Fetal infection: a pragmatic approach to recognition and management

CASE-BASED LEARNING

Fetal infection: a pragmaticapproach to recognitionand managementPriya Agrawal

Joanna Gillham

AbstractViruses and parasites can be transmitted from a pregnant woman to her

fetus via the placenta and can affect development of the fetus. Maternal

infection is often asymptomatic or mild. The implications for the fetus are

dependent on gestation and the presence of maternal immunity. Fetal

infections are a potentially preventable cause of perinatal mortality.

Prenatal diagnosis is often initiated due to exposure of mother to an

infectious contact. Management involves confirmation of maternal infec-

tion and careful consideration of the risks and benefits of fetal diagnosis,

fetal surveillance, intrauterine treatment and possibly a termination of

pregnancy. Empathic and effective counselling of the parents is crucial

and a multidisciplinary approach is important for optimal care. This

review uses cases of two fetal infections to highlight a pragmatic

approach to prenatal diagnosis and management. There is also an over-

view of three other fetal infections which can potentially cause serious

morbidity and mortality.

Keywords cytomegalovirus; parvovirus B19; prenatal diagnosis

Introduction

Fetal infections are a potentially preventable cause of perinatal

mortality. Viruses like rubella, cytomegalovirus, parvovirus,

varicella-zoster virus and parasites like Toxoplasma gondii can

be transmitted from a pregnant woman to her fetus via the

placenta and can affect fetal development. Transplacental

transmission and thus likelihood of fetal infection as well as

consequences for the fetus are dependent on gestation and

possible maternal immunity. This review discusses two fetal

infections in detail, highlighting current approaches to prenatal

diagnosis and management. Routine serum screening is carried

out at booking for rubella, syphilis and hepatitis B. testing is

otherwise initiated, for example for cytomegalovirus, parvovirus

B19 and varicella-zoster, if markers of fetal infection are elicited

on a routine ultrasound scan or in response to maternal exposure

to infection and rarely symptoms of maternal infection. Knowl-

edge of the methods available for prenatal diagnosis and their

Priya Agrawal BMBCh MA MPH is a Specialist Registrar and Academic

Clinical Fellow at St Mary’s Hospital, University of Manchester, UK.

Joanna Gillham MD MRCOG is a Consultant Obstetrician and Sub-specialist

in Maternal and Fetal Medicine at Fetal Management Unit, St Mary’s

Hospital, Hathersage Road, Manchester M13 0JH, UK.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 20:1 22

benefits and limitations is essential for accurate counselling and

treatment of affected pregnant women.

Case 1 (parvovirus)

A 22-year-old woman who is 19 weeks pregnant presents to

you in the antenatal clinic. She has been referred by her

community midwife, as she had contact with a child two weeks

ago who has been diagnosed with parvovirus. She is very

anxious about the well being of her baby.

What would you do?

1. Confirm that the patient has had significant contact

Up to 50% of women are non-immune and thus susceptible to

parvovirus infection. Significant contact is defined as being in the

same room for over 15 min, or face-to-face contact. Transmission

of parvovirus B19 most commonly occurs through respiratory

secretions and hand-to-mouth contact. The incubation period is

5e7 days following exposure, the infected person generally is

infectious for 5e10 days after exposure prior to the onset of the

rash. The person is no longer infectious with the onset of the

rash. The rash can appear up to 18 days following exposure. The

transmissibility of the virus is found to be approximately

50e90% among susceptible household contacts.

2. If contact is confirmed, the pregnant woman should be

investigated for evidence of parvovirus B19 infection

Serum should be collected as soon as possible after contact. The

laboratory will test for parvovirus and rubella despite the clinical

history. Investigation of the serum will facilitate determination of

whether the patient has had a previous infection, susceptibility or

has an acute parvovirus infection (see Figure 1). Serum stored

from booking blood can be tested for evidence of past infection to

help assess the likelihood of an acute seroconversion.

Adults are frequently asymptomatic, although they may

present with erythema infectiosum (fifth disease) e transient

fever, arthralgia and malaise. Transient maternal aplastic crises

can occur in patients with sickle cell anaemia, thalassaemia,

spherocytosis and pyruvate kinase deficiency. Children have

a mild illness presenting with the ‘slapped cheek’ facial rash and

fever. Fetal infection, however, can be serious with fetal hae-

molytic anaemia causing cardiac failure, hydrops and potentially

intrauterine death.

