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Fetal viral infection: a pragmatic approach to recognition and management
CASE-BASED LEARNING
Fetal viral infection: a pragmatic approach to recognition and management
exposure to infection and, rarely, symptoms of maternal infection. Knowledge of the methods available for prenatal diagnosis, and their benefits and limitations, is essential for accurate counselling and treatment of affected pregnant women.
Case 1 (Parvovirus) A 26-year old woman presents to you in the antenatal clinic at 22 weeks gestation. She has been referred by her community midwife because she works in a nursery and two children there have been diagnosed with parvovirus infections. She is very anxious about the well-being of her baby.
Sarah Hamilton Joanna Gillham
What would you do?
Abstract
Firstly, you should confirm that the patient has had significant contact by taking a targeted history. 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 minutes, or face-to-face contact of any duration. Parvovirus is infectious prior to the development of the rash and clarification is therefore needed as to when the patient was in contact with the infected children. Transmission of parvovirus B19 most commonly occurs through respiratory secretions and hand-to-mouth contact. The incubation period is 4e14 days following exposure; the infected person generally is infectious for 7e10 days after exposure, prior to the onset of the rash. The person is no longer infectious one day after the rash appeared. 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.
Viruses can be transmitted from a pregnant woman to her fetus via the placenta and can affect development and growth. Maternal infection is often asymptomatic or mild. The implications for the fetus are dependent on gestation, stage of organogenesis, the presence of maternal immunity and the virus type. Fetal infections are a potentially preventable cause of perinatal morbidity and mortality. Prenatal diagnosis is often initiated due to exposure of mother to an infectious contact. Management involves confirmation of maternal infection and careful consideration of the risks and benefits of fetal diagnosis, fetal surveillance, intrauterine treatment and possibly termination of pregnancy. Empathic and effective counselling of the parents is crucial and a multidisciplinary approach is important for optimal care. This case based review follows three pregnancies to illustrate a pragmatic approach to the prenatal diagnosis and management of three common fetal viral infections.
Keywords chickenpox; congenital infection; cytomegalovirus; parvovirus B19; prenatal diagnosis; vertical transmission
The lady has been confirmed as having significant contact. What would you do next? Introduction
Serum should be collected as soon as possible after contact to investigate for evidence of parvovirus. 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, is still susceptible, or has had an acute parvovirus infection (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. Although fetal infection does not appear to cause teratogenicity it can, however, cause profound fetal anaemia through transient bone marrow suppression which can result in cardiac failure, non-immune hydrops and potentially intrauterine death. The likelihood of fetal infection and damage to the fetus is not dependent on whether maternal infection is asymptomatic or symptomatic. The risk of adverse outcome to the fetus may be reduced by active management of the pregnancy when maternal seroconversion has occurred. The presence of IgG is evidence of previous infection and confers lifelong immunity. Approximately 50e60% of adults will
Fetal infections are a potentially preventable cause of perinatal morbidity and mortality. Viruses such as rubella, cytomegalovirus, parvovirus and varicella-zoster virus can be transmitted vertically from a pregnant woman via the placenta and can affect fetal development. The likelihood of fetal infection, and indeed the consequences of infection for the fetus, via transplacental transmission are dependent on the presence of maternal immunity and gestational age. This review discusses three fetal infections in detail, highlighting current approaches to prenatal diagnosis and management. Routine serum screening is carried out at booking for syphilis and hepatitis B. Viral testing is otherwise initiated, for example for cytomegalovirus, parvovirus B19 and varicella zoster, if markers of fetal infection are identified on a routine ultrasound scan or in response to maternal
Sarah Hamilton MBCHB MRCOG is a Subspecialty Trainee in Maternal and Fetal Medicine at St Mary’s Hospital, Manchester, UK. Conflicts of interest: none declared. Joanna Gillham MD MRCOG is a Consultant Obstetrician and Subspecialist in Maternal and Fetal Medicine at St Mary’s Hospital, Manchester, UK. Conflicts of interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-
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Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
CASE-BASED LEARNING
How should a woman in this situation be counselled regarding the potential risks to the fetus, and how should the pregnancy be managed?
