161 PROFESSIONAL ARTICLE Citomegalovirus infection in pregnancy Copyright (c) 2022 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Citomegalovirus infection in pregnancy Okužba s citomegalovirusom v nosečnosti Sara Vodopivec,1 Miroslav Petrovec,2 Lili Steblovnik3 Abstract Cytomegalovirus (CMV) is the most common viral cause of in utero foetal infection. The virus is neurotropic, so it mainly causes neurological complications. It represents the most common non-genetic cause of sensorineural hearing loss, neu- rological abnormalities, and mental retardation, and is the cause of prematurity, intrauterine foetal death and neonatal mortality. The infection is confirmed by detecting CMV-specific IgM and IgG antibodies, and IgG antibody avidity is used for determining the onset of infection. The presence of the virus is detected by PCR. Congenital infection is the result of viraemia during primary or secondary maternal infection. An intrauterine infection may present itself with characteristic ultrasound features. Prenatal diagnosis of congenital CMV infection is carried out by amniocentesis. Up to 15% of infants of mothers with a confirmed infection during pregnancy are symptomatic at birth. In symptomatic newborns, 40-60% suffer permanent sequelae, the most common of which is sensorineural hearing loss. Counseling a pregnant woman with prima- ry CMV infection is difficult as we cannot accurately predict the foetal outcome based on the currently available data and research results. Estimates of the severity of the infection and possible consequences are based primarily on the timing of the infection, the presence and type of foetal abnormality, and on laboratory parameters. Routine treatment of pregnant women with confirmed CMV infection with the virostatic valacyclovir or with hyperimmune globulins is not recommended in the absence of sufficient evidence of their effectiveness. All pregnant women should be informed about the risks of CMV infection and the preventive measures to protect themselves against CMV infection in pregnancy. The review article sum- marizes the known facts regarding screening, diagnosis and treatment of cytomegalovirus infection in pregnancy, citing the latest findings and evidence, and presents an adaptation of foreign guidelines for good clinical practice in Slovenia. Izvleček Citomegalovirus (CMV) je najpogostejši virusni vzrok okužbe ploda v maternici. Virus je nevrotropen, zato povzroča pred- vsem nevrološke zaplete. Je najpogostejši negenetski vzrok senzorinevralne naglušnosti, nevroloških nepravilnosti in um- ske zaostalosti, hkrati je vzrok tudi za nedonošenost, smrt ploda v maternici in umrljivost novorojenčkov. Okužbo s CMV 1 Division of Gyneacology and Obstetrics, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Perinatal Medicine, Division of Gyneacology and Obstetrics , University Medical Centre Ljubljana, Ljubljana, Slovenia Correspondence / Korespondenca: Lili Steblovnik, e: lili.steblovnik@mf.uni-lj.si Key words: seroconversion; fetal infection; antiviral agents; hyperimmune globulin; screening Ključne besede: serokonverzija; okužba ploda; protivirusna zdravila; hiperimuni globulini; presejanje Received / Prispelo: 20. 1. 2021 | Accepted / Sprejeto: 1. 4. 2021 Cite as / Citirajte kot: Vodopivec S, Petrovec M, Steblovnik L. Citomegalovirus infection in pregnancy. Zdrav Vestn. 2022;91(3–4):161–72. DOI: https://doi.org/10.6016/ZdravVestn.3220 eng slo element en article-lang 10.6016/ZdravVestn.3220 doi 20.1.2021 date-received 1.4.2021 date-accepted Obstetrics, gynaecology, andrology, reproduc- tion, sexuality Porodništvo, ginekologija, andrologija, reproduk- cija, spolnost discipline Professional article Strokovni članek article-type Citomegalovirus infection in pregnancy Okužba s citomegalovirusom v nosečnosti article-title Citomegalovirus infection in pregnancy Okužba s citomegalovirusom v nosečnosti alt-title seroconversion, fetal infection, antiviral agents, hyperimmune globulin, screening serokonverzija, okužba ploda, protivirusna zdravi- la, hiperimuni globulini, presejanje kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2022 91 3 4 161 172 name surname aff email Lili Steblovnik 3 lili.steblovnik@mf.uni-lj.si name surname aff Sara Vodopivec 1 Miroslav Petrovec 2 eng slo aff-id Division of Gyneacology and Obstetrics, University Medical Centre Ljubljana, Ljubljana, Slovenia Ginekološka klinika, Univerzitetni klinični center Ljubljana, Slovenija 1 Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Inštitut za mikrobiologijo in imunologijo, Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija 2 Department of Perinatal Medicine, Division of Gyneacology and Obstetrics , University Medical Centre Ljubljana, Ljubljana, Slovenia Klinični oddelek za perinatologijo, Ginekološka klinika, Univerzitetni klinični center Ljubljana, LJubljana, Slovenija 3 Slovenian Medical Journallovenian Medical Journal 162 OBSTETRICS, GYNAECOLOGY, ANDROLOGY, REPRODUCTION, SEXUALITY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3220 1 Introduction 1.1 Cytomegalovirus (CMV) Cytomegalovirus (CMV) or Human Herpesvirus 5 (HHV-5) belongs to the family of human herpesvirus- es, which are characterised by their ability to establish permanent (latent) infection after recovering from acute primary infection. It is most commonly transmitted through saliva and contact with contaminated objects (among children), semen and vaginal secretions (among adults), and has also been isolated from urine, faeces, breast milk, blood, and tears. Transmission by blood transfusion or transplantation of infected organs is al- so possible (1,2). The primary infection is systemic. The virus multiplies in salivary glands, kidneys, and the re- spiratory tract, and the latent phase is presented by the virus load in the bone marrow. It causes characteristic cytopathic effects with swelling and fusion of cells and the formation of multinucleated giant cells (2,3). CMV is the most common viral cause of in utero foe- tal infection, i.e. congenital infection in the developed world. It occurs in 0.2–1.3% of live births (4). It is the most common non-genetic cause of sensorineural hear- ing loss, neurological abnormalities, and mental retarda- tion. It is the cause of prematurity, foetal death in utero, and neonatal mortality. As such, it represents a major social, health, and economic burden on society (4-9). 1.2 Epidemiology CMV is present all over the world and has no char- acteristic pattern of occurrence. The seroprevalence in women of childbearing age is higher in developing coun- tries (2,8). A German study found that seroprevalence in women of childbearing age was 51.7% of (10). potrjujemo z dokazom za CMV specifičnih protiteles IgM in IgG. Prisotnost virusa dokazujemo s PCR. Za časovno oprede- litev okužbe s CMV določamo avidnost protiteles IgG. Prirojena okužba je posledica viremije ob primarni ali sekundarni okužbi nosečnice. Ob znotrajmaternični okužbi so lahko prisotni značilni ultrazvočni znaki. Prenatalna diagnoza prirojene okužbe s CMV se postavi z amniocentezo. Simptome ob rojstvu ima do 15 % otrok mater s potrjeno okužbo v nosečnosti. Pri novorojenčkih s simptomi pride v 40–60 % do trajnih posledic, od katerih je najpogostejša senzorinevralna naglušnost. Svetovanje nosečnici s primarno okužbo s CMV je težavno, saj po doslej razpoložljivih podatkih in izsledkih raziskav izida za plod še ne znamo natančno napovedati. Ocene resnosti okužbe in možnih posledic temeljijo predvsem na časovni opredelitvi okužbe nosečnice, prisotnosti in vrsti nepravilnosti pri plodu in laboratorijskih parametrih. Rutinsko zdravlje- nje nosečnic s potrjeno okužbo s CMV z virostatikom valaciklovirjem ali s hiperimunimi globulini se zaradi pomanjkanja zadostnih dokazov o učinkovitosti ne priporoča. Vse nosečnice bi morale biti seznanjene o nevarnostih okužbe s CMV in preventivnih ukrepih za zaščito pred okužbo s CMV v nosečnosti. Pregledni članek povzema znana dejstva glede preseja- nja, diagnosticiranja in zdravljenja okužbe s CMV v nosečnosti z navajanjem najnovejših spoznanj in dokazov ter predsta- vlja prilagoditev tujih priporočil za dobro klinično prakso v Sloveniji. According to the data of Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, CMV seroprevalence in Slovenian pregnant women was 70–80% in 2005 and 2006 (2). In a study in two maternity hospitals in eastern Slovenia, the inci- dence of new-borns with congenital CMV infection was approximately 0.14% (11). In the developed world, the prevalence of congenital CMV infection is 0.64% (4). 1.3 Primary and secondary infection The primary infection occurs upon first contact with the virus and is dangerous if it occurs during pregnan- cy. The incidence of primary infection in pregnancy is 0.64–4% (4,8,12). The virus can reactivate later on, called a recurrent or secondary infection, and this also can cause morbidity and mortality in the foetus or new-born (2,13). Second- ary infection (with pre-existing immunity to CMV) can also occur with another strain of CMV virus. The risk of CMV infection in pregnancy and the sequelae of the infection are shown in Figure 1. 