Epidemiology, prenatal diagnosis and maternal treatment

Transcription

1 Societat Catalana d'obstetrícia i Ginecologia Curs de Formació Continuada Del 10 de novembre de 2015 al 14 de juny de 2016 Sala 3 L'Acadèmia - Can Caralleu 15 de diciembre 2015 Epidemiology, prenatal diagnosis and maternal treatment O. U. of Clinical Microbiology, Laboratory of Virology St. Orsola Malpighi University Hospital, University of Bologna, Bologna, Italy.

2 The overall birth prevalence CONGENITAL CMV INFECTION of congenital CMV infection is 0.64% PRIMARY INFECTION NON PRIMARY (reactivation- INFECTION reinfection) PREGNANT WOMEN Transplacental route FOETUS

3 Risk of congenital CMV infection following PRIMARY and d NON PRIMARY infection of the mother during pregnancy Effect of gestational age on transmission in utero. Stagno S. et al. JAMA 1986 Congenital infection the rate of transmission 40-50% Primary infection 70% Primary infection Gestational Age, wk 38-42

4 Risk of congenital CMV infection following PRIMARY and d NON PRIMARY infection of the mother during pregnancy Effect of gestational age on transmission in utero. Stagno S. et al. JAMA 1986 Congenital infection the rate of transmission 1-2% 40-50% Primary infection 70% Non primary Primary infection Gestational Age, wk 38-42

5 Risk of congenital CMV infection following PRIMARY and d NON PRIMARY infection of the mother during pregnancy Effect of gestational age on transmission in utero - disease in the offspring and severe sequelae Stagno S. et al. JAMA 1986 Congenital infection the rate of transmission Symptoms at birth 1-2% Primary Risk 10-15% 15% Non primary - Risk 2-5% Gestational Age, wk 38-42

6 Risk of congenital CMV infection following PRIMARY and d NON PRIMARY infection of the mother during pregnancy Effect of gestational age on transmission in utero - disease in the offspring and severe sequelae Stagno S. et al. JAMA 1986 Congenital infection the rate of transmission Significant Symptoms handicaps at birth 1-2% mental Primary retardation Risk - bilateral 10-15% 15% hearing loss primary Non Risk primary 30-40% 40%; - Risk non 2-5% primary Risk 1-4% Gestational Age, wk 38-42

7 CMV Infection and Pregnancy TOPICS 1. Epidemiology 2. Diagnosis of maternal infection 3. Diagnosis and (prognosis) of fetal infection 4. Maternal treatment

8 CMV Infection and Pregnancy TOPIC 1. Epidemiology 2. Diagnosis of maternal infection 3. Diagnosis and (prognosis) of fetal infection 4. Maternal treatment

9 EPIDEMIOLOGY Prevalence of seropositivity to CMV in various regions of the world Country Ireland Germany France Melbourne Alabama Italy Greece Spain Argentina Brazil Israel Taiwan India Uganda Continent % Europe 30 Europe 42 Europe 51 Australia 57 North America 59 Europe 68 Europe 78 Europe 79 South America 81 South America 84 Asia 85 Asia 91 Asia 99 Africa 100

10 Female % CMV seroprevalence in Italy years 80.00% 70.00% 60.00% 50.00% anni anni anni anni anni anni %pos 59.02% 71.98% 69.21% 68.78% 74.59% 85.42% Vecchia L et al. 2002

11 CMV seroprevalence in Italy %pos % neg 100,00% 80,00% 60,00% 40,00% 20,00% 0,00% gravide 0-6 mesi 7-12 mesi % neg 27,30% 22,66% 63,72% %pos 72,70% 76,40% 33,63% Vecchia L et al Between 30-40% of children at 1 year of age are CMV-infected

12 EPIDEMIOLOGY The management of CMV infection during pregnancy depends on CMV seroprevalence Study % Mothers CMV Ab + % Cong CMV Infection London, UK, Birmingham, USA, 1986(middle SES) Hamilton, Canada, Aarhus-Viborg Viborg,, Denmark, Sao Paulo, Brazil, 1985 (middle SES) Sal Paulo, Brazil, 1985 (lower SES) Birmingham, USA, 1986 (lower SES) Seoul, Korea, Santiago, Chile, Abidjan, Ivory Coast, The higher the rate of maternal seroprevalence, the higher the rate of congenital CMV infection.