EXPOSED TO PARVOVIRUS
The risk of maternal infection crossing the placenta to the fetus is 15% from 5 to 15 weeks, 25% after 15 weeks and increasing up to 70% towards term. Infection before 20 weeks can lead to intrauterine death, with a 5e10% fetal loss rate. Infection after 20 weeks results in a 0.5% fetal loss rate. There is a 3e10% risk of hydrops developing over the next eight weeks following parvovirus infection, resulting in fetal death in approximately 50% of cases. The key mechanism causing hydrops is the development of severe 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 prospective study showed that 7.5% of third trimester fetal deaths in utero were positive for parvovirus B19 in the placental tissues. Thus, testing for parvovirus B19 should be offered in this scenario. Weekly ultrasound monitoring is necessary to identify fetal anaemia, ascites and hydrops (accumulation of fluid in 2 compartments) for up to 12 weeks after maternal exposure (Figure 2 a and b). Doppler ultrasound measurements of the middle cerebral artery peak systolic velocity (MCA-PSV) are used to help predict fetal anaemia. (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.
TEST FOR IgM AND IgG
IgG + IgM -
IgG + IgM + / – IgG IgM +
IgG- IgM -
PAST INFECTION IMMUNE - REASSURE POSSIBLE RECENT INFECTION
COUNSEL RETEST IN 2 WEEKS
MCA DOPPLER FOLLOW UP
HYDROPS OR RAISED MCA DOPPLERS
CORDOCENTESIS AND FETAL BLOOD TRANSFUSION
NO EVIDENCE OF HYDROPS OR ANAEMIA
RESCAN EVERY 1- 2 WEEKS
Figure 1 Serology testing for parvovirus.
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. The lady should be advised to avoid contact with other pregnant women and people who are immunosuppressed until she is no longer infectious.
The Fetal MCA Doppler peak systolic velocity suggests anaemia. What are the options? 30% of cases with fetal hydrops will spontaneously resolve. However, there is no robust method to distinguish these cases 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. Cordocentesis can be performed from 18 weeks onwards. There is a 1e2% 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
Her recent serology is reported as IgG positive and IgM positive for parvovirus B19 infection. Her antenatal screening serology was negative for both IgG and IgM. What is your ongoing management? She has had an acute parvovirus infection and her care should be discussed with the regional Fetal Medicine Unit. She may need to be managed there rather than her district hospital, depending on local scan expertise. A multidisciplinary team including virology, neonatologists and fetal medicine specialists should be involved.
Figure 2 (a) Pleural effusion; (b) Ascites.
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Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
CASE-BASED LEARNING
reactivation. Low avidity IgG is found within the blood 1 week after a recent infection. The immune response matures to show high avidity IgG by 12e16 weeks following an infection, and remains high from this point onwards. Therefore, a low avidity IgG would represent a more recent infection.
What do you do next? The woman should be referred to local fetal medicine services for more detailed counselling regarding the potential risks to the fetus, and options for further management. 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 without significant consequence to the fetus after 27 weeks gestation. Transplacental passage of CMV, and thus presumed fetal infection, 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. As the virus replicates in the fetal kidney it is shed in the fetal urine. Therefore, amniocentesis to detect the virus should be performed after this latency period, and after 21 weeks gestation, as fetal diuresis is not established until then. A negative result before this time 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 can lead 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 suffering neurological sequelae. Of babies who are asymptomatic at birth, 10e15% develop long term sequelae, primarily sensorineural hearing loss. The woman who has evidence of a primary infection, or a reactivation, should be offered a detailed ultrasound scan specifically looking for sonographic features of CMV disease, which include intrauterine growth restriction, microcephaly, ventriculomegaly, intracerebral or hepatic calcifications, leukomalacia and echogenic bowel. (Figures 4 and 5). These features are also found in other infections and cannot be regarded as diagnostic. Testing for maternal CMV infection should form part of the routine assessment of pregnancies with a very small fetus with an abdominal circumference or estimated fetal weight of less than the fifth centile.
Figure 3 MCA doppler screening for fetal anaemia.
ventricles, can be utilized if access to the placental cord insertion is difficult. At later gestations, the risk of cordocentesis and intrauterine transfusion should be balanced against the risk of possible premature delivery. Usually, one intrauterine transfusion is sufficient. The fetal bone marrow suppression will resolve, and fetal red cell production will resume. Fetal transfusion has been shown to improve outcome although the time taken for resolution of hydrops can vary, normally occurring within 6 weeks. The woman can be reassured that following resolution of hydrops, there is no evidence to show that there are any long term adverse consequences of fetal parvovirus infection with severe anaemia.
