ToRCH - Laboratory Investigation and Treatment of Suspected Congenital Infection with Cytomegalovirus, Toxoplasma or Rubella ( ToRCH ) in the Neonate

Publication: 30/09/2007  --
Last review: 23/05/2019  
Next review: 01/05/2022  
Clinical Guideline
CURRENT 
ID: 1183 
Approved By:  
Copyright© Leeds Teaching Hospitals NHS Trust 2019  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Laboratory Investigation and Treatment of Suspected Congenital Infection with Cytomegalovirus, Toxoplasma or Rubella (ToRCH) in the Neonate

Introduction

This document is aimed at healthcare workers responsible for the diagnosis and treatment of suspected congenital infection with Toxoplasma gondii, cytomegalovirus or rubella virus in the neonatal setting. The aim is to facilitate the early diagnosis, treatment and long term follow up.

Traditionally, neonatal infection with herpes simplex virus (HSV) is discussed with this group of organisms however the disease associated with this virus is very rarely congenitally acquired and so is discussed separately (see Guideline for the Investigation and Treatment of Suspected Herpes Simplex Virus Infection in the Neonate).

Congenital infection with rubella and cytomegalovirus are associated with significant viral shedding in the neonatal period and as a result may pose an infection risk to other patients on the Neonatal Unit.

Isolation and barrier precautions should be implemented if either diagnosis is suspected.

In most congenital infection it is usually appropriate to investigate both maternal (post-natal and booking samples) and neonatal specimens. This is not usually necessary in congenital CMV as congenital infection may result from either primary infection or reactivation.

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Clinical Features

 

Rubella

CMV

Toxoplasmosis

Low Birth Weight

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Hepatosplenomegaly, jaundice

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Thrombocytopaenia, petechiae

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Purpura

 

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Microcephaly

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Intracranial calcification

 

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Hydrocephalus

 

 

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Pneumonitis

 

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Cataracts

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Chorioretinitis

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Patent ductus arteriosus, lesions of the pulmonary artery and aorta

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Bone defects

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Sensorineural deafness, mental retardation

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Insulin-dependent diabetes mellitus

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Rubella

Since the introduction of the MMR vaccination programme in 1988 the incidence of this disease has markedly reduced (167 cases in 1987 to 1 case in 2003 in England and Wales). As a result, Congenital Rubella Syndrome (CRS) has virtually disappeared. Cases are now only seen where infection is acquired abroad although there is always the risk of a rubella epidemic at some future time in the U.K. A diagnosis of CRS should be considered:-

  1. When there is a history of travel to rubella endemic countries during the first trimester of pregnancy.
  2. Where there has been migration from a rubella endemic country to the UK after the first trimester.

(Contact Consultant Virologist to assist in risk assessment if history of travel)

Investigation

Treatment
No chemotherapeutic agent has been shown to alter clinical state or viral shedding.

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Toxoplasmosis

The incidence of congenital toxoplasmosis in the UK is low at 3.4/100,000 live births(4). Toxoplasma infections during pregnancy may be asymptomatic. The clinical manifestations may vary considerably with over half asymptomatic (see table 1). Most asymptomatic infants will go on to develop signs and symptoms later in life.

Investigation
Neonatal blood that is negative for toxoplasma IgG excludes congenital infection.

Treatment
Treatment has been shown to benefit patients with symptomatic Congenital Toxoplasmosis if given in the first year of life. The evidence for the benefit of treatment of asymptomatic cases is unclear. However, there are data to suggest the development of adverse sequelae of infection in sub clinical cases not given treatment. As a result, current practice suggests treatment of all laboratory confirmed cases of Congenital Toxoplasmosis. The regimen recommended is:

Pyrimethamine:

loading dose

1mg/kg bd orally for day 1 and day 2

 

then

1mg/kg/day orally for 6 months

 

then

1mg/kg/day 3 times per week orally for 6 months

Plus

 

 

Sulfadiazine:

50mg/kg bd orally to complete 1 year duration

Plus

 

 

Calcium folinate:

5mg 3 times a week orally for first month then
10 mg 3 times per week after 1 month age.
for duration of and 1 week after Pyrimethamine therapy.

FBC should be checked regularly while on treatment.

