Rh blood group comptibility btwn womn hr bby, ldg th isoimmunistion (snsitistion) womn with Rh D ngtiv blood gst Rh D positiv blood. t ws prviously mjor cus prtl mortlity, morbidity, long-trm disbility mntl hicp, ssocitd motionl hlth costs wr high. n th 1960s, it ws dmonstrtd tht dmistrtion Rh D immunoglobul (nti-d) Rh D ngtiv mothrs soon ftr th dlivry Rh D positiv bbis drmticlly rducd th cidnc immunistion. A mchnism for producg Rh D immunoglobul Austrli ws thn sought,, 1968, Austrli bcm th first country th world b slf-suffict Rh D immunoglobul. Howvr, for vrity rsons both with Austrli worldwid, ntibody lvls hv dcld, rcnt yrs thr hs bn suffict nti-d mt Austrlin rquirmnts. Whil th rcruitmnt boostg progrm is still undrwy ntionl production nti-d hs crsd, thr r contug difficultis rctifyg th shortfll mtg th crsd supply. n 1997, th Ntionl Hlth Mdicl Rsrch Council ppotd Workg Prty dvlop guidls which blnc bst prctic th us Rh D immunoglobul with limitd supply. Ths guidls r tndd covr th two yrs from thir publiction, ddrss th priod constrt btwn now futur slf-sufficcy nti-d. Currnt us nti-d Postprtum dmistrtion nti-d ll Rh D ngtiv mothrs with Rh D positiv bbis no prformd nti-d is strd prctic Austrli most prts th world, lthough th dos usd vris btwn countris. Anti-D is usully givn womn durg prgnncy if thy xprc snsitisg vnt which thr is risk ftl blood crossg th mtrnl circultion. Ths clud miscrrig, trmtion prgnncy, cpic prgnncy, gntic studis such s mniocntsis chorionic villus smplg, xtrnl cphlic vrsion, trum ntprtum hmorrhg. Thr r conflictg viws bout th fficcy rout prophylctic us nti-d ntntlly. This hs rsultd consistncis th wy tht nti-d is 1

8 usd prophylcticlly. Th sitution is complictd by th currnt rstrictd supply nti-d, s rout ntntl dmistrtion ll Rh D ngtiv womn would plc immns dms on nti-d supply. Bst prctic for th us nti-d obsttrics Th Workg Prty commissiond rviw th vilbl vidnc rltg th ffctivnss th prophylctic us nti-d obsttrics, rviw th cost ffctivnss nti-d for numbr pplictions. Thr is vry strong vidnc tht th us nti-d postprtum is both ffctiv cost ffctiv. Thr is littl high lvl vidnc supportg th us nti-d ntntlly, but th rsults both rviws support th fficcy cost ffctivnss nti-d for ntntl snsitisg vnts ntntl prophylxis. Thr is no vidnc dvrs ffcts from th dmistrtion nti-d. Howvr, it is blood product this should b clr vrbl writtn formtion givn ptts. Strtgis crs mt nti-d supplis Givn tht th vidnc from th sctific litrtur cost-ffctivnss nlysis supports th crsd us nti-d prvnt Rh D isoimmunistion, th Workg Prty considrs it vitl tht thr is rpid dvlopmnt implmnttion short long-trm strtgis promot th most ffict us xistg supply idntify sustbl mthod crsg supply mt dm. Th m strtgis which could b implmntd improv th fficcy nti-d us clud: us mi-dos nti-d for potntilly snsitisg vnts th first trimstr, lthough it is unlikly tht such dos will b rgistrd th short trm; crsd mor ccurt us tsts ssss th mount fmtrnl hmorrhg; crsd complinc with guidls on nti-d us, supportd by thorough duction ll rs whr nti-d is usd qulity ssurnc progrm for mtnnc th guidls. Scurg futur supply nti-d Whil th sourc nti-d rms blood plsm, th only mchnism crs production will rly on xpg th collction nti-d from humn donors. n Austrli, thr hs bn no cs rportd virl trnsmission from th dmistrtion trmusculr immunoglobul cludg Rh D immunoglobul. 2

9 n ddition, no Rh Projct donor hs bcom fctd s rsult boostg with rd clls from othr donors. Howvr, thr r numbr thicl considrtions ssocitd with th us blood blood products, for both donors rcipts. Approprit procdurs for providg formtion potntil donors obtg thir voluntry consnt should b plc. Thr should b full disclosur formtion on known risks th likly dgr unknown risks, suffict tim llowd for potntil donors considr prticiption, with th opportunity obt furthr dpndnt dvic or counsllg rltion volvmnt. n ordr provid nti-d ll Rh D ngtiv womn who could bnfit from it, fforts crs th numbr donors rcruitd th Rh Projct will contu. Thr is likly b furthr xplortion ltrntiv mthods crsg supply such s rtroduction primry immunistion, th rcruitmnt womn with high lvls nti-d, crsd dontion by plsmphrsis. Howvr, constrts such s low numbrs dividuls willg b boostd or immunisd dont rgulrly, dmnity issus, prclud succss th short trm. As n trim msur whil ths issus r bg rsolvd, considrtion should b givn th rgistrtion import ovrss products, llow rlir troduction ntntl prophylxis. 3

10 SUMMARY OF GUDELNES 1 Gnrl For succssful immunoprophylxis, Rh D immunoglobul should b dmistrd s soon s possibl ftr th snsitisg vnt, but lwys with 72 hours. f Rh D immunoglobul hs not bn frd with 72 hours, dos frd with up 9 10 dys my provid protction. Blood should b tkn from th mothr bfor dmistrtion th Rh D immunoglobul ssss th mgnitud fmtrnl hmorrhg. 2 Postprtum dmistrtion A dos 125 µg (625 U) Rh D immunoglobul should b frd vry Rh D ngtiv womn followg dlivry Rh D positiv bby. Rh D immunoglobul should not b givn womn with prformd nti-d ntibodis, xcpt whr th prformd nti-d is du th ntntl dmistrtion Rh D immunoglobul. Th mgnitud th fmtrnl hmorrhg should b ssssd by mthod cpbl quntifyg hmorrhg 6 ml ftl rd clls (12 ml whol blood). Furthr doss should b dmistrd suffict prvnt mtrnl immunistion. 3 Antntl dmistrtion for potntilly snsitisg vnts First trimstr A dos 50 µg (250 U) Rh D immunoglobul should b frd vry Rh D ngtiv womn with no prformd nti-d ntibodis nsur dqut protction gst immunistion for th followg dictions up cludg 12 wks gsttion: miscrrig; trmtion prgnncy; cpic prgnncy; chorionic villus smplg. A dos 50 µg Rh D immunoglobul is suffict prvnt immunistion by fmtrnl hmorrhg 2.5 ml ftl rd clls (5 ml whol blood). Until 50 µg Rh D immunoglobul vil bcoms vilbl Austrli, 125 µg Rh D immunoglobul should b usd. Th Workg Prty strongly rcommnds tht womn undrgog trmtion prgnncy b tstd dtrm thir Rh D typ, void unncssry us Rh D immunoglobul. 4

