Cytomegalovirus infection in pregnancy

INTRODUCTION — Cytomegalovirus (CMV) is a ubiquitous DNA herpesvirus. As with other herpesviruses, it becomes latent after a primary infection but can reactivate and renew viral shedding. Shedding can occur from multiple sites and for prolonged periods of time. Reinfection with a different viral strain is also possible.

CMV is the most common congenital viral infection, with pooled birth prevalence of 0.67 percent in a meta-analysis of worldwide studies [1-6]. Approximately 90 percent of newborns with congenital CMV infection are apparently asymptomatic at birth and 10 percent are symptomatic. Clinical findings in symptomatic neonates are nonspecific and include petechiae, jaundice, hepatosplenomegaly, small size for gestational age, and microcephaly. Both symptomatic and asymptomatic infected newborns are at risk for adverse outcome, but symptomatic newborns are at higher risk [7-13]. Sensorineural hearing loss is the most common sequela of congenital CMV infection, occurring in 33 to 50 percent of symptomatic infants and approximately 25 percent of asymptomatic infants. Clinical features, management, and long-term sequelae of congenital CMV infection in symptomatic and asymptomatic infected newborns are discussed in detail separately. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis", section on 'Symptomatic neonate' and "Congenital cytomegalovirus infection: Management and outcome".)

MATERNAL ISSUES

Terminology

●Primary maternal CMV infection is defined as acquisition of CMV virus during pregnancy in a person with no preexisting CMV-specific immunoglobulin G (IgG) antibodies. The diagnosis is based on seroconversion (ie, newly detectable CMV-specific antibodies) during pregnancy.

●Nonprimary maternal CMV infection is defined as CMV replication in a pregnant individual with seroimmunity (ie, preexisting CMV-specific IgG antibodies). Like other herpesviruses, CMV establishes latency after the host is initially infected. Maternal antibodies to CMV do not prevent reactivation of latent virus, especially in immunocompromised hosts, or reinfection with a different CMV strain. Reactivation or reinfection during pregnancy can lead to transient viremia and fetal infection [14].

Acquisition and vertical transmission

●Maternal acquisition – CMV has been cultured from multiple body fluids, including urine, saliva, nasopharyngeal secretions, tears, cervical and vaginal secretions, semen, blood, and breast milk. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Transmission'.)

Maternal acquisition from exposure to body fluids can occur via multiple routes, including:

•Close nonsexual contact with saliva or urine, although transmission from respiratory droplets or aerosolized droplets is unlikely [15]

•Sexual contact

•Transfusion

•Organ transplant

●Vertical transmission – Maternal viremia, leading to placental infection, and subsequent transplacental transmission to the fetus is the major route of vertical transmission. Placental cytotrophoblasts are permissive to CMV replication.

Newborns may become infected via intrapartum exposure to cervical/vaginal viral shedding or, more commonly, from consumption of infected breast milk. This is unlikely to cause clinical sequelae in healthy full-term neonates, but symptomatic infection can occur in preterm infants. Very low birth weight infants are especially at risk for severe CMV disease. (See "Overview of cytomegalovirus infections in children", section on 'Early postnatal infection' and "Overview of cytomegalovirus infections in children", section on 'Early postnatal infection'.)

Seroprevalence — CMV infection is common. A systematic survey of the literature estimated 86 percent CMV seroprevalence globally in females of childbearing age [16].

Seroprevalence increases with age and varies by demographic factors [2-4,16,17]. The following characteristics have been associated with positive CMV serology in females of childbearing age:

●Household and/or occupational exposure to children under age 3 years, especially if they are in daycare [3,18,19].

●Age older than 25 to 30 years [3,20].

●Higher parity [21].

●Country of residence. The highest seroprevalences are in the Eastern Mediterranean, Western Pacific, African, and Southern and Southeast Asian regions (seroprevalence 89 to 92 percent) and the lowest in the European region and the Americas (seroprevalence 70 and 79 percent, respectively) [16].

●Income level of maternal country of birth. In a high-income multicultural society, being born in a non-Organisation for Economic Cooperation and Development (OECD) country was the only significant factor associated with seroprevalence in a pregnant population, after adjusting for parity and socioeconomic status of current residential postcode [22]. Neighborhood-level poverty as measured by the Area Deprivation Index (ADI) is a race-independent predictor of local CMV seroprevalence among pregnant people in the United States [23].

Epidemiology of seroconversion — The likelihood of seroconversion depends on social, behavioral, and environmental factors. Annual rates of seroconversion during pregnancy are generally reported to be 1 to 7 percent worldwide in populations with low-to-intermediate CMV seroprevalence [24]. Seronegative pregnant people living in high-seroprevalence areas are at higher risk; estimated annualized rates of seroconversion of 14.8 to 22.5 percent have been reported in these individuals [25-27]. In a large prospective study from Brazil in which 98 percent of participants were CMV seropositive during the first trimester, 5 out of 36 (13.9 percent) seronegative mothers seroconverted during pregnancy [25].

In a systematic review of studies that measured rates of CMV seroconversion, summary annual rates of seroconversion in specific groups were as follows [24]:

●Pregnant individuals – 2.3 percent (95% CI 2.1-2.4 percent). However, in a contemporary study that screened over 200,000 pregnant people less than 23 weeks of gestation in the US, only 0.35 percent had serological evidence of primary CMV infection [28].

●Health care workers, including those caring for infants and children – 2.3 percent (95% CI 1.9-2.9 percent).

●Daycare providers – 8.5 percent (95% CI 6.1-11.6 percent).

●Parents of a young child:

•Not shedding CMV – 2.1 percent (95% CI 0.3-6.8 percent).

•Shedding CMV – 24 percent (95% CI 18-30 percent). In a previously unexposed parent, this is the scenario with the highest risk of acquisition, presumably through sharing drinks, utensils, and care needs. (See 'Behavioral risk reduction interventions' below.)

Other groups with elevated risk of seroconversion included cohabitating individuals with a CMV-shedding member, female adolescents from disadvantaged groups, individuals attending sexually transmitted disease clinics, and immunocompromised individuals.

