Consensus recommendation for prenatal, neonatal and postnatal management of congenital cytomegalovirus infection from the European congenital infection initiative (ECCI)

Introduction

• We recommend advising women on hygienic measures prior to pregnancy (or as soon as possible once pregnant) especially those known CMV seronegative. Grade B
• We recommend implementing strategies to improve the education of women of childbearing age. Grade C
• We recommend improving knowledge among healthcare professionals caring for pregnant women/childbearing age women. Grade B
• We recommend an EU uniform policy for prevention of primary CMV infection in pregnancy. Grade D
• We recommend that women with equivocal CMV IgG results should be considered as seronegative. Grade D
• We recommend to perform CMV serology in the first trimester of pregnancy as early as possible followed in seronegative women by a retest every 4 weeks until 14–16 weeks. CMV serology is not recommended in pregnant women beyond 16 weeks except in cases with ultrasound CMV compatible symptoms Grade A
• Consideration depending on local CMV epidemiology should be given to CMV serology universal screening in the first trimester in women with unknown CMV serostatus or known as seronegative. Grade D
• We recommend to use IgG and IgM testing to diagnose a maternal primary infection. Grade B
• We recommend using IgG avidity testing to exclude a recent (less than 90 days) maternal primary infection in cases with positive IgM and positive IgG. Grade B
• We recommend using a second avidity test for sera with positive IgM, positive IgG and intermediate IgG avidity value. Grade D
• We do not recommend testing for CMV PCR in blood or in urine since it is not helpful for dating maternal primary infection in women with positive IgG and IgM. Grade B
• In cases with an isolated positive IgM, a CMV PCR test in whole blood may exclude if negative or confirm if positive an ongoing primary infection. Grade D
• We do not recommend testing CMV serology or CMV PCR in blood or urine in women known to be seropositive before pregnancy. Grade B
• We recommend the administration of oral valacyclovir at a dose of 8 g/day in cases with maternal primary infection in the periconceptional period or the first trimester of pregnancy, as early as possible after the diagnosis and until the result of the CMV PCR in amniocentesis. Grade A
• We recommend the dose regiment of 2 g 4 times per day to minimize the risk of renal side effects. Grade D
• We recommend against the administration of hyperimmune globulin, at doses of 100 IU/kg every 4 weeks, in pregnant women with primary CMV infection. Grade A
• Administration of hyperimmune globulin at dose of 200 IU/kg every 2 weeks, in women with very recent primary CMV infection in the first trimester may be considered. Grade C
• We recommend performing CMV PCR in amniotic fluid collected from 17 + 0 weeks gestation for the diagnosis of fetal CMV infection, provided that maternal infection occurred at least 8 weeks earlier. Grade B
• Fetal ultrasound assessment and MRI assessment in the third trimester is recommended in infected fetuses, as it can provide information regarding the presence of CMV associated findings which will provide prognostic information. Grade A
• In women with confirmed fetal infection, fetal treatment with valacyclovir 8 g/day may be considered after discussion with an expert team. Grade C
• We recommend reassurance in women with negative CMV PCR in amniotic fluid since late fetal infection (after the amniocentesis) is not associated with long term sequelae. Grade A
• We recommend performing a CMV PCR on a sample collected in the first three weeks of life to confirm a diagnosis of cCMV. Grade D
• We recommend using CMV PCR on urine or saliva for the diagnosis of cCMV in neonates. A positive CMV PCR on saliva should be confirmed by a CMV PCR on a urine sample. Grade B
• We recommend performing CMV PCR on DBS for retrospective diagnosis of cCMV infection, keeping in mind that the negative predictive value of this test depends on the sensitivity of the assay. Grade A
• We recommend not performing IgM CMV testing in the neonate for cCMV diagnosis. Grade B
• We recommend testing for cCMV in all infants born to mothers with suspected or confirmed primary CMV infection during pregnancy. Grade A
• We recommend testing for cCMV in infants with abnormalities on fetal imaging potentially associated with CMV. Grade D
• We recommend testing for cCMV in any infant with suspected hearing loss at birth. Grade A
• We recommend testing for cCMV in infants with symmetric IUGR (i.e., weight and head circumference both affected) of unknown etiology. Grade D
• We recommend testing very preterm infants (<32 weeks gestational age) or very low birth weight infants (<1500 g) at birth, in order to differentiate between congenital and postnatal CMV infection. Grade D
