- Email: [email protected]
Dilemmas regarding the use of CMV-specific immunoglobulin in pregnancy
Journal of Clinical Virology 57 (2013) 95–97
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Virology Question and Answer Scheme (VIROQAS)
Dilemmas regarding the use of CMV-specific immunoglobulin in pregnancy C. Evans a,∗ , A. Brooks b , D. Anumba c , M. Raza a a
Department of Virology, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S5 7AU, United Kingdom Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S57 AU, United Kingdom c Department of Obstetrics and Gynaecology, Jessop Women’s Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom b
a r t i c l e
i n f o
Article history: Received 24 September 2012 Received in revised form 4 December 2012 Accepted 7 December 2012
Clinical case A 33-year old pregnant woman received seasonal Influenza vaccination at 15-weeks gestation. The following day she described symptoms of lethargy and over the following 2-weeks experienced dry cough, coryza, marked reduction in exercise tolerance and prominent headaches. Past medical history included a subarachnoid haemorrhage, for which there were no sequelae. She received no regular medications with the exception of folic acid. The patient lived at home with her husband and 2-year old son who attended a nursery. Both were fit and well with no past medical history. A 12-week foetal ultrasound scan had been reported as normal. Due to concerns the patient had regarding her reduction in exercise tolerance she saw her general practitioner at 17-weeks gestation who found nothing remarkable on examination. However blood tests demonstrated an increased ESR of 27 (normal range 1–15), with an elevated alanine transaminase (ALT) of 68 (normal range 0–32) but normal alkaline phosphatase, aspartate transaminase (AST), bilirubin and white cell count. In the light of the elevated ALT a referral was made to the women’s hospital for additional
∗ Corresponding author. Mobile: +44 07963565405. E-mail address: [email protected] (C. Evans). 1386-6532/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2012.12.007
investigations. 3-weeks following initial presentation the symptoms had subsided and repeat blood tests revealed a fall in ALT to 48 with a mild elevation in AST of 36 (normal range 0–33). A series of serological tests were requested for investigation of her symptoms and deranged liver function. Parvovirus IgM and toxoplasma latex agglutination antibodies were negative, rubella antibody test was positive consistent with a history of vaccination. Coxiella burnetii and Chlamydia psittacosis antibodies were negative as was hepatitis A, B and C. Both CMV IgM and EBV IgM assays were strongly reactive (CMV IgM index 128 and EBV IgM > 160). How would you confirm primary CMV in pregnancy? What further investigations should be considered? Are there any treatment interventions in pregnancy that could be considered? Should screening for CMV be offered in pregnancy? What are the cost implications of offering CMV-IVIG to mothers with confirmed foetal CMV infection?
96
C. Evans et al. / Journal of Clinical Virology 57 (2013) 95–97
Virology Question and Answer Scheme (VIROQAS)
How would you confirm primary CMV in pregnancy?
Although other virological methods exist, serology is the mainstay of CMV diagnosis in this clinical setting. 3 different serological markers are commonly used: CMV IgM, IgG and IgG avidity. The gold standard for confirmation of primary infection is demonstration of seroconversion to IgG antibodies. Presence of both IgM and IgG in the same sample necessitates avidity testing which helps in differentiating between a recent and non-recent primary infection.1 Low avidity antibodies can persist up to 18–20 weeks following primary infection.2 Additional results in this clinical case confirmed presence of EBV IgG and EBNA, plus CMV IgG with low avidity. The booking bloods were requested for comparative testing and confirmed presence of EBV EBNA and were negative for CMV IgM and IgG, confirming primary CMV infection during pregnancy. A blood EDTA was requested for CMV PCR, which was negative. In such cases it is important to demonstrate virological immune control in pregnancy with evolution of the CMV avidity test and a negative CMV PCR. Follow up sample results are shown in Table 1. What further investigations should be considered? The next step is to discuss the risk of CMV transmission to the foetus and potential complications. Transmission rates vary according to gestation at time of primary CMV, approximately 33% of infected foetuses are symptomatic at birth.3 Published data on 248 pregnancies confirmed that CMV transmission rates in the first, second and third trimesters were 30.1%, 38.2% and 72.2%, respectively.4 Going by the timing of her symptoms, infection was likely to have occurred around 13–15 weeks gestation, therefore an estimated 40% risk of transmission to the foetus was predicted.5 