13 Epidemiology CONCLUSION Primary maternal infections have a much greater clinical impact on the fetus than non primary infection Stagno et al Maternal reinfection by new strains of CMV is a major source of congenital infection in populations with seroprevalence approaching 100% (Yamamoto et al. AJOG, 2010). Severe symptoms are almost exclusively due to exogenous reinfections with a different strain of CMV rather than the reactivation of latent virus (Congenital CMV Conference, San Francisco USA 2012).

14 CMV Infection and Pregnancy TOPIC 1. Epidemiology 2. Diagnosis of maternal infection 3. Diagnosis and (prognosis) of fetal infection 1. Prevention/treatment

15 Diagnosis of maternal CMV infection Serological diagnosis reliable Detection of IgG AND IgM

16 Diagnosis of CMV infection Serological diagnosis is reliable The serological reaction employing antibodies linked to a tracer enzymatic or fluorescent or chemiluminescent. Screening tests EIA (ELISA), MEIA, CMIA, ELFA,CLIA EIA (Enzyme( Immuno Assay) ) o ELISA (Enzyme( Enzyme-Linked- ImmunoSorbent-Assay Assay) MEIA (Microparticle( Enzyme Immunoassay) CMIA (Chemiluminescent( Microparticle Immunoassay) ELFA (Enzyme( Enzyme-linked fluorescent assay) CLIA (chemiluminescence( immunoassay)

17 Categories Diagnosis of primary CMV infection in pregnant women Period What does this mean? What should be done IgG IgM- just before pregnancy or during pregnancy Non immune woman High risk of acquiring primary infection IgG + IgM- before 16 WG Past infection Information on hygiene and behavioral measures No further diagnostic investigation is required IgG IgM+ IgG + IgM+ before or during pregnancy acute phase of primary infection?? or IgM false positive result?? before 16 WG Active infection? Primary infection? Non primary? Serological testing performed in the same lab after days Advanced diagnosis Avidity IgG test

18 Diagnosis of primary maternal CMV infection Why in this case would there be problems in the interpretation of IgM positive results?

19 Problems in the interpretation of specific CMV-IgM 1. Virus-specific specific IgM may persist unchanged for months after natural infection 2. Unspecific positive results may arise in subjects with other viral infections (B19 Virus, EBV, etc.) or autoimmune diseases 3. False positive results may also be caused by laboratory methods. 4. IgM test will not distinguish between primary and non-primary infection, and not distinguish acute or recent or late phase of infection.

20 IgM cannot replace a seroconversion Can we do better? Advanced diagnosis AVIDITY TEST

21 Determination of the IgG-CMV avidity CMV-IgG maturation occurs between weeks HIGH Avidity index (%) moderate LOW Weeks after beginning of symptoms et al. Clin Diagn Lab Immunol,, Sensitivity identification of pregnant women at risk of transmitting ting the virus to fetus before weeks gestation sens = 100% after weeks gestation sens = 60% et al. Viral Immunol 2000

22 A high avidity index during the first weeks gestation could be considered as a good indicator of past infection. Ability of the IgG avidity assays to detect and to exclude a recent primary CMV infection et al 1997 Enders et al 2000 Avidity & CMV Nt-Ab Grangeot-Keros et al 2001 Bodéus et al Revello et al 2004 Lagrou et al 2009 Method commercial commercial in-house commercial commercial commercial Before weeks 20 weeks 17 weeks 12 weeks 12 weeks Sens (%) 92.8 nd nd commercial 12 weeks 100 Spec (%)

23 Serum/plasma samples from primarily infected women obtained at different weeks after beginning of infection. Figure 1: Kinetic of LIAISON XL CMV IgG-CLIA avidity LIAISON XL CMV IgG avidity Index y = x R 2 = HIGH avidity MODERATE avidity LOW avidity days after onset of CMV primary infection T et al 2015, 5th International Congenital CMV Conference ence

24 Determination of the CMV - IgG avidity Attention! Interpreting test results is very important because serological tests vary from one laboratory to another so the method used and its reference values must be carefully assessed.