1.4 Clinical picture in immunocompetent adults The majority (90%) of healthy adults and preschool children with primary CMV infection have no symp- toms or sequelae. The virus is excreted in saliva and urine for a long time after infection. In some, the infection manifests itself as a mononucleosis-like syndrome after four to eight weeks of incubation, with malaise, fever, muscle aches, swollen cervical lymph nodes, enlarged liver or spleen, with a third suffering from uncharacter- istic skin rash. Liver tests may be slightly elevated and 163 PROFESSIONAL ARTICLE Citomegalovirus infection in pregnancy lymphocytosis may be present. It is mostly a mild dis- ease with no serious complications (2,14,15). 1.5 Clinical picture in pregnant women About 20% of pregnant women with primary infec- tion have symptoms (16). Usually it is a flu- or an infec- tious-mononucleosis-like syndrome with fever (the most pronounced sign of the disease), fatigue, muscle aches, enlarged cervical lymph nodes, sore throat, headache, enlarged liver or spleen (though rarely), hepatitis, pneu- monia, skin rash, or gastrointestinal symptoms. Lympho- cytosis (in 30–50%) and slightly elevated aminotransfer- ases (in 40%) may stand out in laboratory results (15,17). 1.6 Diagnosis of cytomegalovirus infection There should be close cooperation between a clini- cian and a microbiologist for confirming CMV infection in pregnancy: an agreement needs to be reached on the best time for taking the sample, correct collection and type of sample, storage and transportation of the sample for examination according to the evidence-based meth- od, and to correctly interpret the results (18). 1.6.1 Serological testing For most viral infections, evidence of seroconversion (that is, the appearance of specific IgM antibodies that are an acute response of the immune system to infec- tion), is appropriate to confirm the primary infection. However, in the case of CMV infection, the following should be borne in mind: • IgM antibodies may persist in serum for several months after primary CMV infection; • Specific IgM antibodies may occur with secondary CMV infection; • Cross-reactivity and CMV-specific IgM antibodies may occur due to another viral infection (e.g. Ep- stein-Barr virus infection); • IgM antibodies may occur with non-specific poly- clonal activation of the immune system (17,19,20). Therefore, to estimate the timing of IgM-positive CMV infection, we also test the avidity of IgG antibod- ies that form later during the course of infection. If the IgG antibodies are negative, it is cross-reactivity and not CMV infection. A high IgG antibody avidity index (above 60%), which indicates a high antibody capacity to Figure 1: Risk of cytomegalovirus infection of a pregnant woman and foetus. Taken from SMFM. Congenital CMV diagnosis and antenatal management. Am J Obstet Gynecol 2016 (45). Legend: CMV – cytomegalovirus. Primary CMV infection 30–50% of women of childbearing age are susceptible to primary CMV infection 1–4% get primary CMV infection during pregnancy Secondary CMV infection Infection is transmitted to the foetus in 40% 10–15% of new-borns have symptoms at birth 50–70% of women of childbearing age have been infected – susceptible to secondary CMV infection 0.2–2% of them get secondary CMV infection during pregnancy <1% of new-borns have symptoms at birth 8% of children have sequelae at the age of two 25% of children have sequelae at the age of two 164 OBSTETRICS, GYNAECOLOGY, ANDROLOGY, REPRODUCTION, SEXUALITY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3220 bind to CMV antigen, is very likely to be associated with old (more than three months) or secondary infection. A low avidity index (below 30%) is more likely to indicate a fresh – primary infection (in the last three months) (17,21,22). 1.6.2 Confirmation of infection Proof of viral genome by polymerase chain reaction (PCR) is used to confirm infection (18). 2 Congenital infection The incidence of congenital CMV infection in West- ern Europe, Canada, the United States and Australia is approximately 5–7/1,000 live births (23). Congenital in- fection is the result of viraemia during primary or sec- ondary maternal infection, leading to placental infection and transmission of the virus through the placenta to the foetus, which occurs within four to eight weeks after the onset of viraemia (15,24). 