11 Byond th first trimstr A dos 125 µg Rh D immunoglobul should b frd vry Rh D ngtiv womn with no prformd nti-d ntibodis nsur dqut protction gst immunistion for th followg dictions ftr 12 wks gsttion: gntic studis (chorionic villus smplg, mniocntsis cordocntsis); bdoml trum considrd suffict cus fmtrnl hmorrhg; ch occsion rvld or concld ntprtum hmorrhg (whr th ptt suffrs unxpld utr p th possibility concld ntprtum hmorrhg should b considrd, with viw immunoprophylxis); xtrnl cphlic vrsion (prformd or ttmptd). As vidnc for th fficcy this dos for ths dictions is not vilbl, it is rcommndd tht th mgnitud fmtrnl hmorrhg b ssssd furthr doss dmistrd s for (2), spcilly whr trnsplcntl ccss or punctur ftl blood vssls occurs. 4 Antntl prophylxis Univrsl prophylxis with Rh D immunoglobul Rh D ngtiv womn with no prformd nti-d ntibodis t wks gsttion is gnrlly rgrdd s bst prctic. Howvr, du supply constrts, rout ntntl prophylxis should not b dmistrd until furthr notic. t is notd tht th constrts on supply my ltr th forsbl futur. Thrfor, th bov rcommndtion should b rviwd on rgulr bsis by th Ntionl Hlth Mdicl Rsrch Council mndd ccordg th vilbility supplis Rh D immunoglobul xistg t th tim. 5

12 NTRODUCTON Th discovry, troduction utilistion Rh D immunoglobul (nti-d) 1 for prophylxis gst hmolytic diss th nwborn (HDN) hs bn on th mjor mdicl chivmnts th pst hlf cntury. This condition is cusd by Rh blood group comptibility btwn womn hr bby, ldg th isoimmunistion womn with Rh D ngtiv blood gst Rh D positiv blood. t ws prviously mjor cus prtl mortlity, morbidity, long-trm disbility mntl hicp, th ssocitd motionl hlth costs wr high. Rh D immunoglobul cn b usd prvnt isoimmunistion th possibility HDN occurrg subsqunt prgnncy through dmistrtion: Rh D ngtiv womn with no prformd ntibodis soon ftr dlivry Rh D positiv fnt; durg prgnncy, for potntilly snsitisg vnt such s miscrrig, cpic prgnncy, mniocntsis or bdoml trum; routly durg prgnncy, usully t wks gsttion, Rh D ngtiv womn with no prformd ntibodis. Th ffctivnss cost ffctivnss ths strtgis for prvntg isoimmunistion r discussd this rport. Howvr, bcus nti-d cn only b drivd from humn plsm, thr r numbr issus ssocitd with its supply vilbility tht must b considrd long with gold strd usg idntifid through th sctific litrtur. n Austrli, btwn , supplis nti-d dcld th xtnt tht spcific rmdil ction ws rquird void significnt numbrs womn bg xposd th risk immunistion. Du th shortg loclly mnufcturd product, n ltrntiv product ws importd from th Unitd Stts btwn 1994 August An tnsiv ffort by th blood bnks CSL 2 is skg crs locl supply so tht Austrli cn rg slf-sufficcy nti-d with two yrs, but thr r contug difficultis mtg dm. Until slf-sufficcy is rchd, issus concrng th most ffctiv us limitd nti-d supplis must b considrd crfully. n 1996, th Ntionl Hlth Mdicl Rsrch Council (NHMRC) publishd guidls for th us Rh D immunoglobul (nti-d) obsttrics (NHMRC 1996). Whil ths guidls r gnrlly ccptd s rprsntg bst prctic for th us nti-d obsttrics, it is thought tht thir uniform implmnttion 1 n this rport, th trms Rh D immunoglobul nti-d r usd trchngbly. 2 Formrly known s th Commonwlth Srum Lborris. 7

13 could hv svr implictions for nti-d supplis. For this rson, th NHMRC dcidd issu updtd guidls which blnc bst prctic with limitd supply. Ths guidls r tndd covr th two yrs from thir publiction only, ddrss th priod constrt btwn now futur slfsufficcy nti-d. n 1997 th NHMRC ppotd workg prty rviw th vidnc on th ffctivnss cost ffctivnss nti-d obsttrics, stblish th vilbility nti-d ovr th nxt two fiv yrs, dvlop updtd guidls dvoctg th most ffctiv us th vilbl supply. Th Workg Prty ws lso skd dvlop strtgis crs domstic production nti-d slf-suffict lvl. Th mmbrship trms rfrnc th Workg Prty r t Appndix 1. Mthods Th Workg Prty ok thr m pprochs th collction formtion on which bs trim guidls. Th Mtr Prtl Epidmiology Unit, Brisbn, ws commissiond undrtk systmtic rviw th sctific litrtur rltg th ffctivnss th prophylctic us nti-d obsttrics, s wll s rltd issus such s tstg, complinc, rout dmistrtion ltrntiv sourcs nti-d. Th rsults th rviw r givn Chptr 3 tbls rsults r givn Appndix 5. Dr J Butlr th Ntionl Cntr for Epidmiology Popultion Hlth, Austrlin Ntionl Univrsity, ws commissiond prpr ppr comprg th cost ffctivnss ltrntiv strtgis for th prvntion Rh D isoimmunistion. Ths wr: postprtum dmistrtion only; postprtum plus dmistrtion for potntilly snsitisg vnts durg prgnncy; postprtum plus dmistrtion for potntilly snsitisg vnts durg prgnncy plus ntntl prophylctic us for primigrvid; postprtum plus dmistrtion for potntilly snsitisg vnts durg prgnncy plus rout ntntl prophylctic us. Th rsults this nlysis r discussd Chptr 4, fullr dscription th modl tbls rsults r givn Appndix 6. 8

14 nformtion ws collctd from th blood bnks CSL bout currnt rcruitmnt donors, currnt supply vilbility nti-d, likly supply ovr th nxt two yrs. Lvls clicl vidnc Th guidls hv bn dvlopd wy tht nbls rdrs judg th strngth th vidnc on which rcommndtions r bsd. n rltion issus ffctivnss hlth cr, th guidls us th six-pot rtg systm givn blow idntify th vidnc bs for ky dcision pots. Th rtg systm hs bn dptd from th systm dvlopd by th Unitd Stts Prvntiv Srvics Tsk Forc is rcommndd by th NHMRC (1995). Lvls vidnc rtgs Lvl Lvl Lvl -1 Lvl -2 Lvl -3 Lvl V Evidnc obtd from systmtic rviw rlvnt romisd controlld trils (with mt-nlysis whr possibl). Evidnc obtd from on or mor wll dsignd romisd controlld trils. Evidnc obtd from wll dsignd controlld trils without romistion. Evidnc obtd from wll dsignd cohort or cs-control nlytic studis, prfrbly from mor thn on cntr or rsrch group. Evidnc obtd from multipl tim sris with or without th trvntion. Drmtic rsults uncontrolld xprimnts (such s th rsults th troduction pnicill trtmnt th 1940s) could lso b rgrdd s this typ vidnc. Th opions rspctd uthoritis bsd on clicl xprc, dscriptiv studis or rports xprt committs. Consulttions Durg th guidl dvlopmnt procss, n vittion mk submissions bout th guidls ws dvrtisd ntionlly. Twnty submissions wr rcivd considrd crfully long with th rsults th bov rviws 9