The risk related to parenthood was illustrated in a study in which 15.6 percent of females seronegative at their first pregnancy seroconverted by the time of a subsequent pregnancy that occurred within two years [29]. Twenty-nine percent of the seroconversions occurred periconceptionally or in the first trimester, thereby placing the subsequent fetus at risk of sequelae from primary maternal CMV infection.

Maternal clinical findings

●Primary infection – Primary CMV infection is asymptomatic in approximately 90 percent of those infected. In the remaining 10 percent, clinical manifestations may include fever, rhinitis, pharyngitis, myalgia, arthralgia, headache, and/or fatigue.

The most common presentation of symptomatic CMV infection in immunocompetent adults is a syndrome resembling infectious mononucleosis, characterized by significant, often protracted fevers and lassitude in the setting of absolute lymphocytosis and atypical lymphocytes. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'CMV mononucleosis' and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Organ-specific complications'.)

Pregnancy does not appear to affect the clinical severity of primary CMV infection, but the integrity of the host immune system affects the spectrum of disease. Hosts with impaired cellular immunity are at risk for severe and disseminated infection.

●Nonprimary infection – Reinfection with a different CMV strain or reactivation of virus in pregnant individuals with preexisting antibody is generally asymptomatic in the mother [30].

The clinical manifestations of CMV infection in adults are discussed in more detail separately. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults".)

Role of maternal screening — No professional societies or government health authorities recommend universal serological screening for recent CMV infection for the general obstetric population [31]. Some authorities recommend targeted screening of pregnant people at increased risk of exposure, such as those with close contact with young children.

The rationale against routine universal screening includes:

●No vaccine is available to prevent infection in seronegative individuals.

●Seropositive patients remain at risk of fetal infection from reactivation of latent virus and/or reinfection with a new viral strain.

●Although fetal infection may occasionally be detected, whether the infected fetus will develop significant sequelae cannot be determined reliably.

●Routine screening can lead to unnecessary, and potentially harmful, consequences, such as increased parental anxiety, unnecessary medical interventions, and increased terminations of pregnancy among those at low risk of CMV complications.

In an observational study of over 75,000 pregnant individuals in Israel who underwent prenatal immunoglobulin M (IgM) screening for CMV infection, approximately one percent had a positive test [32]. Among these patients, only one quarter underwent amniocentesis and those who did not undergo amniocentesis were more likely to terminate the pregnancy than those who underwent amniocentesis (35.6 versus 7.3 percent). Even those at low or moderate risk of intrauterine CMV transmission had termination rates of 19.2 and 23.6 percent, respectively, which greatly exceed the expected rates of affected fetuses/children. A 2020 cost-effectiveness analysis of serological screening in France concluded that routine screening would increase poor newborn outcomes 1.66-fold (mostly related to increased pregnancy terminations) without a corresponding decrease in severely symptomatic newborns [33].

●In seropositive pregnant patients, it is difficult to distinguish between primary and nonprimary infection or determine the timing of the infection, which could have occurred many months before conception.

●In seronegative pregnant patients, seroconversion can occur at any time. Repeated serologic screening during pregnancy is not commonly performed but does occur on an ad hoc basis in some countries such as Israel.

The rationale for routine universal screening is:

●Individuals who know they are seronegative and thus at risk of primary infection may adhere better to recommended hygiene measures, which might decrease the risk of seroconversion during pregnancy. (See 'Behavioral risk reduction interventions' below.)

●Emerging evidence from randomized trials of the efficacy of maternal antiviral drug treatment of primary infection for prevention of fetal CMV infection [34]. If these promising findings (described below) are replicated on a large scale, this intervention could be offered within a prenatal serological screening program. A 2023 cost-effectiveness analysis of serological screening strategies in France concluded that universal screening in conjunction with valacyclovir treatment of patients with first-trimester primary CMV infection would be cost-effective [35]. (See 'Antiviral medication' below.)

Candidates for documentation of baseline CMV serology — In our practice, we obtain baseline CMV serology in pregnant patients at increased risk of undergoing diagnostic testing later in pregnancy:

●In patients with a known high-risk exposure (mucosal exposure to known infected body fluids), we obtain baseline IgG and IgM CMV serology and, if negative, we repeat the tests three to four weeks later to assess for seroconversion.

●In patients infected with HIV, we obtain baseline IgG and IgM CMV serology at the first prenatal visit. This facilitates diagnostic testing for CMV in high-risk patients who develop signs/symptoms suggestive of CMV infection or have suggestive fetal ultrasound findings. (See 'Diagnosis' below.)

●In patients who are immunosuppressed for other reasons (eg, on medication for organ transplant management), we individualize decision-making.

Prepregnancy or early pregnancy baseline CMV IgG may be considered for individuals who are at high risk of infection. Early determination of CMV serostatus may aid in distinguishing between primary infection and reactivation/reinfection during pregnancy if clinically indicated, but does not remove the need to follow recommended hygiene measures.

Diagnosis

When to suspect maternal CMV infection — Maternal CMV infection should be suspected and testing performed in the following individuals [36]:

●Pregnant patients with mononucleosis-like or influenza-like illness, especially in the setting of negative Epstein-Barr and influenza virus tests. (See "Infectious mononucleosis" and "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

●Pregnant patients with clinical manifestations of hepatitis (eg, fever, fatigue, loss of appetite, nausea, vomiting, abdominal pain, dark urine, light-colored stools, joint pain, jaundice) in the setting of negative viral hepatitis panel. (See "Hepatitis B virus: Clinical manifestations and natural history" and "Hepatitis B virus: Screening and diagnosis in adults".)

●Pregnant patients in whom fetal ultrasound shows anomalies suggestive of congenital CMV infection (eg, periventricular calcifications, ventriculomegaly). (See 'Ultrasound markers suggestive of congenital CMV infection' below.)

Diagnosis of primary versus past maternal infection

●Seroconversion of CMV-specific IgG in paired acute and convalescent sera collected three to four weeks apart is diagnostic of a new acute infection.