After detailed discussion regarding the risks and ethical implications of investigation, parents are offered a combination of non-invasive (sequential ultrasound (USS)) and invasive (amniocentesis) methods of determining transmission and potential consequences. To minimise the risk of a false negative result, amniocentesis should be performed 6–7 weeks after the presumed date of infection and after 21 weeks gestation.6 This encompasses the foetal incubation period, allows sufficient time for viral replication, as well as sufficient foetal renal development to enable adequate viral urinary excretion into the amniotic fluid. The false negative rate of CMV PCR on amniotic fluid varies from 0 to 10%, influenced by sample timing, varying PCR detection
systems, viral culture techniques and potential foetal infection post amniocentesis. Optimal timing of amniocentesis is vital as results may influence the decision for termination, which must be viewed in the context of the UK law.7,8 USS is recommended every 2–4 weeks to identify foetal abnormalities and help guide foetal prognosis. Foetal MRI for detection of cerebral abnormalities remains controversial.9 One study demonstrated any ultrasound abnormalities to be an independent predictor of poor outcome (p < 0.001).10 In addition, placental thickening determined by USS has been associated with poor outcome, cut off ranges from 22 to 35 mm, with sensitivity and specificity increasing at 28–32 weeks.3,11 Are there any treatment interventions in pregnancy that could be considered? Observational studies have demonstrated a benefit of CMV specific immunoglobulin (CMV-IVIG) in the prevention of congenital CMV.10,12–14 Some European countries advocate its use in confirmed maternal primary CMV infection, particularly in the first trimester. In Italy national serologic screening has resulted in the evaluation of maternal and foetal diagnostic approaches and the use of CMV-IVIG.13 However, randomised clinical trials are required to confirm efficacy in this setting.3,15 In this case a departmental decision to administer CMV-IVIG was made after detailed discussion regarding the potential risks of this unlicensed treatment. An application was made to the local Primary Care Trust for an urgent Individual Funding Request which was rejected and as a result the patient self-funded. The first dose was administered at 21-weeks gestation. Amniocentesis was performed at 23-weeks with a negative CMV PCR result. The patient and obstetrician decided to administer 2 subsequent doses of CMV-IVIG at 24 and 27-weeks gestation due to the patients concerns regarding false negative CMV PCR. To our knowledge this is the first described case of CMV-IVIG administration in pregnancy in England. Should screening for CMV be offered in pregnancy? Eight European countries (France, Belgium, Spain, Italy, Germany, Austria, Portugal and the Netherlands) plus Israel routinely screen their pregnant women for CMV.16 This has resulted in great advances in the management of CMV in pregnancy. Screening is controversial in the UK due to the lack of a CMV vaccine, lack of evidence for effective treatment of primary infection and poor predictors of foetal outcome. However, serial serological screening would identify the 90% of women who are asymptomatic with primary CMV, which in this symptomatic case was valuable as passive immunisation with CMV-IVIG was prescribed. One study suggests universal screening is the preferred and most cost-effective strategy.17 Overall,
Table 1 The serological profiles for CMV IgM, IgG and CMV avidity over a 4 month period. 27/09/11 Booking sample (12 weeks gestation)
8/11/11 3 weeks into illness
17/11/11 20 weeks gestation
15/12/11 24 weeks gestation
06/01/12 27 weeks gestation
CMV IgM
Neg
Pos Index 131
Not tested
Pos Index 78
CMV IgG
Neg
Pos Index 128 (0–240 AU/ml) Pos Index 0.92 (0–22 IU/ml) Low <0.01 (<0.2 negative >0.3 positive)
Pos Index 0.95
Pos Index 1.9
Pos Index 2.2
Low 0.075
Intermediate 0.265
High 0.352
CMV avidity
C. Evans et al. / Journal of Clinical Virology 57 (2013) 95–97
prevention of CMV acquisition is imperative.18 Evidence suggests if susceptible mothers are aware of their serostatus, education regarding hygiene can influence maternal behaviour and decrease CMV seroconversion.19–21 What are the cost implications of offering CMV-IVIG to mothers with confirmed foetal CMV infection? CMV-IVIG is expensive; however the reduction in sequelae in newborns has been demonstrated to be cost-effective.10 Furthermore, a recent cost benefit analysis found universal screening, with CMV-IVIG for confirmed foetal CMV infection, to be the most cost-effective approach. However, this model demonstrated that if treatment with CMV-IVIG were to achieve less than 47% reduction (relative risk, 0.53) in disease, universal screening would no longer be cost-effective.17 Further studies are required to determine the clinical effectiveness of CMV-IVIG. Funding
5.