15 formultg th guidls. Commnts from th submissions formd body xprt, formd cdmic clicl opion on th r Rh D immunoprophylxis. Th m issus risd th submissions cludd: gnrl support for th production 50 µg vil Rh D immunoglobul for dmistrtion for potntilly snsitisg vnts th first trimstr; conflictg viws bout th fficcy ntntl prophylxis; support for th rstriction ntntl prophylxis primigrvid womn, th currnt nvironmnt rstrictd nti-d supply; th importnc rcruitg nw donors; qustiong th nd for nti-d dmistrtion for thrtnd miscrrig. Aftr th rport ws dvlopd, it ws distributd ky orgnistions dividuls for commnt, th drft modifid th light th 13 submissions rcivd. 10

16 CHAPTER 1 BACKGROUND 1.1 Purpos nti-d obsttrics Rh D immunoglobul (nti-d) is givn womn with Rh D ngtiv blood who giv birth bbis with Rh D positiv blood, so tht thy do not bcom isoimmunisd ( snsitisd ) Rh D positiv blood. soimmunistion cn occur if ftl rd blood clls lk th mtrnl circultion durg birth or from n xchng ftl mtrnl blood durg th prgnncy. A womn who hs bn snsitisd durg th prgnncy or birth prvious child producs n ntibody (nti-d) which cn cross th plcnt, bd th ftl Rh D positiv rd blood clls dstroy thm. This cn rsult conditions such s hydrops ftlis, ictrus grvis nmi, which r ll sympms HDN. Svr HDN lds svr odm, hpsplnomgly svr nmi, my rsult dth utro. n its mildr form, HDN rsults mild or modrt nmi with jundic shortly ftr birth. Th us nti-d for prophylxis is bsd on th thory tht womn who hs not lrdy ctivly formd nti-d hr blood, th pssiv dmistrtion nti-d cn rmov ftl rd blood clls from hr circultion so tht snsitistion dos not occur. Howvr, th prcis mchnism ction prophylctic nti-d rms unclr. Sc most css trnsplcntl hmorrhg occur ithr just bfor, durg or shortly ftr dlivry, nti-d is givn Rh D ngtiv mothrs soon ftr th dlivry Rh D positiv bby. 1.2ncidnc Rh D comptibility About 83 pr cnt womn r positiv for Rh D, mng tht bout 17 pr cnt prgnnt womn will b Rh D ngtiv thir bbis, if Rh D positiv, thrfor t risk dvlopg HDN du Rh D comptibility. Although HDN my dvlop bcus comptibilitis othr rd blood cll ntigns, bfor th troduction prophylxis, nti-d ws th most common cus HDN. Thr r two rsons for this: bout 60 pr cnt Rh D ngtiv womn will hv Rh D positiv bby thir first prgnncy, ll subsqunt Rh D positiv bbis born womn who bcom immunisd durg th first prgnncy will b t risk HDN; th D ntign is th most immunognic th rd blood cll ntigns. n study th lt 1940s, it ws found tht ftl dth du HDN cusd by nti-d ccountd for 3.2 dths pr 1,000 births. n tht sris, on 200 prgnnt womn dvlopd nti-d ntibodis ths 20 pr cnt lost thir 11

17 fnts th first ffctd prgnncy 40 pr cnt subsquntly ffctd prgnncis. Until th lt 1960s, HDN du Rh D comptibility ws n importnt cus ftl nontl morbidity mortlity. 1.3 Th Rh Projct Austrli 3 n th 1960s, clicl trils th dmistrtion nti-d Rh D ngtiv mothrs soon ftr th dlivry Rh D positiv bbis wr conductd lrg numbr cntrs, dmonstrtd tht th cidnc immunistion ws drmticlly rducd. Th combd rsults th trils wr prsntd t th sctific mtg th ntrntionl Socity Blood Trnsfusion (SBT) Sydny Aftr th SBT mtg, it bcm immditly pprnt tht mchnism for producg nti-d Austrli ws rquird, stps wr tkn stblish th Rh Projct. This ws jot projct btwn th Rd Cross Ntionl Blood Trnsfusion Committ th Commonwlth Srum Lborris (now CSL) ws fdrlly fundd. Th blood bnks wr skd provid high titr nti-d plsm CSL procssd it Rh D immunoglobul. This ws thn issud fr chrg womn t risk. Plsmphrsis ws troducd mximis th volum plsm obtd. Nw South Wls Wstrn Austrli bgn rcruitg boostg suitbl donors, 1968, Austrli bcm th first country th world b slf-suffict Rh D immunoglobul. Th first donors wr Rh D ngtiv womn who hd producd nti-d, mn who hd bcom immunisd nti-d from blood trnsfusion. Howvr, it bcm pprnt tht not nough high titr nti-d ws bg producd by this group, vn whn thy wr boostd mt high lvls nti-d. Voluntrs with no nti-d prsnt wr thn rcruitd th projct, wr dlibrtly immunisd boostd. Rh D ngtiv ml donors wr pprochd two lrg sris bgn th lt 1960s. Th succss rt t chivg immunistion ws bttr for th scond sris thn for th first, but vn so, not ll donors bcm immunisd dspit frqunt jctions, not ll kpt dontg. n 1977, nothr btch voluntrs ws rcruitd immunisd, th lst mjor rcruitmnt th Rh Projct. Thr r significnt logistic difficultis rcruitg, immunisg rtg Rh D ngtiv donors th progrm. Fortuntly, most th Rh Projct donors (voluntrs who wr dlibrtly immunisd thos who wr lrdy immunisd whn rcruitd th progrm) hv contud dontg rgulrly for 3 Th formtion this sction ws providd by RJ Kimbr, Chirmn, Ntionl Blood Trnsfusion Committ, Austrlin Rd Cross. 12

18 lmost 30 yrs. Boostg donors ws csd Novmbr 1991 whn it pprd tht mor thn dqut mounts nti-d wr bg supplid CSL. Btwn , on million doss Rh D immunoglobul wr producd by CSL dmistrd Austrli. CSL producd issud pproximtly 65,000 doss Rh D immunoglobul nnully, which ovr tht tim mt th ntionl rquirmnts. To mt Austrlin nds t tht tim CSL rquird n put pproximtly U/month. Nw South Wls ws supplyg bout U/month nti-d Wstrn Austrli ws supplyg U/month. Som volums low titr nti-d wr lso comg from othr Stts. 1.4 Rsons for th currnt shortg nti-d Followg th dcision sp boostg Rh Projct donors mt thir high lvls nti-d, th ntibody lvls dcld. By 1994, th supply nti-d from Nw South Wls hd flln U/month. Whn it bcm pprnt tht CSL ws rcivg suffict nti-d mt Austrlin rquirmnts, th blood bnks immditly ok stps rtroduc th boostg donors. Howvr, thr wr numbr stgs considrbl ld tim bfor lvls loclly producd nti-d could crs mt currnt usg pttrns. First, pprovl ws gd from th Ethics Committ th Ntionl Blood Trnsfusion Committ. A sfty rquirmnt ws tht rd clls b usd for boostg should b kpt frozn liquid nitrogn for 12 months. This providd n dditionl wdow priod cs donor dvlopd ny diss with tht priod. Thr wr furthr dlys whn it ws discovrd tht thr ws possibility hptitis B trnsfr through th liquid nitrogn which crt blood bgs wr srd, th mthod frzg rd blood clls for ltr trnsfusion ws chngd. By mid-1994 th sitution wrrntd immdit ction. Boostg donors rcommncd Nw South Wls Wstrn Austrli, by Fbrury 1995 ths Stts wr supplyg two-thirds th Austrlin rquirmnt. Ethicl pprovl ws grntd for th us frsh rd blood clls from long-trm donors llow th xtnsion th boostg progrm, th shortfll ws supplmntd by n importd nti-d product, RhoGAM (Ortho Dignostics Systms nc, Unitd Stts). 13