The likelihood of fetal infection and damage to fetus does not

depend on whether maternal infection is asymptomatic or

symptomatic. The risk of adverse outcome to the fetus may be

reduced by active management of the infected fetus.

The presence of IgG is an evidence of previous infection and

confers lifelong immunity. Approximately 50e60% of adults will

have evidence of previous infection. The seroconversion rate in

pregnant women is an indirect measurement of the primary

infection rate and is approximately 1% per year.

Acute parvovirus B19 infection is confirmed on serology. What is

your ongoing management?

3. Seek advice from the Regional Fetal Management Unit

The patient may need to be managed there rather than her

district hospital, depending on local scan expertise.

� 2009 Elsevier Ltd. All rights reserved.

Test for parvovirus B19, IgM and IgG

IgG+

IgM–

IgG–

IgM–

IgG+

IgM+

IgG–

IgM+

Likely past infection

Reassure*

Susceptible to infection

(possibly seroconverting)Possible acute infection

Possible acute infection

Could be false positive

Repeat tests 2–4 weeks later

or consider PCR

Confirm primary infection by

testing for IgG seroconversion

using pre-exposure booking

blood or DNA PCR

Repeat test in 1–2 weeks

Repeat testing negative:

No acute infection but

is susceptible

Acute maternal infection If IgG+ acute maternal

infection confirmed

Investigations for parvovirus B19 infection

* Parvovirus B19 IgM lasts

approximately 4 weeks. Thus failure

to detect parvovirus B19 specific IgM

excludes infection if the serum was

collected within 4 weeks of exposure

in women with no rash or within 4

weeks after onset of rash.

Figure 1

CASE-BASED LEARNING

A multidisciplinary team including virology, neonatologists

and fetal medicine specialists should be involved.

4. Counsel the woman regarding potential risks to the fetus and

the management plan

The risk of maternal infection crossing the placenta to the

fetus is 15% from 5 to 15 weeks, 25% after 15 weeks, increasing

up to 70% towards term. Infection before 20 weeks can lead to

intrauterine death with a 9% excess fetal loss rate. Hydrops

usually occurs 2e4 weeks after maternal parvovirus infection.

On average, there is a 3e10% risk of hydrops following parvo-

virus infection, with approximately a 50% fetal death rate. The

mechanisms suggested include fetal anaemia as the human

parvovirus B19 targets rapidly dividing cells thereby interrupting

red cell production. This, combined with a shorter half-life of

fetal red blood cells leads to the severe anaemia, hypoxia, high

output cardiac failure associated with fetal hydrops. A prospec-

tive study showed that 7.5% of third trimester fetal deaths in

utero were positive for parvovirus B19 in the placental tissues.

Figure 2 Ascites secondary to parvovirus at 23 weeks gestation.


Thus, testing for parvovirus B19 should be offered in this

scenario.

5. Fetal surveillance

Fetal monitoring to identify fetal anaemia, ascites and hydrops

(accumulation of fluid in two compartments) using weekly

ultrasound examinations for up to 12 weeks after maternal

exposure should be performed (see Figure 2). Doppler ultrasound

measurements of the middle cerebral artery peak systolic velocity

(MCA-PSV) are now used to help predict fetal anaemia (see

Figure 3). A study assessing the predictive value of MCS-PSVs

reported that these Doppler studies had 100% sensitivity for

predicting fetal anaemia in the presence of parvovirus.

Fetal MCAs suggest severe anaemia. What are the options?

6.Active management has been shown to improve outcome

30% of cases with fetal hydrops will spontaneously resolve.

However, there is no robust method to distinguish these cases

Figure 3 Transverse head section showing Doppler colour flow on the

middle cerebral artery.


Figure 4 Echogenic bowel. Figure 6 Ventriculomegaly and increased echogenicity of ventricles.

CASE-BASED LEARNING

from those that will progress to intrauterine death. Thus active

management is considered in all cases.

Cordocentesis is used for fetal blood sampling to diagnose

fetal anaemia. It should be done with full facilities available for

immediate intrauterine blood transfusion if fetal anaemia is

confirmed by the laboratory.

Cordocentesis can be performed from 18 weeks onwards.

There is a 1% risk of procedure-associated miscarriage. The

preferred transfusion site is at the umbilical vein insertion into

the placenta, but the intrahepatic umbilical vein or the cardiac

ventricles can be utilized. At later gestations the risk of cor-

docentesis and intrauterine transfusion should be balanced

against the risk of possible premature delivery and neonatal

transfusion.