• We recommend testing for CMV in infants with unexplained symptoms, laboratory abnormalities and/or image findings consistent with cCMV. Grade D
• In cases of unknown type and timing of maternal infection, we recommend performing retrospective maternal serology on stored samples, when available, to determine the type and timing of maternal infection. Grade A
• As the risk of long-term sequelae is similar, we recommend the same investigation of neonates with cCMV, whether maternal infection was primary, non-primary, or unknown. Grade A
• We recommend a complete anthropometric and physical examination at birth. Grade A
• We recommend performing full blood count, liver enzymes and bilirubin (total and conjugated) at birth. Grade A
• We recommend ophthalmologic assessment at birth. Grade A
• We recommend audiologic assessment at birth. Grade A
• We recommend performing an MRI in all infants with clinical manifestations at birth, SNHL, chorioretinitis or abnormalities detected on cUS. MRI could be undertaken in cases of known maternal CMV primary infection during the first trimester, or where timing of transmission is not known. Grade B
• We recommend the use of fetal and neonatal neuroimaging scoring systems to evaluate the individual risk of long-term sequelae. Grade C
• We recommend against lumbar puncture for the diagnosis or assessment of cCMV, even in infants with symptomatic infection. Grade B
• We recommend 6 months of antiviral treatment in newborns with significant CMV-related symptoms at birth. Grade B
• We recommend antiviral treatment in infants with cCMV and isolated hearing loss. Grade C
• We recommend valganciclovir as the treatment of choice. Ganciclovir may be used for infants unable to take enteral medication or in very severe cases, switching to oral route as soon as possible. Grade B
• We recommend checking the full blood count and liver function tests regularly during antiviral treatment. Grade B
• We recommend starting antiviral treatment as soon as possible, and before 1 month of age. Grade A. Treatment initiated between 1 and 3 months may have benefit. After 3 months of age, case-by-case discussion with an expert is recommended. Grade C
• We recommend 6 weeks of antiviral treatment in infants with isolated persistent hepatitis and no other manifestations of cCMV at birth. Grade D
• We recommend 6 weeks of antiviral treatment in infants with isolated persistent thrombocytopenia and no other manifestations of cCMV at birth. Grade D
• We do not recommend treatment of infants with isolated IUGR, without other manifestations of cCMV at birth. Grade D
• Ophthalmological follow-up is only recommended for those infants with retinitis at birth and not required for newborns with normal retinal examination. Grade B
• We recommend that children with cCMV and confirmed transmission in the first trimester or unknown timing of transmission should be follow-up from birth, through treatment, at 6, and 12 months of age, then annually to school age (by Pediatric Infectious Diseases or General Pediatrics). Grade D
• We recommend that children with clinical symptoms at birth and/or evidence of long-term sequelae (neurologic disease, SNHL, chorioretinitis and/or neurodevelopmental impairment) should be seen on an annual basis at least up to 6 years of age to ensure specialized management. Grade A
• We recommend neurodevelopmental assessment at 24–36 months of age in high-risk children, and further follow-up and interventions according to findings. Grade D
• We recommend evaluation by a pediatric neurologist in all children with neurological symptoms and/or significant findings on neuroimaging as well as in children with neurological concerns that arise during follow-up. Grade A
• Asymptomatic children with normal imaging and documented maternal primary infection in the second or third trimester may follow standard pediatric care. Grade A
• In infants with normal hearing at birth, with unknown timing of CMV infection during pregnancy, or known first trimester infection, we recommend hearing follow-up until at least 5 years of age. Grade A
• The estimated risk of delayed SNHL for asymptomatic children without SNHL at birth and with a proven MPI in the second trimester is low, and there is no full consensus on whether these cases need hearing follow-up. Grade D
• In children with a proven MPI in the third trimester and normal hearing at birth, we do not recommend hearing follow-up. Grade A
• In cases of hearing loss at birth, we recommend regular hearing testing for as long as required (can be lifelong). Grade A
• Vestibular screening tests should be performed within the first year of life in high-risk children (those with first trimester maternal infection, with unknown timing of maternal infection, with hearing loss or developmental delay). Grade B