19 Whil th rcruitmnt boostg progrm is still undrwy th ntionl put nti-d CSL hs crsd, thr r contug difficultis rctifyg th shortfll mtg th crsd supply. Ths clud: th progrssiv rtirmnt Rh Projct donors on th grounds g dclg hlth th vrg g Rh Projct plsmphrsis donors is now ovr 60 yrs; dclg ntibody lvls Rh Projct donors which occur ovr tim, th difficulty crsg ntibody lvls ths donors; lrg vrition th rspons dividul donors boostg, th significnt ffct on put if ny donor withdrws from th progrm. Othr issus thrtng th nti-d supply r discussd th nxt chptr, long with th currnt vilbility us nti-d Austrli. Som strtgis ovrcom ths problms, most ffctivly us xistg supplis nti-d crs futur supply r discussd Chptr 6. 14

20 CHAPTER 2 CURRENT AVALABLTY AND USE OF ANT-D N AUSTRALA 2.1 Currnt vilbility As wll s th logistic difficultis mtg th Rh Projct, thr r widr problms with nti-d supply. A survy 1995 confirmd worldwid shortg nti-d for Rh D immunoglobul thrpy, it is unlikly tht th worldwid supply nti-d will crs grtly th nxt dcd. Thr r vrious rsons why th nti-d supply is thrtnd: thr hs bn fll th numbr womn immunisd durg prgnncy bcus th succss th progrm rcnt dcds; thr r lso fwr mn th community with nti-d it is now unusul trnsfus Rh D ngtiv dividuls with Rh D positiv blood, whrs this ws rltivly common 20 yrs go; th usg Rh D immunoglobul hs probbly crsd du pproprit us som css, rcommndtions for th rout us nti-d ntntlly th givg doubl dos postprtum without dqut lborry ssssmnt fmtrnl hmorrhg (FMH); thr r thicl problms ssocitd with th contud boostg rcruitmnt Rh D ngtiv donors. RhoGAM issus csd t th nd August Rh D immunoglobul (CSL) is now th only nti-d prprtion on issu Austrli. Th Austrlin Rd Cross Blood Srvic (ARCBS) is contug mximis th collction nti-d plsm. Donors r now bg boostd Vicri Qunsl s wll s Nw South Wls Wstrn Austrli. Th mjority th plsm put nti-d CSL coms from ths boostd donors. Howvr, bcus th problms outld bov th prvious chptr, it is bcomg crsgly difficult crs production. Dspit th mximistion nti-d collction ovr th pst two yrs by rcruitg boostg ll possibl ccptbl donors, th combd put from Nw South Wls Wstrn Austrli nti-d hs rngd from s low s U/ month mximum U/month. This trnslts ntionl nnul put pproximtly U. Currntly th yild nti-d from plsm put CSL is 20 pr cnt, so th mount nti-d immunoglobul vilbl ntionlly pr yr is U. 15

21 2.2Currnt dm On th bsis currnt dm for nti-d, which dos not clud rout ntntl prophylxis, Austrli is still not slf-suffict. Bsd on dt from ARCBS CSL, th currnt dm for nti-d is s follows: Avrg nti-d usg ( ) U pr nnum Currnt issus ll Rh D ngtiv mothrs postprtum (bsd on dos U pr nnum 625 U or 125 µg) Currnt issus for bortions, ntprtum hmorrhgs othr ntntl uss U pr nnum Thus currnt ntionl dm pproximtly U slightly xcds currnt supply. An issu ll Rh D ngtiv womn dditionl doss 125 µg t wks gsttion for prophylctic rsons would rquir n dditionl U pr nnum, risg th nnul usg U. At 20 pr cnt yild, this trnslts bout U nti-d plsm pr nnum, which is lmost tripl th currnt put. An issu ll Rh D ngtiv womn xpctg thir first bby would rquir pproximtly U nti-d plsm pr nnum. 2.3 Currnt prctic Thr is vry strong vidnc, from th lt 1960s onwrds, tht th prctic dmistrg nti-d postprtum hs drmticlly rducd th cidnc immunistion HDN. Postprtum dmistrtion nti-d ll Rh D ngtiv womn with no prformd nti-d ntibodis who dlivr Rh D positiv bbis is strd prctic Austrli most prts th world, lthough th dos usd vris btwn countris. Th issu ntntl nti-d dmistrtion is lss clr. Thr pprs b wid vrition prctic som vidnc for pproprit us nti-d crt situtions. Anti-D is usully givn Rh D ngtiv womn with no prformd nti-d ntibodis durg prgnncy if thy xprc snsitisg vnt which thr is risk ftl blood crossg th mtrnl circultion. Ths clud miscrrig, trmtion prgnncy, cpic prgnncy, gntic studis such s mniocntsis chorionic villus smplg, xtrnl cphlic vrsion, trum ntprtum hmorrhg. Thr r conflictg viws bout th fficcy rout prophylctic us nti-d ntntlly. This hs rsultd vritions th wy tht nti-d is usd 16

22 prophylcticlly. Th sitution is complictd by th currnt rstrictd supply nti-d, s rout ntntl dmistrtion ll Rh D ngtiv womn would plc immns dms on nti-d supply. Spcific rcommndtions for th most pproprit us nti-d hv bn dvlopd by th Workg Prty, bsd on rviw th litrtur, costffctivnss nlysis, considrtion th currnt supply nti-d (s Chptr 5). Dos nti-d Th dos nti-d rquird prvnt isoimmunistion is dirctly rltd th volum FMH. Th strd dos givn Austrli is 125 µg. As shown Pollck t l (1971) now gnrlly ccptd, 20 µg (100 U) nti-d will protct gst FMH 1 ml ftl rd blood clls (2 ml whol blood), so this dos is suffict protct gst FMH 6 ml ftl rd blood clls (12 ml whol blood). Th mjority ftl blds r lss thn 5 ml rd blood clls. n bout 50 pr cnt css, th blds r lss thn 0.05 ml. n bout 5 pr cnt css, trnsplcntl hmorrhgs grtr thn 0.5 ml occur. n bout 3 pr cnt css, trnsplcntl hmorrhgs grtr thn 1 ml occur. Studis don 1977 Nw South Wls Wstrn Austrli showd tht pr cnt prgnncis r covrd by 250 µg dos, whil r covrd by th currnt Austrlin dos 125 µg. Howvr, FMH mong this rsidul 0.43 pr cnt my b s lrg s 30 ml, puttg thm t risk if suffict xtr nti-d is not givn s rquird. Anothr study found tht FMH 30 ml or mor occurs up 0.6 pr cnt dlivris (Zipursky 1977). Thr is no uniformity btwn diffrnt countris th dos nti-d givn postntlly, nor policis nsur tht suffict nti-d hs bn dmistrd. For xmpl, µg nti-d is givn Cnd, 100 µg th Unitd Kgdom, Swdn Hungry, 300 µg th Unitd Stts µg othr Europn countris. As most ntntl FMHs r vry smll volum, prticulrly th first trimstr, th dmistrtion 50 µg dos womn undrgog snsitisg vnts th first trimstr hs bn dvoctd. A dcision rgistr 50 µg vil for us durg th first trimstr hs bn dfrrd tmporrily whil som issus r ddrssd by CSL. Th mttr should b rsolvd with th nxt 9 12 months. 17

