Cytomegalovirus (CMV) in Pregnancy (674)

CMV is a member of the human herpesvirus family and is the most common viral cause of congenital infection, affecting 0.2-2.2% of all live births. It is responsible for significant morbidity, especially for infants who are symptomatic in the neonatal period. It is the leading cause of sensorineural hearing loss (SNHL) and a major cause of neurological disability. Around 10-15% of neonates with congenital infection will be symptomatic at birth, with a similar percentage developing problems later in childhood.

CMV infection may be acquired for the first time during pregnancy (primary infection) or women may experience secondary CMV infection, either by reactivation of prior CMV infection or by a new infection with a different strain of the virus. Transmission is more likely following maternal primary infection than following reactivation or recurrent infection with a different strain.

Table 1: CMV and risk of congenital infection

The risk of congenital infection varies according to gestation at which infection occurs; 30% in the first trimester increasing to 47% in the second trimester. Although transmission is lower earlier in pregnancy, the proportion of cases with a prenatal diagnosis of severe fetal infection is higher when transmission occurs in the first compared with the third trimester. Although CMV transmission is more likely with primary infection, at the population level, especially in populations with high CMV seroprevalence, the majority (around two thirds) of infants with congenital CMV infection are born to women with pre-existing CMV immunity. (Seroprevalence in UK women is 58%)

Transmission of the virus to the fetus can occur antenatally by the transplacental route, during labour and delivery through contact with cervicovaginal secretions and blood or postnatally through breast milk.

The majority of women who acquire CMV infection for the first time (primary infection) will remain asymptomatic. However a minority of women will experience symptoms including fever, malaise, myalgia, cervical lymphadenopathy. Rare complications include hepatitis and pneumonia.

The UK does not offer CMV IgG screening as part of the antenatal screening programme for healthy mothers. There is also no role for CMV screening for pregnant women who work in close contact with young children or who may be in contact with a congenitally infected child. This is because CMV seropositivity does not rule out the risk of congenital CMV infection due to reactivation or reinfection with another strain.

In the following circumstances CMV testing should be considered

1. Pregnant woman with symptoms of fever, malaise, myalgia and or cervical lymphadenopathy where no other aetiology has been found (i.e. respiratory sample is negative)
2. Pregnant woman with hepatitis (defined as LFT’s at least two times above the upper limit of pregnancy specific range) and testing for hepatitis A,B,C and E is negative

Please send an EDTA blood sample for CMV IgM testing. Epstein Barr virus (EBV) IgM is automatically tested along with CMV IgM and there are no implications to the fetus due to maternal EBV infection. Do NOT send a sample for testing if pruritis is the ONLY symptom.

1. Antenatal Ultrasound Findings

Maternal CMV testing should be considered if fetal ultrasound identifies any of the following:

Please send an EDTA blood sample for CMV IgG testing. If this is positive the laboratory will then reflex test the antenatal booking blood for CMV IgG and CMV IgM to look for evidence of past infection or seroconversion. Seroconversion would indicate a primary infection has occurred between the time of the booking blood and the current blood. It will take 6 weeks after maternal infection for the fetus to excrete CMV in urine and this can be reliably detected in amniotic fluid from 20 to 21 weeks gestation.

2. Unexplained Intrauterine death

Placenta should be sent to the West of Scotland Virology centre for CMV PCR. If CMV is detected by PCR then contact the virus laboratory to discuss serological testing on stored maternal blood samples. Regardless of gestation age a placental sample should be sent for testing.

The laboratory can perform both CMV serology and CMV PCR (viral detection) depending on the clinical symptoms, initial laboratory results and the type of sample sent.

Table 2: Samples required for CMV testing

Maternal CMV IgM and CMV IgG

CMV serology testing comprises of IgM, IgG and IgG avidity testing. A CMV IgM positive result alone does NOT indicate primary CMV infection. CMV IgM can be positive due to primary infection, previous infection with persisting IgM levels or cross-reactivity in the laboratory assay. In pregnancy, nonspecific polyclonal stimulation can lead to false positive results in IgM tests. If the patient is IgM positive the laboratory carries out further investigations including CMV IgG testing and CMV avidity. Depending on the gestational age of testing, the laboratory will re-test the antenatal booking blood for CMV IgG and CMV IgM to help clarify the current patient result.

Maternal CMV avidity

CMV avidity measures the maturity of the antibody and can determine if the patient has had a recent CMV infection. A low avidity is suggestive of a recent infection within the past four months.

A condition of the avidity assay used is that it can only be tested on patients where the IgM and IgG are both positive.