6.
7.
8.
9.
10.
11.
12.
No external funding was sourced for this work. 13.
Competing interests None declared by the authors of this article.
14.
Ethical approval No ethical approval was required for the submission of this case report. The case patient has consented to the publication of this article.
15. 16. 17.
References 1. Dollard SC, Staras SA, Amin MM, Schmid DS, Cannon MJ. National prevalence estimates for cytomegalovirus IgM and IgG avidity and association between high IgM antibody titer and low IgG avidity. Clin Vaccine Immunol 2011;18(November (11)):1895–9. 2. Lazzarotto T, Spezzacatena P, Pradelli P, Abate DA, Varani S, Landini MP. Avidity of immunoglobulin G directed against human cytomegalovirus during primary and secondary infections in immunocompetent and immunocompromised subjects. Clin Diagn Lab Immunol 1997;4(July (4)):469–73. 3. Adler SP. Screening for cytomegalovirus during pregnancy. Infect Dis Obstet Gynecol 2011;2011:1–9. 4. Enders G, Daiminger A, Bader U, Exler S, Enders M. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus
18. 19.
20.
21.
97
infection in relation to gestational age. J Clin Virol 2011;52(November (3)): 244–6. Bodeus M, Kabamba-Mukadi B, Zech F, Hubinont C, Bernard P, Goubau P. Human cytomegalovirus in utero transmission: follow-up of 524 maternal seroconversions. J Clin Virol 2010;47(February (2)):201–2. Yinon Y, Farine D, Yudin MH. Screening, diagnosis, and management of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv 2010;65(November (11)):736–43. Lazzarotto T, Varani S, Guerra B, Nicolosi A, Lanari M, Landini MP. Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 2000;137(July (1)): 90–5. Guerra B, Lazzarotto T, Quarta S, Lanari M, Bovicelli L, Nicolosi A, et al. Prenatal diagnosis of symptomatic congenital cytomegalovirus infection. Am J Obstet Gynecol 2000;183(August (2)):476–82. Bonalumi S, Trapanese A, Santamaria A, D’Emidio L, Mobili L. Cytomegalovirus infection in pregnancy: review of the literature. J Prenat Med 2011;5(January (1)):1–8. Nigro G, Adler SP, La Torre R, Best AM, Congenital Cytomegalovirus Collaborating G. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353(September (13)):1350–62. La Torre R, Nigro G, Mazzocco M, Best AM, Adler SP. Placental enlargement in women with primary maternal cytomegalovirus infection is associated with fetal and neonatal disease. Clin Infect Dis 2006;43(October (8)): 994–1000. Buxmann H, Stackelberg OM, Schlosser RL, Enders G, Gonser M, Meyer-Wittkopf M, et al. Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis. J Perinat Med 2012;40(4):439–46. Nigro G, Adler SP, Parruti G, Anceschi MM, Coclite E, Pezone I, et al. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy – a case–control study of the outcome in children. J Infect Dis 2012;205(January (2)):215–27. Visentin S, Manara R, Milanese L, Da Roit A, Forner G, Salviato E, et al. Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis 2012;55(August (4)):497–503. Adler SP, Nigro G. Findings and conclusions from CMV hyperimmune globulin treatment trials. J Clin Virol 2009;46(December (Suppl. 4)):S54–7. Forsgren M. Prevention of congenital and perinatal infections. Euro Surveill 2009;14(March (9)):2–4. Cahill AG, Odibo AO, Stamilio DM, Macones GA. Screening and treating for primary cytomegalovirus infection in pregnancy: where do we stand? A decision-analytic and economic analysis. Am J Obstet Gynecol 2009;201(November (5)), 466 e1–7. Griffiths PD. Strategies to prevent CMV infection in the neonate. Semin Neonatol 2002;7(August (4)):293–9. Revello MG, Fabbri E, Furione M, Zavattoni M, Lilleri D, Tassis B, et al. Role of prenatal diagnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20-year experience. J Clin Virol 2011;50(April (4)):303–7. Vauloup-Fellous C, Picone O, Cordier AG, Parent-du-Chatelet I, Senat MV, Frydman R, et al. Does hygiene counseling have an impact on the rate of CMV primary infection during pregnancy? Results of a 3-year prospective study in a French hospital. J Clin Virol 2009;46(December (Suppl. 4)):S49–53. Johnson J, Anderson B, Pass RF. Prevention of maternal and congenital cytomegalovirus infection. Clin Obstet Gynecol 2012;55(June (2)):521–30.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Virology Question and Answer Scheme (VIROQAS)
Dilemmas regarding the use of CMV-specific immunoglobulin in pregnancy C. Evans a,∗ , A. Brooks b , D. Anumba c , M. Raza a a
Department of Virology, Northern General Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S5 7AU, United Kingdom Department of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S57 AU, United Kingdom c Department of Obstetrics and Gynaecology, Jessop Women’s Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom b