23 Tstg ssss fmtrnl hmorrhg Thr r numbr tsts vilbl ssss th volum FMH llow dditionl nti-d b givn whr pproprit. Th m tsts usd r: th Klihur cid lution tst which is widly usd but rlis on subjctiv trprttion; flow cymtry which is rlibl ccurt, but not widly vilbl outsid mtropolitn rs; th Rostt tst qulittiv tst which if positiv nds b followd up by quntittiv tst dtrm th volum FMH. Th ccurcy prcticlity th rout us ths tsts is vribl thy r not usd uniformly ll cntrs. Ths tsts th vidnc for thir most pproprit us r discussd grtr dtil Chptr 6. Filurs nti-d prophylxis Prophylxis is not succssful vry cs whr Rh D immunoglobul is givn postntlly, lthough mortlity from HDN du Rh comptibility is now uncommon. A numbr womn r still bcomg immunisd nti-d through filur rciv th nti-d jction ftr vry snsitisg vnt. Snsitistion Rh D ngtiv mothrs who hv rcivd pproprit trtmnt hs bn shown b du ithr mjor FMH for which th nti-d prophylxis ws dqut, or th dvlopmnt nti-d ntntlly. mmunistion occurs durg prgnncy bout 1.5 pr cnt Rh D ngtiv womn crryg Rh D positiv fnt. t hs bn shown tht this immunistion rt cn b rducd 0.2 pr cnt or lss by th dmistrtion nti-d immunoglobul durg prgnncy, t 28 wks 34 wks, s wll s ftr dlivry. Howvr, s discussd, this issu rms controvrsil bcus th qulity th vidnc th crsd mount nti-d rquird should ntntl dmistrtion bcom rout prctic. As mntiond, this prctic would rquir t lst thr tims s much nti-d production s t prsnt sc mny doss would b givn womn who subsquntly dlivrd Rh D ngtiv bby. 18

24 Docr-ptt communiction Th Workg Prty flt strongly tht th issu communiction with th ptt hr fmily should b ddrssd s mttr xtrm importnc. Th currnt rstrictd supply nti-d th consqunt limittions on its us mk clos monirg Rh D ngtiv womn ffctiv communiction btwn docr ptt spcilly importnt. Th NHMRC (1992) stts tht ptts r ntitld mk thir own dcisions bout trtmnts should b givn dqut formtion on which bs thos dcisions. nformtion should b providd form which hlps womn undrst th problm th options vilbl. Ethicl issus rlvnt formd consnt r discussd Sction 6.2. n th pst, ptt formtion shts hv vrid considrbly thir contnt th ffcts tht thy my b xpctd hv on ptt ccptnc prophylxis whn frd. A concis, comprhnsiv, usr-frdly ptt formtion sht is rquird, which is pplicbl Austrlin producd Rh D immunoglobul, but cn b modifid pply ovrss nti-d if importtion rsums th short trm. At prsonl lvl, it is clr tht thr should b n mphsis on formtion pssg btwn th docr th ptt, th rsponsibility for this cnnot b dlgtd ny lrg dgr. Th importnc such communiction should b strssd th prssion cludd ny formtion tht is issud whn th guidls r fully distributd. 19

25 CHAPTER 3 BEST PRACTCE FOR THE USE OF ANT-D N OBSTETRCS Th Mtr Prtl Epidmiology Unit, Brisbn ws commissiond undrtk rviw th vilbl vidnc rltg th ffctivnss th prophylctic us nti-d obsttrics. Th vidnc for th m pplictions nti-d is discussd this chptr. Othr issus such s tstg ssss FMH, complinc, th thics boostg dmistrtion sourcs supply nti-d r discussd Chptr 6. Dtils th srch strtgy tbls rsults from dividul studis r givn Appndix 5. Th srch strtgy cludd rticls gog bck Accptnc or rjction rticls ws dtrmd by th rviw tm ccordg rlvnc qulity vidnc. All mtril rlvnt th pics ws rviwd only rptitiv lvl V vidnc consistg dscriptiv studis or unsubstntitd xprt opion ws xcludd. Th bstrcts forign lngug rfrncs wr rviwd th full rticl sought whr ncssry rtrivd if vilbl. Th litrtur ws ssssd for mthodologicl qulity givn qulity vidnc rtg s dscribd th ntroduction. 3.1 Postprtum us nti-d Th bst vidnc (lvl ) on th postprtum us nti-d coms from th Cochrn Dtbs Systmtic Rviws (Crowthr & Middln 1997). This rviw lookd t ll publishd, unpublishd, ongog romisd trils with rportd dt which ssss outcoms Rh D ngtiv womn without ntibodis ( thir bbis) who wr givn postprtum nti-d immunoglobul prophylxis comprd with Rh D ngtiv womn without ntibodis ( thir bbis) not givn prophylxis. Th m outcoms considrd wr subsqunt dvlopmnt Rh D immunistion, mtrnl concrns dvrs ffcts trtmnt, nontl morbidity subsqunt prgnncy. Th trils postprtum nti-d prophylxis vrsus no prophylxis show Rh D isoimmunistion is lss common six months ftr dlivry womn who rcivd nti-d. n ddition, th dmistrtion nti-d immunoglobul rducs th cidnc Rh D immunistion subsqunt prgnncy. Th systmtic rviw found tht prophylxis with postprtum nti-d immunoglobul is ffctiv rducg th risk snsitistion ftr prgnncy subsqunt prgnncy, irrspctiv th blood group mothr bby. Th rviwd trils found tht prophylxis is ffctiv whn nti-d is givn with 72 hours birth. Th vidnc on th optiml mount nti-d rcommnd for prophylxis is limitd. Rcommndtions diffrnt countris dpnd on th rltiv vilbility costs nti-d th costs lborry ssssmnts th volum FMH. As discussd Chptr 2, th strd Austrlin dos 125 µg should 21

