Cytomegalovirus in pregnancy: prevention, maternal screening, and the role of antivirals.

In 1847, Ignaz Phillip Semmelweis proposed hand washing with chlorinated lime solution as a method of hand disinfection to reduce the incidence of puerperal fever. Obstetricians should feel part of this legacy because Semmelweis made this suggestion while working in an obstetric clinic in Vienna. At the time, Semmelweis could not explain the mechanism of his proposal and understandably it created much controversy and conflict. Over a century later, we continue to reap the benefits of Semmelweis's pioneering thinking. In the early 1860s, Louis Pasteur, the French biologist and chemist, became one of the pioneers of the germ theory of disease and a founder of bacteriology. Soon after, Joseph Lister at the University of Glasgow produced his pioneering work on antiseptic surgery and went on to promote hand washing and sterilisation of surgical instruments. After 150 years we continue to audit our practice of ‘bare below the elbows’ and hand washing before contact with our patients. Over the last two decades, The Obstetrician & Gynaecologist (TOG) has contributed to upholding the legacy of these pioneers and maintaining interest and awareness in managing infection in obstetrics and gynaecology. Nunns and Scott (TOG 2001;3:32–5) described the differential diagnoses of ulcers and erosions of the vulva. For readers in the Western world, it is important to remember that primary infective ulcers of the vulva can appear in the form of lymphogranuloma venereum or chancroid, or be caused by Donovanosis, amoebiasis and, of course, syphilis. One of the most common infections is caused by Candida, and group B streptococcus is a common resident in cervicovaginal secretions. Although Higgins (TOG 2001;4:184–8) writes under the heading of recurrent vulvovaginal candidiasis, he also informs us about the characteristics and management of other genital infections. Many of the infective diseases are sexually transmitted, where confidentiality forms an important part of management. Kausar and Bradbeer (TOG 2006;8:240–4) wrote about patient confidentiality in sexually transmitted infections (STIs). They refer to the guidance by the General Medical Council on this matter and also provide guidance on when confidential information can be disclosed. Sinha and Otiffy (TOG 2012;14:106–14) highlighted the role of sepsis in maternal deaths, reviewed the risk factors and described the features of septicaemic shock. They also recommended the use of a modified obstetric early warning scoring system for the early recognition of serious illness. During in vitro fertilisation, both males and females are prone to infection. Although such infection is rare, when it occurs it can have devastating effects. Sowerby and Parsons (TOG 2006;8:159–63) provide an eloquent review of methods of reducing the risk of such infection. Genital tuberculosis (TB) may be asymptomatic, go unrecognised or masquerade as other gynaecological conditions. In their review of genital TB, Gatongi et al. (TOG 2005;7:75–9) discussed the diagnosis, investigation and management of the condition. Five years later, Mahendru and colleagues (TOG 2010;12:163–71) wrote on the difficulties of diagnosing and managing TB in pregnancy. In 2007, Harris et al. (TOG 2008;10:17–21) described the investigation and treatment of recurrent urinary tract infection (UTI). In the same year, McCormick et al. (TOG 2008;10:156–62) highlighted the importance of diagnosing and treating UTIs in pregnancy, as they can be asymptomatic and are associated with significant maternal and perinatal morbidity and mortality. Moore and colleagues (TOG 2002;4:197–200) reviewed HIV in pregnancy. We learned that the incidence of heterosexually acquired HIV infection was rising and that HIV disease progression is monitored by serum viral count and T-helper cell (CD4) count. The authors also covered the risk factors that increased mother-to-child transmission (MTCT). Six years later, Kelly et al. (TOG 2008;10:42–8) presented a review of the drug treatment of HIV and outlined the impact of the virus on gynaecological practice. Although treatments are available for HIV, they are not curative and there is no guarantee against MTCT. Another 4 years later, Byrne, Fakoya and Harding (TOG 2012;14:17–24) provided an international perspective on HIV infection. They mentioned that MTCT accounted for 90% of HIV infection in childhood and that in the developing world, prevention of MTCT was limited by resources, lack of infrastructure and stigma. Infections in pregnancy that affect the fetus have arguably remained somewhat of an enigma. Cytomegalovirus (CMV) is one of them. In their 2009 paper, McCarthy et al. (TOG 2009;11:96–100) comprehensively reviewed CMV infection in pregnancy, which serves as a useful guide for those involved in caring for this group of women. More recently, Navti et al. (TOG 2016;18:301–7) provided an update on CMV in pregnancy and discussed the difficulties in prenatal diagnosis and options for management. It is important to remember that CMV is the most common cause of congenital viral infection and up to 90% of CMV infections remain asymptomatic at birth. A very useful and easily readable article was authored by To et al. (TOG 2009;11:108–16). It deals with CMV, parvovirus, toxoplasmosis, varicella-zoster virus and rubella infection in pregnancy. We learn that detection of virus alone is not synonymous with fetal damage, and that a negative result does not completely exclude the possibility of fetal infection. Human parvovirus infection in pregnancy was reviewed by Ismail and Kilby (TOG 2003;5:4-9). Among other important information in this review, we get to know that transplacental transmission occurs in approximately one-third of cases of maternal infection. Malaria in pregnancy has serious maternal and fetal complications. Pregnant women who are not immune and who plan to travel to areas with malaria should be warned of the risks. If such travel is inevitable, appropriate prophylactic measures should be advised. Gitau and Eldred (TOG 2005;7:5–11) highlight aspects of diagnosis, treatment and prophylaxis of malaria in pregnancy. Genital tract sepsis is one of the leading causes of maternal death in the UK. A significant proportion of these are due to community acquired group A streptococcal (GAS) infection. GAS infection is a life-threatening cause of puerperal sepsis. Palaniappan et al.'s (TOG 2012;14:9–16) review of GAS infection is a very useful reminder of this serious infection. Group B streptococcal (GBS) disease in pregnancy can be transmitted from mother to fetus and may lead to neonatal sepsis, pneumonia, meningitis or even death. To screen or not to screen is a trending question in the minds of many. In 2005, Abd El Malek and colleagues (TOG 2005;7:34–9) presented an update to this commonly encountered problem. Cockell et al. (TOG 2008;10:171–6) reminded us of the importance of women's views in the production of the Royal College of Obstetricians and Gynaecologists’ patient information leaflets on GBS infection in babies. Muggleston et al. (TOG 2014;16:87–92) presented a useful summary of the National Institute for Health and Care Excellence 2012 guideline on the use of antibiotics in early onset infection (arising within 72 hours of birth) of the neonate. An online collection of all TOG articles on infection in obstetrics and gynaecology is available at onlinetog.org.