Fetal transfusion has been shown to improve outcome

although the time taken for resolution of hydrops can vary but

normally occurs within 6 weeks. The woman can be reassured

that following resolution of hydrops, there is no evidence to

show that there are any adverse long-term effects to be

expected.

Figure 5 Severe ventriculomegaly in a fetus with þve CMV-PCR from

amniotic fluid.


Case 2 (cytomegalovirus)

A 27-year-old woman is 17 weeks pregnant. She is a late

booker and gives a vague history of contact with someone with

a rash. She cannot give any more details on the rash or when

she had this contact. The booking midwife requested a TORCH

screen at the time of seeing the patient who has now come to

see you (the obstetrician) at 19 weeks with the following blood

results: CMV IgG negative, CMV IgM positive.

How do you interpret these results?

1. She has an acute cytomegalovirus infection

CMV infection is one of the most common congenital infections

with a reported incidence of 0.5e2%. 50e70% of women have

had previous CMV infection (IgGþ). Both primary and recurrent

infections can lead to fetal infection but risk of transmission and

severity is greater in a primary infection. Primary infection is

usually asymptomatic but can present with vague symptoms of

fever, malaise and lethargy.

CMV IgG is present within 2 weeks of primary infection and is

lifelong.

Figure 7 Large placenta, anhydramnios and intrauterine growth restriction

on a fetus with positive CMV from a chorionic villus biopsy.


A summary of other common fetal infections (presentation, diagnosis and management)

Toxoplasmosis Rubella Varicella-zoster

Proportion of young women susceptible 90% 1e2% 10%

Infection acquired

through.

Ingestion of toxoplasma

tissue cysts in undercooked

meat/cat excrement/contaminated

soil/water

Close contact Close contact

Presentation of primary infection Asymptomatic (60e70%) or

malaise, fever, lymphadenopathy

Asymptomatic or malaise, headache, coryza,

fine maculopapular rash

Fever, malaise, pruritic maculopapular rash

(vesicular)

Risk of transplacental transmission Increases with gestation

<4 weeks e less than 1%

13 weeks e 4e15%

36 weeks e >60%

<11 weeks e 90%

11e16 weeks e 55%

>16 weeks e 45%

<28 weeks e 5e10%

28e36 weeks e 25%

>36 weeks e 50%

Risk of adverse fetal outcome Decreases with gestation <11 weeks e 90%

11e16 weeks e 20%

16e20 weeks e small risk of deafness

>20 weeks e no increased risk

Fetal varicella syndrome (FVS):

<13 weeks e 1%

13e20 weeks e 2%

4 weeks prior to delivery to 7 days post

delivery e 20% neonatal varicella

Sequelae of fetal infection Mainly affects the central nervous

system (CNS) and eyes

Congenital rubella syndrome includes hearing

loss, learning difficulties, cardiac and ocular

defects

FVS includes limb defects, damage to eyes,

skin and CNS

Diagnosis of maternal infection Serological testing for toxoplasma-

specific IgG and IgM

Serological testing for rubella-specific IgG

seroconversion (compared to booking serum)

Serological testing for VZV-specific IgG. It

appears within 10 days and confers lifelong

immunity OR immunofluorescence of lesion

scraping

Diagnosis of fetal infection Amniocentesis for detection of

Toxoplasma gondii DNA in

amniotic fluid

Usually only performed for infections occurring

at 16e20 weeks: amniocentesis for detection

of viral nucleic acid in amniotic fluid or

cordocentesis for detection of RNA or rubella-

specific IgM

Amniocentesis for detection of VZV DNA in

amniotic fluid and ultrasound surveillance

Management Spiramycin if maternal infection

(reduces risk of fetal infection

by 60e70%)

Pyrimethamine/sulfadiazine if

fetal infection confirmed

Ultrasound surveillance

Termination

Termination

Ultrasound surveillance/echocardiography

Termination if FVS on USS <20 weeks

Ultrasound surveillance

VZIG may help

Table 1

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�2009

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CASE-BASED LEARNING

What do you do next?