26 protct gst FMH up 12 ml. Th dt on comprtiv doss show tht doss up 50 µg nti-d, comprd with highr doss up 200 µg, crs th risk snsitistion subsqunt prgnncy. Thr is no vidnc show tht lowr dos 100 µg nti-d is substntilly lss ffctiv thn highr dos 150 µg nti-d, lthough th numbr immunistions shown r fw. Thr is pucity formtion bout th ttituds womn wrds immunistion th hlth fnts subsqunt prgnncis. No dvrs ffcts th trtmnt r rportd, though th risks rr dvrs ffcts snsitivity rctions trnsmission fctious disss rm. Summry fdgs postprtum us nti-d Prophylxis with postprtum nti-d is ffctiv rducg th risk snsitistion ftr prgnncy subsqunt prgnncy, irrspctiv th ABO sttus mothr bby. Prophylxis is ffctiv whn nti-d is givn with 72 hours birth. mplictions for rsrch No furthr plcbo controlld trils r wrrntd stblish th ffctivnss nti-d prophylxis postprtum. As th vidnc on th optiml dos nti-d rcommnd for postprtum prophylxis is limitd, furthr good qulity comprtiv dos fdg trils would b pproprit. n prticulr, th cost ffctivnss smllr doss nti-d immunoglobul combd with scrng for th dgr FMH dmistrg dditionl nti-d s ncssry should b comprd with th us lrgr doss nti-d. n furthr trils th ttituds womn wrds immunistion th hlth fnts subsqunt prgnncis should b vlutd. Any dvrs ffcts th trtmnt cludg snsitivity rctions trnsmission fctious disss should b documntd (Crowthr & Middln 1997). 22

27 3.2 Anti-D for ntntl snsitisg vnts Abortion, cpic prgnncy gntic studis Studis wr considrd xmg th dmistrtion nti-d immunoglobul Rh D ngtiv womn up 20 wks gsttion ftr: thrtnd, spontnous, mdicl surgicl bortion; cpic prgnncy; chorionic villus smplg mniocntsis. Th cidnc immunistion FMH wr th m outcom msurs xmd. Forty-ight rticls wr cludd. No lvl vidnc ws vilbl. Only four lvl thr lvl -1 studis wr rtrivd. No studis wr xcludd. A tbl summrisg th rsults dividul studis is t Appndix 5. Th vilbl vidnc stblishs tht trnsplcntl hmorrhg (TPH) cn occur ftr six wks gsttion cn b ssocitd with mdicl, surgicl spontnous bortion, rupturd cpic prgnncy, mniocntsis probbly chorionic villus smplg. On th difficultis dtrmg which womn r t risk bcomg immunisd rly prgnncy is th vilbility ccurt tsts ssss th quntity TPH t low lvls. Th litrtur rports tht ml Rh D positiv ftl blood is rquird for mtrnl Rh D immunistion lthough th Klihur tst cn dtct TPH lss thn 0.1 ml thr r problms with spcificity fls positiv rsults. With ths problms tstg for smll but potntilly immunisg TPH, dcisions nd b md bout which vnts rly prgnncy crs th risk Rh D immunistion. Studis on th rt immunistion nd b comprd th bsl rt control group. Th studis rviwd hv th followg limittions: Thy tn do not diffrntit btwn womn xprcg spontnous bortion thos xprcg n ducd bortion. Som studis do not spcify if curttg followd spontnous bortion. Othr studis rport on th cidnc TPH but do not provid follow-up dtrm th cidnc immunistion. 23

28 Spontnous or ducd bortion On lvl -1, on lvl -2 ight lvl -3 studis rportd n crsd rt immunistion followg spontnous bortion with strumnttion or ducd bortion. Ascri (1971, lvl V) rportd tht Rh D immunistion rngd from 0 13 pr cnt n prospctiv studis womn xprcg ithr spontnous or ducd bortion. Brgstrom t l (1967, lvl V) rportd on on cs which Rh D ntign ws prsnt on ftl rd blood clls s rly s th 38th dy post concption. Spontnous or thrtnd bortion (miscrrig) Thr is vry littl litrtur rportg th cidnc immunistion womn xprcg spontnous thrtnd bortion (miscrrig). Som studis providg lowr lvl vidnc rport FMH followg ths vnts but thr is no clr lk with th cidnc immunistion. Thr is only on study dictg tht immunistion cn occur followg rly lt spontnous bortion (Goldmn & Eckrlg 1972, lvl -1). Kullr t l (1994, lvl ) cludd womn xprcg thrtnd bortion up 20 wks gsttion found th cidnc FMH btwn womn xprcg thrtnd bortion controls ws not sttisticlly significnt. Mtthws Mtthws (1969, lvl -3) found tht lthough thr ws vidnc TPH css spontnous bortion, it ws wll blow th miml potntil immunisg dos. Goldmn Eckrlg (1972, lvl -1) rportd rducd rt immunistion usg 200 µg nti-d both first scond trimstr surgiclly ducd spontnous bortions. Howvr, thy fild stt which womn xprcg spontnous bortion lso hd curttg. Thr is low lvl vidnc rportd by Whitfild (1997) Portmnn t l (1997) immunistion followg thrtnd bortion t lss thn 12 wks gsttion. Eklund t l (1982) rport tht pr cnt th ntibody crosss th plcnt th ftl circultion. Thr is no vidnc th ffct this on th mbryo or ftus. No vidnc ws rtrivd on th timg nti-d dmistrtion if bldg contus. Howvr, Howrd t l (1997) rportd tht nti-d should b givn vry six wks if womn contu bld, s rcommndd th Ntionl Blood Trnsfusion Srvics mmunoglobul Workg Prty guidls (NBTS mmunoglobul Workg Prty 1991). Surgicl or mdicl bortion t hs bn rportd tht immunistion cn occur followg surgicl bortion from ight wks gsttion (Frd t l 1970). No vidnc ws rtrivd on th cidnc immunistion followg mdicl bortion. Avilbl vidnc (lvl, -3) supports us 50 µg dos nti-d for surgiclly ducd bortion th first trimstr prvnt immunistion most css. 24

29 Ecpic prgnncy Th dt r scnt but tht which is vilbl on cpic prgnncy confirms tht FMH cn occur ssocition with rupturd cpic prgnncy. Thr r two cs study rports immunistion followg cpic prgnncy (Krus & Goh 1996; Ktz & Mrcus 1972). Gntic studis No vidnc ws rtrivd on th cidnc immunistion followg chorionic villus smplg. Of th ight lvl -3 studis rviwd on gntic mniocntsis, Hill t l (1980) Golbus t l (1982) rportd th cidnc immunistion ws crsd Tbor t l (1986) rportd no diffrnc th cidnc immunistion. Tbsh t l (1984), Brnburg t l (1989) Goldst Pzzlo (1978), rportd nti-d ws succssful rducg th rt snsitistion followg gntic mniocntsis. Lnk t l (1985) comprd visul ssssmnt trmniotic bldg with lph-f prot (AFP) Klihur tstg found no corrltion btwn plcntl loction, plcnt ndl trvrsl FMH. Thy rportd no corrltion btwn plcntl loction FMH. Hnry t l (1976) rportd tht postrior plcntl loclistion rducs th cidnc bloody smpl. Thr is lck formtion rgrdg th ttituds womn wrds immunistion th hlth fnts subsqunt prgnncis. Summry fdgs nti-d for ntntl snsitisg vnts Thr is no lvl vidnc vilbl support th us nti-d for potntilly snsitisg vnts durg prgnncy. Th vilbl vidnc dicts tht trnsplcntl hmorrhg cn occur ftr six wks gsttion cn b ssocitd with mdicl, surgicl spontnous bortion, rupturd cpic prgnncy, mniocntsis probbly chorionic villus smplg. Thr is vidnc risk immunistion followg surgicl bortion, rupturd cpic prgnncy mniocntsis, supportg th us nti-d for ths potntilly snsitisg vnts (lvl vidnc, ). Thr is suffict conflictg vidnc bout whthr Rh D ngtiv womn xprcg thrtnd miscrrig or spontnous miscrrig without curttg should rciv nti-d. 25

