Valaciclovir to Prevent Vertical Transmission of Cytomegalovirus After Maternal Primary Infection During Pregnancy: A Randomized, Double-blind, Placebo-Controlled Trial

Cytomegalovirus (CMV) is a congenital infection that has a high rate of maternal morbidity after infection. There is a relatively high rate of vertical transmission to the fetus following a maternal infection of 30% to 40%. Valaciclovir, ganciclovir, and valganciclovir are treatment options that have been proposed to possibly improve outcomes for an affected fetus. However, there is currently no therapy proven to prevent vertical transmission to the fetus following a primary infection of the mother early in pregnancy. The goal of this study was to determine if valaciclovir is able to prevent the transmission of CMV from a pregnant woman with a primary infection to her fetus. This prospective, randomized, double-blind, placebo-controlled trial was performed at the Infectious Feto-Maternal Clinic of Rabin Medical Center in Petach Tikvah, Israel. Patients were included if they were older than 18 years and had serologic evidence of a primary CMV infection early in pregnancy (during the periconceptional period or the first trimester of pregnancy). Upon confirmation of CMV and after informed consent was obtained, participants were randomly assigned to the treatment or control group. Participants assigned to the treatment group were given 8 mg of valaciclovir per day. Participants in the control group were given the same number of identical-looking placebo tablets. Participants later underwent amniocentesis at 21 to 22 weeks of gestation, and transmission was assessed by polymerase chain reaction from amniotic fluid. In all, 100 patients were enrolled in the study from November 15, 2015, to October 8, 2018; 50 were assigned to the treatment group and 50 to the placebo group. Ten patients were excluded for various reasons, leading to 45 patients from the valaciclovir group (all singleton pregnancies) and 45 patients from the placebo group (43 singletons and 2 sets of twins) included in the analyses. The median gestational age at the introduction of therapy was 76 days (interquartile range, 69- 95 days). Five amniocenteses (11%) were positive for CMVin the valaciclovir group, whereas 14 (30%) were positive in the placebo group (P = 0.027; odds ratio, 0.29; 95% confidence interval, 0.09-0.90, for verticalCMVtransmission). ACMVinfection in the valaciclovir group (2 [11%] of 19 amniocenteses) was significantly less likely during the first trimester compared with the placebo group (11 [48%] of 23 amniocenteses; P = 0.020). There were no statistically significant differences between the 2 groups during the periconceptional period (3 [12%] of 26 amniocenteses in the valaciclovir group vs 3 [13%] of 24 amniocenteses in the placebo group; P = 0.91). The rate of adverse events was not different between the 2 groups (P = 0.49). In terms of fetal outcomes, 43 fetuses in the valaciclovir group were carried to term, and 2 pregnancies were terminated. In the placebo group, 41 fetuses were carried to term, and 4 were terminated. Fetal CMV-related infection was observed in 3 fetuses/infants (7%) in the valaciclovir group compared with 7 (16%) in the placebo group. Lastly, participants in the valaciclovir group had a lower chance of morbidity related to a CMV infection compared with the placebo group (odds ratio, 0.38; 95% confidence interval, 0.09-1.56). Overall, valaciclovir reduced the rate of vertical transmission of CMV following a primary maternal infection. This intervention could potentially help prevent delivery of infants with congenital CMV, reduce the rate of CMV present in neonates overall, and alleviate morbidity related to a CMV infection.