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Cytomegalovirus (CMV)

Aims & Objectives
Summary of Guideline
Background
Diagnosis
Investigation
Treatment / Management
Audit and Monitoring Compliance
References and Evidence levels

Summary of Guideline

This guideline aims to guide the diagnosis and management of babies with symptomatic congenital cytomegalovirus (CMV) infection. Symptomatic CMV infection in the neonate can present with a wide clinical spectrum and significant long term neuro-disability. Symptomatic infection is usually evident at birth or in the early neonatal period.  Diagnosis is made on a constellation of clinical findings and investigations. Treatment with anti-viral agents is indicated in disseminated disease in a sick infant or where there is evidence of neurological disease.

Background

Symptomatic CMV infection in the neonate can present with a wide clinical spectrum and significant long term neuro-disability. Approximately 20% of moderate to severe sensorineural hearing loss in children is attributable to CMV, making it the most common non-genetic cause of deafness in this population 1. There is emerging evidence that treatment of the neonate with symptomatic CMV infection reduces long term hearing loss and may improve neurodevelopmental outcomes2.
Congenital Cytomegalovirus: The greatest risk of transmission to the fetus occurs during maternal primary CMV infection (32%)3 however most congenital infections follow non- primary maternal infections (reactivation or reinfection). While the rate of transmission in CMV seropositive women is very low and babies are rarely symptomatic, the ubiquitous nature of the infection results in a greater population of seropositive pregnant women who then have symptomatic infants4.

Symptomatic infection is usually evident at birth or in the early neonatal period.  About 50% of symptomatic infants will have long term sequelae compared to 10-15% of seemingly asymptomatic cases who subsequently develop sensorineural hearing loss 5.

Perinatal or early postnatal infection: Infection in this period is rarely symptomatic and does not result in neurodevelopmental sequelae6.

Diagnosis

The clinical features of congenital CMV infection include low birth weight, hepatosplenomegaly, jaundice, thrombocytopenia, purpura, microcephaly, chorioretinitis and pneumonitis. Imaging may reveal intracranial calcifications. Sensorineural hearing impairment is identified on audiology assessment.

Testing for CMV can be considered in the intrauterine growth restricted infant (<10th centile for weight or OFC) with no clear antenatal risk factors (for example, smoking, placental factors, low maternal weight) and no obvious genetic or chromosomal abnormality.

Investigation

CMV testing
CMV is present in all bodily fluids (including saliva and urine) and is readily detected by PCR. Urine CMV PCR is the gold standard for testing and is used to make a diagnosis of congenital CMV in neonates under three weeks of age. Over three weeks, a positive urine PCR may also represent perinatal or postnatal infection. A retrospective diagnosis of congenital infection can be made by analysing the dried blood spot (Guthrie card) taken in the first week of life. The sensitivity of this test is approximately 70%7. PCR of saliva samples which are easier to obtain may become more commonly utilized in the future for the assessment of babies who fail their newborn hearing screen.

Serology testing on maternal booking blood if available, may support the diagnosis of congenital infection if primary infection is identified. However as discussed earlier, seropositive pregnancies result in a larger proportion of babies with congenital CMV infection though the transmission rate is low.

Other investigations
Following a positive PCR result, a cranial ultrasound scan, liver function tests, full blood count, audiology screen and ophthalmologic assessments are indicated.

Treatment / Management

Who to treat 3

  1. Symptomatic CMV infection: The unwell symptomatic infant with disseminated infection or an infant with neurological disease (intracranial calcification) will require treatment. What is more difficult to determine is whether to treat neonates presenting with symptoms that are not definitely attributable to CMV, for instance microcephaly, abnormal liver function or hematological derangement. The judgement of the clinician in these cases will be required to decide who to treat based on the presenting clinical symptoms and host immunity.
  2. Otherwise asymptomatic CMV infection with a failed newborn hearing screen. This scenario is more likely to be encountered in the follow up of babies who fail their newborn hearing test. A pathway to ensure a repeat hearing test, CMV sampling and an audiology review within 3 weeks where indicated, is currently being developed.
  3. There is insufficient evidence to support the treatment of asymptomatic CMV infection with a normal newborn hearing screen.

Medication

The antiviral agents used for the treatment of CMV are ganciclovir given intravenously and the oral formulation- valganciclovir.

