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Cost-Effectiveness of the Management of Rh-Negative Pregnant Women

      Abstract

      Objective

      The purpose of this study was to determine the most cost-effective option to prevent alloimmunization against the Rh factor.

      Methods

      A virtual population of Rh-negative pregnant women in Quebec was built to simulate the cost-effectiveness of preventing alloimmunization. The model considered four options: (1) systematic use of anti-D immunoglobulin; (2) fetal Rh(D) genotyping; (3) immunological determination of the father’s Rh type; (4) mixed screening: immunological determination of the father’s Rh type, followed if positive by fetal Rh(D) genotyping. Two outcomes were considered, in addition to the estimated costs: (1) the number of babies without hemolytic disease, and (2) the number of surviving infants.

      Results

      In a first pregnancy, two options emerged as the most cost-effective options: systematic prophylaxis and immunological Rh typing of the father, with overlapping confidence intervals between them. In a second pregnancy, the results were similar. In all cases (first or second pregnancy or a combination of the two) fetal genotyping was not found to be a cost-effective option.

      Conclusion

      Routine prophylaxis and immunological Rh typing of the father are the most cost-effective options for the prevention of Rh alloimmunization. Considering that immunological typing of the father would probably not be carried out by the majority of clinicians, routine prophylaxis remains the preferred option. However, this could change if the cost of Rh(D) fetal genotyping fell below $140 per sample.

      Résumé

      Objectif

      Cette étude avait pour objectif d’identifier l’option la plus rentable pour la prévention de l’allo-immunisation contre le facteur Rh.

      Méthodes

      Une population virtuelle québécoise de femmes enceintes séronégatives pour le facteur Rh a été créée pour simuler la rentabilité de la prévention de l’allo-immunisation. Ce modèle a pris en considération quatre options : (1) l’utilisation systématique d’immunoglobuline anti-D; (2) le génotypage Rh(D) fœtal; (3) la détermination immunologique du type Rh du père; (4) le dépistage mixte : détermination immunologique du type Rh du père, suivie (en présence de résultats positifs) du génotypage Rh(D) fœtal. Deux critères d’évaluation ont été pris en considération, en plus des coûts estimés : (1) le nombre d’enfants nés sans maladie hémolytique et (2) le nombre de nouveau-nés survivants.

      Résultats

      Dans le cas d’une première grossesse, deux options se sont avérées les plus rentables : la prophylaxie systématique et la détermination immunologique du type Rh du père; leurs intervalles de confiance se chevauchaient. Dans le cas d’une deuxième grossesse, les résultats ont été semblables. Dans tous les cas (première ou deuxième grossesse, ou une combinaison des deux), nous avons constaté que le génotypage fœtal ne constituait pas une option rentable.

      Conclusion

      La mise en œuvre systématique d’une prophylaxie et la détermination immunologique du type Rh du père constituent les options les plus rentables pour la prévention de l’allo-immunisation contre le facteur Rh. Puisqu’il est peu probable que la détermination immunologique du type Rh du père soit mise en œuvre par la majorité des cliniciens, la prophylaxie systématique demeure l’option à privilégier. Cependant, cela pourrait changer si le coût du génotypage Rh(D) fœtal chutait en deçà de 140 $ par prélèvement.

      Key Words

      INTRODUCTION

      Despite the availability of prophylactic measures, alloimmunization to the Rh(D) antigen during pregnancy remains the most common cause of hemolytic disease of the newborn (1:1000 newborns).
      • Eder A.F.
      Update on HDFN : new information on long-standing controversies.
      Alloimmunization is the occurrence of an immune response to the presence of an antigen (alloantigen) that an individual lacks, but that is present in other individuals of the same species. In humans, this situation is observed only in special circumstances: pregnancy (immunization of an Rh-negative mother by her Rh-positive fetus), blood transfusion, or transplantation of tissues or organs.
      • Carbonne B.
      • Cortey A.
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      • Brossard Y.
      Non invasive fetal RhD genotyping using maternal blood: time for use in all RhD negative pregnant women.
      Early determination of the fetal Rh blood type in pregnant Rh-negative women allows better monitoring of the risk of alloimmunization and better prevention of its feared consequences (hemolytic disease of the fetus [HDF] and stillbirth, due to the passage of maternal immunoglobulins through the placenta) by the administration of prophylactic anti-D immunoglobulin (IgG).
      • Mannessier L.
      Immunohematological surveillance of the pregnant woman: new prevention policy.
      Currently accepted recommendations for the prevention of alloimmunization are the routine injection of anti-D IgG at 28 weeks’ gestation for all Rh-negative non-sensitized women when fetal Rh type is positive or unknown.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
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      • National Blood Authority
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      • College National de Gynecolegues et Obstetriciens Francais. Guidelines for prevention of fetomaternal rhesus-D allo-immunization [article in French]
      Such a measure is necessary because there is no practical therapeutic intervention that will slow the process of alloimmunization once it has been initiated.

      Beaulieu, M.-D. Dépistage de l’isoimmunisation D (Rh) pendant la grossesse, Adaptation d’un rapport préparé pour le compte du U.S. Preventive Services Task Force. 2006. Agence de la santé publique du Canada: 132–43. Available at : http://www.phac-aspc.gc.ca/publicat/clinic-clinique/pdf/s1c11f.pdf. Accessed June 10, 2013.

