Progress towards interrupting intrauterine transmission of cytomegalovirus?

Disease caused by congenital CMV infection is a major medical problem which is routinely ignored by most health care systems throughout the world. In reality health care is a misnomer; we have systems for sickness care which respond to patients who present with symptoms. The difficulty with congenital CMV infection is that a pregnant woman does not usually have any symptoms to report and, therefore, remains oblivious to the danger, while CMV crosses the placenta, infects her fetus and causes progressive damage to the developing central nervous system (CNS). Approximately 40 000 babies with congenital CMV are born annually in the USA (1% of all births). Approximately 7% have symptoms at birth including microcephaly, intracranial calcifications, thrombocytopenic purpura, hepatosplenomegaly and hearing loss [1]. The damage caused by CMV continues after birth, manifesting as progressive hearing loss and mental retardation with failure to reach developmental milestones(1). A randomised controlled trial showed that 6 weeks of intravenous ganciclovir significantly decreased progressive hearing loss in symptomatic children with CNS disease at birth [2] and this has become the standard of care for such cases because of the importance of preserving hearing. Despite this advance, the outcome for these unfortunate children remains poor. Furthermore, progressive damage to the inner ear and brain structures occurs in many of those born without overt symptoms. This risk continues for years, with approximately 15% ultimately developing disease [3], thus causing more cases of disease than occurring in those who presented with symptoms at birth. A report from the Institute of Medicine estimates that the health care and educational costs for children born with congenital CMV infection approximate to $3 billion annually in the USA [4]. Many babies who were asymptomatic at birth were undoubtedly misdiagnosed in the past because of the difficulty of distinguishing congenital CMV from the more common, but clinically benign, perinatal CMV infection [1]. The ability to return to routinely collected, neonatal dried blood spots and amplify CMV DNA by polymerase chain reaction (PCR) has provided a tractable way of diagnosing individual cases of congenital CMV(5). This infection is now reported to be the cause of many cases of hearing loss or ‘leukoencephalopathy’ previously labelled idiopathic or presumed to result from recessive parental genes [6–8]. Thus, even the dramatic figures from the Institute of Medicine may prove to be underestimates of the toll attributable to congenital CMV. Diagnosis has also improved for pregnant women who are seronegative and, therefore, at risk of primary maternal infection. Conventional serological diagnosis was based on IgG seroconversion and/or IgM testing but the addition of avidity assays for IgG antibodies has markedly improved the specificity of diagnosing primary infection during pregnancy [9]. Thus, screening could now be offered as a routine, but this is not done in most countries because of the limited number of options available for management of infected cases [10]. Serial ultrasound scans can be used to monitor fetal growth, while intrauterine infection can be diagnosed by PCR after 21 weeks once fetal renal function is sufficiently established to excrete CMV into the amniotic fluid [11,12]. Yet termination of an affected pregnancy is distressing at this late stage and would not prevent the birth of all cases destined to suffer from CMV because much of the damage occurs after birth and some damage occurs following primary maternal infection in the third trimester [13,14]. Thus, despite having the tools to diagnose primary infection in pregnant women, we remain stuck in a classic ‘Catch 22’ because improved treatment options cannot be developed and evaluated unless cases are diagnosed routinely and recruited into controlled clinical trials. This ‘Catch 22’ has now been broken by research carried out in Italy which is one country that has screened for CMV during pregnancy [11]. In a recent report, women with serologically proven primary infections received detailed ultrasound E D I T O R I A L