2.1 Probability of congenital infection The possibility of transmission to the foetus is higher with primary infection in pregnancy and increases with the duration of pregnancy: • infection in the first trimester: 30–42%; • infection in the second trimester: 38–44%; • infection in the third trimester: 59–73% (7,24). In secondary infection, the overall risk of infection of the foetus is low, 0.15–2%, but it can also be manifested by symptoms. As the population of seropositive women is large, more congenital infections occur in these preg- nant women (13,25-28). 2.2 Symptoms and signs of congenital infection In 85–90% of congenital infections, new-borns have no symptoms. Up to 15% of infected children have symptoms at birth, most of which occur during the pri- mary infection of a pregnant woman in the first trimes- ter of pregnancy. Mortality of new-borns with symptoms is 5–15% (25). The virus is neurotropic, therefore causing main- ly neurological complications (1). In new-borns with symptoms, 40–60% have permanent sequelae, the most common of which is sensorineural hearing loss (27,29). Typical signs of congenital infection, that may be transient, are the following: • small for gestational age; • microcephaly; • hepatomegaly; • splenomegaly; • petechiae; • jaundice; • thrombocytopenia; • anaemia (17,30,31). The long-term severe sequelae of congenital CMV infection are the following: • sensorineural hearing loss; • mental retardation; • cerebral paralysis; • visual impairment; • epileptic seizures; • cerebral or cerebellar atrophy and other disorders of neurological development (23,32-34). However, when an infection occurs in the third tri- mester, new-borns rarely have symptoms (16,23,24,34). The risk of severe neurological sequelae decreases with the duration of pregnancy (16,24,34). In new-borns with asymptomatic infection, neu- rological and developmental abnormalities occur in 15–25% of cases later in childhood, most often senso- rineural hearing loss, less often psychomotor retarda- tion, cognitive deficits, seizures, and visual impairment (2,27,33,35). A long-term prospective study of the asso- ciation between congenital CMV infection showed an incidence of hearing loss in 12.7% of infected children. Hearing impairment is more common in cases of prima- ry CMV infection in pregnant women in the first trimes- ter and when signs of foetal or neonatal infection were seen by ultrasound (US) or magnetic resonance imaging (MRI) (36). Children with late sequelae of congenital in- fections account for the majority of the disease burden of congenital CMV infection (37). 3 Prenatal diagnosis Testing a pregnant woman for CMV infection is in place in the case of: • acute symptoms characteristic of a virus or a mono- nucleosis syndrome; • foetal abnormalities, detected by ultrasound, charac- teristic of CMV infection (38,39). 165 PROFESSIONAL ARTICLE Citomegalovirus infection in pregnancy 3.1 Signs of cytomegalovirus infection on ultrasound The positive predictive value of the ultrasound ex- amination for the prognosis of congenital infection is 35% (38). Ultrasound signs are non-specific and present in less than 50% of infected foetuses (38,40). The most common are the following (frequency of occurrence, %): • calcifications in the central nervous system, mainly periventricular (0.6–17.4); • microcephaly (14.5); • hyperechogenic bowel (4.5–13); • intrauterine growth restriction (IUGR) (1.9–13); • cerebral ventriculomegaly (4.5–11.6); • ascites (8.7); • pericardial effusion (7.2); • hepatomegaly (4.3); • hydrops foetalis (0.6); • placentomegaly (4.3); • calcifications in the liver; • polymicrogyria; • cerebellar hypoplasia (16,38,41). 3.2 Serological testing The primary maternal CMV infection can be confirmed: • by seroconversion – evidence of de novo appearance of CMV-specific IgG antibodies – gold standard (two serum samples, past and present, required); • with evidence of CMV-specific IgM antibodies with concomitant low avidity of IgG antibodies (21,39,42). To identify the infection, microbiological labora- tories often use serums taken earlier for screening for toxoplasmosis, syphilis or hepatitis B, which have been archived for at least one year (43). 