●In the absence of documented recent seroconversion, the diagnosis of primary CMV infection versus past infection is based on serology (IgG, IgM, and IgG avidity), as described in the table (table 1). Laboratory testing protocols vary. Most laboratories will perform IgG avidity testing if the patient is both CMV IgG and IgM positive, but whether avidity testing has to be specifically requested in this scenario or whether it occurs as a reflex test is subject to local procedures.

IgM alone is not helpful for timing the onset of infection because (1) it is present in only 75 to 90 percent of individuals with acute infection, (2) it can remain positive for over one year after an acute infection, (3) it can revert from negative to positive in individuals with CMV reactivation or reinfection with a different strain, and (4) it can become positive in response to other viral infections, such as Epstein-Barr virus. Rising titers alone also are not diagnostic.

Because CMV-specific IgG may represent primary infection, reactivation, reinfection, or latent disease, determining IgG avidity is helpful for assessing the acuity of the infection and thus the risk of in utero transmission [37-42]. High antibody avidity suggests infection occurred more than three months in the past, while low avidity suggests recent infection within three months. However, commercial avidity antibody assays have varying performance characteristics [43], the interpretation of intermediate avidity and the optimal cutoffs for low and high avidity are not well established [44,45], and the cutoffs for low and high avidity vary among laboratories.

The diagnosis of CMV is discussed in more detail separately. (See "Overview of diagnostic tests for cytomegalovirus infection".)

Prognostic counseling at the time of maternal diagnosis

●Frequency of fetal infection after seroconversion – Patients who seroconvert to CMV positive during pregnancy are at highest risk for maternal-fetal transmission and the frequency of vertical transmission increases with advancing gestational age at the time of seroconversion. In a review that pooled data from 10 studies of maternal-fetal CMV transmission in nearly 3000 patients who seroconverted just before or during pregnancy, the rates fetal infection were [46]:

•Preconception period (up to 12 weeks before the last menstrual period) – 5.5 percent

•Periconceptional period (four weeks before to six weeks after the last menstrual period) – 21.0 percent

•First trimester – 36.8 percent

•Second trimester – 40.3 percent

•Third trimester – 66.2 percent

●Frequency of clinical sequelae after seroconversion – Although the frequency of vertical transmission increases with advancing gestational age, the frequency of clinical sequalae in the fetus/newborn decreases with advancing gestational age and clinical sequalae are unlikely when maternal infection occurs in the second half of pregnancy [46-49]. In a review of pooled data from 10 studies (796 fetuses), the rates of clinical sequelae (neurologic symptoms at birth or termination of pregnancy because of CMV-associated findings in the central nervous system on ultrasonography or magnetic resonance imaging [MRI]) by gestational age of maternal seroconversion were [46]:

•Periconceptional period (four weeks before to six weeks after the last menstrual period) – 28.8 percent (95% CI 2.4-55.1)

•First trimester – 19.3 percent (95% CI 12.2-26.4)

•Second trimester – 0.9 percent (95% CI 0-2.4)

•Third trimester – 0.4 percent (95% CI 0-1.5)

●Frequency of fetal infection in patients with preconception CMV seroimmunity – Preconception seroimmunity provides substantial but not complete protection against the occurrence of fetal infection [50]. The risk of fetal infection in this population is estimated to be about 1 percent (0.15 to 2 percent) [7,20,25,47]. Since the seroimmune population is much larger than the population with documented seroconversion during pregnancy, 75 percent of congenitally-infected infants in the United States have been attributed to nonprimary maternal infection [51].

Pregnant patients with HIV appear to be an exception to the observation that frequency of fetal infection is low among seropositive pregnant patients. Advanced maternal immunocompromise has been associated with a higher birth prevalence of congenital CMV infection, despite maternal antiretroviral prophylaxis [8,52-55]. A study from the United States reported congenital CMV rates remained high in HIV-exposed but uninfected infants born during the era of antiretroviral therapy [56], whereas a French study reported congenital CMV prevalence decreased in infants born to mothers on antiretroviral therapy [57].

Maternal care — In addition to routine prenatal care, immunocompetent pregnant patients with symptomatic CMV infection should be offered supportive care for symptomatic relief, as needed (eg, acetaminophen for fever). Use of antiviral drugs for maternal treatment of CMV infections in immunocompetent adults, including pregnant patients, is rarely indicated. Several medications (eg, ganciclovir, foscarnet, cidofovir) are available to treat severe end-organ CMV disease in nonpregnant adults but experience in pregnancy is limited. Maternal treatment is discussed in more detail separately. (See "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Therapy'.)

Pregnant patients with suspected CMV infection often experience uncertainty, anxiety, and stress, which can be exacerbated by their health care professional's lack of knowledge and lack of patient information [58]. Patients and families should be offered well-informed counselling and support following a suspected/confirmed diagnosis of congenital CMV. Referral to a maternal-fetal medicine specialist can be useful. Consumer-led support groups are available in a growing number of countries and include the National CMV Foundation (United States), CMV Canada, , and CMV Australia.

FETAL ISSUES

Ultrasound markers suggestive of congenital CMV infection — The following ultrasonographic markers are suggestive, but not diagnostic, of fetal CMV infection [3,59-67]. The abnormalities can appear 12 or more weeks after maternal infection [67,68]. Some infected fetuses do not develop ultrasound abnormalities.

●Periventricular calcifications (image 1)

●Cerebral ventriculomegaly (image 2)

●Microcephaly

●Pseudocysts, periventricular or adjacent to the occipital or temporal horn

●Hyperechogenic fetal bowel (image 3)

●Fetal growth restriction

●Ascites (image 4)

●Pleural and/or pericardial effusion (image 4 and image 5)

●Hepatosplenomegaly

●Hepatic calcifications

●Polymicrogyria

●Cerebellar hypoplasia

●Large cisterna magna

●Amniotic fluid abnormalities (oligohydramnios or polyhydramnios)

●Hydrops

●Placental thickening and enlargement, heterogeneous appearance, calcifications

The most characteristic sonographic finding of fetal CMV infection is bilateral periventricular hyperechogenicities (calcifications) (image 1) [69,70]. These calcifications or hyperechoic foci can be highly reflective and may not cast an acoustic shadow [71]. Branching linear echogenic areas in the thalami also occur and correspond to arteries in the basal ganglia and thalamus [72,73]. The presence of intraventricular filmy, thin adhesions and linear edges traversing the ventricle is typical in CMV infection of the brain [65,74-82].