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? The maternal serology suggests that she has had an acute cytomegalovirus infection. CMV infection is one of the most common congenital infections with a reported incidence of 0.2e2.2%. 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. Maternal 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 life-long. The presence of CMV IgM suggests a recent infection, or reactivation, but there are also ‘persistent IgM secretors’. If the booking sample is negative for CMV IgG, an infection during this current pregnancy can be assumed. Avidity testing may be helpful in helping to clarify the timing of a primary infection, or if IgG and IgM are both positive. Avidity testing can be helpful in distinguishing between and primary CMV infection or a
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-
The amniocentesis is performed, the fetus is of normal size and there are no fetal abnormalities seen on scan. The patient wants to know whether she can be reassured by the normal scan findings. What advice would you give? The absence of sonographic features is reassuring, however, only 25% of infected fetuses will demonstrate ultrasound features.
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Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
CASE-BASED LEARNING
Case 3 (Chicken pox) A GP contacts you for advice. A 32-year old woman who is 18 weeks pregnant has attended his clinic because her 4 year old daughter has just developed a rash which she suspects is chicken pox. The GP is asking your advice about how to proceed as the woman does not think she has ever had chicken pox.
What would your advice be? It is important to identify whether there has been significant contact, the type of varicella zoster virus (VZV) infection and the timing of the exposure. In this situation there has obviously been significant contact. Chicken pox is infectious for 2 days prior to the outbreak of the rash and remains infectious until the last vesicle has crusted over. Significant contact is considered face-toface contact or presence in the same room for 15 minutes. If the woman is unsure whether she has previously had chicken pox it is possible to use her antenatal booking serology blood test to check for VZV IgG (evidence of previous infection). If VZV IgG is present, the woman can be reassured and no further treatment is necessary. Up to 90% of woman in this country will be VZV IgG positive and therefore immune.
Figure 4 Echogenic bowel.
The GP contacts you again 48 hrs later, stating that the woman is VZV IgG negative and asks how should he proceed. What would you advise? You should advise that VZIG should be administrated at the earliest opportunity if the woman is still within 10 days of initial exposure, as this is thought to prevent chicken pox developing or reduce the severity of any infection. It may also reduce the risk of the baby developing fetal varicella syndrome (FVS). The woman should be advised that if she develops a rash she should contact her GP immediately. Consideration should be given to commencing Aciclovir, if she presents within 24 hours of developing the rash, as this can reduce the length of the symptoms of chicken pox. The dose used in the randomised controlled study was 800 mg five times a day. She should also be warned that if she develops any respiratory symptoms or deteriorates following development of the rash she should attend the hospital. Pregnant women with chickenpox, who require review in hospital, should be seen in locations other than the maternity department to prevent exposure of other non-immune pregnant women, and newborns.
Figure 5 Severe ventriculomegaly in a fetus with positive CMV-PCR from amniotic fluid.
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 abnormalities despite having no prenatal ultrasound abnormalities. The role of MRI in these cases maybe beneficial.
This woman has the VZIG but then goes on to have a very mild chicken pox infection. What follow up should she have with regards to the baby?
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 management options
She should be informed that the chance of her baby developing FVS is low, particularly because she received the immunoglobulin. FVS occurs in approximately 1e2% of pregnancies where chickenpox occurs at less than 20 weeks’ gestation, and less than this if VZIG has been given in a timely manner. She should be followed up by the local fetal medicine department for screening for FVS; the first scan should be approximately 5 weeks following the infection. FVS syndrome is characterised by microcephaly, mental retardation, bowel or bladder dysfunction, eye defects such as cataracts or chorioretinitis and limb hypoplasia.