Maternal CMV DNA detection by PCR

Maternal Blood: CMV DNA can be detected in maternal blood two to six weeks post infection and will only be tested by the laboratory in cases where the CMV IgM is positive and the CMV IgG is negative. Clinicians should NOT request CMV PCR on maternal blood samples; this will be done internally by the laboratory.

On confirmation of maternal infection, the presence of fetal infection and possible severity can be determined by the following investigations:

Amniocentesis for detection of fetal urinary excretion of CMV: It will take 6 weeks after maternal infection for the fetus if infected to excrete CMV in urine and this can be reliably detected in amniotic fluid from 20 to 21 weeks gestation (the sensitivity of CMV PCR detection before 20 weeks gestation is only 45% (Rawlinson et al 2017)) . If fetal ultrasound has demonstrated anomalies which may also have an association with fetal karyotype anomalies discuss fetal karyotyping at the time of amniocentesis and ensure an adequate sample (40 mls) is obtained for both investigations if indicated.

Antenatal management of confirmed fetal infection

• When fetal CMV infections has been confirmed by amniocentesis, serial ultrasound examination of the fetus (including growth and intracranial anatomy) should be performed every 2-3 weeks until delivery.
• In infected fetuses consider fetal cerebral MRI (T1 and T2 and diffusion sequences) at 28-32 weeks gestation as complementary investigation to ultrasound assessment for fetal brain sequelae.
• In infected fetuses with non-cerebral ultrasound abnormalities consider fetal blood sampling (for platelet count) to aid estimation of prognosis as described below. Fetal blood sampling is associated with a 1% risk of fetal loss but this risk will be significantly greater in thrombocytopenic fetuses.
• In infected fetuses with no ultrasound abnormalities the risk and possible prognostic benefit of fetal blood sampling should be discussed taking into account the estimated timing of fetal infection.

Infected fetuses may be classified into one of three prognostic categories:

1. Asymptomatic fetuses: defined as those with no ultrasound abnormalities, normal cerebral MRI findings and normal platelet count. The prognosis is generally good for these fetuses but with a residual risk of hearing loss. For counselling of the parents with regard to their baby’s post-natal management refer to the GGC guideline Cytomegalovirus (CMV) Congenital Infection in Neonates, WoS MCN guidelines.
2. Severely symptomatic fetuses: defined as those with severe cerebral ultrasound anomalies (e.g. ultrasound findings of microcephaly, ventriculomegaly, intracerebral haemorrhage, MRI findings of white matter abnormalities, cavitation or delayed cortical maturation). The prognosis is poor and counselling including the option of termination should be offered.
3. Mild or moderately symptomatic fetuses: defined as those with thrombocytopenia:
   • Without brain abnormalities OR
   • With an isolated ultrasound finding of hyperechogenic bowel, mild ventriculomegally or isolated calcification

The prognosis of these mild or moderately symptomatic fetuses is uncertain and options include termination of pregnancy or conservative management with ongoing follow up with ultrasound (+/- repeat MRI at a 4-week interval if the latter performed at advanced fetal gestational age would influence parental choice of continuing with the pregnancy or not).

Both hyperimmuneglobulin (HIG) and valaciclovir have been used in clinical trials but there are currently no recommended antiviral treatment options for primary CMV infection in pregnancy. The current treatments for CMV of ganciclovir and foscarnet cannot be given during pregnancy.

No CMV vaccination exits. Prevention is based on reducing contact with CMV contaminated fluids (urine or saliva) in the environment. All pregnant women should be informed in methods to reduce CMV exposure. Preventative measures have been described by Rawlinson et al (2017). These include: (1) wash hands for 15 to 20 seconds with soap and water after changing nappies/ feeding young children or wiping a young child’s nose or saliva, (2) avoid contact with saliva when kissing a child, (3) avoid sharing food, drinks or cooking utensils, (4) do not put a young child’s dummy in your mouth and (5) try to wash down areas that a young child’s urine or saliva may have been e.g. toys

There is no evidence of nosocomial infection from seronegative staff working with CMV infected secretions from a baby as long as standard hand hygiene is adhered to within the neonatal unit (Luck S, Sharland M 2009).

To discuss sample testing or laboratory results contact the West of Scotland Specialist Virology Centre. Email: west.ssvc2@nhs.scot, the email is monitored by the clinical team between 9am - 5pm Monday-Friday and 9am-2pm at weekends. Phone 0141 201 8722  (ask to speak to a member of the clinical team) Monday-Friday 9am-5pm.

If phoning out of hours or weekends please contact the switchboard and ask to speak to the on-call virologist.