3.3 Magnetic Resonance Imaging (MRI) of the foetus In the presence of ultrasound signs of central nervous system (CNS) abnormalities, an additional diagnostic method is MRI (44). In foetuses with confirmed infec- tion, the use of ultrasound and MRI is 95% sensitive to the detection of structural abnormalities of the CNS. If the MRI result is within normal limits, the outcome is generally good for the foetus. However, a normal MRI of the foetal head does not reliably predict a good neu- rological development for the foetus, as sensorineural hearing loss in the case of congenital CMV infection is developing progressively (45,46). 3.4 Confirming foetal infection Prenatal diagnosis of congenital CMV infection is confirmed by amniocentesis to prove viral DNA in am- niotic fluid by PCR (42,47,48). For optimal sensitivity of the method, it is important to perform amniocentesis six to eight weeks after the onset of maternal infection/ after proven seroconversion (thus allowing time for suf- ficient replication of the virus in the infected foetus and its excretion in the foetal urine) and after the 20th week of pregnancy, when the foetal urination is established (17,42,47). Amniocentesis to prove infection should be per- formed in pregnant women with primary CMV infec- tion. In pregnant women with secondary infection, there is no consensus on whether confirmation of foetal in- fection is reasonable, as the risk of transmitting the in- fection to the foetus is very low. However, the literature does also describe cases of severe sequelae for the foe- tus in the case of secondary maternal infection, so am- niocentesis should be considered in these cases as well (49,50). If performed within the recommended time window, a negative PCR result for CMV is 97–100% sensitive (47,51). If the test is performed earlier than recommend- ed, the likelihood of a false-negative outcome is higher (20). In the absence of ultrasound signs of infection and a negative amniocentesis result, the likelihood of infec- tion with symptoms and neurological sequelae in these new-borns is significantly lower (52). According to the data available so far, quantitative determination of DNA for CMV in the amniotic sac is not relevant for predict- ing the outcome of the disease (53). The main limitation of prenatal diagnosis of congen- ital CMV infection is that confirmation of infection can- not predict whether a new-born will have symptoms and whether he or she will develop late neurological sequelae (45,53,54). 3.5 Confirmation of infection after birth To prove congenital infection, the gold standard is to isolate the virus and its DNA from the urine of the new- born taken in the first three weeks after birth (2,17,55). It is also possible to confirm viral DNA in dried blood samples on paper cards taken for screening for detecting metabolic diseases, but this method is less sensitive than detecting the virus from a fresh sample (42). Children 166 OBSTETRICS, GYNAECOLOGY, ANDROLOGY, REPRODUCTION, SEXUALITY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3220 under the age of two excrete the virus in saliva and urine for an average of 24 months and can thus be an import- ant source of infection for their surroundings (56). 4 Prevention of cytomegalovirus infection in pregnancy and prevention of its sequelae 4.1 Screening Various international recommendations do not rec- ommend routine CMV screening of pregnant women because: • there is no effective vaccine to prevent infection in seronegative women; • in seropositive pregnant women, it is difficult to dis- tinguish between primary and secondary infection; • seropositive women are not protected against infec- tion and may experience reactivation of the virus or become infected with another strain, which can also lead to a congenital infection; • we do not have a proven effective treatment that could be offered to pregnant women; • despite the proven infection of the foetus, the sequel- ae for its health cannot be predicted; • routine screening could lead to unnecessary, poten- tially harmful, measures (3,45,53). In some countries, despite clear recommendations, screening is carried out in some centres (57). In France, screening was carried out by 14% of hospitals in 2012 (58). In Germany, recommendations for the diagnosis of viral infections in pregnancy are followed, which recom- mend screening in early pregnancy for women at high risk of CMV infection due to occupational or family ex- posure to young children (59). 