Early initiation of treatment within three weeks can prevent the development or progression of sensorineural hearing loss and may have a positive impact on neurodevelopmental outcomes. A six-month course of antiviral therapy for symptomatic congenital CMV resulted in 84% improvement or maintenance of normal hearing compared to 59% in untreated neonates. Deterioration in hearing at one year of age occurred in 21% of treated infants versus 68% untreated infants.8
A 2015 RCT by Kimberlin et al. also suggests improvement in neurodevelopmental scores at the age of two following a six month course of treatment compared to six weeks.2

Neutropenia is the predominant acute side effect of concern. Occasionally other bone marrow suppression, renal impairment and increased liver enzymes can occur. These are reversible within 3-7 days of discontinuing medication.

Wang and Smith8 in 2014 reported that a quarter of neonates treated with IV ganciclovir developed neutropenia, with 8.8% having severe neutropenia <0.5x10 9.  However, PO Valganciclovir was not associated with a statistically significant difference in the development of neutropenia compared to placebo in the 2015 RCT by Kimberlin et al. A transient transaminitis occurred around 4 to 5 months of therapy but was not shown to be clinically significant.2
Ganciclovir and valganciclovir are both considered potential carcinogens and teratogens so care should be taken with handling.10

Dosage:
Non-life threatening infection:
Oral Valganciclovir 16mg/kg/dose twice a day for six months. (level B evidence 2) Dose adjustment with weight is required.
Severe or disseminated infection:
Intravenous ganciclovir 6mg/kg/dose twice a day. Intravenous medication should be followed by oral valganciclovir to complete a six month course. (level B evidence)9,2
Monitoring for intravenous ganciclovir:
 FBC, LFTs,U+Es - alternate days for the first week of treatment
                       Weekly for six weeks
                       Alternate weeks for one month
                       Monthly till end of therapy or switch to oral
Monitoring for Oral Valganciclovir (level C evidence)
FBC -weekly for 6 weeks
         Alternate weeks for one month
         Monthly till end of therapy
LFT's- end of week one
           Monthly subsequently

Viral load
While there is no clear correlation between viral load and symptoms and levels are not used to determine duration of therapy, levels may be helpful for dose adjustment in the unwell infant on intravenous therapy.

Source isolation
CMV is a ubiquitous virus resulting in infection of the majority of the population. Discussion with the local infection prevention and control team may be warranted.

Follow up
Neonatal follow up till the age of two is recommended given the potential long term neurodevelopmental effects of congenital infection.
The initial ophthalmologic assessment will determine whether further monitoring is required. An established pathway within audiology exists for the follow up of children with symptomatic congenital CMV.

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Provenance

Record: 1183
Objective:

Effective investigation of infants with suspected ToRCH infection

(Cytomegalovirus (CMV)
Aims

To guide the diagnosis and management of babies with symptomatic congenital cytomegalovirus (CMV) infection

Objectives
To provide evidence-based recommendations for appropriate investigation and management of babies with suspected symptomatic congenital CMV infection

Clinical condition:

Congenital infection

Target patient group: Newborn Infants
Target professional group(s): Secondary Care Doctors
Midwives
Secondary Care Nurses
Adapted from:

