Clinical and epidemiological features of congenital cytomegalovirus infection globally

Human cytomegalovirus (CMV) is the most common non-genetic cause of congenital disability. As a herpesvirus that infects the majority of the population, CMV is able to establish a lifelong latent infection in the host. Any time during pregnancy, a primary CMV infection, reactivation of latent CMV or a new viral strain can infect the placenta and the developing foetus, resulting in congenital CMV infection. Each year, an estimated 2000 children are born with congenital CMV infection in Australia, leaving ~500 children with permanent disabilities such as hearing or vision loss, or mental disability. Despite the clinical importance of congenital CMV, there is limited awareness and knowledge in the medical and general community about congenital CMV infection. This article reviews the global epidemiology and clinical features of maternal and congenital CMV infections.

Human CMV is a member of the Herpesviridae family of viruses, which includes Herpes simplex virus type 1 and type 2, Varicella zoster virus, Epstein-Barr virus, Human herpesvirus 6A, Human herpesvirus 6B, Human herpesvirus 7, and Human herpesvirus 8^1,2. The genome of human CMV is ~235 kbp and is one of the largest among the Herpesviridae³.

Human CMV infects most individuals in the world and can be acquired anytime during life: as a foetus, neonate, toddler, child or an adult. Initial infection (also known as primary infection) occurs following close personal contact. CMV is typically transmitted via body fluids, particularly breast milk, urine, genital secretions, and blood⁴. In addition, CMV can infect the placenta and the developing foetus⁵. Once infected, the human body does not clear the virus. CMV is able to persist in a latent form in either low or undetectable levels in peripheral blood mononuclear cells (CD14⁺) and bone marrow cells (CD34⁺ and CD33⁺)⁶. Stimuli such as inflammation, immune impairment due to pregnancy, medical treatment with immunomodulating agents such as corticosteroids, chemotherapy, and immunosuppressive therapy post organ transplantation may stimulate reactivation and growth of latent CMV⁷. Considering CMV secretion in urine and cervical-vaginal fluids increases during pregnancy with increasing gestational age, hormonal changes related to pregnancy may also stimulate reactivation of CMV⁸.

CMV is a common cause of infections worldwide. Antibodies to CMV, representing a previous infection, can be detected in 45 to >90% of women of reproductive age⁹. The percentage of women that are infected with CMV varies between countries and tends to be the lowest in Western Europe, Australia, Canada and the United States and the highest in South America, Africa and Asia⁹. Particularly, in Australia, the average seroprevalence rate of CMV for women between the ages of 14 to 44 years is 58%¹⁰. However, even within countries the rate of CMV infected women varies by socio-economic status and ethnicity^9,11.

Approximately 1–2% of initially uninfected pregnant women will acquire CMV by the time of delivery¹². A possible source of CMV for these women is young children whose saliva and urine contain high levels of CMV¹³. In addition, a partner who is infected with CMV is an additional possible risk factor for infection during pregnancy, as CMV is present in semen, and can be transmitted sexually¹². Among the women who acquire a primary infection during pregnancy 32% transmit CMV to the foetus via the placenta, resulting in congenital CMV (cCMV) infection¹⁴. Only a percentage of cCMV infected children will exhibit symptoms at birth or develop CMV associated symptoms later in life, as further described in detail below.

The foetus can also be infected by a woman’s latent virus or re-infection with a different strain of CMV (secondary infection)¹⁵. The risk of transmitting CMV to the foetus is reported to be higher when a pregnant woman acquires a primary infection during the first half of the pregnancy compared to secondary infections, or infection in the second half of pregnancy¹⁶. Kenneson¹⁴ reported 1.4% of secondary infections lead to foetal infection. However, considering the high seroprevalence of CMV, it is estimated that more than two-thirds of CMV infected children are born to mothers who were already infected with CMV¹⁷.

Intrauterine CMV infection occurs in 0.2 to 2% (average of 0.64%) of live births in the Unites States, Australia and Western Europe (Table 1)^14,18–20. In addition, the limited studies of regions in Latin America, Africa, and Asia have reported a birth prevalence of cCMV infection ranging from 0.6 to 6.1% of pregnancies²⁰. Based on the number of live births per year²² and reported cCMV prevalence^14,18–20, this translates to an estimated ~0.12 million cCMV infections in developed countries per year, and ~0.7 million to 4.5 million cCMV infections annually in developing countries. Particularly in Australia, an estimated ~2000 children are born with cCMV infection in Australia each year (Table 1). Nonetheless, in practice, most congenital CMV infections remain undiagnosed¹⁸.

Table 1. Estimated annual number of cases of cCMV infection in Australia, United States, Western Europe, Latin America, Africa, and Asia.

The majority of CMV infections in immunocompetent individuals do not cause symptoms; however, clinical manifestations could include glandular fever (mononucleosis) syndrome characterised by flu-like symptoms, or occasionally persistent fever²⁴. Several studies reported that pregnant women, who acquired a primary CMV infection, experienced mononucleosis, fever, fatigue, and headache²⁵. Additionally, Nigro²⁴ observed a significantly higher number of pregnant women with primary CMV infection presenting with symptoms compared to pregnant women with recurrent or latent CMV infection. A review of congenital CMV cases in Australia reported more than half of the mothers had evidence of, or could recall experiencing symptoms of fever during pregnancy²⁶. In addition to clinical symptoms, laboratory examination may show an increase in lymphocytes in the blood and increased serum levels of liver enzymes (alanine transaminase and aspartate transaminase)²⁴. Since all of these clinical manifestations are not only observed upon a CMV infection, they do not represent specific indicators of maternal CMV infection. However, collection of the clinical history and laboratory examination may be extremely useful for dating the onset of infection to determine the risk of CMV transmission to the foetus and risk of cCMV disease.

A minority (~10%) of cCMV infected children present symptoms at birth (Table 2). Physical signs such as petechiae, jaundice, and hepatosplenomegaly are common and have been observed in 28 to 50% of children with cCMV infection^18,27. Neurological abnormality, including microcephaly and intracranial calcification has been reported to occur in 18–38% of cCMV infected children. The majority of these affected children develop sensorineural hearing loss, mental disability, motor deficits, chorioretinitis and seizures^16,23,26.

Table 2. Clinical symptoms of congenital cytomegalovirus infection^18,23,26.

A significant amount (~15%) of initially asymptomatic CMV infected children will encounter developmental difficulties, neurological problems, or hearing loss before the age of five^9,18,28. Among those with hearing loss ~40% of children may develop severe to profound impairment of both ears²³. Other neurological complications such as microcephaly, neuromuscular defects, and chorioretinitis may also develop in initially asymptomatic CMV infected children, but at a lower rate compared to symptomatic infection¹.

Congenital CMV infection may also result in adverse pregnancy outcomes, as cCMV has been associated with fetal death in utero, neonatal death, preterm birth and maternal pregnancy complications, including preeclampsia^29–33.

CMV continues to be the leading infectious cause of congenital malformation in developed countries. More children may be affected by cCMV than by any other childhood disorder, such as down syndrome, fetal alcohol syndrome, and spina bifida. Each year in Australia, an estimated 2000 children are born with cCMV infection, leaving ~500 children with permanent disabilities such as hearing or vision loss, or mental disability. Even though the rates of maternal and cCMV infection are still lacking for many parts of the world, which likely underestimates the global impact of cCMV infection, the importance of cCMV infection and disease as a large public health problem is self-evident.