Treatment with valacyclovir during pregnancy for prevention of congenital cytomegalovirus infection: real-life data from Italy (MEGAL-ITALI study)

Background: Valacyclovir (VCV) is the only treatment demonstrated to be effective for prevention of vertical transmission of Cytomegalovirus (CMV) within a clinical randomized, placebo controlled, trial and is reimbursed by the Italian National System since 2020. Objectives: We report the results of a real-life Italian multicenter observational study (MEGAL-ITALI) on CMV infection in pregnancy evaluating the impact of the introduction of VCV in the clinical practice for the prevention of vertical transmission of CMV. Study design: The outcomes of women who received VCV treatment and their fetuses / newborns were compared with those of a retrospective cohort observed between 2010 and 2019 who did not receive the antiviral treatment. Inclusion criteria was diagnosis of CMV primary infection occurring in the periconceptional period or up to 24 weeks gestation. Primary outcome was the transmission by the time of amniocentesis. Secondary outcomes were termination of pregnancy, transmission at birth, symptomatic infection at birth, and a composite outcome (termination of pregnancy or transmission at birth). Results: 447 pregnant women from 10 centers were enrolled, 205 treated with valacyclovir (called VCV group, including one twin pregnancy) and 242 untreated (including two twin pregnancies, called no-VCV group). VCV treatment was significantly associated with reduction of cCMV diagnosis by the time of amniocentesis (weighted odds ratio, OR, 0.39, 90% CI, 0.22-0.68; p = 0.005, relative reduction 61%), termination of pregnancy (weighted OR, 0.36, 90% CI, 0.17-0.75; p = 0.0021, relative reduction 64%), symptomatic cCMV infection at birth (weighted OR, 0.17, 90% CI, 0.06-0.49; p = 0.006, relative reduction 83%). The treatment had no significant effect on the rate of cCMV diagnosis at birth (weighted OR, 0.85, 90% CI, 0.57-1.26; p = 0.500), but the composite outcome (termination of pregnancy or diagnosis of cCMV at birth) occurred more frequently in the no VCV group (weighted OR, 0.62, 90% C, 0.44-0.88; p=0.024) Of note, the three symptomatic newborns with cCMV in the VCV group were among those with positive amniocentesis. Nineteen women (9.3%) complained an adverse reaction to valacyclovir treatment classified as mild in 17 cases and moderate in 2 cases. Four women presented renal toxicity (1.9%) with a slight increase of creatinine, reversible after treatment suspension. Conclusions: Our real-life data confirms that valacyclovir significantly reduces the cCMV rate at the time of amniocentesis with a good tolerability profile and shows that the treatment is associated with reduction of termination of pregnancy and symptomatic cCMV at birth.