Evidence base

  1. Congenital rubella syndrome births (source: National Congenital rubella Surveillance Programme 1971-2004) and rubella-associated terminations (source: Office for National Statistics 1971-2003)
  2. P Morgan-Capner, NS Crowcroft, on behalf of the PHLS Joint Working Party of the Advisory Committees of Virology and Vaccines and Immunisation. Guidelines on the management of, and exposure to, rash illness in pregnancy (including consideration of relevant antibody screening programmes in pregnancy). Commun. Dis. Public Health.2002; 5(1): 59-71.
  3. Salisbury D., Ramsay M., Noakes K., editors. Immunisation Against Infectious Disease - “The Green Book”. 3rd ed. London: TSO; 2006.
  4. Gilbert R., Tan H. R., Cliffe S., Guy E., Stanford M. Symptomatic toxoplasma infection due to congenital and postnatally acquired infection. Archives of Disease in Childhood. 2006; 91:495-498
  5. Collier L., Oxford J. Intrauterine and Perinatal Infections In: Human virology. 2nd ed. Oxford: OxfordUniversity Press. 2000. p. 215-223
  6. Crumpacker C. S., Wadhwa S. Cytomegalovirus. In: Mandell G. L., Bennett J. E., Dolin R., editors. Principles and Practice of Infectious Diseases. 6th ed. Pennsylvania: Elsevier. 2005. p. 1786-1801
  7. Montoya J. G., Kovacs J. A., Remington J. S. Toxoplasma gondii. In: Mandell G. L., Bennett J. E., Dolin R., editors. Principles and Practice of Infectious Diseases. 6th ed. Pennsylvania: Elsevier. 2005. p. 3170-3198
  8. Gershon A. A. Rubella (German Measles). In: Mandell G. L., Bennett J. E., Dolin R., editors. Principles and Practice of Infectious Diseases. 6th ed. Pennsylvania: Elsevier. 2005. p. 1921-1926
  9. Remington J. S., McLeod R., Thulliez P., Desmonts G. Toxoplasmosis. In: Remington J. S., Klein J. O., Wilson C. B., Baker C. J., editors. Infectious Diseases of the Fetus and Newborn Infant. 6th ed. Philadelphia: Elsevier. 2006. p. 947-1091
  10. Stagno S., Britt W. Cytomegalovirus Infections. In: Remington J. S., Klein J. O., Wilson C. B., Baker C. J., editors. Infectious Diseases of the Fetus and Newborn Infant. 6th ed. Philadelphia: Elsevier. 2006. p. 739-781.
  11. Great Ormond Street Hospital Medicines Formulary.
  12. Management of congenital cytomegalovirus infection: an evidence-based approach. Gandhi Acta Paediatrica,  v. 99  no. 4, pp. 509-15  Date: 2010
  13. Recommendations of the clinical virology network in response to British Association of Paediatric Audiologist (BAPA) 2009 Guidance

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References  and Evidence levels (Cytomegalovirus (CMV)):

  1. Grosse SD et al. Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment. J Clin Virol. 2008 Feb;41(2):57-62. Epub 2007 Oct 24
  2. Kimberlin DW, Jester PM, Sanchez PJ, et al. Valganciclovir for symptomatic congenital cytomegalovirus disease. N Engl J Med 2015; 372:933–943
  3. Uptodate. Congenital cytomegalovirus infection: Clinical features and diagnosis. Gail J Demmler-Harrison, MD
  4. Chengbin Wang, Xingyou Zhang, Stephanie Bialek, Michael J. Cannon; Attribution of Congenital Cytomegalovirus Infection to Primary Versus Non-Primary Maternal Infection, Clinical Infectious Diseases, Volume 52, Issue 2, 15 January 2011, Pages e11–e13, https://doi.org/10.1093/cid/ciq085
  5. Hearing loss and congenital CMV infection: a systematic review. Goderis J, De Leenheer E, Smets K, Van Hoecke H, Keymeulen A, Dhooge I Pediatrics. 2014;134(5):972. 
  6. Mussi-Pinhata, Marisa Márcia et al. Perinatal or early-postnatal cytomegalovirus infection in  preterm infants under 34weeks gestation born to CMV-seropositive mothers within a high-seroprevalence population. 2004.The Journal of Pediatrics , Volume 145 , Issue 5 , 685 - 688
  7. Yamamoto AY et al. Usefulness of blood and urine samples collected on filter paper in detecting cytomegalovirus by the polymerase chain reaction technique. 2001. J Virol Methods. 2001 Sep;97(1-2):159-64
  8. .Wang, Yu, and Katherine P. Smith. “Safety of Alternative Antiviral Agents for Neonatal Herpes Simplex Virus Encephalitis and Disseminated Infection.” The Journal of Pediatric Pharmacology and Therapeutics : JPPT 19.2 (2014): 72–82. PMC. Web. 17 Apr. 2017.
  9. Kimberlin DW, Lin CY, Sanchez PJ, et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003; 143:16–25
  10. BFNC. August 2018. Valganciclovir. Handling and storage

Strength of evidence
A. Meta-analyses, randomised controlled trials/systematic reviews of RCTs
B. Robust experimental or observational studies
C. Expert consensus.
D. Leeds consensus. (where no national guidance exists or there is wide disagreement with a level C recommendation or where national guidance documents contradict each other)

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Document history

LHP version 1.0

Related information

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