Diagnosis and management of congenital Cytomegalovirus: Critical Appraisal of Clinical Practice Guidelines.

Cytomegalovirus (CMV) infection in pregnancy is the most common viral cause of congenital infection and is associated with serious sequelae. This study aimed to review and compare the recommendations from published guidelines on screening, diagnosis, and management prevention of CMV infection during pregnancy, as well as neonatal management. A descriptive review of guidelines from the Society for Maternal-Fetal Medicine, the Royal College of Obstetricians & Gynecologists, the Royal Australian and New Zealand College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynecologists of Canada, and the European Congenital Infection Initiative (ECCI) on CMV infection in pregnancy was conducted. There is a consensus on the importance of prevention, whereas all guidelines underline that the severity of fetal infection results mainly from primary maternal infection occurring during the early periconceptional period or first trimester of pregnancy. Controversy exists regarding universal screening for CMV, with the Society for Maternal-Fetal Medicine, the Royal College of Obstetricians & Gynecologists, and the Royal Australian and New Zealand College of Obstetricians and Gynecologists stating against it, the Society of Obstetricians and Gynecologists of Canada recommending testing for CMV early for women at high-risk only in areas where avidity testing is available, and ECCI recommending routine screening up to 16 weeks of pregnancy. Moreover, there is relative consensus on the diagnosis of maternal infection, either with CMV immunoglobulin G seroconversion or with positive immunoglobulin M CMV in combination with low immunoglobulin G avidity, with ECCI recommending only the latter. Moreover, there is a disagreement among the reviewed guidelines on the antenatal management of maternal and fetal infection, whereas ECCI offers the most comprehensive recommendations in neonatal management compared with the other guidelines. CMV infection in pregnancy is considered a major contributor to severe neurodevelopmental disability and hearing impairment in infants. Hence, consistent global guidelines should be issued to be integrated into everyday practice to achieve the optimal perinatal outcome. Obstetricians and gynecologists, family physicians. After participating in this activity, the learner should be better able to discuss hygiene strategies for the prevention of maternal infection from CMV; describe diagnostic methods for maternal CMV infection; and explain the optimal management of pregnant women with CMV infection.

