Treatment with valacyclovir during pregnancy for prevention of congenital cytomegalovirus infection: a real-life multicenter Italian observational study

Lorenzo Zammarchi; Lina Rachele Tomasoni; Giuseppina Liuzzi; Giuliana Simonazzi; Camilla Dionisi; Laura Letizia Mazzarelli; Anna Seidenari; Giuseppe Maria Maruotti; Sara Ornaghi; Francesco Castelli; Isabella Abbate; Licia Bordi; Stefania Mazzotta; Paolo Fusco; Carlo Torti; Francesca Ippolita Calò Carducci; Michela Baccini; Giulia Modi; Luisa Galli; Daniele Lilleri; Milena Furione; Maurizio Zavattoni; Alessandra Ricciardi; Alessia Arossa; Antonella Vimercati; Sofia Lovatti; Serena Salomè; Francesco Raimondi; Laura Sarno; Anita Sforza; Anna Fichera; Leonardo Caforio; Michele Trotta; Tiziana Lazzarotto; MEGAL-ITALI Working Group

doi:10.1016/j.ajogmf.2023.101101

Treatment with valacyclovir during pregnancy for prevention of congenital cytomegalovirus infection: a real-life multicenter Italian observational study

Am J Obstet Gynecol MFM. 2023 Oct;5(10):101101. doi: 10.1016/j.ajogmf.2023.101101. Epub 2023 Jul 27.

Authors

Lorenzo Zammarchi¹, Lina Rachele Tomasoni², Giuseppina Liuzzi³, Giuliana Simonazzi⁴, Camilla Dionisi⁴, Laura Letizia Mazzarelli⁵, Anna Seidenari⁴, Giuseppe Maria Maruotti⁵, Sara Ornaghi⁶, Francesco Castelli⁷, Isabella Abbate³, Licia Bordi³, Stefania Mazzotta³, Paolo Fusco⁸, Carlo Torti⁸, Francesca Ippolita Calò Carducci⁹, Michela Baccini¹⁰, Giulia Modi¹¹, Luisa Galli¹², Daniele Lilleri¹³, Milena Furione¹³, Maurizio Zavattoni¹³, Alessandra Ricciardi¹⁴, Alessia Arossa¹⁵, Antonella Vimercati¹⁶, Sofia Lovatti², Serena Salomè¹⁷, Francesco Raimondi¹⁷, Laura Sarno¹⁷, Anita Sforza², Anna Fichera¹⁸, Leonardo Caforio¹⁹, Michele Trotta²⁰, Tiziana Lazzarotto²¹; MEGAL-ITALI Working Group

Affiliations

¹ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (Dr Zammarchi and Dr Modi); Infectious and Tropical Disease Unit, Careggi University Hospital, Florence, Italy (Dr Zammarchi and Dr Trotta); Tuscany Regional Referral Center for Infectious Diseases in Pregnancy, Florence, Italy (Dr Zammarchi and Dr Trotta). Electronic address: lorenzo.zammarchi@unifi.it.
² Department of Infectious and Tropical Diseases, Azienda Socio-Sanitaria Territoriale (ASST) Spedali Civili, University of Brescia, Brescia, Italy (Dr Tomasoni, Dr Lovatti, and Dr Sforza).
³ National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, Rome, Italy (Dr Liuzzi, Dr Abbate, Dr Bordi, and Dr Mazzotta).
⁴ Obstetric Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (Dr Simonazzi, Dr Dionisi, and Dr Seidenari); Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy (Dr Simonazzi, Dr Dionisi, Dr Seidenari, and Dr Lazzarotto).
⁵ Department of Public Health, University of Naples Federico II, Naples, Italy (Dr Mazzarelli and Dr Maruotti).
⁶ Department of Obstetrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy (Dr Ornaghi); University of Milano-Bicocca School of Medicine and Surgery, Monza, Italy (Dr Ornaghi).
⁷ Infectious and Tropical Diseases Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy (Dr Castelli).
⁸ Infectious and Tropical Diseases Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy (Dr Fusco and Dr Torti).
⁹ Infectious Disease Unit, Bambino Gesù Children's Hospital, Rome, Italy (Dr Calò Carducci).
¹⁰ Department of Statistics, Computer Science, Applications "G. Parenti," University of Florence, Florence, Italy (Dr Baccini).
¹¹ Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy (Dr Zammarchi and Dr Modi).
¹² Infectious Diseases Unit, Meyer Children's Hospital IRCCS, Florence, Italy (Dr Galli); Department of Health Sciences, University of Florence, Florence, Italy (Dr Galli).
¹³ Microbiology and Virology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (Dr Lilleri, Dr Furione, and Dr Zavattoni).
¹⁴ Infectious Diseases Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (Dr Ricciardi).
¹⁵ Department of Obstetrics and Gynecology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy (Dr Arossa).
¹⁶ Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy (Dr Vimercati).
¹⁷ Division of Neonatology, Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy (Dr Salomè and Dr Raimondi, and Dr Sarno).
¹⁸ Division of Obstetrics and Gynecology, Department of Clinical and Experimental Sciences, ASST Spedali Civili, University of Brescia, Brescia, Italy (Dr Fichera).
¹⁹ Fetal and Perinatal Medicine and Surgery Unit, Bambino Gesù Children's Hospital, Rome, Italy (Dr Caforio).
²⁰ Infectious and Tropical Disease Unit, Careggi University Hospital, Florence, Italy (Dr Zammarchi and Dr Trotta); Tuscany Regional Referral Center for Infectious Diseases in Pregnancy, Florence, Italy (Dr Zammarchi and Dr Trotta).
²¹ Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Bologna, Italy (Dr Simonazzi, Dr Dionisi, Dr Seidenari, and Dr Lazzarotto); Microbiology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy (Dr Lazzarotto).