Although there is a considerable overlap in imaging findings between congenital CMV infection and congenital Zika syndrome, severe microcephaly, evidence of fetal brain collapse (fetal brain disruption sequence), and contractures are most characteristic of fetal Zika virus infection [83]. In addition, the distribution of intracerebral calcifications is subcortical in congenital Zika syndrome but periventricular in congenital CMV infection.

Late-onset isolated fetal growth restriction is unlikely to be related to CMV. A systematic review investigating the yield of maternal TORCH serology for fetal ultrasound abnormalities found that the rate of congenital CMV among infants with isolated late-onset growth restriction was 0.4 percent (2 out of 496) [84], while a multicenter cohort study of fetuses with late-onset fetal growth restriction reported a congenital CMV rate of rate of 0.2 percent (3 out of 1246) [85]. These rates are similar to the birth prevalence of CMV in high-income countries. For this reason, the Society for Maternal-Fetal Medicine in the US states that routine CMV serology may not be warranted for the investigation of fetal growth restriction in the absence of risk factors or ultrasound markers of fetal infection [86].

Diagnosis of fetal infection

Diagnosis

●Fetal CMV infection should be suspected in patients with maternal serology consistent with a primary infection or ultrasound findings (other than isolated growth restriction) suggestive of congenital infection. (See 'Diagnosis' above and 'Ultrasound markers suggestive of congenital CMV infection' above.)

However, maternal serology for CMV infection is of limited clinical utility when investigating fetal ultrasound abnormalities in the second or third trimester. Although the combination of CMV IgG- and IgM-negative results exclude CMV as a cause of the ultrasound finding, the combination of a CMV IgG-positive result and a CMV IgM-negative result after 16 weeks does not because this serology result could still occur following maternal primary or nonprimary first-trimester infection.

●The diagnosis of fetal infection is confirmed in pregnancies by positive polymerase chain reaction (PCR) for CMV DNA in amniotic fluid; sensitivity ranges from 70 to 100 percent [59-61,68,87]. Viral culture is less desirable because of several limitations, discussed separately. (See "Overview of diagnostic tests for cytomegalovirus infection".)

Diagnostic amniocentesis

●Candidates and rationale – We offer amniocentesis for prenatal (fetal) diagnosis when fetal infection is suspected based on maternal serology consistent with a primary infection or ultrasound findings are suggestive of congenital infection. (See 'Diagnosis' above and 'Ultrasound markers suggestive of congenital CMV infection' above.)

The rationale for offering prenatal diagnosis is that the frequency of fetal infection after a maternal primary infection ranges from 36.8 to 66.2 percent [46] and ultrasound findings are not reliable for diagnosing fetal CMV infection. Some parents may use this information in decision-making regarding termination of pregnancy. It helps others prepare for the birth of an infected and possibly clinically affected child (see "Congenital cytomegalovirus infection: Clinical features and diagnosis"). In addition, knowing that the fetus is infected may change ongoing fetal surveillance (eg, frequency of ultrasound examination, offer of fetal brain MRI), is informative for the pediatricians caring for the child, and may prompt selective use of maternal antiviral therapy to reduce fetal infection and/or clinical sequelae. (See 'Maternal treatment for fetal benefit' below.)

In a prospective study of 55 amniocentesis procedures performed for maternal primary CMV infection before 24 weeks, results were positive for CMV in 25 percent [88]. The neonates of all 12 subjects with a positive amniocentesis and available results had CMV confirmed after birth, as did 2 neonates from 41 subjects with a negative amniocentesis, resulting in sensitivity 86 percent (95% CI 57-98), specificity 100 percent (95% CI 91-100), positive predictive value 100 percent (95% 74-100), and negative predictive value 95 percent (95% CI 83-99).

●Timing – In patients with a primary CMV infection, an interval of at least eight weeks between diagnosis and amniocentesis is desirable for high diagnostic sensitivity, since it takes six to eight weeks for placental infection and replication, transmission to the fetus, viral replication in the fetal kidney, and excretion into amniotic fluid [67].

Traditionally, sensitivity has been reported to be highest after 21 weeks of gestation; however, emerging data suggest that an interval of eight weeks following maternal primary infection is a more appropriate benchmark.

•In a prospective study of maternal valacyclovir treatment for secondary prevention of fetal infection, amniocentesis for diagnosis of fetal infection performed at 17 to 20 weeks and at least 8 weeks from maternal primary infection had sensitivity 95.8 percent (95% CI 79.8-99.8 percent), specificity 100 percent (95% CI 91.8-100.0), positive predictive value 100 percent (95% CI 85.7-100.0) and a negative predictive value 97.7 percent (95% CI 88.2-99.9) [89].

•In a retrospective study that reviewed 264 pregnancies at 17 to 23 weeks of gestation with at least 8 weeks between seroconversion and amniocentesis, diagnostic sensitivity was similar before versus after 21 weeks (87.2 and 92.1 percent, respectively), as was negative predictive value (93.6 and 96.8 percent, respectively) [90].

●Procedure – The first 1 mL of fluid obtained should be discarded to reduce the risk of maternal cell contamination [59-61,90]. Rarely, false-positive results occur from contamination of the amniotic fluid sample by maternal fluids. (See "Diagnostic amniocentesis".)

CMV DNA in maternal blood at the time of amniocentesis does not appear to be a significant risk factor for iatrogenic antepartum transmission [91].

Predicting outcome after confirmation of fetal infection

Primary versus nonprimary maternal infection — Although fetal infection is less likely in individuals with seroimmunity [20], when it occurs, the frequency of symptomatic newborn disease and long-term sequelae is similar to that of offspring of mothers with primary CMV infection during pregnancy [92].

Normal versus abnormal ultrasound findings

●Normal ultrasound examination – A normal ultrasound examination is reassuring but does not completely exclude the possibility of a symptomatic neonate or development of long-term neurologic morbidity. Serial ultrasound examinations at two- to four-week intervals can be useful to detect development of sonographic abnormalities, which can appear 12 or more weeks after a periconceptional or early pregnancy maternal infection, or not at all [67,68].

