Valacyclovir for cytomegalovirus infection in pregnancy: additional evidences, additional questions

Shortly after the acceptance of our review [1] an additional study on the use of valacyclovir in pregnant women with primary cytomegalovirus (CMV) infection to prevent vertical transmission has been published by De Santis et al [2]. The authors reported a case series of 12 pregnant women treated with off-label valacyclovir 8g per day following primary CMV infection in the first half of pregnancy and stopped in case of negative amniocentesis. The observed rate of positivity at amniocentesis was 17% (2 positive amniocentesis of 12 performed) compatible with a ≈50% reduction of vertical transmission when compared to the 30-35% rate reported in literature [3]. These results are consistent to those reported by Shahar-Nissan K et al in the preliminary report on their clinical placebo-controlled trial [4] and confirm that valacyclovir may reduce the rate of vertical transmission by the time of amniocentesis. However, among the 10 pregnant women with a negative amniocentesis described by De Santis, three delivered a congenitally infected newborn of which one developed moderate unilateral sensory neural loss at 18 months of age. Amongst these three women with negative amniocentesis who delivered a congenitally infected newborn, two presented a new CMV DNAemia after valacyclovir discontinuation. The authors interpret their finding as the result of an efficient control of viral replication and prevention of during the antiviral treatment, with subsequent resurgence of viral and vertical transmission. They suggested the need of controlled trial to evaluate valacyclovir treatment prolonged until the delivery regardless of amniocentesis results. However the possibility of false negative amniocentesis cannot be completely excluded. In particular the authors used 0.4mL of amniotic fluids to extract the CMV-DNA which is lower compared to those used in other reference laboratory (1mL) [5] and this could have affected the sensitivity of the test. In another recent paper (not captured by our review of literature since indexed with the keyword “citomegalovirus” unlike “cytomegalovirus”), De Santis et al described a case series on the use of high dose valacyclovir (8g/day) until delivery in confirmed fetal asymptomatic CMV infections [6]. Of the eleven in utero treated newborns, only one was symptomatic at birth and he developed profound bilateral hearing loss at six month requiring bilateral cochlear implant. Another developed a sensorineural hearing loss at 8 months of age. Surprisingly, three newborns had negative serology and virological tests at birth inducing authors to speculate that treatment can even allow viral clearance in case of low amniotic fluids viral load. To sum up, these two studies confirmed data from previous literature, namely the excellent maternal tolerance and the benefit of valacyclovir in reducing fetal CMV infections at time of amniocentesis [4] and the possible role of the drug in the in utero treatment of confirmed fetal infection [7]. We look forward to see the results of the still partially published randomized, double-blind, placebo-controlled study [4], which will probably add further important information