There are no treatments that are licensed and proven to be effective in pregnancy. Experimental treatment includes CMVspecific hyperimmune globulin which may be effective. A termination 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 its associated mortality.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-
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Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-
Rubella
Varicella-zoster
60e90% Ingestion of toxoplasma tissue cysts in undercooked meat/cat excrement/ contaminated soil/water Asymptomatic (60e70%) or malaise, fever, lymphadenopathy Increases with gestation <4 weeks e less than 1% 13 weeks e 4e15% 36 weeks e >60% Decreases with gestation
1e2% Close contact
10% Close contact
Asymptomatic or malaise, headache, coryza, fine maculopapular rash <11 weeks e 90% 11e16 weeks e 55% >16 weeks e 45%
Fever, malaise, pruritic maculopapular rash (vesicular) <28 weeks e 5e10% 28e36 weeks e 25% >36 weekse50%
<11 weeks e 90% 11e16 weeks e 20% 16e20 weeks e small risk of deafness >20 weeks e no increased risk
Sequelae of fetal infection
Mainly affects the central nervous system (CNS) and eyes
Diagnosis of maternal infection
Serological testing for toxoplasma-specific IgG and IgM
Congenital rubella syndrome includes hearing loss, learning difficulties, cardiac and ocular defects Serological testing for rubella-specific IgG seroconversion (compared to booking serum)
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 FVS includes limb defects, damage to eyes, skin and CNS
Diagnosis of fetal infection
Amniocentesis for detection of toxoplasma gondii DNA in amniotic fluid
Management
Spiramycin if maternal infection may reduce risk of fetal infection. Pyrimethamine/sulfadiazine if fetal infection confirmed. Ultrasound surveillance. Offer termination.
Proportion of young women susceptible Maternal infection acquired by.
Presentation of primary infection Risk of transplacental transmission
Risk of adverse fetal outcome
Ó 2018 Published by Elsevier Ltd.
Table 1
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 rubellaspecific IgM. Offer termination. Ultrasound surveillance/echocardiography
Serological testing for VZV-specific IgG. It appears within 10 days and confers lifelong immunity OR immunofluorescence of lesion scraping Amniocentesis for detection of VZV DNA in amniotic fluid and ultrasound surveillance
Offer termination if FVS on USS <20 weeks. Ultrasound surveillance. VZIG may help
CASE-BASED LEARNING
Toxoplasmosis
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Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
A summary of other common fetal infections (presentation, diagnosis and management)
CASE-BASED LEARNING
RCOG. Green-top guideline No. 13, September 2007 e chickenpox in pregnancy. € ldebrand-Sparre L, Tolfvenstam T, Papadogiannakis N, Wahren B, Skjo Broliden K, Nyman M. Parvovirus B19 infection: association with third-trimester intrauterine fetal death. BJOG 2000 Apr; 107: 476e80. SOGC. Clinical practice guideline No 240 April 2010 cytomegalovirus infection in pregnancy. 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. The Obstetrician & Gynaecologist 2009; 11: 108e16.
Amniocentesis can be offered to identify whether there is VZV DNA is present within the amniotic fluid. This test has a strong negative predictive value but a poor positive predictive value. Therefore if there is no VZV DNA present in the amniotic fluid, the women can be reassured. However, if it is positive, a large proportion of these babies will be born with no evidence of FVS. Neonatologists should be informed about any baby that has been exposed to varicella virus while in utero. A summary of other fetal infections is shown in Table 1. A FURTHER READING Delle Chiaie L, Buck G, Grab D, Terinde R. 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. Guidance on Viral Rash in Pregnancy. Investigation, diagnosis and management of viral rash illness or exposure to viral rash illness in pregnancy. Health Protection Agency Rash Guidance Working Group January, 2011. Hutto C. Congenital and Perinatal Infections- a concise guide to diagnosis. Humana Press, 2006. Lamont RF, Sobel JD, Vaisbuch E, Kusanovic JP, Mazaki-Tovi S, Kim SK, Uldbjerg N, Romero R. Parvovirus B19 infection in human pregnancy. BJOG 2011; 118: 175e86.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-
Practice points C
C
C
C
C
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Maternal infections in pregnancy can lead to detrimental effects on the developing fetus. Careful history, investigations and follow up are necessary components of management. Parvovirus B19 is not teratogenic but can cause profound fetal anaemia. The absence of ultrasound features of infection does not guarantee that fetal infection has not occurred. Primary maternal infections in pregnancy tend to cause the most harm to the developing fetus.
Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
Fetal viral infection: a pragmatic approach to recognition and management
exposure to infection and, rarely, symptoms of maternal infection. Knowledge of the methods available for prenatal diagnosis, and their benefits and limitations, is essential for accurate counselling and treatment of affected pregnant women.
Case 1 (Parvovirus) A 26-year old woman presents to you in the antenatal clinic at 22 weeks gestation. She has been referred by her community midwife because she works in a nursery and two children there have been diagnosed with parvovirus infections. She is very anxious about the well-being of her baby.
Sarah Hamilton Joanna Gillham
What would you do?
Abstract
Firstly, you should confirm that the patient has had significant contact by taking a targeted history. 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 minutes, or face-to-face contact of any duration. Parvovirus is infectious prior to the development of the rash and clarification is therefore needed as to when the patient was in contact with the infected children. Transmission of parvovirus B19 most commonly occurs through respiratory secretions and hand-to-mouth contact. The incubation period is 4e14 days following exposure; the infected person generally is infectious for 7e10 days after exposure, prior to the onset of the rash. The person is no longer infectious one day after the rash appeared. 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.
Viruses can be transmitted from a pregnant woman to her fetus via the placenta and can affect development and growth. Maternal infection is often asymptomatic or mild. The implications for the fetus are dependent on gestation, stage of organogenesis, the presence of maternal immunity and the virus type. Fetal infections are a potentially preventable cause of perinatal morbidity and mortality. Prenatal diagnosis is often initiated due to exposure of mother to an infectious contact. Management involves confirmation of maternal infection and careful consideration of the risks and benefits of fetal diagnosis, fetal surveillance, intrauterine treatment and possibly termination of pregnancy. Empathic and effective counselling of the parents is crucial and a multidisciplinary approach is important for optimal care. This case based review follows three pregnancies to illustrate a pragmatic approach to the prenatal diagnosis and management of three common fetal viral infections.
Keywords chickenpox; congenital infection; cytomegalovirus; parvovirus B19; prenatal diagnosis; vertical transmission
The lady has been confirmed as having significant contact. What would you do next? Introduction
Serum should be collected as soon as possible after contact to investigate for evidence of parvovirus. 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, is still susceptible, or has had an acute parvovirus infection (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. Although fetal infection does not appear to cause teratogenicity it can, however, cause profound fetal anaemia through transient bone marrow suppression which can result in cardiac failure, non-immune hydrops and potentially intrauterine death. The likelihood of fetal infection and damage to the fetus is not dependent on whether maternal infection is asymptomatic or symptomatic. The risk of adverse outcome to the fetus may be reduced by active management of the pregnancy when maternal seroconversion has occurred. The presence of IgG is evidence of previous infection and confers lifelong immunity. Approximately 50e60% of adults will
Fetal infections are a potentially preventable cause of perinatal morbidity and mortality. Viruses such as rubella, cytomegalovirus, parvovirus and varicella-zoster virus can be transmitted vertically from a pregnant woman via the placenta and can affect fetal development. The likelihood of fetal infection, and indeed the consequences of infection for the fetus, via transplacental transmission are dependent on the presence of maternal immunity and gestational age. This review discusses three fetal infections in detail, highlighting current approaches to prenatal diagnosis and management. Routine serum screening is carried out at booking for syphilis and hepatitis B. Viral testing is otherwise initiated, for example for cytomegalovirus, parvovirus B19 and varicella zoster, if markers of fetal infection are identified on a routine ultrasound scan or in response to maternal
Sarah Hamilton MBCHB MRCOG is a Subspecialty Trainee in Maternal and Fetal Medicine at St Mary’s Hospital, Manchester, UK. Conflicts of interest: none declared. Joanna Gillham MD MRCOG is a Consultant Obstetrician and Subspecialist in Maternal and Fetal Medicine at St Mary’s Hospital, Manchester, UK. Conflicts of interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE --:-
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Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
CASE-BASED LEARNING
How should a woman in this situation be counselled regarding the potential risks to the fetus, and how should the pregnancy be managed?