PMID: 37516151
DOI: 10.1016/j.ajogmf.2023.101101

Abstract

Background: Valacyclovir is the only treatment demonstrated to be effective for the prevention of vertical transmission of cytomegalovirus within a clinical randomized, placebo-controlled trial and has been reimbursed by the Italian National Health System since December 2020.

Objective: This study reported the results of a real-life Italian multicenter observational study on cytomegalovirus infection in pregnancy evaluating the effect of the introduction of valacyclovir in the clinical practice for the prevention of vertical transmission of cytomegalovirus.

Study design: The outcomes of women who received valacyclovir treatment and their fetuses or newborns were compared with those of a retrospective cohort observed between 2010 and 2020 who did not receive the antiviral treatment. The inclusion criterion was the diagnosis of cytomegalovirus primary infection occurring in the periconceptional period or up to 24 weeks of gestation. The primary outcome was the transmission by the time of amniocentesis. The 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: A total of 447 pregnant women from 10 centers were enrolled, 205 women treated with valacyclovir (called the valacyclovir group, including 1 twin pregnancy) and 242 women not treated with valacyclovir (called the no-valacyclovir group, including 2 twin pregnancies). Valacyclovir treatment was significantly associated with a reduction of the diagnosis of congenital cytomegalovirus infection by the time of amniocentesis (weighted odds ratio, 0.39; 90% confidence interval, 0.22-0.68; P=.005; relative reduction of 61%), termination of pregnancy (weighted odds ratio, 0.36; 90% confidence interval, 0.17-0.75; P=.0021; relative reduction of 64%), symptomatic congenital cytomegalovirus infection at birth (weighted odds ratio, 0.17; 90% confidence interval, 0.06-0.49; P=.006; relative reduction of 83%). The treatment had no significant effect on the rate of diagnosis of congenital cytomegalovirus infection at birth (weighted odds ratio, 0.85; 90% confidence interval, 0.57-1.26; P=.500), but the composite outcome (termination of pregnancy or diagnosis of congenital cytomegalovirus infection at birth) occurred more frequently in the no-valacyclovir group (weighted odds ratio, 0.62; 90% confidence interval, 0.44-0.88; P=.024). Of note, the only symptomatic newborns with congenital cytomegalovirus infection in the valacyclovir group (n=3) were among those with positive amniocentesis. Moreover, 19 women (9.3%) reported an adverse reaction to valacyclovir treatment, classified as mild in 17 cases and moderate in 2 cases. Lastly, 4 women (1.9%) presented renal toxicity with a slight increase in creatinine level, which was reversible after treatment suspension.

Conclusion: Our real-life data confirm that valacyclovir significantly reduces the rate of congenital cytomegalovirus diagnosis at the time of amniocentesis with a good tolerability profile and show that the treatment is associated with a reduction of termination of pregnancy and symptomatic congenital cytomegalovirus infection at birth.

Keywords: congenital; cytomegalovirus; fetal; immunoglobulin; pregnant; screening; valaciclovir; women.