In a systematic review including 1178 fetuses with a normal ultrasound examination at the time of maternal diagnosis of CMV infection, [93]:

•An associated CNS anomaly was detected on follow-up ultrasound in 4.4 percent of cases (95% CI, 1.4-8.8 percent).

•An associated extra-CNS anomaly was detected on follow-up ultrasound in 2.9 percent of cases (95% CI, 0.8-6.3 percent).

•Symptomatic infection occurred in 1.5 percent of cases (95% CI, 0.7-2.7 percent), and the overall rate of a neurodevelopmental anomaly in these cases was 3.1 percent (95% CI, 1.6-5.1 percent).

•Hearing problems affected 6.5 percent of children (95% CI 3.8-10 percent).

•Motor and cognitive delays and visual problems occurred in 2.3, 1.1, and 1 percent of children, respectively.

Importantly, when trimester of primary maternal infection was considered:

•An anomaly was subsequently detected only among fetuses infected in the first trimester.

•Abnormal childhood neurodevelopment outcome only occurred among fetuses infected in the first trimester, and the rate was 5.4 percent in this group.

•Hearing problems occurred in 11.4 percent of children infected in the first trimester, 7 percent of those infected in the second trimester, and none of those infected in the third trimester.

●Abnormal ultrasound – Fetal abnormalities, such as ventriculomegaly, periventricular calcifications, microcephaly, growth restriction, and hydrops, suggest severe disease and a high risk of long-term neurodevelopmental impairment. (See "Congenital cytomegalovirus infection: Management and outcome", section on 'Outcome'.)

Of note, there are no fetal imaging findings (ultrasound or MRI) specifically predictive of postnatal hearing loss.

Other tests — None of the following tests are useful routinely. All provide information about the status of the fetus at the time of the test, but none substantially improves prediction of a normal versus abnormal neurodevelopmental outcome compared with ultrasound alone.

●Viral load in amniotic fluid – The prognostic value of CMV viral load in amniotic fluid has been studied as a possible predictor of symptomatic disease at birth for fetuses with normal ultrasound [3,94-96]. One study found that a viral load >100,000 copies/mL of amniotic fluid at weeks 21 to 23 of gestation distinguished the seven fetuses/newborns with signs and/or symptoms of congenital CMV infection from the 16 who appeared normal and asymptomatic [94]. Another retrospective study calculated a negative predictive value for symptoms at birth or at termination of pregnancy of 93 percent for ultrasound alone versus 95 percent for ultrasound and viral load in amniotic fluid [96]. However, the viral load threshold for predicting symptoms at birth has not been robustly defined or validated in independent prospective cohorts.

●MRI – The value of MRI after a normal neurosonogram by an expert sonologist is unclear. If an abnormality is suspected on ultrasound and clarification is needed, MRI may be helpful. The cost of the additional imaging and likelihood of gaining information that will alter management should be considered.

In a systematic review, MRI detected a central nervous system anomaly after a normal ultrasound in approximately 6 percent of fetuses with CMV [93]. Nevertheless, detection of subtle nonprogressive findings on MRI are not necessarily predictive of neurodevelopmental impairment, particularly when the ultrasound is normal [97]. In addition, although the combination of normal fetal ultrasound and normal MRI had a high negative predictive value in another systematic review [98], these findings do not completely exclude the possibility of development of postnatal hearing loss, a common sequelae of congenital CMV infection [67,99].

●Fetal blood sampling – Cordocentesis for evaluation of fetal CMV disease is not recommended. Abnormal liver function tests, hematologic tests (especially thrombocytopenia), and beta-2 microglobulin level are signs of severe disease, but this information is not substantially more predictive of an unfavorable long-term outcome than an abnormal ultrasound, and cordocentesis is associated with a 2 percent risk of procedure-related fetal loss [96,100,101]. (See "Fetal blood sampling", section on 'Complications'.)

DELIVERY AND NEWBORN CARE

●Timing and route of birth – The timing and route of birth are determined by standard obstetric indications. Recovery of CMV from the cervix or urine is not an indication for cesarean birth.

●Newborn care – Newborns considered to be at increased risk of congenital CMV infection because of ultrasound or placental findings or maternal history should be tested within the first 21 days of life even if a prior diagnostic amniocentesis was negative because at least 8 percent of such newborns have detectable CMV at birth after a negative amniocentesis [102]. These neonates appear to be at extremely low risk of long-term sequalae, but should be offered regular hearing and vision screening in accordance with local clinical guidelines [103]. (See "Congenital cytomegalovirus infection: Clinical features and diagnosis" and "Congenital cytomegalovirus infection: Management and outcome".)

●Breastfeeding – Although CMV can be transmitted through breast milk, the demonstrated benefits of breastfeeding probably outweigh the minimal risk to a healthy term newborn from acquiring CMV from individual actively shedding CMV. However, we advise consultation with the pediatric provider if a lactating individual with active CMV viral shedding desires to provide breastmilk to a preterm or unwell neonate [104-106]. Treatment of breast milk by freezing/thawing or pasteurization can reduce or prevent transmission of CMV. (See "Overview of cytomegalovirus infections in children", section on 'Prevention of neonatal transmission'.)

HIV-infected mothers in areas where formula is readily available are advised to not breastfeed because of a possible risk of HIV transmission. (See "Prenatal evaluation of women with HIV in resource-rich settings", section on 'Counseling'.)

●Placental pathology – The classic histopathologic placental findings associated with CMV infection include the following, although not all may be present:

•Lymphoplasmacytic villitis (diffuse chronic villitis with plasma cells)

•Sclerosis of the villous capillaries

•Chorionic vessel thromboses

•Necrotizing villitis

•Hemosiderin deposition in the villous stroma

•Normoblastemia

CMV replication has been demonstrated in smooth muscle cells of arteries and veins in floating villi and the chorion [107]. Large fibrinoids with many avascular villi and edematous villi and inflammation, changes that likely impair placental transport, have been observed in births complicated by intrauterine growth restriction and primary or nonprimary CMV infection. Progressive fetal thrombotic vasculopathy has been observed in stillbirths.