4.2 Primary prevention – prevention of cytomegalovirus infection in pregnancy Research has shown that consistent counselling on the importance of preventing CMV infection in preg- nancy reduces seroconversion rates in previously se- ronegative pregnant women (54). As contact with the bodily secretions of young children is the greatest risk for women of childbearing age, preventive hygiene mea- sures to prevent primary infection in pregnant women and thus congenital CMV infections are essential (60). Pregnant women should avoid contact with the sali- va, urine and tears of children. It is important they wash their hands regularly with soap and water after contact with body secretions, to avoid kissing pre-schoolers on the mouth, to not share food, drinks, cutlery with chil- dren, and to regularly clean toys and other surfaces that come in contact with the bodily secretions of children (23,54,60). 4.3 Secondary prevention – prevention of transmission of infection from a mother to the foetus and treatment of foetal infections during pregnancy When maternal infection is confirmed, the goal is to prevent the transmission of the infection to the foetus (3). In recent years, the possibilities of treatment with immunotherapy and virostatics have been intensively studied. 4.3.1 CMV-specific hyperimmune globulins (HIG) At the time of primary infection, the pregnant wom- an has no developed effective antibodies to prevent transmission of the infection to the foetus. A promis- ing method of treatment is passive immunisation, this is intravenous injection of high doses of highly avid CMV-specific antibodies – hyperimmune globulins (HIG) (7). The results of observational and randomised studies do not yet support the routine use of HIG to treat preg- nant women with primary CMV infection. For now, the decision to treat with HIG is made individually and for research purposes (17,31). In a review article on the treatment of CMV infection in pregnancy, Rawlinson et al. analysed the data from research showing that there is a trend towards the ef- fectiveness of HIG administration in preventing foetal transmission and treating foetal infection (61). A large randomised prospective study is underway in the United States to evaluate the effectiveness of HIG in reducing the transmission of primary CMV infection in pregnan- cy to the foetus, which could provide acceptable answers regarding the use of HIG in primary CMV infection in pregnancy (clinicaltrials.gov: NCT01376778). Howev- er, according to the published protocol, lower doses of HIG (100 IU/kg) are used in this study and only once a month, which is contrary to the pharmacokinetic find- ings of Kagan et al. This could be reflected in underesti- mating the results of the study or lower efficacy of HIG compared to a dose of 200 IU/kg every 14 days (3). Based on the data available in the literature, the man- ufacturer of HIG (Cytocect ® CP) recommends: • “off-label use” of HIG in pregnancy to prevent infec- tion of the foetus, as experts only recommend it in 167 PROFESSIONAL ARTICLE Citomegalovirus infection in pregnancy research situations; • informing the manufacturer of the intention to use Cytotect to treat a pregnant woman; • the manufacturer records the use of Cytotect during pregnancy and is available to assist with treatment protocol decisions. 4.3.2 Virostatics The only virostatic that does not cause teratogenic and toxic effects is valaciclovir, which has poor effect against CMV (17). To date, two studies have been published ex- amining the efficacy of antiviral therapy with valaciclo- vir (62). The use of valaciclovir (8g daily) was associated with a significantly higher proportion of asymptomat- ic new-borns with congenital infection compared with the historical cohort (62). A major randomised study is currently underway to evaluate the effectiveness of va- laciclovir in the transmission of primary CMV infection from a pregnant woman to the foetus. Routine prenatal treatment with valaciclovir is not recommended due to lack of evidence of efficacy (31,45). 4.3.3 Vaccine Despite active research, the CMV vaccine is not yet available (3). The problem with doing research on a suit- able vaccine is the fact that even new-borns of seroposi- tive mothers (with pronounced immunity to CMV) may develop symptomatic infection and have long-term neu- rological sequelae. 