30 mplictions for rsrch Furthr formtion is ndd on: th risk immunistion followg spontnous bortion thrtnd bortion t vrious gsttions; th risk immunistion followg mdiclly ducd bortion t vrious gsttions; th rlist gsttion t which immunistion cn occur followg surgicl bortion or cpic prgnncy; th dos nti-d rquird protct womn from immunistion th scond trimstr whn xprcg bortion, rupturd cpic prgnncy, chorionic villus smplg or mniocntsis; th ttituds womn wrds immunistion th hlth thir fnts subsqunt prgnncis. Any dvrs ffcts th trtmnt cludg snsitivity rctions trnsmission fctious disss should b documntd (Crowthr & Middln 1997); th ffcts nti-d on th mbryo ftus t rly gsttions sc pr cnt nti-d ntibody crosss th plcnt (Eklund t l 1982). Extrnl cphlic vrsion, trum ntprtum hmorrhg All publishd, unpublishd, ongog studis commntris with rportd dt wr considrd which ssss th cidnc immunistion or th prvntion immunistion Rh D ngtiv womn undrgog xtrnl cphlic vrsion (ECV), or xprcg bdoml trum or ntprtum hmorrhg. Extrnl cphlic vrsion Thr is no lvl or lvl vidnc on th prvntion Rh D immunistion followg ECV. Of th four studis rviwd, th only lvl -1 vidnc ws from tril with smll smpl. Thr wr thr lvl -3 studis rviwd. No studis wr xcludd. Thr is vry littl vidnc bout th risk immunistion or th cidnc FMH rltg ECV. Murry t l (1974) showd no sttisticl diffrnc th cidnc immunistion btwn womn undrgog ECV control group. Th othr thr studis dmonstrtd tht significnt FMH ws dtctd followg this procdur. Thy did not follow-up th womn rport on th cidnc immunistion. 26

31 Summry fdgs xtrnl cphlic vrsion Th vilbl vidnc (lvl -3) supports th prophylctic us nti-d followg xtrnl cphlic vrsion, lthough dosg lvls hv not bn considrd. mplictions for rsrch Furthr rsrch is wrrntd quntifiction FMH t ECV ordr dtrm pproprit dosg. Trum durg prgnncy ntprtum hmorrhg No vidnc on th prophylctic us nti-d for ithr ths conditions ws rtrivd. 3.3Rout ntntl us nti-d Study typs Th studis considrd wr ll publishd, unpublishd ongog studis commntris which rportd dt ssssg outcoms Rh D ngtiv womn without ntibodis ( thir bbis) who wr givn nti-d immunoglobul t 28 wks or mor prgnncy. Outcom msurs vrid but clud on or mor th followg: th numbr nwly snsitisd womn t dlivry th currnt prgnncy thr dys ftr dlivry with th currnt prgnncy six months postprtum durg th subsqunt prgnncy (with Rh D positiv bby) t dlivry subsqunt prgnncy (with Rh D positiv bby); cidnc, mortlity from, HDN. Ntn studis wr cludd. Two lvl studis on lvl -1 study wr rtrivd. Th rmdr wr lvl -3 or lvl V vidnc. Th Cochrn rviw Anti-D Admistrtion Prgnncy (Crowthr & Middln 1996), hs bn considrd this rport s lvl vidnc bcus only on romisd controlld tril (Hucht 1987) ws cludd. Lvl V rticls which rptd xprt opion which providd no nw formtion wr xcludd. 27

32 Rsults Th cidnc trprgnncy immunistion without rout ntntl prophylxis first prgnncy is stimtd b btwn pr cnt, with n vrg 0.9 pr cnt (Dvy & Zipursky 1979). ntrprgnncy immunistion is most likly occur ftr th 28th wk gsttion (Dvy & Zipursky 1979). This ppr rports th cidnc ftl clls mtrnl circultion s 8 14 pr cnt th first trimstr, pr cnt th scond trimstr pr cnt th third trimstr. n n ffort furthr rduc th cidnc Rh D immunistion, rout ntntl nti-d hs bn dmistrd Rh D ngtiv womn usg vrity rgimns. Th six rgimns rout ntntl prophylxis dscribd th rviwd litrtur r s follows: µg t 28 wks 34 wks (Bowmn & Pollock 1978) µg t 34 wks (Bowmn & Pollock 1978) µg t 28 wks (Bowmn & Pollock 1983) 250 µg t wks (Hrmnn t l 1979) 100 µg t wks (Hucht t l 1987) 50 µg t wks (L & Rwlson 1995). Thr is no lvl vidnc support th rout us nti-d ntntlly. Th Hucht t l tril (1987) provids lvl vidnc supportg th rout us two doss ntntl nti-d t dos 100 µg t wks rducg th cidnc immunistion. Th L Rwlson (1995) tril provids lvl vidnc showg no rduction th cidnc immunistion t lowr dos nti-d. Mny studis providg lowr lvl vidnc (on -1 study six -3 studis) support th us rout ntntl nti-d with dos rng qul or highr thn th Hucht t l tril (1987) which usd 100 µg. On lvl -3 study lso showd no rduction snsitistion, g usg lowr dos µg (Dvy 1975). Howvr, th studis wr not ll wll dsignd or conductd. Th studis rviwd fild : follow-up womn with Rh D positiv bbis subsqunt prgnncy dtrm th cidnc HDN with without ntntl trtmnt. Both nd b ssssd dtrm th svrity diss subsqunt prgnncis womn snsitisd thir first prgnncy; 28

33 dtrm if low lvl ntibody production th first prgnncy which ntibodis pprd ws prdictiv th cidnc HDN subsqunt prgnncis with Rh D positiv bbis. Godl t l (1968) rportd tht womn who tst wkly positiv for ntibodis t dlivry my tst ngtiv for ntibodis t six months vn without postprtum nti-d dmistrtion; follow-up womn subsqunt prgnncy with Rh D positiv bby dtrm th ctul filur protction ithr womn rcivg ntntl postntl nti-d or thos rcivg only postntl nti-d. Tstg only for immunistion postntlly, bfor subsqunt prgnncy, will undrstimt filurs protction bcus proportion immunisd womn only form dtctbl ntibodis whn nxt xposd Rh D positiv clls (nxt prgnncy with Rh D positiv ftus) (Dvy 1975). Accurcy snsitivity th tsts usd diffrd btwn studis mny studis comprd th rsults thir xprimntl group with hisricl controls which hd ntibody stimtions prformd usg diffrnt tst tchniqu. This probbly ffcts th cidnc immunistion rportd cludg th bsl lvl trprgnncy immunistion. Most studis did not rport on msurs tkn control for ccptd snsitisg vnts prgnncy lik mniocntsis or xtrnl cphlic vrsion. Non th studis cludd long-trm ffcts for th fnt or mothr. n ddition, ltrntiv mthods rducg th risk snsitistion prgnncy which cus HDN, othr thn rout ntntl nti-d dmistrtion, wr not discussd th studis rviwd. Mcknzi (1997) rportd rduction immunistion without rout ntntl prophylxis btwn Hnsligh (1983) sttd tht th cidnc Rh D diss is on downwrd trnd du th dcrsg pool isoimmunisd womn, dcrsg fmily siz, dcrsg prcntg Rh D ngtiv womn th popultion du n crsd proportion non- Cucsin womn th uptk fmily plnng options mong womn who r lrdy immunisd. Likly impct ntntl prophylxis Th purpos tryg prvnt Rh D immunistion is rduc th cidnc modrt svr HDN. Th first Rh D positiv bby is unlikly b svrly ffctd (Tovy t l 1983) thrfor it is subsqunt prgnncy whr srious morbidity or mortlity my occur. Dvy Zipursky (1979) rport bout 40 pr cnt fnts from snsitisd womn rquir no trtmnt, 20 pr cnt rquir phothrpy only, lvg 20 pr cnt which rquir on or mor 29