25 Attention! Commercial kits for determination of the CMV - IgG avidity Range and interpretation of results (according to manufacturer s s instructions) AI AI Kit 1 <50% low 50 to 60 % grey zone >60% high Kit 2 <0.4 low 0.4 to 0.65 moderate >0.65 high Kit 3 <0.4 low 0.4 to 0.55 grey zone >0.55 high Kit 4 <0.2 low 0.2 to 0.3 moderate >0.3 high Kit 5 <30% low 30 to 40% borderline >40% high Kit 6 <40% low 40 to 60% equivocal range >60% high Kit 7 <35% low 35 to 45% moderate >45% high Kit 8 <25% low 25 to 45% moderate >45% high Kit 9 <45% low 45 to 55% grey zone >55% high AI

26 Roche Symposium CMV IgG avidity: value and limits Liliane Grangeot-Keros (Clamart,, France) The value of CMV IgG avidity helps to interpret a positive result for CMV IgM. Attention! The limits of CMV IgG avidity: 1) the kinetics of CMV IgG avidity depend on the kit used, 2) with some of these kits,, the results may depend on CMV IgG concentration.

27 CLINICAL CASE Screening tests weeks of gestation a 35-year-old woman in her second pregnancy CMV-IgG UA/mL Weak Positive Neg < 6.0 Equivocal 6 x<156 Pos 15 CMV-IgM 6.34 Index Positive Neg < 0.85 Equivocal 0.85 x<1 Pos 1 Advanced diagnosis 10 weeks CMV-IgG of gestation UA/mL Positive CMV-IgM Index Positive CMV-IgG IB Positive CMV-IgM IB Positive CMV IgG avidity 0.43 (high AI) FALSE Undetectable CMV-DNA Real Time PCR Whole blood copies/ml Comment: the very low titer of IgG anti CMV does not allow an accurate evaluation of the IgG avidity test resulting undetectable. ACUTE PHASE OF PRIMARY CMV INFECTION

28 2015

29 NATURAL HISTORY OF HUMAN CYTOMEGALOVIRUS PRIMARY INFECTION SALIVA CMV-DNA POSITIVE Neg URINE CMV-DNA POSITIVE + + Neg CMV DNAemia POSITIVE + Neg days months Time after onset of CMV infection

30 Real Time PCR Pregnant women with primary CMV infection enrolled at the moment of serological diagnosis n. of patients total n. of positive patients sensitivity Whole blood % saliva % urine % Pregnant women with non-primary CMV infection enrolled at the moment of serological diagnosis Real Time PCR n. of patients total n. of positive patients sensitivity Whole blood % saliva % urine % 2014

31 Conclusion - primary CMV infection Serological diagnosis Antibodies IgG and IgM with screening tests <12 WG Virological diagnosis DNA Saliva Real Time PCR Whole blood - Real Time PCR Avidity IgG test <16 WG RELIABLE Urine - Real Time PCR CAN BE RELIABLE VIROLOGICAL DIAGNOSIS 1. can support the serological diagnosis of primary CMV infection 2. plays a role in the diagnosis of non primary CMV infection

32 Diagnosis of non primary CMV infection 1. IgG + IgM + high avidity 16WG Absence of CMV in biological fluids High risk of non-primary CMV infection 3. IgG+ + and IgM+ + and high avidity 16WG Presence of CMV in urine/saliva/blood (Real time PCR) Non-primary CMV infection not always feasible 2. IgG + IgM - high avidity 16WG Presence of CMV in biological fluids Non-primary CMV infection Attention! No optimal diagnostic method