      • Carbonne B.
      • Castaigne V.
      • Cynober E.
      Follow-up of pregnances with red-cell allo-immunisation: state-of-the art.
      • Rigal D.
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      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.
      Non-invasive determination of fetal Rh status is now possible through the analysis of cell-free circulating fetal DNA in maternal plasma as early as the 10th week of pregnancy; that is, before the alloimmunization process is triggered. Non-invasive determination of fetal Rh status is expected to reduce the number of women who receive anti-D IgG unnecessarily and undergo surveillance testing according to current recommendations.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      • Daniels G.
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      • Summers J.
      Fetal RhD genotyping: a more efficient use of anti-D immunoglobulin.
      However, although the diagnostic performance of this new approach is high (clinical sensitivity and specificity approaching 100%), it is not universally available. Its introduction into regular follow-up of pregnancies still requires evidence about its value compared with more traditional approaches. Indeed, two economic studies were performed on non-invasive fetal Rh(D) genotyping. However, those studies should be considered as cost-minimizing studies because they did not estimate clinical outcomes.
      • Benachi A.
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      • Freeman K.
      A new fetal RHD genotyping test: costs and benefits of mass testing to target antenatal anti-D prophylaxis in England and Wales.
      Thus, information on the cost-effectiveness of the various options is still unavailable.
      Computer-based simulation modelling is a recognized approach to comparing the putative cost-effectiveness of several clinical interventions for a specific condition.
      • Gagné G.
      • Reinharz D.
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      • Rousseau F.
      Hereditary hemochromatosis screening: effect of mutation penetrance and prevalence on cost-effectiveness of testing algorithms.
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      • Rousseau F.
      • et al.
      Cost-effectiveness and accuracy of prenatal Down syndrome screening strategies: should the combined test continue to be widely used?.
      • Gekas J.
      • Gagné G.
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      • Douillard D.
      • Forest J.-C.
      • Reinharz D.
      • et al.
      Comparison of different strategies in prenatal screening for Down’s syndrome: cost effectiveness analysis of computer simulation.
      • Nshimyumukiza L.
      • Durand A.
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      • Douville X.
      • Morin S.
      • Lindsay C.
      • et al.
      An economic evaluation: simulation of the cost/effectiveness and cost/utility of universal prevention strategies against osteoporosis-related fractures.
      It is especially useful to compare the effectiveness of a large number of different interventions in the same cohort of patients, because that would require a very large, costly, and sometimes impossible clinical trial.
      • Gafni A.
      • Walter S.D.
      • Birch S.
      • Sendi P.
      An opportunity cost approach to sample size calculation in cost-effectiveness analysis.

      METHODS

      We built a virtual population of 10 000 Rh-negative pregnant women. This number was considered sufficient to perform statistically meaningful simulations given that 150 cases of Rh(D) incompatibility would be expected. The model assumed that 55% of women will have a second pregnancy,

      Institut de la statistique du Québec. Naissances selon le rang et le groupe d’âge de la mère, Québec, 2001–2011. Quebec 2008 [cited 2012]. Available at: http://www.stat.gouv.qc.ca/donstat/societe/demographie/naisn_deces/naissance/406.htm. Accessed May 24, 2013.

      on average 3.15 years after the first.

      Institut de la statistique du Québec. Naissances selon la durée écoulée depuis la dernière naissance et le rang de naissance, Québec. Quebec 2009 [updated 2012; cited 2012]. Available at: http://www.stat.gouv.qc.ca/donstat/societe/demographie/naisn_deces/naissance/408.htm. Accessed May 24, 2013.

      The Rh type of the fetus was established based on the probability of the father being either homozygously or heterozygously Rh positive.
      • Hudon L.
      • Moise Jr., K.J.
      • Hegemier S.E.
      • Hill R.M.
      • Moise A.A.
      • Smith E.O.
      • et al.
      Long-term neurodevelopmental outcome after intrauterine transfusion for the treatment of fetal hemolytic disease.
      Besides the estimated costs, two clinical outcomes were considered: (1) the number of babies without hemolytic disease, and (2) the number of surviving infants.
      Modelling was performed using a previously described agent-based, hybrid-state, and time-driven simulator called SCHNAPS.
      • Hudon L.
      • Gagné C.
      • Gardner M.
      • Rousseau F.
      • Giguère Y.
      • Reinharz D.
      • et al.
      • Durand A.
      • Gagné C.
      • Nshimyumukiza L.
      • Rousseau F.
      • Giguère Y.
      • Reinharz D.
      Population-based simulation for public health: generic software infrastructure and its application to osteoporosis.
      Two decision trees were built (Figure 1). The first decision tree applied to the first pregnancy of an Rh negative woman. The second applied to an eventual second pregnancy in 55% of those women.

      Institut de la statistique du Québec. Naissances selon le rang et le groupe d’âge de la mère, Québec, 2001–2011. Quebec 2008 [cited 2012]. Available at: http://www.stat.gouv.qc.ca/donstat/societe/demographie/naisn_deces/naissance/406.htm. Accessed May 24, 2013.