Cytomegalovirus Infection in Pregnancy

BackgroundMaternal CMV infection during pregnancy, either primary or non-primary, may be associated with fetal infection and long-term sequelae. While guidelines recommend against it, screening for CMV in pregnant women is a prevalent clinical practice in Israel. Our aim is to provide updated, local, clinically relevant, epidemiological information about CMV seroprevalence among women at childbearing age, the incidence of maternal CMV infection during pregnancy and the prevalence of congenital CMV (cCMV), as well as to provide information about the yield of CMV serology testing.MethodsWe performed a descriptive, retrospective study of women at childbearing age who were members of Clalit Health Services in the district of Jerusalem and had at least one gestation during the study period (2013–2019). We utilized serial serology tests to determine CMV serostatus at baseline and at pre/periconception and identified temporal changes in CMV serostatus. We then conducted a sub-sample analysis integrating inpatient data on newborns of women who gave birth in a single large medical center. cCMV was defined as either positive urine CMV-PCR test in a sample collected during the first 3 weeks of life, neonatal diagnosis of cCMV in the medical records, or prescription of valganciclovir during the neonatal period.ResultsThe study population Included 45,634 women with 84,110 associated gestational events. Initial CMV serostatus was positive in 89% women, with variation across different ethno-socioeconomic subgroups. Based on consecutive serology tests, the detected incidence rate of CMV infection was 2/1000 women follow-up years, among initially seropositive women, and 80/1000 women follow-up years, among initially seronegative women. CMV infection in pregnancy was identified among 0.2% of women who were seropositive at pre/periconception and among 10% of women who were seronegative. In a subsample, which included 31,191 associated gestational events, we identified 54 newborns with cCMV (1.9/1000 live births). The prevalence of cCMV among newborns of women who were seropositive at pre/periconception was lower than among newborns of women who were seronegative (2.1 vs. 7.1/1000). Frequent serology tests among women who were seronegative at pre/periconception detected most primary CMV infections in pregnancy that resulted in cCMV (21/24). However, among women who were seropositive, serology tests prior to birth detected none of the non-primary infections that resulted in cCMV (0/30).ConclusionsIn this retrospective community-based study among women of childbearing age characterized by multiparity and high seroprevalence of CMV, we find that consecutive CMV serology testing enabled to detect most primary CMV infections in pregnancy that led to cCMV in newborns but failed to detect non-primary CMV infections in pregnancy. Conducting CMV serology tests among seropositive women, despite guidelines' recommendations, has no clinical value, while it is costly and introduces further uncertainties and distress. We thus recommend against routine CMV serology testing among women who were seropositive in a prior serology test. We recommend CMV serology testing prior to pregnancy only among women known to be seronegative or women whose serology status is unknown.

Cytomegalovirus (CMV) is the most common cause of perinatal viral infection, affecting 0.2-2.2% of all neonates, with variation among different study populations. It can cause serious long-term neurological sequelae, being the leading cause of non-genetic congenital hearing loss. The risk of congenital infection is highest after primary maternal infection, varying between 30-70% and depending on the gestational age at the time of infection. Although CMV can have serious neurodevelopmental consequences, in most developed countries current guidelines do not recommend routine screening for CMV in pregnancy, since current tests have a low predictive value for cases with serious adverse outcome and efficient therapeutic options are not standardized yet. In Romania there is a routine clinical practice to offer screening for most common causes of infections, including CMV, in the first trimester of pregnancy In these settings, this review summarizes the current methods of diagnosis and management of CMV infection in pregnancy.

Human cytomegalovirus (CMV) is under-recognised, despite being the leading infectious cause of congenital malformation, affecting ~0.3% of Australian live births. Approximately 11% of infants born with congenital CMV infection are symptomatic, resulting in clinical manifestations, including jaundice, hepatosplenomegaly, petechiae, microcephaly, intrauterine growth restriction and death. Congenital CMV infection may cause severe long-term sequelae, including progressive sensorineural hearing loss and developmental delay in 40-58% of symptomatic neonates, and ~14% of initially asymptomatic infected neonates. Up to 50% of maternal CMV infections have nonspecific clinical manifestations, and most remain undetected unless specific serological testing is undertaken. The combination of serology tests for CMV-specific IgM, IgG and IgG avidity provide improved distinction between primary and secondary maternal infections. In pregnancies with confirmed primary maternal CMV infection, amniocentesis with CMV-PCR performed on amniotic fluid, undertaken after 21-22 weeks gestation, may determine whether maternofetal virus transmission has occurred. Ultrasound and, to a lesser extent, magnetic resonance imaging are valuable tools to assess fetal structural and growth abnormalities, although the absence of fetal abnormalities does not exclude fetal damage. Diagnosis of congenital CMV infection at birth or in the first 3 weeks of an infant's life is crucial, as this should prompt interventions for prevention of delayed-onset hearing loss and neurodevelopmental delay in affected infants. Prevention strategies should also target mothers because increased awareness and hygiene measures may reduce maternal infection. Recognition of the importance of CMV in pregnancy and in neonates is increasingly needed, particularly as therapeutic and preventive interventions expand for this serious problem.

Maternal Facial Nerve Palsy and a Perinatal Infection.