33 CMV Infection and Pregnancy TOPIC 1. Epidemiology 2. Diagnosis of maternal infection 3. Diagnosis and (prognosis) of fetal infection 4. Maternal treatment

34 Invasive prenatal Non invasive diagnosis prenatal diagnosis Amniocentesis + + COUNSELLING Amniocentesis CONGENITAL CMV INFECTION Prenatal diagnosis Ultrasound examination COUNSELLING When should prenatal diagnosis be performed? after weeks from the onset of maternal infection CMV is a slow replication virus and weeks is the time required from maternal infection to virus detection in AF amniocentesis is performed between weeks gestation Fetus excretes CMV via urine into the AF and a sufficient amount of fetal diuresis is produced only after WG

35 Amniocentesis: weeks gestation Maternal primary infection (the first half of gestation) Observation of ultrasound abnormalities Which tests? Virus isolation (shell vial) Viral DNA by Real Time PCR

36 Virus isolation and Real Time PCR in 796 samples of amniotic fluids of primarily infected women and congenital CMV infection CONGENITAL INFECTION Yes No Total SNS % SPE % PPV % NPV % Virus isolation Pos Neg Total Real Time PCR Copies/mL Pos Neg Total ( T et al. CMV San Francisco 2012) PCR is more sensitive than virus isolation and the specificity of o f the two tests is the same. Among the 646 cases with negative result: No congenital CMV infection was identified in 607 cases, while 39 newborns were infected but were asymptomatic at birth and during subsequent monitoring (NPV 94%)

37 Literature reports since Sensitivity, specificity, and predictive values of PCR tests for CMV detection in amniotic fluid Author Publication year SENS % SPE % PPV % Goegebuer et al nd NPV % Revello et al Revello et al Enders et al Gouarin et al Azam et al nd Liesnard et al nd nd: : not done nd nd nd

38 Fetal CMV infection - counseling after prenatal diagnosis AF Virus isolation AF DNA PCR Ultrasound findings OUTCOME - FETUSES NO infection ( 94%) or - + Low viral load (<1000 copies/ml) + + High viral load (>10 5 copies/ml) + + High viral load (>10 5 copies/ml) asymptomatic infection ( 6%) YES infection (100%) asymptomatic infection (100%) YES infection (100%) YES severe infection (100%) YES infection (100%) symptomatic or asymptomatic infection????? Under evaluation, UO di Microbiologia, Università di Bologna

39 CMV prenatal diagnosis Why is it important to offer a comprehensive (invasive and non invasive) prenatal diagnosis?

40 It is currently accepted that ultrasound examinations do not identify more than 20% of infected fetuses and the sensibility is further reduced if the ultrasound is performed when the state of the CMV fetal infection is unknown. Guerra, et al Out of 600 pregnant women who underwent ultrasound examinations with complete follow up, there were 51 abnormal ultrasound findings. From these 51 findings, only 23 fetuses were actually infected. SENS 14.9% SPEC 93.7% PPV 45.0% NPV 76.1%

41 Diagnosis of fetal CMV infection weeks gestation Prenatal diagnosis is reliable Amniotic fluid is the most appropriate material for diagnosis of CMV fetal infection Fetal blood does not give any additional diagnostic value because the tests used are not sensitive enough to detect the virus. It also carries a high risk of fetal demise and therefore should not be performed. Is cordocentesis useful for prognostic purposes in fetuses with CMV infection?

42 Prognosis of fetal CMV infection weeks gestation The level of specific IgM and viral blood load is not correlated with a poor outcome. It has been proposed that platelet count gives a better indication. (Benoist et al. AJOG 2008) The determination of multiple markers (haematological, biochemical and virological markers) in fetal blood following virus detection in AF, is predictive of perinatal outcome in fetuses with CMV infection. (Fabbri et al. BJOG 2011).

