Congenital infection by cytomegalovirus (CMV) is among the most important congenital infections in terms of the morbidity it causes in affected newborns. In the general population, it frequency ranges from 0.3%–2.4%.1 It is in the group of congenital diseases known as the TORCH infections (toxoplasmosis, rubella, CMV and syphilis, among others)2 that share similar characteristics, chief of which are transmission through the placenta or through direct contact during or after delivery, the tendency to go undetected during pregnancy, diagnosis through serology or molecular techniques (polymerase chain reaction [PCR]) and a similar clinical presentation.

Screening programmes in pregnant women and ongoing research in the field have managed to significantly reduce the incidence of congenital infections in recent years. At present, there is a tendency to perform postnatal assessments of newborns with risk factors for some of the congenital infections that are not included in the routine newborn screening programme, such as CMV. In this context, it has been several years since postnatal screening techniques for CMV have been established for diagnosis of this congenital infection in newborns.

For years, efforts have been made to establish the association of low birth weight with neurodevelopmental abnormalities later in life. However, Lohaugen et al.3 evinced that low birth weight in isolation did not increase the probability of impaired cognitive function, with the probability increasing when it was associated with other risk factors, such as microcephaly. Still, TORCH screening strategies have been implemented for years in this group of infants assuming an association with low birth weight. In opposition to this, Krishnamurthy et al.4 found that low birth weight as an isolated risk factor did not warrant performance of screening in newborns, as results were not significantly different in the comparison of congenital infections in this risk group versus the general population.

Previous studies have attempted to evince an association between abnormalities in prenatal ultrasound examinations5 and the classification of foetuses as having intrauterine growth restriction (IUGR) type 1 or 2 in relation to the eligibility for CMV screening, finding a similarly low risk in both groups, without significant differences between them.6

Notwithstanding, many facilities continue to screen low birth weight newborns for CMV infection. Some of the factors that probably contribute to this practice is the high prevalence of CMV infection in the general population and its silent course in a majority of cases, which makes it difficult to diagnose in pregnant women. Screening in newborns is usually performed by collecting a urine sample at birth to carry out a PCR test for detection of the virus and/or performance of a cranial ultrasound to assess for lesions compatible with congenital CMV infection. Other methods are available, such as serology testing in blood samples, but they are not commonly used for screening on account of their invasiveness.

Due to the lack of stringent written protocols, decisions regarding screening usually rest with the clinician in charge. In addition to the emotional burden placed on families by the performance of these tests, these screening strategies are quite costly for the health care system, as there is a large number of newborns with low birth weight as the sole risk factor, resulting in a considerable number of screening tests. Yet, screening continues to be a customary practice in many facilities.

The primary objective of the study was to assess the clinical yield of ordering a PCR test for detection of CMV in urine and transfontanellar ultrasound in newborns born at term or near term whose only risk factor for congenital CMV infection is low birth weight for gestational age. The secondary objective was to determine whether this was a cost-effective strategy.

Between January and December 2019, we included 259 patients in the study. The sample was divided in 2 groups. Group 1 included newborns with a birth weight, length and head circumference below the 10th percentile.10 Group 2 included newborns with a birth weight below the 10th percentile but with a head circumference and length above the 10th percentile. Group 1 included 53 newborns (20.5%) and group 2, 206 (79.5%), and we made a descriptive analysis of the risk factors associated with infection by CMV.

In group 1, we found a higher frequency of late preterm birth (.02), twin pregnancy (.01), admission unrelated to congenital CMV (.047) and maternal illicit substance use during pregnancy (.04), without significant differences in the rest of the variables (Table 1). In addition, the mean gestational age was lower in this group (Table 2), in part related to 10 of the 53 deliveries (18.9%) in group 1 being induced due to IUGR and 7 (13.2%) due to nonreassuring foetal status based on cardiotocographic features.

A total of 186 CMV urine PCR tests and 214 transfontanellar ultrasound exams were performed in the sample under study, and both tests were performed significantly more frequently in group 1 compared to group 2 (.002).

In group 1, none of the urine PCR tests were positive for CMV. In group 2, only 1 patient had a positive result with 704 058 copies/mL, amounting to 0.54% of the total subset of patients in whom a urine PCR test was performed. This patient had a history of IUGR diagnosed antenatally by Doppler ultrasound. The postnatal transfontanellar ultrasound did not detect any abnormalities and the patient received a diagnosis of asymptomatic congenital CMV infection after the positive urine PCR test. The patient underwent a follow-up magnetic resonance scan at 3 weeks post birth that evinced mild bilateral alteration of signal intensity in the periatrial region and, less noticeably, the frontal region, with no clear association with white matter involvement due to CMV infection, leading to recommendation of an additional magnetic resonance scan that was not performed in the end, as the patient remained asymptomatic in the follow-up and the hearing test was normal. The patient was followed up in the infectious disease and otorhinolaryngology departments and did not require antiviral treatment.

The transfontanellar ultrasound found abnormalities in 2 cases, both in group 2, amounting to 0.93% of the total ultrasound examinations performed. The alterations were chance findings, subsequently confirmed by magnetic resonance, unrelated to congenital CMV infection: an ischaemic lesion in the caudate nucleus and right cerebellar hypoplasia and bleeding.