Cytomegalovirus infection in pregnancy – An update

Congenital cytomegalovirus (cCMV) is the most common congenital infection in the United States, with 1 of 200 live births affected. It is the leading viral cause of intrauterine fetal demise and miscarriage. It is a common cause of neonatal hearing loss, second only to genetic factors. Yet, health care provider awareness remains low. The purpose of this article is to provide a brief overview of the epidemiology, presentation, diagnosis, and treatment of antenatal cytomegalovirus (CMV) infection and cCMV in the neonate. Maternal CMV infection in pregnancy often presents with mild cold-like symptoms or is asymptomatic. The virus can be vertically transmitted to a growing fetus, the risk of transmission and severity of fetal impact varying by timing of exposure during pregnancy. Most neonates born with cCMV show no signs at birth, yet 15% to 25% will have long-term adverse neurodevelopmental conditions. Misconceptions that cCMV cannot be prevented or that neonates born without signs of the disease will be unaffected are common. Evidence supporting antenatal education around behavioral change to lower a woman's risk of acquiring CMV during pregnancy is mounting. CMV infection during pregnancy should be co-managed with a maternal-fetal medicine specialist. There is early evidence for the use of antiviral medication in reducing risk of vertical transmission. Identification of cCMV during pregnancy may help ensure the neonate receives timely treatment after birth. Midwives can play an important role in providing antenatal education about cCMV risk reduction and in initiating a diagnostic evaluation when there is clinical suspicion.

Congenital cytomegalovirus infection is the most common nongenetic cause of sensorineural hearing loss in childhood and an important cause of neurodisability. There is no licensed cytomegalovirus (CMV) vaccine and no antenatal treatment for congenital CMV that is routinely recommended in clinical practice in the United Kingdom. To review the published literature for studies that evaluated preventative hygiene-based interventions in pregnancy for their impact on knowledge about CMV prevention, the uptake of preventative behaviors or the acquisition of CMV in pregnancy. Searches were carried out in Medical Literature Analysis and Retrieval System Online and Cumulative Index of Nursing and Allied Health Literature databases. All human studies, limited to women of childbearing age were included. Two reviewers independently assessed the quality of the methods and results of included articles. Extracted data were classified using Cochrane guidelines. Seven studies met the inclusion criteria. These show that preventative measures are acceptable to pregnant women, can impact their behavior and have the potential to reduce CMV in pregnancy. They are limited by several factors; sample size, nonrandomized trial design and interventions that are beyond routine clinical practice. An effective intervention that changes behavior in pregnancy and reduces the risk of CMV acquisition is needed as part of routine care. There is currently insufficient evidence about the form that this intervention should take. PROSPERO registration number: CRD42017069666.

Clinical manifestations and abnormal laboratory findings in pregnant women with primary cytomegalovirus infection

To compare the clinical manifestations and laboratory abnormalities associated with primary cytomegalovirus (CMV) infection in pregnancy with recurrent and non-active CMV infection (controls). A prospective cohort study. Rome, Latium and other Italian regions. Three hundred and sixteen pregnant women with CMV infection: 102 had primary infection, 105 had recurrent infection and 109 with non-active infection were followed up as controls. CMV diagnosis was based on serological examinations (CMV IgG, IgM and IgG avidity) and detection of CMV DNA by polymerase chain reaction in maternal serum, urine and cervical samples. The clinical history and laboratory evaluations were carried out at enrollment and at each subsequent visit, every one to three months. Identification of clinical and laboratory indicators of primary CMV infection in pregnancy. Compared with women with recurrent or non-active infection, women with primary infection had a statistically significant higher prevalence of fever, asthenia, myalgia and flu-like syndrome (P < 0.001). In particular, relevant symptomatology was observed in 32 women (31.4%), of whom 25 had flu-like syndrome and 7 persistent fever as a single manifestation. Moreover, women with primary infection showed a significantly increased rate of lymphocytes >or=40% (39.2% vs 5.7% or 3.7%, respectively, P < 0.001) and elevated aspartate aminotransferase and/or alanine aminotransferase levels (35.3% vs 3.9% or 0.9%, respectively, P < 0.001): lymphocytosis and/or increased aminotransferases occurred in 53 patients (52%). In total, clinical manifestations and/or laboratory abnormalities occurred in 61 women with primary infection (59.8%) compared with 20 with recurrent infection (19%) and 13 controls (11.9%) (P < 0.001). Clinical manifestations (i.e. flu-like syndrome, fever) and abnormal laboratory findings (i.e. lymphocytes >or=40%, elevated aminotransferases) may suggest the presence of primary CMV infection and should prompt subsequent virological investigations.

Guideline No. 420: Cytomegalovirus Infection in Pregnancy.

Management of cytomegalovirus infection in pregnancy: is it time for valacyclovir?