EXPOSED TO PARVOVIRUS
The risk of maternal infection crossing the placenta to the fetus is 15% from 5 to 15 weeks, 25% after 15 weeks and increasing up to 70% towards term. Infection before 20 weeks can lead to intrauterine death, with a 5e10% fetal loss rate. Infection after 20 weeks results in a 0.5% fetal loss rate. There is a 3e10% risk of hydrops developing over the next eight weeks following parvovirus infection, resulting in fetal death in approximately 50% of cases. The key mechanism causing hydrops is the development of severe 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 prospective study showed that 7.5% of third trimester fetal deaths in utero were positive for parvovirus B19 in the placental tissues. Thus, testing for parvovirus B19 should be offered in this scenario. Weekly ultrasound monitoring is necessary to identify fetal anaemia, ascites and hydrops (accumulation of fluid in 2 compartments) for up to 12 weeks after maternal exposure (Figure 2 a and b). Doppler ultrasound measurements of the middle cerebral artery peak systolic velocity (MCA-PSV) are used to help predict fetal anaemia. (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.
TEST FOR IgM AND IgG
IgG + IgM -
IgG + IgM + / – IgG IgM +
IgG- IgM -
PAST INFECTION IMMUNE - REASSURE POSSIBLE RECENT INFECTION
COUNSEL RETEST IN 2 WEEKS
MCA DOPPLER FOLLOW UP
HYDROPS OR RAISED MCA DOPPLERS
CORDOCENTESIS AND FETAL BLOOD TRANSFUSION
NO EVIDENCE OF HYDROPS OR ANAEMIA
RESCAN EVERY 1- 2 WEEKS
Figure 1 Serology testing for parvovirus.
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. The lady should be advised to avoid contact with other pregnant women and people who are immunosuppressed until she is no longer infectious.
The Fetal MCA Doppler peak systolic velocity suggests anaemia. What are the options? 30% of cases with fetal hydrops will spontaneously resolve. However, there is no robust method to distinguish these cases 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. Cordocentesis can be performed from 18 weeks onwards. There is a 1e2% 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
Her recent serology is reported as IgG positive and IgM positive for parvovirus B19 infection. Her antenatal screening serology was negative for both IgG and IgM. What is your ongoing management? She has had an acute parvovirus infection and her care should be discussed with the regional Fetal Medicine Unit. She may need to be managed there rather than her district hospital, depending on local scan expertise. A multidisciplinary team including virology, neonatologists and fetal medicine specialists should be involved.
Figure 2 (a) Pleural effusion; (b) Ascites.
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Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
CASE-BASED LEARNING
reactivation. Low avidity IgG is found within the blood 1 week after a recent infection. The immune response matures to show high avidity IgG by 12e16 weeks following an infection, and remains high from this point onwards. Therefore, a low avidity IgG would represent a more recent infection.
What do you do next? The woman should be referred to local fetal medicine services for more detailed counselling regarding the potential risks to the fetus, and options for further management. 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 without significant consequence to the fetus after 27 weeks gestation. Transplacental passage of CMV, and thus presumed fetal infection, 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. As the virus replicates in the fetal kidney it is shed in the fetal urine. Therefore, amniocentesis to detect the virus should be performed after this latency period, and after 21 weeks gestation, as fetal diuresis is not established until then. A negative result before this time 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 can lead 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 suffering neurological sequelae. Of babies who are asymptomatic at birth, 10e15% develop long term sequelae, primarily sensorineural hearing loss. The woman who has evidence of a primary infection, or a reactivation, should be offered a detailed ultrasound scan specifically looking for sonographic features of CMV disease, which include intrauterine growth restriction, microcephaly, ventriculomegaly, intracerebral or hepatic calcifications, leukomalacia and echogenic bowel. (Figures 4 and 5). These features are also found in other infections and cannot be regarded as diagnostic. Testing for maternal CMV infection should form part of the routine assessment of pregnancies with a very small fetus with an abdominal circumference or estimated fetal weight of less than the fifth centile.
Figure 3 MCA doppler screening for fetal anaemia.
ventricles, can be utilized if access to the placental cord insertion is difficult. At later gestations, the risk of cordocentesis and intrauterine transfusion should be balanced against the risk of possible premature delivery. Usually, one intrauterine transfusion is sufficient. The fetal bone marrow suppression will resolve, and fetal red cell production will resume. Fetal transfusion has been shown to improve outcome although the time taken for resolution of hydrops can vary, normally occurring within 6 weeks. The woman can be reassured that following resolution of hydrops, there is no evidence to show that there are any long term adverse consequences of fetal parvovirus infection with severe anaemia.