43 CMV-IgM index and CMV load in fetal blood of primarily infected women and congenital CMV infection Zavattoni et al. J Med Virol 2014 with symptoms without symptoms with symptoms without symptoms

44 Study population, UO di Microbiologia, Università di Bologna 15 pregnant women at WG with diagnosis of CMV fetal infection. In all cases: amniotic fluids were positive for viral isolation and qpcr with a high viral load (> 10^5 copies / ml). At the moment of amniocentesis all pregnant women underwent ultrasound examinations. As negative control we studied 4 CMV-seronegative pregnant women at WG. Study design - After elective pregnancy termination, 2 ml of fetal blood were collected from the umbilical cord. - Virological, haematological and biochemical markers in fetal blood were studied. This study (SA43GABR) was approved by the Ethical Committee of St. Orsola-Malpighi General Hospital, Bologna.

45 19 pregnant women RESULTS electively terminated their pregnancy at WG 15 CMV infected fetuses 4 fetuses non CMV infected histological evaluation 12 fetuses CMV-pos brain (IHC) brain histological damage 3 fetuses CMV-neg brain (IHC) no brain histological damage 1 fetus cardiac malformations 2 spina bifida 1 trisomy 21 CMV antigen expression and inflammatory response were studied in all fetal tissues using immunohistochemical staining procedures. Gabrielli et al. J Clin Virol 2009 Gabrielli et al. CMI 2012, UO di Microbiologia, Università di Bologna

46 Case # ULTRASOUND at WG 1 Negative Brain damage 3 Negative Brain damage 4 Negative Brain damage 12 Negative Brain damage 18 Negative Brain damage 23 Negative Brain damage 0 Microcephaly Brain damage 2 16 Prognosis of fetal CMV infection Cerebral periventricular echogenicity, hyperechogenic bowel Microcephaly, intraventricular septa, hyperechogenic bowel Brain damage Brain damage 19 Cerebral ventriculomegaly Brain damage 20 Hyperechogenic bowel Brain damage 24 Cerebral periventricular echogenicity Brain damage AUTOPSY 12 CMV POSITIVE BRAINS (IHC) with histological damage 7 Negative Negative 3 CMV 8 Negative Negative 9 Negative Negative NEGATIVE BRAINS (IHC) without histological damage US examinations were performed by one experienced ultrasonographer working in S. Orsola-Malpighi Hospital in Bologna, Italy (Dr. G. Simonazzi). Findings detected by ultrasound and correlation with or without histological brain damage in the 15 fetuses studied 6/12 fetuses with histological brain damage had a pathological US (50%). Sens: : 50% Spec: 100% PPV: 100% NPV: 34%

47 Prognosis of fetal CMV infection Fetal blood samples taken at weeks gestation Serological markers detected in fetal plasma of CMV-infected fetuses and correlation with fetal brain damage VIDAS ToRC panel 12 fetuses with brain damage 3 fetuses without brain damage CMV IgM CMV IgM P Fisher s s exact test When comparing the blood of infected fetuses with and without brain damage, we observed no statistical difference in detection of CMV specific IgM antibodies.

48 Prognosis of fetal CMV infection Fetal blood samples taken at weeks gestation Virological markers detected in fetal whole blood of CMV-infected fetuses and correlation with fetal brain damage HCMV ELITe MGB kit 12 fetuses with brain damage Median values (range) 3 fetuses without brain damage 104,408 Real time PCR 104,408 (1,470 1,993,500) P 0.02 Wilcoxon test 1,428 (0 16,335) On the contrary, when comparing the blood of infected fetuses with and without brain damage, we observed a statistical difference in median values of CMV-DNAemia levels.

49 Prognosis of fetal CMV infection Fetal blood samples taken at weeks gestation Virological markers detected in fetal whole blood of CMV-infected fetuses and correlation with fetal brain damage without brain damage CMV-infected fetuses with brain damage CMV DNA load in fetal blood samples is significantly higher in fetuses with brain damage.