4.4 Tertiary prevention – treatment of new-borns with confirmed congenital cytomegalovirus infection New-borns with symptomatic congenital CMV in- fection should be treated, as research has shown that antiviral therapy reduces or prevents the progression of hearing loss and improves long-term neurodevelop- mental sequelae (63). The treatment of choice is oral val- ganciclovir, but if the new-born is receiving parenteral feeding, ganciclovir is given intravenously. The drugs act virostatically; they prevent viral replication by inhibit- ing viral DNA synthesis. The treatment should be start- ed within the first month after birth. The recommended duration of treatment is from six weeks to six months, depending on the severity of symptoms. Children treat- ed for congenital CMV infection should be monitored by audiologists and ophthalmologists until the age of six (37,63). 5 Management of a pregnancy, complicated with cytomegalovirus infection Councelling to a pregnant woman with CMV in- fection is complex as we cannot accurately predict the foetal outcome based on currently available data and re- search results. Estimates of the severity of the infection and the pos- sible sequelae are based primarily on: • the timing of a maternal infection; • the presence and type of foetal anomalies; • laboratory parameters (17). Once foetal CMV infection has been confirmed, reg- ular ultrasound examinations every two to four weeks are required to monitor for signs of CMV infection in the foetus (17,53). Based on current knowledge, the most im- portant ultrasound predictor for predicting foetal status seems to be the presence of brain abnormalities (64,65). RCOG proposes to divide foetuses with confirmed congenital infection into three prognostic categories, ac- cording to the ultrasound report (17): 1. Asymptomatic foetuses – without symptoms no ul- trasound abnormalities are found, MRI of the CNS is normal. The prognosis is good, there is only the possibility of sensorineural hearing loss. 2. Foetuses with mild to moderate symptoms – no ul- trasound abnormalities of the CNS, with the pres- ence of other individual ultrasound abnormalities. The prediction of the outcome is uncertain, so it is necessary to continue ultrasound and MRI monitor- ing for a better prediction of the outcome. It can be explained to the parents that there is no unequivocal evidence of the effectiveness of the treatment, but we can offer treatment. It is necessary to talk about the possibility of terminating the pregnancy. 3. Foetuses with severe symptoms – with ultrasound abnormalities of the CNS. The prognosis of the out- come is extremely poor. A pregnant woman has the option to decide to terminate the pregnancy (17,53). Leruez-Ville et al. tried to predict the risk of neuro- logical sequelae in congenital infection based on ultra- sound findings, dividing them into three categories: • severe CNS abnormalities (microcephaly, severe ven- triculomegaly >15 mm); • mild CNS abnormalities (borderline ventriculomeg- aly); • ultrasound findings outside the CNS (hyperechogen- ic bowel, hepatomegaly, IUGR). 168 OBSTETRICS, GYNAECOLOGY, ANDROLOGY, REPRODUCTION, SEXUALITY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3220 Figure 2: Scheme of intervention in case of established primary cytomegalovirus infection in pregnancy. Taken from RCOG 2018, Tanimura 2019 (18,39). Legend: CMV – cytomegalovirus; MRI – magnetic resonance imaging; CNS – central nervous system; HIG – human immunoglobulin. A pregnant woman with clinical suspicion of CMV infection (mononucleosis syndrome, ultrasound signs) Serological testing of CMV IgG and IgM Negative result Ig G-positive, low avidity IgM-positive IgG-positive, high avidity IgM-negative No infection Primary infection Secondary infection Advice on preventive measures Amniocentesis six–eight weeks aer seroconversion, aer 21 weeks of pregnancy - CMV DNA PCR from the placenta – confirmed infection Accurate ultrasound examination of the foetus every two–four weeks – MRI of the foetal CNS at 28–32 weeks, possibly repeated in three–four weeks Foetus without symptoms Foetus with mild symptoms Foetus with severe symptoms Consideration of foetus treatment in uteroExpectative pregnancy management Advise on the possibility of terminating a pregnancy HIG? VALACICLOVIR? Newburn: CMV DNA from urine, histopathological and microbiological examination of the placenta positive negative Additional diagnosis: hearing test, head ultrasound, ophthalmoscopy, neurological examination. Valganciclovir treatment? Asymptomatic – risk of hearing impairment in 10–15% Symptomatic – in 50% developmental disorders, hearing impairment, in 25% visual impairment Examination of the placenta, oering the possibility of an autopsy 169 PROFESSIONAL ARTICLE Citomegalovirus infection in pregnancy The results have shown that women from the first group most often terminated the pregnancy. In the sec- ond group, the probability of giving birth to a new-born with symptoms was 60%, and in the case of the third group this possibility was 10% (66). Women with CMV infection during pregnancy can breast-feed, as most new-borns will be infected with the virus sooner or later, and most will be asymptomatic (67). 