Viral inclusions (picture 1), which can be subtle, are observed in 10 percent of cases in fetal infection but are more often visible in cases associated with stillbirth. Immunohistochemistry may detect many inclusions not identified with routine hematoxylin-eosin stains [108].

STRATEGIES FOR PREVENTION OF MATERNAL AND/OR FETAL INFECTION

Behavioral risk reduction interventions — Although no actions can eliminate all risks of becoming infected with CMV, seroconversion rates may be reduced by preventive behavioral interventions [62,109-113]. In one study of patients who were seronegative at 11 to 12 weeks of gestation, seroconversion occurred in 1.2 percent of those who received specific hygiene information and were prospectively tested for CMV until delivery [111]. By comparison, seroconversion occurred in 7.6 percent of patients enrolled at delivery who were neither tested for nor informed about CMV during pregnancy, and who had a serum sample stored at the time of fetal aneuploidy screening. However, in at least one study, risk reduction information did not significantly affect seroconversion rates in nonpregnant females, even in those trying to conceive [110]. While these data are from low-quality studies, hygiene advice for people in early pregnancy or trying to conceive is reasonable based on the known methods of transmission.

●Counseling for all pregnant individuals – Practice good personal hygiene throughout pregnancy, especially after contact with body fluids from young children. This includes:

•Hand washing with soap and water after changing diapers or wiping a child's nasal secretions or saliva.

•Avoiding getting a child's saliva in your mouth. Suggested risk-reducing behaviors include not sharing food, utensils, or cups with a child, and kissing children on the forehead instead of the lips.

●Counseling health care workers – The risk of CMV infection among health care workers appears to be no greater than that among the general public. This is probably due, at least in part, to adherence to standard precautions by health care providers when handling body fluids and less personal contact in the health care setting than in the family setting.

●Counseling females about timing of conception after recent primary CMV infection

•Because CMV DNA has been detected in blood of 20 percent of immunocompetent patients as long as six months after diagnosis of primary infection, some experts suggest that an individual wait at least six months after a primary infection before attempting to conceive; however, data on the risk of congenital CMV in nonprimary maternal infection are limited [3]. Others suggest waiting a minimum of three or four months and/or documenting the presence of high-avidity CMV IgG antibodies before attempting to conceive [114].

•The use of high-dose valacyclovir during pregnancy may delay the maternal adaptive immune response to CMV. One case of severe fetal CMV infection has been reported in an immunocompetent pregnant patient treated with valacyclovir during their first affected pregnancy [115]. The patient conceived 10 weeks after cessation of valacyclovir treatment and had high-avidity IgG antibodies. The subsequent pregnancy was infected by the same strain of CMV. Pregnancy termination was performed because of severe fetal sequalae. The authors suggest that a longer interval between pregnancies should be advised if a patient has been treated with valacyclovir during the prior pregnancy. Further research is needed to determine if valacyclovir alters the natural history of maternal immunity and the risk of congenital CMV in nonprimary maternal infection.

Use of CMV-negative blood when transfusion is indicated — CMV-seronegative pregnant individuals, fetuses, and newborns should be transfused, when necessary, with blood from CMV-seronegative donors. (See "Practical aspects of red blood cell transfusion in adults: Storage, processing, modifications, and infusion", section on 'Specialized modifications and products'.)

Maternal treatment for fetal benefit

Antiviral medication — We suggest high-dose valacyclovir to patients who have a primary CMV infection during early pregnancy, after a comprehensive discussion of the potential benefits and risks. While increasing evidence (discussed below) supports the potential benefit of maternal antiviral therapy for reducing fetal infection in those with primary CMV infection during early pregnancy, it is not a routine treatment as only limited data are available on maternal, perinatal and long-term outcomes and serious maternal toxicity is possible (reversible kidney failure in approximately 2 percent patients [111,116]) [115]. Most patients have been treated as part of a research study. If used outside of a clinical trial, we strongly recommend monitoring and reporting maternal and infant outcomes, with periodic review to ensure that the intervention is safe, effective, appropriately integrated into prenatal care, and continuously improved based on accumulating data. (See "Valacyclovir: An overview", section on 'Toxicity'.)

●Evidence for preventing vertical transmission – Secondary prevention strategies involving antiviral therapy for preventing vertical transmission are challenging given that most maternal infections are asymptomatic and screening for CMV is not routinely performed. However, for those who are identified as having a primary infection in early pregnancy, valacyclovir is an option, with the above caveats regarding monitoring for side effects and maternal and perinatal outcomes.

•The highest-quality evidence for valacyclovir treatment to reduce fetal infection comes from a double-blinded randomized trial in which 100 pregnant people with serological evidence of first-trimester or periconception (four weeks before to three weeks after the last menstrual period) primary CMV infection were administered oral valacyclovir (8 g daily in two to four doses) or placebo prior to 14 weeks gestation [117]. The intervention reduced the rate of CMV-positive amniotic fluid in amniocentesis performed at >21 weeks gestation (30 versus 11 percent; OR 0.29, 95% CI 0.09-0.90). When stratified by timing of maternal infection, a significant treatment effect was observed in the first-trimester infection group (48 versus 11 percent), but not the periconception group (12 versus 13 percent). This discrepancy was presumed to be due to the later initiation of treatment in those with primary periconception infection. For the three fetal infections in the valacyclovir treated periconception group, the time interval between periconception infection and initiation of treatment was 10, 12, and 14 weeks, respectively. However, the overall rate of congenital CMV infection was not different between the two groups. Although participants in valacyclovir group had a lower risk of adverse outcomes, the duration of follow-up of infected children to monitor outcomes was not clear.

The authors subsequently revised their protocol to begin antiviral treatment earlier (up to nine weeks from the assumed time of periconception infection or up to eight weeks from the assumed time of first-trimester infection) and found that earlier initiation of valacyclovir was associated with significantly larger treatment effects in an observational study [118].

•In a 2023 individual patient data meta-analysis of one randomized trial (described above) and two observational studies (total 527 participants), maternal valacyclovir therapy of periconceptional or first trimester primary CMV infection was associated with reduced [34]:

-Vertical transmission (11.1 versus 25.5 percent; adjusted odds ratio [aOR] 0.34, 95% CI 0.18-0.61).