2. Counsel the woman regarding potential risks to the fetus and

the management plan and offer amniocentesis

The risk of transplacental transmission to the fetus is 40% in the

first and second trimesters. The risk of fetal injury is greatest after

primary CMV and when maternal infection occurs in the first or

early second trimester. The risk of transmission is greater (80%) in

the third trimester but usually asymptomatic after 27 weeks.

Transplacental passage of CMV and thus presumed fetal infec-

tion can be confirmed by detection of CMV DNA in amniotic fluid

by polymerase chain reaction (PCR). If the amniotic fluid CMV-PCR

is negative, the woman can be reassured. Amniocentesis should be

delayed for a minimum of 6 weeks after maternal serum is positive

to allow levels of CMV in the amniotic fluid to be detectable. The

amniocentesis should also be performed after 20e22 weeks

gestation, as fetal diuresis is not established until then. A negative

result before this should be treated with caution as it could be

a false negative due to the CMV levels being too low to be detected.

Fetal infection leads to a variety of sequelae including ocular

defects, sensorineural deafness, intrauterine growth restriction,

microcephaly, hepatosplenomegaly, jaundice, thrombocytopenic

purpura, pneumonitis and neurodevelopmental consequences

such as cerebral palsy. The earlier the fetus is affected, the worse

the severity of disease.

The overall risk of damage in fetuses infected as a result of

primary CMV is approximately 25%. 10% of infected fetuses are

clinically symptomatic at birth, with a reported mortality of 30%

and 90% of the survivors can have severe neurological sequelae.

In the babies who are asymptomatic at birth, a further

10e15% of these develop some long-term sequlae, primarily

sensorineural hearing loss.

3. She should have a detailed ultrasound scan looking for

sonographic features of CMV disease

Sonographic features of CMV include: intrauterine growth

restriction, microcephaly, ventriculomegaly, intracerebral or

hepatic calcifications, leukomalacia and echogenic bowel (see

Figures 4e7).

The fetus is of normal size and there are no fetal abnormalities

seen.

The patient asks you ‘Does this mean my baby is okay doctor?’

What do you say?

Not all infected fetuses will have features of disease seen on

ultrasound imaging. Though the absence of sonographic features


is reassuring, monthly ultrasound surveillance is needed as the

disease may manifest later in pregnancy, at birth or even later as

an infant.

It has been reported that in cases of confirmed CMV vertical

transmission, 19% of cases had postnatal neurological abnor-

malities despite having no prenatal ultrasound abnormalities.

CMV is detected in the amniotic fluid. Another ultrasound scan

shows no fetal abnormalities. The woman understands about

fetal surveillance and wants to know about alternative manage-

ment options.

There are no treatments that are licensed and proven to be

effective in pregnancy. Experimental treatment includes CMV-

specific hyperimmue globulin which may be effective. A termi-

nation of pregnancy can be offered and most centres would offer

this before 24 weeks gestation. However, there may be a case for

a late termination due to the possibility of disease presenting at

birth or later and the associated mortality.

Table 1 gives an overview of other important fetal infections

to be considered. A

FURTHER READING

Greenough A, Osborne J, Sutherland S, eds. Congenital, perinatal and

neonatal infections. Edinburgh: Churchill Livingstone, 1991.

Komischke K, Searle K, Enders G. Maternal serum alpha feto protein and

human chorionic gonadotrophin in pregnant women with acute

parvovirus B19 infection with and without fetal complications. Prenat

Diag 1997; 17: 1039e46.

Morgan-Capner P, Crowcroft NS. 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: 59e71.

Prediction of fetal anaemia with Doppler measurement of the middle

cerebral artery peak systolic velocity in pregnancies complicated by

maternal blood group alloimmunization or parvovirus B19 infection.

Ultrasound Obstet Gynecol 2001 Sep; 18: 232e6.

RCOG Green-top Guideline No. 13, September 2007 e chickenpox in

pregnancy.

Skjoldebrand-Sparre L, Tolfvenstam T, Papadogiannakis N, Wahren B,

Broliden K, Nyman M. Parvovirus B19 infection: association

with third-trimester intrauterine fetal death. BJOG 2000 Apr; 107:

476e80.

Stagno S, Pass RF, Dworski ME, Alford CA. Congenital and perinatal

cytomegalovirus infections. Semin Perinatol 1983; 7: 31e42.

To M, Kidd M, Maxwell D. Prenatal diagnosis and management of fetal

infections. TOG 2009; 11: 108e16.


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Fetal infection: a pragmatic approach to recognition and management