Screening for Cytomegalovirus: An Analysis of Guidelines

Background: Congenital cytomegalovirus is the most prevalent cause of infection-related neurological impairment. Screening for cytomegalovirus is in practice offered to many women in the western world. In this study we present an overview of official guidelines concerning screening/non-screening for cytomegalovirus worldwide. Methods: An Internet search for guidelines concerning screening for cytomegalovirus during pregnancy worldwide. Results: From the 24 guidelines we found worldwide, there were only 7 with a guideline regarding screening for cytomegalovirus during pregnancy. Six of them gave the following advice: there is insufficient evidence to support routine screening in all pregnant women for cytomegalovirus infection. Currently there is no routine screening for cytomegalovirus recommended during pregnancy. The “Federaal kenniscentrum voor de gezondheidszorg” (KCE) gave the extra advice that performing a single serological test prior to pregnancy can be useful as it may encourage (non-immune) women to take preventive measures and it can reassure (at least partially) those who are immune. They also recommend discussing primary prevention measures with pregnant women to reduce the risk of cytomegalovirus infection. The American Society for Reproductive Medicine recommends routinely screening for cytomegalovirus during the pre-conceptional screening of the female recipient of sperm donation. Conclusion: No guideline recommends routine screening for cytomegalovirus during pregnancy.


Introduction
Congenital cytomegalovirus (CMV) is the most prevalent infectionrelated cause of neurological damage (impaired development, mental retardation, and neurosensory hearing deficit) since implementation of universal rubella vaccination [1].
It occurs in 0.6-0.7% of all new-borns. This equates to a birth prevalence of approximately 7/10,000 affected infants, not dissimilar to conditions for which screening is currently recommended, such as early onset groups B streptococcus infection, with a prevalence of 4.3/10,000 and Down syndrome with a birth prevalence of 11/10,000 births [2]. The probability of intrauterine transmission following primary infection is much higher than after secondary infection, with a transmission rate of respectively 30-40% and 1%. Fetal infection does not equate to an affected fetus; 10-15% of the affected fetuses will have symptoms at birth, with a neonatal mortality rate of 20%, whereas 5% to 15% of the asymptomatic infected neonates will develop sequelae later. Children with congenital CMV infection following first trimester infection are more likely to have central nervous system sequelae, whereas infection acquired in the third trimester has a high rate of intrauterine transmission but a favourable outcome [3]. As discussed by Walker et al. [1] "Universal screening for CMV to identify seronegative women at the beginning of pregnancy could potentially reduce the burden of congenital CMV in one of three ways. The risk of acquiring the infection during pregnancy has been shown to be reduced by institution of simple hygiene measures (primary prevention). Among women who seroconvert during pregnancy, CMV hyper immune globulin (CMV HIG) shows promise in reducing the risk of perinatal transmission (secondary prevention), and CMV HIG and/or antivirals may be effective in reducing the risk of clinical sequelae among those known to be infected (tertiary prevention). The reports from these studies have reignited interest in universal screening for CMV, but against the potential benefit of these exciting therapies need to be weighed the challenges associated with the implementation of any universal screening in pregnancy.
These include: the optimal test and timing of screening, to maximize detection; an approach to the management of equivocal results, and the cost effectiveness of the proposed screening program [1]. These arguments in favour and against universal screening result in contradictory advice given to pregnant women. For example, although routinely screening in France is not recommended, 14% of the hospitals were still conducting this screening in 2012 [4]. In this study we want to present an overview of current screening/non-screening strategies worldwide.

Materials and Methods
First, we started searching for general guidelines in Europe and the USA by entering the search terms: guideline and screening in the web search engine Google and Google scholar and in PubMed. Afterwards we started looking more specific for guidelines for gynaecology and obstetrics and for paediatrics in Europe, USA, Canada, Australia and worldwide by using the additional search terms: pregnancy and prenatal.
While browsing through the various guidelines we used the search terms: cytomegalovirus, CMV, screening, pregnancy, congenital infections and infections.
The guidelines were required to be in Dutch, English, French, German or Spanish, but no other language. We assessed the guidelines on the 4th of February 2016. Table 1 gives an overview of the various guidelines we consulted during the search for guidelines regarding screening for CMV during pregnancy.    Worldwide there were only 7 guidelines with a guideline regarding screening for CMV during pregnancy. Of these, there was one from Belgium, one from the UK, one from Canada, two from the US, one from Australia and one global. Six of them gave the following advice: there is insufficient evidence to support routine screening in all pregnant women for cytomegalovirus infection. Currently there is no routine screening for CMV recommended during pregnancy [5][6][7][8][9][10].

General guidelines in Belgium
The KCE gave the extra advice that performing a single serological test prior to pregnancy can be useful as it may encourage (non-immune) women to take preventive measures and it can reassure (at least partially) those who are immune. They also recommend discussing primary prevention measures with pregnant women to reduce the risk of cytomegalovirus infection [5]. The ASRM recommends routinely screening for CMV during the preconceptional screening of the female recipient of sperm donation [11]. The detailed results of the various guidelines are listed in Table 3. Despite a lack of clearly proven benefit, discuss primary prevention measures with pregnant women to reduce the risk of cytomegalovirus infection, such as [new KCE 2015]: -Regularly wash your hands, especially after contact with saliva or urine of small children (e.g. changing diapers) or wear protective gloves when changing diapers or handling children's dirty laundry.
-Clean toys, countertops, and other surfaces that come into contact with young children's bodily fluid.
More data on the diagnostic accuracy of serological tests, value of amniocentesis and imaging, clinical evolution of infected infants and harmful effects for healthy pregnancies need to be collected in the Belgian context in order to evaluate the benefits and harms, both on the short term and on the long term, of CMV screening appropriately.

Discussion
Worldwide, there are not many guidelines regarding screening for CMV during pregnancy. The ones that exist are all very short and unambiguously about their recommendation: routine screening for CMV is not recommended during pregnancy.
While no single guideline recommends routine screening for CMV during pregnancy, doctors still screen frequently for CMV infection in the blood, especially in Europe and Israel. For example, although routinely screening in France is not recommended, 14% of the hospitals were still conducting this screening in 2012. [1,2,4,12] One of the reasons is the anxiety of the clinicians to miss the diagnosis and the anxiety and the pressure of the parents. Another reason is the legal system in some countries. A women employed in a sector with young children, may not work during her pregnancy by the occupational health if she is negative for CMV, since small children are a major source of contamination. Soper showed that in a survey of 9 day-care centers in the USA and Sweden, 22-72% of the children were shedding CMV in their urine and saliva [13].
The evidence for these recommendations is low, but still strongly recommended. Systematic screening of pregnant women could lead to: anxiety, an increased number of amniocentesis and therefore of miscarriages, with possible medico-legal implications, and an unjustified number of termination of pregnancies that would be performed even in the absence of a bad prognosis such as ultrasound markers. TOP may be restricted in some countries after certain weeks of pregnancy and such policy may be difficult to undertake [2]. The KCE strongly recommends discussing primary prevention measures with pregnant women to reduce the risk of cytomegalovirus infection and reinfection. Even with a reinfection, there is a 1% transmission ratio to the fetus. Congenital CMV usually occurs in the second and third pregnancy. Especially young mothers who already have one or more children (1-6y) at home must be careful. Further research is needed into the ideal screening method, follow-on method and possible treatment for congenital CMV before universal screening can be offered.