-Neonatal infection (19.2 versus 41.1 percent; aOR 0.30, 95% CI 0.19-0.47)

-Termination of pregnancy due to CMV-associated severe fetal abnormalities (0.9 versus 4.5 percent; aOR 0.23, 95% CI 0.22-0.24).

The reductions in vertical transmission and neonatal infection were similar for periconception and first-trimester infections.

Earlier treatment initiation improved prevention rates. The number needed to treat to prevent a positive CMV amniocentesis was 6.9. Severe maternal side effects occurred in 2.1 percent and consisted of acute obstructive kidney failure, which may occur because of deposition of crystalline byproduct in the kidney and may be minimized by volume repletion [102,119]. On GRADE assessment, the quality of evidence that valacyclovir can reduce the risk of congenital CMV infection and adverse perinatal outcomes was very low.

•Italy has added valacyclovir therapy for the secondary prevention of congenital CMV to its national medicines reimbursement system. A multicenter observational study from Italy (MEGAL-ITALI) including 447 pregnant people (205 treated with valacyclovir, 242 untreated) reported treatment was associated with statistically significant reductions in CMV diagnosis at amniocentesis and in the composite outcome of "termination of pregnancy or diagnosis of congenital CMV at birth" (24.7 versus 34.4 percent) [120]. Of note, however, the rate of congenital CMV at birth was higher in the treated group (15.5 versus 6.7 percent), though most were asymptomatic. The authors concluded that the use of valacyclovir likely modifies the disease course and produces a rebound viremia after treatment cessation and fetal infection after a negative amniocentesis. While previous reports provide reassurance regarding the low risk of significant sequalae following second- or third-trimester fetal CMV infection, these data come from patients who did not receive valacyclovir [102]. Long-term follow-up of newborns with asymptomatic congenital CMV after prenatal valacyclovir therapy is essential to fully understand the impact of antiviral treatment during pregnancy.

●Evidence for improving the outcome of infected fetuses – Maternal valacyclovir administration has also been used for tertiary prevention of complications in infected fetuses. In a 2023 meta-analysis, although infected pregnant people treated with valacyclovir had a reduction in congenital CMV infection and an increased likelihood that the infection would be asymptomatic, there was no improvement in any other CMV-related perinatal outcome (eg, perinatal death, neurological symptoms, hearing symptoms, anomalies on follow-up prenatal or postnatal imaging) [116]. However, the number of adverse neonatal outcomes was low and confidence intervals were wide, highlighting the need for validation of the findings in large, well-designed randomized trials.

One study not included in the meta-analysis has reported promising findings in a subset of infected fetuses with ultrasound abnormalities. In this multicenter, open-label, phase II study of oral valacyclovir administration to pregnant patients carrying a CMV-infected fetus with an isolated nonsevere cerebral abnormality and/or measurable extracerebral findings compatible with CMV infection, maternal treatment improved neonatal outcome [121]. Fetuses with severe brain anomalies and those with no abnormalities at presentation were excluded from the study because treatment was unlikely to modify outcome in these fetuses. Compared with a historical cohort obtained by a meta-analysis, the use of valacyclovir increased the proportion of asymptomatic neonates from 43 percent without treatment to 82 percent with treatment, and asymptomatic neonates remained asymptomatic at 12 months postnatal age. Valacyclovir 8 g daily was initiated at a median of 25.9 weeks of gestation and continued until delivery or termination of pregnancy. Adherence to treatment was >90 percent despite the need to take 16 pills/day, and there was a low rate of discontinuation due to maternal side effects (2 out of 41 patients reported headaches, treatment was suspended for 10 days in one). However, the findings are limited by the open-label study design and should be confirmed in a randomized trial to better determine the efficacy of in utero treatment before it can be recommended. Long-term pediatric follow-up is also needed.

Other agents — CMV-specific hyperimmune globulin therapy of pregnant patients with primary CMV infection in early pregnancy is not recommended. This investigational approach was ineffective in two randomized trials that initiated immunoglobulin therapy in the second trimester (no reduction in congenital infection, death, preterm birth, symptomatic infection) [28,122]. One of the trials with long-term follow-up found that CMV hyperimmune globulin did not improve two-year hearing or developmental outcomes [123].

Observational studies using biweekly first-trimester regimens for CMV hyperimmune immunoglobulin have had more promising results but need to be evaluated in a randomized trial [124,125]. Given these mixed findings, CMV hyperimmune globulin therapy should only be used in research settings until more data are available.

Development of a vaccine — No CMV vaccine is available for use in humans, despite being ranked as the top priority for vaccine development by the Institute of Medicine in 1999 [126]. Although several candidate vaccines have been developed and tested in clinical trials, it is unlikely that an effective CMV vaccine will be available for several years [127-129]. One of the major barriers is the lack of an established maternal immune marker that indicates protection against transplacental CMV infection. Counterintuitively, CMV-neutralizing antibodies may not be relevant for protection against placental and fetal infection, and nonneutralizing antibodies involved in cellular phagocytosis may better correlate with prevention of congenital CMV [130]. (See "Society guideline links: Cytomegalovirus in solid organ transplant recipients".)

In a phase 2 trial that included 464 CMV-seronegative females of childbearing age, an MF59-adjuvanted CMV glycoprotein B subunit vaccine had 50 percent efficacy at preventing CMV infection, which was the primary endpoint [127]. The trial was not powered to assess efficacy in preventing maternal-fetal transmission. An international multicenter trial of a mRNA vaccine is currently underway in healthy (nonpregnant) adults in more than 10 countries and is expected to be completed in 2026 [131].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Avoiding infections in pregnancy (The Basics)" and "Patient education: Cytomegalovirus (The Basics)")

●Beyond the Basics topic (see "Patient education: Avoiding infections in pregnancy (Beyond the Basics)" and "Patient education: Cytomegalovirus infection and pregnancy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Primary versus nonprimary infection

•Terminology – Cytomegalovirus (CMV) infections in pregnant individuals are classified as primary if the initial acquisition of virus occurs during pregnancy (seroconversion), and nonprimary if maternal antibody to CMV was present before conception (ie, seroimmunity). Nonprimary infection may be due to reactivation of latent virus or reinfection with a new strain. (See 'Terminology' above.)