      The first model reflected the natural evolution of a first pregnancy for an Rh negative pregnant woman and the health of her baby up to 28 days after delivery. The choice of a 28-day follow-up neonatal period was based on the fact that the consequences of alloimmunization and hemolytic disease of the newborn are manifest during this period.
      • Haugen G.
      • Husby H.
      • Helbig A.
      • Schimidt-Melbye A.
      Ultrasonographic monitoring of pregnancies complicated by red blood cell alloimmunization in a cohort with mild to moderate risk according to previous obstetric outcome.
      • Leclerc C.
      • Grégoire J.
      Memo-Périnatalité : guide pratique, période prénatale, travail et accouchement, période post-partum, nouveau-né.
      Weekly cycle units were chosen for the time-driven simulations, which correspond to the usual time interval of events in the pregnancy literature.
      • L’Institut national de santé publique du Québec
      A probability of being alloimmunized was assigned to each Rh-negative woman depending on (1) the probability of the fetus being Rh positive, (2) the gestational age, and (3) the use of anti-D prophylaxis at 28 weeks and/or after delivery.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      • Parant O.
      Comparison of the efficacy of different methods for the prevention of anti-D allo-immunization during pregnancy: targeted strategy limited to risk situations or associated with systematic prevention in the 3rd trimester.
      The probability of the fetus being Rh positive was assigned depending on the father’s probable Rh type. Following clinical guidelines, a non-alloimmunized woman had nine prenatal visits, one ultrasound examination, an indirect Coombs test, and administration of prophylactic anti-D IgG at 28 weeks’ gestation.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      • Rigal D.
      • Meyera F.
      • Mayranda E.
      • Dupraza F.
      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.
      • American College of Obstetricians and Gyneologists
      ACOG Practice Bulletin no. 75. Management of alloimmunization during pregnancy.
      • Wilson R.D.
      SOGC Genetics Committee. Cell-free fetal DNA in the maternal circulation and its future uses in obstetrics. Society of Obstetricians and Gynaecologists of Canada Technical Update no. 153, January 2005.
      If the indirect Coombs test is positive, the woman is followed from 28 weeks as an alloimmunized woman.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      Alloimmunized women (those with a positive indirect Coombs test at 12 or 28 weeks), are monitored by measuring the level of anti-D antibodies, and have an ultrasound examination every four weeks until 28 weeks, every two weeks from 28 to 37 weeks, and thereafter weekly until delivery, as suggested by the Canadian guidelines.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      This close monitoring is maintained even if the Coombs test becomes negative.
      In cases of HDF, medical consultation including ultrasound assessment is performed every four weeks until 20 weeks’ gestation, every two weeks from 20 to 37 weeks, and weekly thereafter until delivery.
      • Nizard J.
      Immunisation sanguine foeto-maternelle.
      In addition, between 15 and 35 weeks, three Doppler ultrasound examinations are performed to measure the peak systolic velocity in the middle cerebral artery.
      • Mannessier L.
      Immunohematological surveillance of the pregnant woman: new prevention policy.
      HDF is categorized into three levels of severity,

      Beaulieu, M.-D. Dépistage de l’isoimmunisation D (Rh) pendant la grossesse, Adaptation d’un rapport préparé pour le compte du U.S. Preventive Services Task Force. 2006. Agence de la santé publique du Canada: 132–43. Available at : http://www.phac-aspc.gc.ca/publicat/clinic-clinique/pdf/s1c11f.pdf. Accessed June 10, 2013.

      • Rigal D.
      • Meyera F.
      • Mayranda E.
      • Dupraza F.
      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.
      • Nizard J.
      Immunisation sanguine foeto-maternelle.
      • Minon J.
      • Gérard C.
      • Dricotm J.
      • Neve C.
      • Senterre J.
      Schaaps J, et al.
      and the distribution of severity follows Canadian data.

      Beaulieu, M.-D. Dépistage de l’isoimmunisation D (Rh) pendant la grossesse, Adaptation d’un rapport préparé pour le compte du U.S. Preventive Services Task Force. 2006. Agence de la santé publique du Canada: 132–43. Available at : http://www.phac-aspc.gc.ca/publicat/clinic-clinique/pdf/s1c11f.pdf. Accessed June 10, 2013.