34 xchng trnsfusions 20 pr cnt with svr HDN rquirg tr-utr trnsfusion or othr spcil msurs. Lvl vidnc would suggst tht th 1.5 pr cnt immunistion rt could b rducd pr cnt through rout ntntl prophylxis (Hucht t l 1987; Bowmn & Pollock 1978; Hrmnn t l 1984), rlivg virtully ll this burdn mortlity modrt svr morbidity. Summry fdgs rout ntntl us nti-d Thr is no lvl vidnc support th rout dmistrtion nti-d ntntlly ll unsnsitisd Rh D ngtiv womn t ny gsttion. Howvr, thr is considrbl lowr lvl vidnc supportg th fficcy this prctic. mplictions for rsrch Dmonstrtg ffctivnss rout ntntl nti-d dmistrtion Bsd on th xtnt this problm Austrli, it would sm unlikly tht furthr romisd controlld trils r justifid vlut th ffctivnss rout nti-d prophylxis. dntifyg prvntg ntntl immunistion for womn t risk Scott t l (1977) stt tht th dvlopmnt rlibl mthod for dtctg slctivly trtg thos womn who r dstd bcom Rh D immunisd bfor prturition my b mor cost ffctiv lss risky thn rout ntntl nti-d dmistrtion. t my b bnficil vstigt th fcrs volvd thos countris which rport low rts trprgnncy snsitistion. Sfty for th ftus/fnt Th studis which lookd t sfty for th ftus providd dt limitd vlution th cord hmoglob, bilirub dirct Coombs tsts. Non th lrg clicl trils rportd comprbl dt on sris outcoms. Ths clud ftl dth, birth wight, nontl morbidity mortlity, nontl immunologicl sttus, childhood illnsss th ffcts on Rh D ngtiv fml ftuss xposd Rh D immunoglobul utro who dulthood br Rh D positiv ftuss. 30

35 CHAPTER 4 COSTS AND COST EFFECTVENESS OF ANT-D USE A considrtion cost ffctivnss is prticulrly importnt th dvlopmnt guidls for nti-d us bcus th limitd supply nti-d vilbl rltiv th numbr womn bbis who my bnfit from its us. Thrfor, som womn who my potntilly bnfit from nti-d will b unbl obt it. Undr ths circumstncs, it is ncssry considr th costs bnfits ltrntiv policis rgrdg th dmistrtion nti-d, dtrm whthr thr r som groups womn, for xmpl groups t rltivly low risk xprcg Rh D isoimmunistion, for whom th us nti-d is costly comprison with th bnfits chivd. Th Workg Prty commissiond cost-ffctivnss nlysis fiv ltrntiv strtgis for th prvntion Rh D isoimmunistion Austrli. A brif dscription th modl, gthr with th rsults conclusions, is givn this chptr. A full discussion th ssumptions dt usd th ccompnyg tbls figurs r prsntd Appndix 6. Th modl is dsignd vstigt th cost ffctivnss ltrntiv policis rgrdg th dmistrtion nti-d Rh D ngtiv mothrs. Six scnrios wr considrd: no nti-d givn stimts th costs hlth ffcts ssocitd with isoimmunistion Rh D ngtiv mothrs th bsnc ny nti-d bg dmistrd; postprtum only postprtum dmistrtion vil nti-d ll Rh D ngtiv mothrs with no prformd nti-d followg th birth Rh D positiv bby; ntntl with dictions + postprtum ntntl dmistrtion vil nti-d Rh D ngtiv mothrs with no prformd nti-d whn spcific dictions r prsnt (th potntilly snsitisg vnts discussd Sction 3.2), gthr with postprtum dmistrtion; ntntl prophylxis (primigrvid only) + postprtum ntntl dmistrtion vil nti-d ll Rh D ngtiv mothrs with no prformd nti-d xpctg thir first bby, t 28 wks g t 34 wks prgnncy, or whn spcific dictions r prsnt (s Sction 3.2), gthr with postprtum dmistrtion; ntntl prophylxis (primigrvid only) + ntntl with dictions + postprtum ntntl prophylxis for primigrvid s dfd bov, gthr with ntntl dmistrtion vil Rh D immunoglobul Rh D ngtiv mothrs xprcg thir scond or subsqunt prgnncy whn spcific dictions r prsnt (s Sction 3.2), gthr with postprtum dmistrtion; 31

36 ntntl prophylxis + postprtum ntntl dmistrtion vil nti-d Rh D ngtiv mothrs who do not miscrry or trmt with no prformd nti-d, t 28 wks g t 34 wks prgnncy, dmistrtion vil nti-d Rh D ngtiv mothrs who miscrry or trmt, postprtum dmistrtion. n th bov dscriptions, th dosg nti-d hs bn spcifid trms vils rthr thn µg or U bcus th Austrlin product is prsntly supplid only 125 µg vil, th rcommndd dosg is gnrlly 125 µg or lss, on vil cnnot b usd supply mor thn on dos nti-d. Th modl thn vstigts th cost ffctivnss th fiv prvntion strtgis. 4.1 Dt A rng probbilitis ws drivd for dcision mkg durg first subsqunt prgnncis, for ch strtgy. Th cost stimts rquird for th modl cn b ctgorisd brodly s th dirct costs HDN, th dirct costs HDN, th cost prvntion. Dirct costs clud th costs for cut trtmnt mothrs bbis born with HDN, th contug costs providg ongog support thos with long-trm squl. Th dirct cost n illnss is th lost production tht rsults, ithr from rducd productivity whil t work, from tim f work, or from prmtur dth. n th cs HDN, dirct costs ris from HDN dths from thos with HDN who surviv with long-trm squl (thos who surviv with long-trm squl lso giv ris dirct costs s bov). For n dividul womn hr bby, th cost prvntion usg nti-d compriss th cost on or mor vils nti-d, th costs tsts ssocitd with dmistrg tht nti-d. Th costs tstg dtrm Rh D sttus nti-d sttus for ll strtgis wr cludd, long with th cost tstg for FMH (Klihur tst) t birth. 32