a r t i c l e
i n f o
Article history: Received 24 September 2012 Received in revised form 4 December 2012 Accepted 7 December 2012
Clinical case A 33-year old pregnant woman received seasonal Influenza vaccination at 15-weeks gestation. The following day she described symptoms of lethargy and over the following 2-weeks experienced dry cough, coryza, marked reduction in exercise tolerance and prominent headaches. Past medical history included a subarachnoid haemorrhage, for which there were no sequelae. She received no regular medications with the exception of folic acid. The patient lived at home with her husband and 2-year old son who attended a nursery. Both were fit and well with no past medical history. A 12-week foetal ultrasound scan had been reported as normal. Due to concerns the patient had regarding her reduction in exercise tolerance she saw her general practitioner at 17-weeks gestation who found nothing remarkable on examination. However blood tests demonstrated an increased ESR of 27 (normal range 1–15), with an elevated alanine transaminase (ALT) of 68 (normal range 0–32) but normal alkaline phosphatase, aspartate transaminase (AST), bilirubin and white cell count. In the light of the elevated ALT a referral was made to the women’s hospital for additional
∗ Corresponding author. Mobile: +44 07963565405. E-mail address: [email protected] (C. Evans). 1386-6532/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2012.12.007
investigations. 3-weeks following initial presentation the symptoms had subsided and repeat blood tests revealed a fall in ALT to 48 with a mild elevation in AST of 36 (normal range 0–33). A series of serological tests were requested for investigation of her symptoms and deranged liver function. Parvovirus IgM and toxoplasma latex agglutination antibodies were negative, rubella antibody test was positive consistent with a history of vaccination. Coxiella burnetii and Chlamydia psittacosis antibodies were negative as was hepatitis A, B and C. Both CMV IgM and EBV IgM assays were strongly reactive (CMV IgM index 128 and EBV IgM > 160). How would you confirm primary CMV in pregnancy? What further investigations should be considered? Are there any treatment interventions in pregnancy that could be considered? Should screening for CMV be offered in pregnancy? What are the cost implications of offering CMV-IVIG to mothers with confirmed foetal CMV infection?
96
C. Evans et al. / Journal of Clinical Virology 57 (2013) 95–97
Virology Question and Answer Scheme (VIROQAS)
How would you confirm primary CMV in pregnancy?
Although other virological methods exist, serology is the mainstay of CMV diagnosis in this clinical setting. 3 different serological markers are commonly used: CMV IgM, IgG and IgG avidity. The gold standard for confirmation of primary infection is demonstration of seroconversion to IgG antibodies. Presence of both IgM and IgG in the same sample necessitates avidity testing which helps in differentiating between a recent and non-recent primary infection.1 Low avidity antibodies can persist up to 18–20 weeks following primary infection.2 Additional results in this clinical case confirmed presence of EBV IgG and EBNA, plus CMV IgG with low avidity. The booking bloods were requested for comparative testing and confirmed presence of EBV EBNA and were negative for CMV IgM and IgG, confirming primary CMV infection during pregnancy. A blood EDTA was requested for CMV PCR, which was negative. In such cases it is important to demonstrate virological immune control in pregnancy with evolution of the CMV avidity test and a negative CMV PCR. Follow up sample results are shown in Table 1. What further investigations should be considered? The next step is to discuss the risk of CMV transmission to the foetus and potential complications. Transmission rates vary according to gestation at time of primary CMV, approximately 33% of infected foetuses are symptomatic at birth.3 Published data on 248 pregnancies confirmed that CMV transmission rates in the first, second and third trimesters were 30.1%, 38.2% and 72.2%, respectively.4 Going by the timing of her symptoms, infection was likely to have occurred around 13–15 weeks gestation, therefore an estimated 40% risk of transmission to the foetus was predicted.5 After detailed discussion regarding the risks and ethical implications of investigation, parents are offered a combination of non-invasive (sequential ultrasound (USS)) and invasive (amniocentesis) methods of determining transmission and potential consequences. To minimise the risk of a false negative result, amniocentesis should be performed 6–7 weeks after the presumed date of infection and after 21 weeks gestation.6 This encompasses the foetal incubation period, allows sufficient time for viral replication, as well as sufficient foetal renal development to enable adequate viral urinary excretion into the amniotic fluid. The false negative rate of CMV PCR on amniotic fluid varies from 0 to 10%, influenced by sample timing, varying PCR detection