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? The maternal serology suggests that she has had an acute cytomegalovirus infection. CMV infection is one of the most common congenital infections with a reported incidence of 0.2e2.2%. 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. Maternal 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 life-long. The presence of CMV IgM suggests a recent infection, or reactivation, but there are also ‘persistent IgM secretors’. If the booking sample is negative for CMV IgG, an infection during this current pregnancy can be assumed. Avidity testing may be helpful in helping to clarify the timing of a primary infection, or if IgG and IgM are both positive. Avidity testing can be helpful in distinguishing between and primary CMV infection or a
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The amniocentesis is performed, the fetus is of normal size and there are no fetal abnormalities seen on scan. The patient wants to know whether she can be reassured by the normal scan findings. What advice would you give? The absence of sonographic features is reassuring, however, only 25% of infected fetuses will demonstrate ultrasound features.
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Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003
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Case 3 (Chicken pox) A GP contacts you for advice. A 32-year old woman who is 18 weeks pregnant has attended his clinic because her 4 year old daughter has just developed a rash which she suspects is chicken pox. The GP is asking your advice about how to proceed as the woman does not think she has ever had chicken pox.
What would your advice be? It is important to identify whether there has been significant contact, the type of varicella zoster virus (VZV) infection and the timing of the exposure. In this situation there has obviously been significant contact. Chicken pox is infectious for 2 days prior to the outbreak of the rash and remains infectious until the last vesicle has crusted over. Significant contact is considered face-toface contact or presence in the same room for 15 minutes. If the woman is unsure whether she has previously had chicken pox it is possible to use her antenatal booking serology blood test to check for VZV IgG (evidence of previous infection). If VZV IgG is present, the woman can be reassured and no further treatment is necessary. Up to 90% of woman in this country will be VZV IgG positive and therefore immune.
Figure 4 Echogenic bowel.
The GP contacts you again 48 hrs later, stating that the woman is VZV IgG negative and asks how should he proceed. What would you advise? You should advise that VZIG should be administrated at the earliest opportunity if the woman is still within 10 days of initial exposure, as this is thought to prevent chicken pox developing or reduce the severity of any infection. It may also reduce the risk of the baby developing fetal varicella syndrome (FVS). The woman should be advised that if she develops a rash she should contact her GP immediately. Consideration should be given to commencing Aciclovir, if she presents within 24 hours of developing the rash, as this can reduce the length of the symptoms of chicken pox. The dose used in the randomised controlled study was 800 mg five times a day. She should also be warned that if she develops any respiratory symptoms or deteriorates following development of the rash she should attend the hospital. Pregnant women with chickenpox, who require review in hospital, should be seen in locations other than the maternity department to prevent exposure of other non-immune pregnant women, and newborns.
Figure 5 Severe ventriculomegaly in a fetus with positive CMV-PCR from amniotic fluid.
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 abnormalities despite having no prenatal ultrasound abnormalities. The role of MRI in these cases maybe beneficial.
This woman has the VZIG but then goes on to have a very mild chicken pox infection. What follow up should she have with regards to the baby?
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 management options
She should be informed that the chance of her baby developing FVS is low, particularly because she received the immunoglobulin. FVS occurs in approximately 1e2% of pregnancies where chickenpox occurs at less than 20 weeks’ gestation, and less than this if VZIG has been given in a timely manner. She should be followed up by the local fetal medicine department for screening for FVS; the first scan should be approximately 5 weeks following the infection. FVS syndrome is characterised by microcephaly, mental retardation, bowel or bladder dysfunction, eye defects such as cataracts or chorioretinitis and limb hypoplasia.
There are no treatments that are licensed and proven to be effective in pregnancy. Experimental treatment includes CMVspecific hyperimmune globulin which may be effective. A termination 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 its associated mortality.