6 Recommendations for good clinical practice in the treatment of primary cytomegalovirus infection in pregnancy The recommendations are taken from (17,31,45,53). The recommended action scheme is summarised in Fig- ure 2. 6.1 Prevention of congenital cytomegalovirus infection • All pregnant women should be informed about the dangers of CMV infection and about preventive mea- sures for protection against CMV infection during pregnancy. • Routine screening of pregnant women for CMV in- fection with serological testing is not recommended. • Seronegative pregnant women who work with chil- dren (in kindergartens, in health care) may be of- fered serological monitoring during pregnancy in the future. Seronegative pregnant women who have children in kindergarten could also be serologically monitored. 6.2 Diagnosis of primary infection in pregnancy Serological testing of pregnant women for CMV in- fection is performed in cases where the pregnant wom- an suffers from mononucleosis-like symptoms and signs that cannot be explained otherwise, or when ultrasound examination of the foetus reveals abnormalities charac- teristic of congenital CMV infection which also cannot be explained otherwise. • The diagnosis of primary infection in pregnancy is made on the basis of confirmed seroconversion – the occurrence of CMV-specific IgG antibodies in the serum of previously seronegative pregnant women – or when there is evidence of CMV-specific IgM anti- bodies in the presence of low-avidity IgG antibodies. • The diagnosis of secondary infection is made with a significant increase in IgG antibody titre with or without the presence of specific IgM antibodies. Once secondary infection is confirmed, amniocentesis can be performed, but the likelihood of transmission to the foetus is lower than with primary infection, and the risk-benefit ratio of amniocentesis is lower than with primary infection. • With the primary infection of the pregnant woman, parents should be informed that the possibility of transmission of the infection to the foetus is 30–40%, and the possibility of sequelae for the infected foetus is 20–25%. 6.3 Intervention • Prenatal diagnosis of congenital CMV infection is made by amniocentesis, which is performed at least six weeks after the estimated time of primary mater- nal infection and after the 21st week of pregnancy. • In the case of confirmed congenital CMV infection, regular ultrasound examinations of the foetus every two to three weeks before delivery are necessary in order to detect characteristic changes or abnormali- ties of the foetus, which can help us assess the prog- nosis of the outcome for the foetus. The absence of abnormalities visible with ultrasound is not a reli- able predictor of a favourable course of infection (no symptoms). • Diagnosis of CMV infection in the new-born and early monitoring of the child with the possibility of contracting CMV in utero (determination of virae- mia through urine, check-ups at an infectologist, ENT, etc.). 6.4 Treatment • Routine treatment of pregnant women with valaci- clovir to prevent transmission of the infection to the foetus or to prevent sequelae in a foetus with con- firmed infection is not recommended due to a lack of sufficient evidence of efficacy. • Routine treatment of pregnant women with hyper- immune globulins to prevent transmission of the in- fection to the foetus or to prevent sequelae in a foetus with confirmed infection is not recommended due to a lack of sufficient evidence of efficacy. • Treatment of a pregnant woman with antiviremics or hyperimmune globulins should be given careful consideration when the benefits outweigh the risks, although no reliable efficacy data are available. • In cases of severe CNS abnormalities and poor prog- nosis, termination of pregnancy may be considered. 170 OBSTETRICS, GYNAECOLOGY, ANDROLOGY, REPRODUCTION, SEXUALITY Zdrav Vestn | March – April 2022 | Volume 91 | https://doi.org/10.6016/ZdravVestn.3220 References 1. 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