      • Georges A.
      Enfermedad Hemolitica perinatal.
      In cases of severe HDF, the model considers four intrauterine transfusions.
      • Mannessier L.
      Immunohematologic surveillance of the pregnant woman and the new prevention policy of anti-RH1 allo-immunization.
      At its birth, a baby with moderate or severe HDF is monitored in NICU for 21 days, and subsequently for a further seven days in hospital.
      • Chabaud F.
      • David-Tchouda S.
      • Belin V.
      • Fau S.
      • Equy V.
      • Carraby S.
      • et al.
      Influence of hospital location on short-term fate of premature infants born at 34 weeks of gestation [article in French].
      The probability of a newborn being premature (born between 34 and 37 weeks’ gestation
      • Chabaud F.
      • David-Tchouda S.
      • Belin V.
      • Fau S.
      • Equy V.
      • Carraby S.
      • et al.
      Influence of hospital location on short-term fate of premature infants born at 34 weeks of gestation [article in French].
      • Gobalakichenane P.
      • Lardennois C.
      • Galène-Gromez S.
      • Brossard V.
      • Marpeau V.
      • Verspyck E.
      • et al.
      Prise en charge périnatale et devenir neurologique à moyen terme des nouveau-nés hospitalisés pour maladie hémolytique par immunisation anti-D.
      • Institut Canadien d’Information sur la Santé
      ) was assigned to each fetus according to its status, i.e., HDF versus non-HDF.
      • Gobalakichenane P.
      • Lardennois C.
      • Galène-Gromez S.
      • Brossard V.
      • Marpeau V.
      • Verspyck E.
      • et al.
      Prise en charge périnatale et devenir neurologique à moyen terme des nouveau-nés hospitalisés pour maladie hémolytique par immunisation anti-D.
      • Institut Canadien d’Information sur la Santé
      A premature baby is hospitalized for 21 days in NICU, and then followed-up for seven days in a pediatric ward.
      • Chabaud F.
      • David-Tchouda S.
      • Belin V.
      • Fau S.
      • Equy V.
      • Carraby S.
      • et al.
      Influence of hospital location on short-term fate of premature infants born at 34 weeks of gestation [article in French].
      Finally, the probability of death for each baby was assigned depending on whether the baby was healthy, was premature, or had HDF, and if the mother was already alloimmunized.
      • Institut de la statistique du Québec
      In the model of the second pregnancy the probability of being alloimmunized was dependent on the state of alloimmunization at the end of the first pregnancy, the prophylaxis given during the first pregnancy and the uptake of prophylaxis at 28 weeks in the second pregnancy.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      The model assumed that if a woman had a baby with HDF during her first pregnancy, her second baby would also have the disease if Rh positive.
      All scenarios considered were in agreement with the Canadian guidelines for the prevention of maternal–fetal Rh alloimmunization.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      • Wilson R.D.
      SOGC Genetics Committee. Cell-free fetal DNA in the maternal circulation and its future uses in obstetrics. Society of Obstetricians and Gynaecologists of Canada Technical Update no. 153, January 2005.
      Four scenarios were compared:
      • 1.
        the current situation, i.e., the routine use of anti-D immunoglobulin at 28 weeks’ gestation without determination of fetal Rh type;
      • 2.
        fetal Rh(D) genotyping by PCR of fetal free circulating DNA in maternal blood;
      • 3.
        immunological determination of the father’s Rh type; and
      • 4.
        mixed screening: immunological determination of the father’s Rh type, followed, if the result is positive, by fetal Rh(D) genotyping by PCR on fetal free circulating DNA in maternal blood (Table 1).
        Table 1Scenarios
        Scenario 1Systematic prophylaxis: the routine use of anti-D immunoglobulin at 28 weeks’ gestation
        Scenario 2Fetal Rh(D) genotyping by PCR of fetal free circulating DNA in maternal blood
        Scenario 3Immunological determination of the father’s Rh type
        Scenario 4Mixed screening: immunological determination of the father’s Rh type, followed if positive by fetal Rh(D) genotyping
      In the first scenario, there are two possible outcomes depending on the results of the indirect Coombs test done at 12 weeks. If the result is positive, the woman is considered alloimmunized and at risk of HDF if the titre is ≥ 1/16. If the result is negative, monitoring continues as for a healthy pregnancy, with a repeat indirect Coombs test at 28 weeks and the administration of prophylactic anti-D IgG if negative. After delivery, non-alloimmunized mothers receive an additional dose of anti-D IgG.
      In the second scenario, fetal genotyping is offered. If the woman refuses the test, the course of treatment will be the same as for the first scenario. If she accepts and the test is positive, follow-up indirect Coombs tests are performed as described in the first scenario. If fetal genotyping is negative, the course of treatment is the same as for a healthy pregnancy (Figure 2).
      Figure thumbnail gr2
      Figure 2Sequence of services consumed in each scenario
      Figure thumbnail gr3
      Figure 2Sequence of services consumed in each scenario
      Figure thumbnail gr4
      Figure 2Sequence of services consumed in each scenario
      Figure thumbnail gr5
      Figure 2Sequence of services consumed in each scenario
      In the third scenario, the father’s Rh type is routinely determined. If the father is Rh positive, the response is the same as described in the second scenario with positive fetal genotyping. If the father is Rh negative, there is no need for prophylactic administration of anti-D IgG or an indirect Coombs test. The model considers the probability (2.6%) that the father is unknown or undeclared.
      • Institut de la statistique du Québec
      In this case, women are followed as described in the first scenario.
      In the fourth scenario, if the father is Rh positive, fetal Rh genotyping of fetal DNA circulating in maternal plasma is performed by PCR. If the test shows that the fetus is Rh negative, no further action is taken and follow-up is as for a healthy pregnancy.
      • Carbonne B.
      • Cortey A.
      • Rouillac-Le Sciellour C.
      • Brossard Y.
      Non invasive fetal RhD genotyping using maternal blood: time for use in all RhD negative pregnant women.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      • Rigal D.
      • Meyera F.
      • Mayranda E.
      • Dupraza F.
      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.
      • Drummond M.