•Sequelae of congenital infection – Clinical findings in symptomatic neonates are nonspecific and include petechiae, jaundice, hepatosplenomegaly, small size for gestational age, and microcephaly. Long-term sequelae include sensorineural hearing loss and other neurodevelopmental disabilities. (See 'Introduction' above and "Congenital cytomegalovirus infection: Clinical features and diagnosis".)

•Risk for congenital infection – Primary maternal infection carries the highest risk for maternal-fetal transmission. The occurrence of congenital infection increases with advancing gestational age at the time of maternal diagnosis, while the occurrence of fetal/newborn complications from infection decreases with advancing gestational age at the time of maternal diagnosis. The risk of severe sequalae in offspring is high with first-trimester infection and very low with infection at or near term. (See 'Prognostic counseling at the time of maternal diagnosis' above.)

Preconception seroimmunity provides substantial but not complete protection against the occurrence of congenital infection. When fetal infection occurs, the frequency of symptomatic newborn disease and long-term sequelae is similar to that of offspring of mothers with primary CMV infection during pregnancy. (See 'Prognostic counseling at the time of maternal diagnosis' above and 'Primary versus nonprimary maternal infection' above.)

●Maternal clinical findings, screening, diagnosis, and treatment

•Clinical findings – CMV infection may cause a mild maternal febrile illness and other nonspecific symptoms but is asymptomatic in 90 percent of individuals. Maternal care is supportive. (See 'Maternal clinical findings' above and 'Maternal care' above.)

•Screening – No professional societies or government health authorities recommend universal serological screening for CMV infection for the general obstetric population. (See 'Role of maternal screening' above.)

•Baseline serology – For those with a known exposure to CMV, we obtain baseline CMV serology at the time of the exposure and, if negative, we repeat the serology three to four weeks later to assess for seroconversion. We also obtain baseline CMV serology at the initial prenatal visit in patients infected with HIV. Prepregnancy or early pregnancy baseline CMV immunoglobulin G (IgG) may be considered for individuals who are at high risk of infection. Early determination of CMV serostatus may aid in distinguishing between primary infection and reactivation/reinfection during pregnancy if clinically indicated, but does not remove the need to follow recommended hygiene measures. (See 'Candidates for documentation of baseline CMV serology' above.)

•Indications for diagnostic testing – Diagnostic testing for CMV is indicated as part of the evaluation of individuals with mononucleosis-like illnesses or when a fetal anomaly consistent with congenital CMV infection is detected on prenatal ultrasound examination. (See 'When to suspect maternal CMV infection' above.)

•Diagnosis – The gold standard for maternal diagnosis of clinically suspected primary CMV infection is IgG seroconversion (table 1). In the absence of documented seroconversion, the presence of anti-CMV IgG and anti-CMV immunoglobulin M (IgM) may represent primary infection, reactivation, reinfection, or latent disease. In these cases, IgG avidity testing is essential for interpretation: High-antibody avidity suggests infection occurred more than three months in the past, while low avidity suggests recent infection within three months. (See 'Diagnosis of primary versus past maternal infection' above.)

●Diagnosis of fetal infection – Fetal CMV infection should be suspected in patients with maternal serology consistent with a primary infection or ultrasound findings suggestive of congenital infection. (See 'Diagnosis' above and 'Ultrasound markers suggestive of congenital CMV infection' above.)

We offer amniocentesis for fetal diagnosis when fetal infection is suspected. The diagnosis of fetal infection is confirmed in pregnancies with positive polymerase chain reaction (PCR) for CMV DNA in amniotic fluid; sensitivity ranges from 70 to 100 percent. Amniocentesis should be performed at least eight weeks after the presumed time of maternal infection. (See 'Diagnosis' above and 'Diagnostic amniocentesis' above.)

●Predicting postnatal prognosis

•The predicted outcome of first-trimester primary infection is shown in the algorithm (algorithm 1).

•Serial ultrasound examinations at two- to four-week intervals can be useful to detect development of sonographic abnormalities, which can appear 12 or more weeks after a periconceptional or early pregnancy maternal infection, or not at all. An abnormal fetal ultrasound examination suggests a poor postnatal prognosis, but a normal ultrasound examination does not exclude the possibility of a symptomatic neonate or development of long-term neurologic morbidity, especially after first-trimester infection. There are no fetal imaging findings specifically predictive of postnatal hearing loss. (See 'Predicting outcome after confirmation of fetal infection' above.)

●Treatment of congenital CMV infection – Data on late pregnancy initiation of maternal valacyclovir administration for treatment of infected fetuses are limited and have not demonstrated an improvement in serious CMV-related perinatal outcomes (eg, perinatal death, anomalies on follow-up prenatal or postnatal imaging, postnatal neurological symptoms and hearing loss). (See 'Antiviral medication' above.)

●Prevention

•Prevention of congenital CMV infection – For patients with periconception or first-trimester primary CMV infection, we suggest high-dose valacyclovir rather than no therapy (Grade 2C). Emerging evidence suggests that maternal antiviral therapy with high-dose oral valacyclovir may substantially reduce the risk of congenital infection, especially if begun prior to 14 weeks gestation and within eight weeks of the maternal infection. However, high-dose valacyclovir (8 grams daily in two to four doses) can have serious maternal side effects (reversible kidney failure in 2 percent of patients) and appears to impact the natural history of maternal adaptive immunity. (See 'Antiviral medication' above and 'Other agents' above.)

•Prevention of maternal CMV infection – Approximately 2 percent of seronegative pregnant individuals will contract a primary CMV infection during pregnancy, but this risk can be reduced with use of preventative hygiene interventions (eg, good hand hygiene, minimizing exposure to body fluids from high-risk individuals, and using CMV-negative blood products when transfusing seronegative pregnant individuals). (See 'Strategies for prevention of maternal and/or fetal infection' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jeanne S Sheffield, MD, who contributed to earlier versions of this topic review.