50 Prognosis of fetal CMV infection Fetal blood samples taken at weeks gestation Median values (range) Median values (range) Fetal blood parameters 12 fetuses with brain damage 3 fetuses without brain damage P value 3 fetuses no CMV-infected White blood cells 9.05x10^3/µL ( ) 8.1x10^3/µL ( ) NS 10.1x10^3/µL ( ) Erythroblasts 10.2x10^3/µL ( ) 1.8x10^3/µL ( ) NS 4.6x10^3/µL ( ) Hemoglobin 11.8 G/dL ( ) 11.7 G/dL ( ) NS 8.5 G/dL ( ) T lymphocytes 3 469/mmc ( ) 3 334/mmc ( ) NS 1 719/mmc ( ) CD4/CD8 0.6 ( ) 0.8 ( ) NS 3.5 ( ) Natural killer 1 821/mmc ( ) 1 429/mmc ( ) NS 1 079/mmc ( ) ß2- Microglobulin 18.9 ng/ml ( ) 7.7 ng/ml ( ) ng/ml ( )* Platelet count 93x10^3/µL (18-161) 265x10^3/µL ( ) x10^3/µL ( ) * statistical values obtained from 4 uninfected fetuses Wilcoxon test The parameters that showed a statistically significant difference between the two groups are the ß2-microglobulin and the platelet count.

51 Prognosis of fetal CMV infection Fetal blood samples taken weeks gestation Prognostic markers in compliance of severe fetal CMV disease 1) ß2- microglobulin > 11 ng/ml 2) Platelet count 110x10^3 /µl/ 3) CMV DNAemia levels > copies/ml (Zavattoni 2014) Markers Agreement 9 fetuses with brain damage 3 fetuses without brain damage total SENS % SPE % PPV % NPV % YES NO total , UO di Microbiologia, Università di Bologna Therefore, prenatal counseling based on the compliance of these specific markers can be misleading.

52 CLINICAL CASE #1 Primary infection in the first trimester of pregnancy Prenatal diagnosis at 20 weeks of gestation Amniotic fluid Virological testings Results Virus isolation (shell vial) Positive Real Time PCR Positive copies/ml Ultrasound Findings and Cerebral Magnetic resonance negative Fetal blood cut-off Results ß2- Microglobulin (> 11 ng/ml) 14.6 ng/ml Platelet count ( 110x10^3 /µl)/ 161x10^3 /µl/ CMV DNAemia levels (> copies/ml ml) copies/ml Autopsy: symptomatic fetus had CMV positive brain with severe histological brain damage and necrosis of cerebral tissue.

53 CLINICAL CASE #7 Primary infection in the first trimester of pregnancy Prenatal diagnosis at 21 weeks of gestation Amniotic fluid Virological testings Results Virus isolation (shell vial) Positive Real Time PCR Positive copies/ml Ultrasound Findings and Cerebral Magnetic resonance negative Fetal blood cut-off Results ß2- Microglobulin (> 11 ng/ml) 9.7 ng/ml Platelet count ( 110x10^3 /µl)/ 126x10^3 /µl/ CMV DNAemia levels (> copies/ml ml) copies/ml Autopsy: CMV infected fetus without brain damage

54 STUDY LIMITATION Limited sample size does not allow firm conclusions. However these data indicate the need to take further caution when: 1) offering cordocentesis for fetal prognosis of CMV infection; 2) evaluating blood markers for fetal prognosis of CMV infection.

55 CONCLUSIONS Further studies in a larger number of symptomatic and asymptomatic cases should be performed to verify the prognostic efficacy of determination of different parameters in fetal blood. At present, fetal blood sampling at weeks gestation cannot be justified for the prognosis of fetal CMV infection due to the high risk of fetal demise.