      • Scupher M.
      • Torrance G.
      • O’Brien B.
      • Stoddart G.
      Methods for the economic evaluation of health care programmes.
      • Mannessier L.
      Suivi de l’alloimmunisation foeto maternelle.
      In the second, third, and fourth scenarios, the model considers the acceptance rate for screening (including fetal genotyping and/or immunological Rh typing of the father) reported in the literature.
      • Gekas J.
      • Durand A.
      • Bujold E.
      • Vallee M.
      • Forest J.C.
      • Rousseau F.
      • et al.
      Cost-effectiveness and accuracy of prenatal Down syndrome screening strategies: should the combined test continue to be widely used?.
      • Gekas J.
      • Gagné G.
      • Bujold E.
      • Douillard D.
      • Forest J.-C.
      • Reinharz D.
      • et al.
      Comparison of different strategies in prenatal screening for Down’s syndrome: cost effectiveness analysis of computer simulation.
      • Forest J.C.
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      • Massé J.
      • Moutquin J.M.
      • Kharfi A.
      • Ness R.B.
      • et al.
      Early occurrence of metabolic syndrome after hypertension in pregnancy.
      As specific information about the acceptance of genetic testing for fetal Rh and the Rh type of the father has not been published to date, we made assumptions based on the values found in recent Canadian studies on topics considered relevant for this study.
      • Gagné G.
      • Reinharz D.
      • Laflamme N.
      • Adams P.C.
      • Rousseau F.
      Hereditary hemochromatosis screening: effect of mutation penetrance and prevalence on cost-effectiveness of testing algorithms.
      • Gekas J.
      • Durand A.
      • Bujold E.
      • Vallee M.
      • Forest J.C.
      • Rousseau F.
      • et al.
      Cost-effectiveness and accuracy of prenatal Down syndrome screening strategies: should the combined test continue to be widely used?.
      • Gekas J.
      • Gagné G.
      • Bujold E.
      • Douillard D.
      • Forest J.-C.
      • Reinharz D.
      • et al.
      Comparison of different strategies in prenatal screening for Down’s syndrome: cost effectiveness analysis of computer simulation.
      • Forest J.C.
      • Girouard J.
      • Massé J.
      • Moutquin J.M.
      • Kharfi A.
      • Ness R.B.
      • et al.
      Early occurrence of metabolic syndrome after hypertension in pregnancy.
      In addition, our model includes an estimate of the likelihood that physicians will offer a genetic test.
      • Riley M.
      • Galang S.
      • Green L.A.
      The impact of clinical reminders on prenatal care.
      Sensitivity analyses were performed to take into account the variability of published results.
      Costs relate to the publicly funded health care system in Quebec. Only direct costs were estimated. The simulation analyses included services provided for the monitoring of Rh negative women as outpatients and services provided during hospitalizations of the mother and her baby, as already defined in the province of Quebec
      • L’Institut national de santé publique du Québec
      and as described in Canadian guidelines.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      The sequence of services provided in each scenario is summarized in Figure 2.
      Baseline values on the management of alloimmunization were retrieved from Canadian guidelines.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      When these values were not available, data from peer-reviewed studies
      • Mannessier L.
      Immunohematological surveillance of the pregnant woman: new prevention policy.
      • Rigal D.
      • Meyera F.
      • Mayranda E.
      • Dupraza F.
      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.
      • Hudon L.
      • Moise Jr., K.J.
      • Hegemier S.E.
      • Hill R.M.
      • Moise A.A.
      • Smith E.O.
      • et al.
      Long-term neurodevelopmental outcome after intrauterine transfusion for the treatment of fetal hemolytic disease.
      and the opinions of experts in obstetrics and laboratory medicine were used. Extensive sensitivity analyses were performed. Unit prices for services consumed were calculated from the 2010 to 2011 fiscal year administrative data of the Quebec public health care system. The lowest prices from the list of drugs covered by Quebec public health care insurance (Régie d’assurance maladie du Québec [RAMQ]), were used to estimate the cost of medication, to which were added 6% for wholesalers and the pharmacist fee paid by RAMQ. All-Patient-Diagnosis-Related-Groups (APR-DRG) data were used to calculate the average cost of hospitalization, to which we added the physician fees paid by RAMQ. The Ministry of Health data bank (Système d’information financière et opérationnelle [SIFO])
      • Ministère de la Santé et des Services sociaux
      was used to calculate activity centre unit prices for ambulatory care services. These prices were increased to reflect the contribution of support activity centres to clinical services, using the direct method.
      • Drummond M.
      • Scupher M.
      • Torrance G.
      • O’Brien B.
      • Stoddart G.
      Methods for the economic evaluation of health care programmes.
      Simulations were performed using the SCHNAPS platform (Synchronous Population and Agent-based Simulator) and run on the CLUMEQ network of supercomputers.
      • Hudon L.
      • Gagné C.
      • Gardner M.
      • Rousseau F.
      • Giguère Y.
      • Reinharz D.
      • et al.
      • Durand A.
      • Gagné C.
      • Nshimyumukiza L.
      • Rousseau F.
      • Giguère Y.
      • Reinharz D.
      Population-based simulation for public health: generic software infrastructure and its application to osteoporosis.
      Each simulation was repeated 1000 times with newly generated virtual populations in order to produce a distribution of estimates. As the follow-up was less than one year, no discounting was performed.
      The decision tree and the parameters were validated by consensus of four experts in obstetrics and medical biology (J.G., E.B., V.M., and M.V.). Interpretation of the results was also submitted to the expert committee. Each stage of the simulation was validated to ensure that data generated by the simulator matched expected data (proportion of fetal and father’s Rh types, number of pregnancies per woman, number of alloimmunized women, number of cases of HDF, and costs).
      • Mannessier L.
      Immunohematological surveillance of the pregnant woman: new prevention policy.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      • Rigal D.
      • Meyera F.
      • Mayranda E.
      • Dupraza F.
      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.

