Effectiveness and Safety of Prenatal Valacyclovir for Congenital Cytomegalovirus Infection: Systematic Review and Meta-analysis

ABSTRACT One of the most common causes of infection-related fetal malformations is congenital cytomegalovirus (CMV), which affects approximately 0.5% to 2% of newborns. Several approaches have been investigated for screening, prevention, and treatment; one drug that shows activity against CMV is valacyclovir, and prenatal administration of this drug has been investigated in the context of preventing fetal disorders due to CMV. Although studies and clinical trials have been done regarding the safety and effectiveness of valacyclovir, clinical attitudes regarding universal CMV screening and prenatal valacyclovir treatment have yet to change. This article is a systematic review and meta-analysis of the safety and effectiveness of prenatal valacyclovir in CMV-infected pregnancies. Inclusion criteria included pregnancies with CMV infection diagnosed through serology, with a primary outcome of incidence of congenital CMV confirmed by polymerase chain reaction from amniocentesis. Secondary outcomes included symptomatic infection (rash, jaundice, microcephaly, seizures, hepatosplenomegaly, hearing loss, visual loss, retinitis, and central nervous system anomalies), asymptomatic infection, perinatal death, pregnancy termination, fetal anomaly, or severe symptoms. Adverse events related to the administration of valacyclovir were also recorded. Because relatively few studies were available for inclusion, the authors were unable to assess publication bias, but other risk of bias was assessed using standard tools. Final analysis included 8 studies and 620 pregnant women with CMV in 2 randomized controlled trials and 6 observational studies. One randomized controlled trial focused on valacyclovir treatment for CMV infection acquired in early pregnancy, and the other assessed valacyclovir treatment between 34 and 38 weeks' gestation to reduce risk of CMV within 1 year of delivery. The latter of the 2 studies was not included in pooled data synthesis because of inclusion criteria differences. Three studies focused on valacyclovir treatment for confirmed maternal CMV infection; pooled data analysis showed that valacyclovir-treated pregnancies had lower risk of congenital CMV (odds ratio [OR], 0.37; 95% confidence interval [CI], 0.21–0.64; P < 0.001). When contracted in the first trimester, risk of vertical transmission was lower in those who were treated with valacyclovir (OR, 0.34; 95% CI, 0.15–0.74; P = 0.001); however, there was no effect observed in those with CMV in the periconceptual period. Analysis additionally showed that prenatal valacyclovir treatment was more likely to result in asymptomatic children (OR, 2.98; 95% CI, 1.18–7.55; P = 0.021), but no other significant perinatal differences were observed. These results show that treatment of CMV with prenatal valacyclovir reduces the risk of congenital CMV and its associated complications. Limitations of this analysis include the heterogeneity of inclusion and measurement criteria, as well as small samples to assess perinatal outcomes. Risks associated with the drug were small, and adverse events resolved after patients discontinued valacyclovir. The findings are consistent with previous research showing the benefit of valacyclovir. Further research should assess perinatal outcomes associated with valacyclovir treatment, as well as the role of valacyclovir in secondary versus primary infection. In particular, larger randomized controlled trials should be implemented to determine the association of valacyclovir treatment with the risk of fetal structural anomalies, symptomatic infection, and neurocognitive impairment.