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Rubella
Varicella-zoster
60e90% Ingestion of toxoplasma tissue cysts in undercooked meat/cat excrement/ contaminated soil/water Asymptomatic (60e70%) or malaise, fever, lymphadenopathy Increases with gestation <4 weeks e less than 1% 13 weeks e 4e15% 36 weeks e >60% Decreases with gestation
1e2% Close contact
10% Close contact
Asymptomatic or malaise, headache, coryza, fine maculopapular rash <11 weeks e 90% 11e16 weeks e 55% >16 weeks e 45%
Fever, malaise, pruritic maculopapular rash (vesicular) <28 weeks e 5e10% 28e36 weeks e 25% >36 weekse50%
<11 weeks e 90% 11e16 weeks e 20% 16e20 weeks e small risk of deafness >20 weeks e no increased risk
Sequelae of fetal infection
Mainly affects the central nervous system (CNS) and eyes
Diagnosis of maternal infection
Serological testing for toxoplasma-specific IgG and IgM
Congenital rubella syndrome includes hearing loss, learning difficulties, cardiac and ocular defects Serological testing for rubella-specific IgG seroconversion (compared to booking serum)
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 FVS includes limb defects, damage to eyes, skin and CNS
Diagnosis of fetal infection
Amniocentesis for detection of toxoplasma gondii DNA in amniotic fluid
Management
Spiramycin if maternal infection may reduce risk of fetal infection. Pyrimethamine/sulfadiazine if fetal infection confirmed. Ultrasound surveillance. Offer termination.
Proportion of young women susceptible Maternal infection acquired by.
Presentation of primary infection Risk of transplacental transmission
Risk of adverse fetal outcome
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Table 1
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 rubellaspecific IgM. Offer termination. Ultrasound surveillance/echocardiography
Serological testing for VZV-specific IgG. It appears within 10 days and confers lifelong immunity OR immunofluorescence of lesion scraping Amniocentesis for detection of VZV DNA in amniotic fluid and ultrasound surveillance
Offer termination if FVS on USS <20 weeks. Ultrasound surveillance. VZIG may help
CASE-BASED LEARNING
Toxoplasmosis
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A summary of other common fetal infections (presentation, diagnosis and management)
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RCOG. Green-top guideline No. 13, September 2007 e chickenpox in pregnancy. € ldebrand-Sparre L, Tolfvenstam T, Papadogiannakis N, Wahren B, Skjo Broliden K, Nyman M. Parvovirus B19 infection: association with third-trimester intrauterine fetal death. BJOG 2000 Apr; 107: 476e80. SOGC. Clinical practice guideline No 240 April 2010 cytomegalovirus infection in pregnancy. 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. The Obstetrician & Gynaecologist 2009; 11: 108e16.
Amniocentesis can be offered to identify whether there is VZV DNA is present within the amniotic fluid. This test has a strong negative predictive value but a poor positive predictive value. Therefore if there is no VZV DNA present in the amniotic fluid, the women can be reassured. However, if it is positive, a large proportion of these babies will be born with no evidence of FVS. Neonatologists should be informed about any baby that has been exposed to varicella virus while in utero. A summary of other fetal infections is shown in Table 1. A FURTHER READING Delle Chiaie L, Buck G, Grab D, Terinde R. 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. Guidance on Viral Rash in Pregnancy. Investigation, diagnosis and management of viral rash illness or exposure to viral rash illness in pregnancy. Health Protection Agency Rash Guidance Working Group January, 2011. Hutto C. Congenital and Perinatal Infections- a concise guide to diagnosis. Humana Press, 2006. Lamont RF, Sobel JD, Vaisbuch E, Kusanovic JP, Mazaki-Tovi S, Kim SK, Uldbjerg N, Romero R. Parvovirus B19 infection in human pregnancy. BJOG 2011; 118: 175e86.
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Practice points C
C
C
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Maternal infections in pregnancy can lead to detrimental effects on the developing fetus. Careful history, investigations and follow up are necessary components of management. Parvovirus B19 is not teratogenic but can cause profound fetal anaemia. The absence of ultrasound features of infection does not guarantee that fetal infection has not occurred. Primary maternal infections in pregnancy tend to cause the most harm to the developing fetus.
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Please cite this article in press as: Hamilton S, Gillham J, Fetal viral infection: a pragmatic approach to recognition and management, Obstetrics, Gynaecology and Reproductive Medicine (2018), https://doi.org/10.1016/j.ogrm.2018.09.003