56 Now I would like to conclude my presentation with the latest information on the treatment of CMV-infected pregnant women

57 CHIP study: a randomized, double-blind, blind, placebo-controlled, controlled, prospective trial (phase 2B) for the evaluation of the efficacy of CMV-specific hyperimmune globulin Cytotect administered in pregnant women with acute phase of primary CMV infection for prevention of intrauterine transmission (Italian study). Cytotect study: a phase 3 prospective trial for the evaluation of the efficacy of CMV- specific hyperimmune globulin Cytotect administered in pregnant women who seroconverted in the first trimester to protect against transmission of the virus v to the unborn child and thereby prevent injury to the child (European study). Cymeval study: a randomized double-blind blind placebo-controlled controlled prospective trial evaluating the efficacy of valacyclovir (the oral prodrug of acyclovir). The drug is given orally to pregnant women in cases of confirmed fetal CMV infection (amniotic fluid PCR-positive) and with extracerebral signs visible on ultrasound that can be attributed to the infection for the reduction of number of o f cases with unfavourable outcomes (children symptomatic at birth) and medically-indicated indicated terminations of pregnancy (French study). USA - Cytogam (CMV-IGIV) study - Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): a randomized, double-blind, placebocontrolled, prospective trial (phase 3) The purpose of this research study is to determine whether treating pregnant women who have a primary CMV infection with CMV antibodies will reduce the number of babies infected with CMV.

58 CHIP study: a randomized, double-blind, blind, placebo-controlled, controlled, prospective trial (phase 2B) for the evaluation of the efficacy of CMV-specific hyperimmune globulin Cytotect Published administered study in pregnant in NEJM women with acute phase of primary CMV April 3rd, 2014 infection for prevention of intrauterine transmission (Italian study). Cytotect study: a phase 3 prospective trial for the evaluation of the efficacy of CMV- specific hyperimmune globulin Cytotect administered in pregnant women who seroconverted This in was the first an trimester open single-arm to protect against study. transmission of the virus v to the unborn child and This thereby study prevent ended injury to this the child year(european study). and publication expected soon Cymeval study: a randomized double-blind blind placebo-controlled controlled prospective trial evaluating the efficacy of valacyclovir (the oral prodrug of acyclovir). The drug Estimated is given orally Enrollment: to pregnant 43 women Pregnant in cases of women confirmed fetal CMV infection (amniotic fluid PCR-positive) Start Date: and with July extracerebral 2011 signs visible on ultrasound that can be attributed This to the study infection ended for the reduction in 2014of number of o f cases with unfavourable outcomes (children symptomatic at birth) and medically-indicated indicated terminations and of pregnancy publication (French expected study). soon. USA - Cytogam (CMV-IGIV) study - Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): a randomized, double-blind, placebocontrolled, Estimated prospective Enrollment: trial (phase 800 3) Pregnant women The purpose of this Start research Date: study July is to determine 2012 whether treating pregnant women who have a Completion primary CMV infection Date: with December CMV antibodies 2018will reduce the number of babies infected with CMV. This study is currently IN PROGRESS.

59 Bando 2007 NCT C H I P study Congenital HCMV Infection Prevention Nigro G. et al. NEJM 2005 Non randomized study Prevention Group Received HIG NO HIG Revello MG et al. NEJM 2014 Randomized study Prevention Group Received HIG NO HIG Patients hyper-immune globulin therapy/iv 100U per kilogram every month until delivery 100 U per kilogram every month until delivery Congenital CMV 16% 40% 30% 44% P=0.04 P= % 95% CI (-31.7/ +2.2)

60 Current Issue: April 3, 2014

61 UNIVERSITY OF BOLOGNA DIMES - School of Medicine St. Orsola Malpighi University Hospital Operative Unit of Clinical Microbiology Laboratory of Virology L. Gabrielli, G. Piccirilli, C. Pavia, A. Chiereghin Department of Obstetrics and Gynecology G.. Simonazzi, B. Guerra, F. Cervi, N. Rizzo Department of Pediatrics - Division of Neonatology M. Lanari,, M.G. Capretti,, G. Faldella

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