systems, viral culture techniques and potential foetal infection post amniocentesis. Optimal timing of amniocentesis is vital as results may influence the decision for termination, which must be viewed in the context of the UK law.7,8 USS is recommended every 2–4 weeks to identify foetal abnormalities and help guide foetal prognosis. Foetal MRI for detection of cerebral abnormalities remains controversial.9 One study demonstrated any ultrasound abnormalities to be an independent predictor of poor outcome (p < 0.001).10 In addition, placental thickening determined by USS has been associated with poor outcome, cut off ranges from 22 to 35 mm, with sensitivity and specificity increasing at 28–32 weeks.3,11 Are there any treatment interventions in pregnancy that could be considered? Observational studies have demonstrated a benefit of CMV specific immunoglobulin (CMV-IVIG) in the prevention of congenital CMV.10,12–14 Some European countries advocate its use in confirmed maternal primary CMV infection, particularly in the first trimester. In Italy national serologic screening has resulted in the evaluation of maternal and foetal diagnostic approaches and the use of CMV-IVIG.13 However, randomised clinical trials are required to confirm efficacy in this setting.3,15 In this case a departmental decision to administer CMV-IVIG was made after detailed discussion regarding the potential risks of this unlicensed treatment. An application was made to the local Primary Care Trust for an urgent Individual Funding Request which was rejected and as a result the patient self-funded. The first dose was administered at 21-weeks gestation. Amniocentesis was performed at 23-weeks with a negative CMV PCR result. The patient and obstetrician decided to administer 2 subsequent doses of CMV-IVIG at 24 and 27-weeks gestation due to the patients concerns regarding false negative CMV PCR. To our knowledge this is the first described case of CMV-IVIG administration in pregnancy in England. Should screening for CMV be offered in pregnancy? Eight European countries (France, Belgium, Spain, Italy, Germany, Austria, Portugal and the Netherlands) plus Israel routinely screen their pregnant women for CMV.16 This has resulted in great advances in the management of CMV in pregnancy. Screening is controversial in the UK due to the lack of a CMV vaccine, lack of evidence for effective treatment of primary infection and poor predictors of foetal outcome. However, serial serological screening would identify the 90% of women who are asymptomatic with primary CMV, which in this symptomatic case was valuable as passive immunisation with CMV-IVIG was prescribed. One study suggests universal screening is the preferred and most cost-effective strategy.17 Overall,
Table 1 The serological profiles for CMV IgM, IgG and CMV avidity over a 4 month period. 27/09/11 Booking sample (12 weeks gestation)
8/11/11 3 weeks into illness
17/11/11 20 weeks gestation
15/12/11 24 weeks gestation
06/01/12 27 weeks gestation
CMV IgM
Neg
Pos Index 131
Not tested
Pos Index 78
CMV IgG
Neg
Pos Index 128 (0–240 AU/ml) Pos Index 0.92 (0–22 IU/ml) Low <0.01 (<0.2 negative >0.3 positive)
Pos Index 0.95
Pos Index 1.9
Pos Index 2.2
Low 0.075
Intermediate 0.265
High 0.352
CMV avidity
C. Evans et al. / Journal of Clinical Virology 57 (2013) 95–97
prevention of CMV acquisition is imperative.18 Evidence suggests if susceptible mothers are aware of their serostatus, education regarding hygiene can influence maternal behaviour and decrease CMV seroconversion.19–21 What are the cost implications of offering CMV-IVIG to mothers with confirmed foetal CMV infection? CMV-IVIG is expensive; however the reduction in sequelae in newborns has been demonstrated to be cost-effective.10 Furthermore, a recent cost benefit analysis found universal screening, with CMV-IVIG for confirmed foetal CMV infection, to be the most cost-effective approach. However, this model demonstrated that if treatment with CMV-IVIG were to achieve less than 47% reduction (relative risk, 0.53) in disease, universal screening would no longer be cost-effective.17 Further studies are required to determine the clinical effectiveness of CMV-IVIG. Funding
5.
6.
7.
8.
9.
10.
11.
12.
No external funding was sourced for this work. 13.