      Institut de la statistique du Québec. Naissances selon le rang et le groupe d’âge de la mère, Québec, 2001–2011. Quebec 2008 [cited 2012]. Available at: http://www.stat.gouv.qc.ca/donstat/societe/demographie/naisn_deces/naissance/406.htm. Accessed May 24, 2013.

      • Hudon L.
      • Moise Jr., K.J.
      • Hegemier S.E.
      • Hill R.M.
      • Moise A.A.
      • Smith E.O.
      • et al.
      Long-term neurodevelopmental outcome after intrauterine transfusion for the treatment of fetal hemolytic disease.
      • Parant O.
      Comparison of the efficacy of different methods for the prevention of anti-D allo-immunization during pregnancy: targeted strategy limited to risk situations or associated with systematic prevention in the 3rd trimester.
      • Ministère de la Santé et des Services sociaux
      • Ministère de la Santé et des Services sociaux
      When a discrepancy between calculated and expected data of more than an arbitrary threshold of 5% was found, the underlying erroneous parameter was sought, identified, and corrected.
      Sensitivity analyses were performed on the SCHNAPS platform’s sensitivity analyses module, with the variables expected to have the most influence on the outcomes (Table 2).
      Table 2Input variables for the analyses
      VariableBaseline valuesValues used in sensitivity analysesReferences
      Nulliparous pregnancy
       At 12 weeks’ gestation fetus Rh+0.17%0.11% to 2.8%
      • Parant O.
      Comparison of the efficacy of different methods for the prevention of anti-D allo-immunization during pregnancy: targeted strategy limited to risk situations or associated with systematic prevention in the 3rd trimester.
       Probability of alloimmunization without prophylaxis (at 28 weeks) fetus Rh+2.08%1.33% to 2.8%
      • Parant O.
      Comparison of the efficacy of different methods for the prevention of anti-D allo-immunization during pregnancy: targeted strategy limited to risk situations or associated with systematic prevention in the 3rd trimester.
       Probability of alloimmunization after prophylaxis (at 28 weeks) fetus Rh+0.33%0% to 1.17%
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      Subsequent pregnancy
       Probability of alloimmunization after prophylaxis (at 28 weeks) in non-alloimmunized women fetus Rh+0.33%0% to 1.17%
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
       Probability of alloimmunization for non-alloimmunized women and postpartum prophylaxis fetus Rh+2.92%2.67% to 3.17%
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
       Probability of alloimmunization for non-alloimmunized women and no prophylaxis fetus Rh+23.33%20% to 26.67%
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      Unknown father2.6%7% (mothers stating being single)
      • Institut de la statistique du Québec
      Genotypingspecificity