We performed a cost-effectiveness analysis and found that the cost of screening with transfontanellar ultrasound and CMV testing in urine amounted to approximately Є17 000 in total for the detection of a single case of congenital CMV infection, in this case, an asymptomatic one. Due to the absence of symptomatic cases, we were unable to calculate the number needed to treat. If newborns with risk factors related to prenatal low weight are not taken into account, the cost would decrease to Є15 800. If the performed transfontanellar ultrasound examinations are not taken into account, the cost of screening only with the CMV urine PCR test would be Є4050 for the detection of a single case.

We found a low frequency of positive CMV screening tests in asymptomatic term and near term neonates in our sample (0.54%), which was consistent with similar studies that have found a prevalence ranging from 0.2% to 2.5%.1,11

Despite its low prevalence, CMV continues to be the most frequent cause of congenital viral infection in Spain. It can cause important sequelae, such as hearing loss, intellectual disability, cerebral palsy, seizures and learning disabilities, which may occur in up to 20% of infected infants.12 Congenital CMV infection is the leading non-inherited cause of sensorineural hearing loss. The incidence and severity of these sequelae may decrease with early treatment of newborns with congenital CMV infection, which is the reason that some authors, such as Rawlinson et al.,13 have suggested the possibility of universal screening, a strategy that Gantt et al. advocate for, as they consider it cost-effective.14 However, many other cost-effectiveness studies do not support universal screening on account of its low yield and high cost, also given that the same authors do not recommend treatment of asymptomatic newborns.2,15

At present, PCR testing of urine for detection of CMV is one of the most widely used screening methods because it is non-invasive and has exhibited a high sensitivity.16,17 Other screening methods have been proposed in recent studies, such as PCR testing in saliva samples, on account of the ease of sample collection,18 and PCR testing of the dry blood spot sample collected for newborn screening of metabolic and endocrine diseases, on account of its potential low cost and high yield.19

In our sample, the only patient that had a positive CMV urine PCR test did not receive any treatment and was followed up in the paediatric infectious disease unit, with resolution of the infection without complications, which is the usual outcome. Similarly, a study by Baquero Artiago et al. found that only 13% of asymptomatic newborns with a positive PCR test developed symptoms during the follow-up.11

Another widely used screening strategy is performance of a transfontanellar ultrasound in low birth weight newborns to assess for abnormalities characteristic of congenital CMV infection, such as intracranial calcifications, ventriculomegaly, cortical atrophy or cystic lesions in the germinal matrix.8 However, some authors argue that these findings are not very specific to congenital CMV infection.4,20,21 In our study, the prevalence of abnormal findings in the ultrasound examination was 0.93%; however, most of these abnormalities could be considered chance findings unrelated to CMV infection. The performance of transfontanellar ultrasound as a CMV screening strategy in asymptomatic low birth weight infants, based on our data and the findings of similar studies, does not seem cost-effective.11

Low birth weight has been traditionally associated with congenital infection, but other risk factors for IURG are identified in up to 40% of these infants (maternal HTN, maternal smoking, twin gestation…) that could justify low birth weight. In the study by Vaundry et al., the prevalence of congenital CMV infection in the subset of low birth weight newborns did not differ from the prevalence in the general population.22

Some studies have found an association between symmetrical IUGR and congenital CMV infection.23 However, a study by Espiritu et al. found a low risk of congenital CMV infection in both the symmetrical IUGR and the asymmetrical IUGR groups, without significant differences between groups.6 In our sample, out of the 186 newborns screened with the urine PCR test, only 1 had a positive result, a patient that belonged to group 2 (low birth weight only).

In the period under study, a total of, 186 CMV urine PCR tests and 214 transfontanellar were performed. This amounts to a total cost of Є17 000 for diagnosis of a single case. To this cost, we must add the anxiety and worry elicited in the family by the performance of diagnostic tests for the detection of a disease with a low prevalence.6 Based on these findings, screening of asymptomatic newborns whose only risk factor is low birth weight could be considered, in specific settings and populations with a low prevalence, a strategy that is not cost-effective.24

Until recently, due to the lack of effective treatment for congenital CMV infection acquired during gestation that would change patient outcomes, the implementation of universal screening of CMV infection in pregnant women did not seem to be cost-effective. However, recent studies25 have found encouraging results for the efficacy of valaciclovir given to pregnant women with primary infection in reducing the incidence of congenital CMV infection in the offspring.26 In the future, these outcomes could warrant contemplating universal screening of pregnant women for early detection and possible treatment of congenital CMV infections. The introduction of screening during pregnancy, combined with the treatment of pregnant women with primary infection and the low incidence of congenital CMV infection in low birth weight infants, may be reasons not to routinely screen for congenital CMV infection in this subset of patients.

There are several limitations to our study, such as its retrospective design; since the newborns were selected from those who attended the newborn evaluation in the neonatal clinic, we may have missed information, a drawback that we tried to palliate through the exhaustive review of the health records of mothers and infants and diagnostic tests records. In addition, there may have been false negative results in the CMV urine PCR test.

In conclusion, in our population, routine performance of tests for screening of congenital CMV infection does not appear to be cost effective in asymptomatic term and near-term newborn infants whose only risk factor is low birth weight, especially screening by means of transfontanellar ultrasound. The performance of the PCR test in urine could be reserved for patients with low birth weight and no associated risk factors for this status (twin gestation, maternal hypertension, etc). Transfontanellar ultrasound does not seem to be indicated in this context. However, to generalise these results, further research should be conducted in other populations.