Competing interests None declared by the authors of this article.
14.
Ethical approval No ethical approval was required for the submission of this case report. The case patient has consented to the publication of this article.
15. 16. 17.
References 1. Dollard SC, Staras SA, Amin MM, Schmid DS, Cannon MJ. National prevalence estimates for cytomegalovirus IgM and IgG avidity and association between high IgM antibody titer and low IgG avidity. Clin Vaccine Immunol 2011;18(November (11)):1895–9. 2. Lazzarotto T, Spezzacatena P, Pradelli P, Abate DA, Varani S, Landini MP. Avidity of immunoglobulin G directed against human cytomegalovirus during primary and secondary infections in immunocompetent and immunocompromised subjects. Clin Diagn Lab Immunol 1997;4(July (4)):469–73. 3. Adler SP. Screening for cytomegalovirus during pregnancy. Infect Dis Obstet Gynecol 2011;2011:1–9. 4. Enders G, Daiminger A, Bader U, Exler S, Enders M. Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus
18. 19.
20.
21.
97
infection in relation to gestational age. J Clin Virol 2011;52(November (3)): 244–6. Bodeus M, Kabamba-Mukadi B, Zech F, Hubinont C, Bernard P, Goubau P. Human cytomegalovirus in utero transmission: follow-up of 524 maternal seroconversions. J Clin Virol 2010;47(February (2)):201–2. Yinon Y, Farine D, Yudin MH. Screening, diagnosis, and management of cytomegalovirus infection in pregnancy. Obstet Gynecol Surv 2010;65(November (11)):736–43. Lazzarotto T, Varani S, Guerra B, Nicolosi A, Lanari M, Landini MP. Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 2000;137(July (1)): 90–5. Guerra B, Lazzarotto T, Quarta S, Lanari M, Bovicelli L, Nicolosi A, et al. Prenatal diagnosis of symptomatic congenital cytomegalovirus infection. Am J Obstet Gynecol 2000;183(August (2)):476–82. Bonalumi S, Trapanese A, Santamaria A, D’Emidio L, Mobili L. Cytomegalovirus infection in pregnancy: review of the literature. J Prenat Med 2011;5(January (1)):1–8. Nigro G, Adler SP, La Torre R, Best AM, Congenital Cytomegalovirus Collaborating G. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353(September (13)):1350–62. La Torre R, Nigro G, Mazzocco M, Best AM, Adler SP. Placental enlargement in women with primary maternal cytomegalovirus infection is associated with fetal and neonatal disease. Clin Infect Dis 2006;43(October (8)): 994–1000. Buxmann H, Stackelberg OM, Schlosser RL, Enders G, Gonser M, Meyer-Wittkopf M, et al. Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis. J Perinat Med 2012;40(4):439–46. Nigro G, Adler SP, Parruti G, Anceschi MM, Coclite E, Pezone I, et al. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy – a case–control study of the outcome in children. J Infect Dis 2012;205(January (2)):215–27. Visentin S, Manara R, Milanese L, Da Roit A, Forner G, Salviato E, et al. Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis 2012;55(August (4)):497–503. Adler SP, Nigro G. Findings and conclusions from CMV hyperimmune globulin treatment trials. J Clin Virol 2009;46(December (Suppl. 4)):S54–7. Forsgren M. Prevention of congenital and perinatal infections. Euro Surveill 2009;14(March (9)):2–4. Cahill AG, Odibo AO, Stamilio DM, Macones GA. Screening and treating for primary cytomegalovirus infection in pregnancy: where do we stand? A decision-analytic and economic analysis. Am J Obstet Gynecol 2009;201(November (5)), 466 e1–7. Griffiths PD. Strategies to prevent CMV infection in the neonate. Semin Neonatol 2002;7(August (4)):293–9. Revello MG, Fabbri E, Furione M, Zavattoni M, Lilleri D, Tassis B, et al. Role of prenatal diagnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20-year experience. J Clin Virol 2011;50(April (4)):303–7. Vauloup-Fellous C, Picone O, Cordier AG, Parent-du-Chatelet I, Senat MV, Frydman R, et al. Does hygiene counseling have an impact on the rate of CMV primary infection during pregnancy? Results of a 3-year prospective study in a French hospital. J Clin Virol 2009;46(December (Suppl. 4)):S49–53. Johnson J, Anderson B, Pass RF. Prevention of maternal and congenital cytomegalovirus infection. Clin Obstet Gynecol 2012;55(June (2)):521–30.