      97%
      sensitivity

      100%
      specificity sensitivity 97% to 100% 100%
      • Rigal D.
      • Meyera F.
      • Mayranda E.
      • Dupraza F.
      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.
      ,
      • Wilson R.D.
      SOGC Genetics Committee. Cell-free fetal DNA in the maternal circulation and its future uses in obstetrics. Society of Obstetricians and Gynaecologists of Canada Technical Update no. 153, January 2005.
      Father Rh (immunological)97.9%100%83% to 97.9% 50.3% to 100%
      • Novaretti M.C.
      • Jens E.
      • Pagliarini T.
      • Bonifacio S.L.
      • Dorlhiac-Llacer P.E.
      • Chamone D.A.
      Comparison of conventional tube test technique and gel microcolumn assay for direct antiglobulin test: a large study.
      Indirect Coombs test positive84%95%84% 90% to 100%
      • Novaretti M.C.
      • Jens E.
      • Pagliarini T.
      • Bonifacio S.L.
      • Dorlhiac-Llacer P.E.
      • Chamone D.A.
      Comparison of conventional tube test technique and gel microcolumn assay for direct antiglobulin test: a large study.
      ,
      • Chabert C.
      • Renier J.
      • Quillet P.
      • Beaufine-Ducrocq H.
      Comparison of 6 enzyme treatment protocols of hematic samples for the research of irregular agglutinins [article in French].
      Compliance of patients with genotyping70.0%60% to 98%
      • Forest J.C.
      • Girouard J.
      • Massé J.
      • Moutquin J.M.
      • Kharfi A.
      • Ness R.B.
      • et al.
      Early occurrence of metabolic syndrome after hypertension in pregnancy.
      Compliance of physician with recommendations73%60% to 98%
      • Rigal D.
      • Meyera F.
      • Mayranda E.
      • Dupraza F.
      Les allo-immunisations foeto-maternelles anti-erythrocytaires : état de l’art en 2008.
      Compliance of patients with postpartum prophylaxis84%81% to 87%
      • MacKenzie I.Z.
      • Findlay J.
      • Thompson K.
      • Roseman F.
      Compliance with routine antenatal rhesus D prophylaxis and the impact on sensitisations: observations over 14 years.
      Outcomes in alloimmunized women
      • Ben-David G.
      • Sheiner E.
      • Levy A.
      • Erez O.
      • Mazor M.
      An increased risk for non allo-immunization related intrauterine fetal death in RhD-negative patients.
      ,
      • MacKenzie I.Z.
      • Bowell P.J.
      • Selinger M.
      Deaths from haemolytic disease of the newborn.
       Prenatal death9.1/10008.4/1000 to 11.2/1000
       Neonatal death4.95/10003.96/1000 to 6.27/1000
       Prematurity8.1%
      HDFExpert opinion
      • Gobalakichenane P.
      • Lardennois C.
      • Galene-Gromez S.
      • Brossard V.
      • Marpeau L.
      • Verspyck E.
      • et al.
      Perinatal management and neurological outcome of newborns hospitalized with Rhesus hemolytic disease [article in French].
      ,
      • Tomashek K.M.
      • Shapiro-Mendoza C.K.
      • Davidoff M.J.
      • Petrini J.R.
      Differences in mortality between late-preterm and term singleton infants in the United States, 1995–2002.
       Prenatal death1.4%0.7% to 2.1%
       Neonatal death0.6%0.3% to 0.9%
       Prematurity57%40% to 70%
      Prematurity
       Death11%5% to 18%
      • Agence de la santé publique du Canada
      Moderate and severe HDF without treatment
      • Wirthner D.
      • Hohlfeld P.
      • Tissot J.D.
      Perinatal hemolytic disease. Part 1: physiopathology [article in French].
       Prenatal death32.2%
       Neonatal death13.8%
       Prematurity57%40% to 70%
      Cost of fetal genotyping$471$70 to $470
      • Ministère de la Santé et des Services sociaux
      ,
      • Régie de l’assurance maladie du Québec
      Prophylaxis (anti-D immunoglobulin)$81$71 to $91Quebec Ministry of Health
      HDF treatment
       11 to 21 days NICU

      7 days pediatric unit
      $47 228$22 656 to $47 228
      • Ministère de la Santé et des Services sociaux
      ,
      • Novaretti M.C.
      • Jens E.
      • Pagliarini T.
      • Bonifacio S.L.
      • Dorlhiac-Llacer P.E.
      • Chamone D.A.
      Comparison of conventional tube test technique and gel microcolumn assay for direct antiglobulin test: a large study.
      Prematurity treatment
       14 to 21 days NICU$47 228$26 408 to $47 228
      • Ministère de la Santé et des Services sociaux
      ,
      • Novaretti M.C.
      • Jens E.
      • Pagliarini T.
      • Bonifacio S.L.
      • Dorlhiac-Llacer P.E.
      • Chamone D.A.
      Comparison of conventional tube test technique and gel microcolumn assay for direct antiglobulin test: a large study.
       7 days pediatric unit

      RESULTS

      When the development of HDF and neonatal survival at 28 days were considered as clinical outcomes, two options emerged as the most cost-effective: routine prophylaxis and immunological Rh typing of the father in the first pregnancy (Table 3). However, confidence intervals overlapped between these options.
      Table 3Cost-effectiveness simulation analysis: first pregnancy results
      ScenariosTotal costs, $ / 10000 pregnancies (95% CI)No. of babies without HDF/10000 pregnancies (95% CI)No. of surviving babies / 10 000 pregnancies (95% CI)Costs / number of babies without HDF, $ (95% CI)Costs / number of surviving babies, $ (95% CI)
      Systematic prophylaxis101 848 991(101 772 528 to 101 925 454)9974.75(9974.44 to 9975.06)9810.91(9810.08 to 9811.75)10 211(10 203 to 10 219)10 381(10 373 to 10 389)
      Immunological Rh typing of the father101 911 011(101 835 182 to 101 986 840)9974.79(9974.47 to 9975.11)9811.77(9810.92 to 9812.61)10 217(10 209 to 10 225)10 387(10 379 to 10 395)
      Mixed typing102 864 181(102 790 395 to 102 937 967)9974.63(9974.31 to 9974.95)9810.81(9809.95 to 9811.67)10 313(10 306 to 10 320)10 485(10 477 to 10 493)
      Fetal genotyping103 310 771(103 234 860 to 103 386 682)9974.68(9974.36 to 9975.00)9811.18(9810.32 to 9812.04)10 357(10 349 to 10 365)10 530(10 522 to 10 538)
      In the second pregnancy, when the outcome of number of babies without HDF was considered, the immunological Rh typing of the father emerged as the most cost-effective option (Table 4). When neonatal survival at 28 days was the clinical outcome considered, two options emerged as the most cost-effective: routine prophylaxis and immunological Rh typing of the father. Here also the confidence intervals overlapped between these options.
      Table 4Cost-effectiveness simulation analysis: second pregnancy results
      ScenariosTotal costs, $ / 10000 pregnancies (95% CI)No. of babies without HDF/10000 pregnancies (95% CI)No. of surviving babies / 10 000 pregnancies (95% CI)Costs / number of babies without HDF, $ (95% CI)Costs / number of surviving babies, $ (95% CI)
      Immunological Rh typing of the father106 362 892(106 238 547 to 106 487 238)9912(9907 to 9918)9808(9802 to 9814)10 731(10 719 to 10 742)10 845(10 833 to 10 856)
      Systematic prophylaxis106 687 882(106 562 891 to 106 812 874)9912(9906 to 9917)9807(9801 to 9813)10 764(10 753 to 10 775)10 879(10 868 to 10 890)
      Mixed typing106 837 257(106 718 431 to 106 956 082)9914(9908 to 9919)9808(9802 to 9813)10 777(10 766 to 10 788)10 894(10 883 to 10 904)
      Fetal genotyping107 193 950(107 069 446 to 107 318 454)9914(9909 to 9920)9808(9803 to 9814)10 812(10 801 to 10 824)10 929(10 918 to 10 940)
      The combination of first and second pregnancies showed that routine prophylaxis and immunological Rh typing of the father are the more cost-effective options. In all cases (first or second pregnancy or the combination), the fetal genotyping option did not appear to be cost-effective.
      Sensitivity analyses using the ranges of variables presented in Table 2 showed that when the cost of fetal genotyping is $140 or less (estimated through linear regression), fetal genotyping became the most cost-effective option in the first or second pregnancy, and also when considering both pregnancies in combination.

      DISCUSSION

      Our results suggest that the four proposed strategies for prevention and treatment of Rh(D) alloimmunization are similar in terms of effectiveness. This was expected as all the options include giving anti-D IgG prophylaxis to women who need it. Moreover, the specificity and sensitivity of both fetal genotyping and immunological Rh typing of the father are high, which means that women who need prophylaxis are generally properly identified. In addition, all women who refuse testing (30%) either for fetal genotyping or immunological Rh typing of the father receive prophylaxis at 28 weeks.
      We also found that the options of routine prophylaxis and immunological Rh typing of the father are the least expensive in the first and second pregnancies. The costs of both options are similar. In terms of cost-effectiveness, however, two options are superior: routine prophylaxis and immunological Rh typing of the father. However, we recognize that combining these options is unlikely to be widely accepted by the medical community.
      Overall, our results show that the fetal genetic testing option is not a cost-effective option unless its cost is considerably lower than at present. In many countries, Rh genotyping remains costly and is performed by only a few laboratories.
      • Carbonne B.
      • Cortey A.
      • Rouillac-Le Sciellour C.
      • Brossard Y.
      Non invasive fetal RhD genotyping using maternal blood: time for use in all RhD negative pregnant women.
      The test is not currently automated in Canada, which contributes to its high cost, but in Germany the cost of the test after automation was estimated at €26.
      • Legler T.J.
      • Muller S.P.
      • Haverkamp A.
      • Grill S.
      • Hahn S.
      Prenatal RhD testing: a review of studies published from 2006 to 2008.
      As automation of Rh genotyping should be implemented in the next few years throughout the world, it is reasonable to predict that the cost of the test will soon be less than $140, at which point it would be cost-effective. Until then, our results support the economic logic of the current guidelines
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      • National Blood Authority
      Guidelines on the prophylactic use of RhD immunoglobulin (anti-D) in obstetrics.
      • College National de Gynecolegues et Obstetriciens Francais. Guidelines for prevention of fetomaternal rhesus-D allo-immunization [article in French]
      that propose routine anti-D IgG prophylaxis and eventually immunological Rh typing of the father, in order to reduce the incidence of fetomaternal Rh(D) alloimmunization.
      • Fung K.
      • Eason E.
      Prevention de l’alloimmunisation foeto-maternelle Rh.
      As with any economic evaluation, the most important limitation of our study is the uncertain external validity of the results, because the costs cited apply to a single jurisdiction. The characteristics of different populations will likely result in different findings. However, we believe that our extensive sensitivity analyses help to mitigate this limitation. The second important limitation is associated with the methodological approach based on simulations. Simplifications of real life are difficult to avoid. However, we attempted to limit the biases due to this simplification. For example, the anticipated compliance of physicians and patients was quantified, and sensitivity analyses were performed on variables deemed likely to affect the results. Finally, the perspective of the study was limited to the public health care system. A pregnancy bears important costs for women and their families. There are also important indirect costs, and these should be considered in future studies.

      CONCLUSION

      Until automation of Rh(D) fetal genotyping is implemented and the cost of screening falls below $140, immunological Rh typing of the father and routine anti-D IgG prophylaxis are the most cost-effective options. Because routine immunological Rh typing of the father would probably not be adopted by the majority of Canadian clinicians, routine prophylaxis remains the preferred option, as recommended by the Canadian guidelines for the prevention of maternal–fetal Rh alloimmunization.

      ACKNOWLEDGEMENTS

      The work that led to this manuscript was supported by a grant from the Canadian Institutes for Health Research (grant number CFBA-49658), and also in part by the FQR-S Réseau de médecine génétique appliquée, and the APOGÉE-Net/CanGèneTest Research and Knowledge Network in Genetic health Services, funded by the Canadian Institutes for Health Research (www.cangenetest.org), (grant number ETG-92250). This work also involved the FRSQ/MSSS/CHUQ Research Chair in Technology Assessment and Evidence-Based Laboratory Medicine.

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