Clinical trial NCT03973359: Epidemiology and Prevention of Congenital HCMV in Immune Mothers. Congenital HCMV Infection Lombardy
Official title: Incidence, Outcome and Prevention of Congenital Human Cytomegalovirus (HCMV) Infection in HCMV-seropositive Pregnant Women
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Congenital Cytomegalovirus Infection
Maternal Cytomegalovirus Infection
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
Collaborators: name: Fondazione Regionale per la Ricerca Biomedica
First posted: 2019-06-04
Enrollment: 23500
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

Brief summary: Human cytomegalovirus (HCMV) is the leading infectious agent causing congenital disabilities such as mental retardation, psychomotor delay, hearing loss, speech and language disabilities, behavioural disorders and visual impairment. About 0.6% newborns are HCMV-congenitally infected and, among these, about 20% are symptomatic at birth or will develop long-term sequelae. The public health impact of congenital HCMV is substantial although greatly unrecognized. In Italy, estimated direct costs per affected child exceed €100.000 for a total of €60-70M. HCMV is also a significant cause of infection/disease in the immunocompromised host.

Epidemiological studies and population-based models have preliminarily documented that most of the burden associated to congenital HCMV would be due to non-primary maternal infection. Presently, reinfections are believed to be responsible for the great majority of infected fetuses born to immune mothers.

This study addresses incidence, outcome and prevention of congenital HCMV infection in seropositive pregnant women.The study includes 2 parts: part 1 in which the incidence and outcome of congenital HCMV is investigated in a large population of HCMV seropositive pregnant women and HCMV shedding and immune response is closely monitored in a subset of participants (nested study); part 2 in which the efficacy of an hygiene intervention is assessed.

Detailed description: Part 1. Epidemiologic study. To investigate incidence and outcome of congenital infection in immune mothers, clinical records of pregnant women are reviewed for HCMV serostatus at ≤ 13 weeks' gestation. Women with HCMV serology compatible with a remote infection are asked to participate in the study. Consenting women are given a pre-stamped, pre-addressed envelope containing a swab to collect newborn's saliva. Envelopes are sent by courier to a centralized diagnostic facility for HCMV testing.

Women can also be enrolled at delivery, provided that the woman has records of presence of virus-specific IgG and absence of IgM early during gestation(or in a previous pregnancy) or, in case of unknown serostatus, a sample of serum/plasma stored at ≤ 13 weeks' gestation is available for retrospective antibody testing (retrospective part of the epidemiology study).

Part 1. Nested study. A subset of IgG pos IgM neg women selected among those enrolled at ≤13 weeks' gestation in the epidemiology study are included in a nested study. These women are monitored at enrolment, 20, 30 weeks of gestation and at delivery by prospective determination of HCMV DNA excretion in different bodily fluids. In DNA-positive specimens selected HCMV genes will be sequenced.

Part 2. Prevention study. To assess the effectiveness of hygiene measures for prevention of congenital infection HCMV seropositive pregnant women are enrolled at ≤ 13 weeks' gestation. Part 2 starts when enrolment of Part 1 is completed. In practice, part 2 is a continuation of part 1 with the only addition of delivering hygiene information at enrolment.

Part 2 will not be performed in case congenital infection rate in Part 1 is \<0.4% and clear maternal risk factor for intrauterine transmission cannot be identified at interim analysis (i.e. after examination of 5000 newborns).

In case HCMV DNA is detected in newborn's saliva, a urine sample is obtained for confirmation of congenital infection. Infants with documented congenital infection are clinically assessed at the time of diagnosis (for Part 1 and 2) and at one year of age (Part 1 only).

Eligibility criteria: Inclusion Criteria:

* Adult (≥ 18 years old) pregnant women at ≤13 weeks gestation
* Presence of HCMV IgG and absence of IgM or presence of high avidity IgG with or without IgM
* Presence of HCMV-specific IgG and absence of IgM or presence of high avidity IgG in case of positive IgM at ≤13 weeks gestation documented by medical report or by retrospective antibody determination on samples stored at ≤13 weeks (for women enrolled at delivery)
* Willingness to participate in the study
* Ability to understand information material
* Written informed consent

Exclusion Criteria:

* Unreliable women as judged by the investigator
* Women not willing to give written consent

Primary outcomes:
measure: Part 1. Epidemiology study. Incidence and clinical outcome of congenital HCMV infection in pregnant women with preconception immunity.
timeFrame: Within 21 days of life
measure: Part 2. Prevention study. Efficacy of hygiene counseling in reducing congenital HCMV infection in pregnant women with preconception immunity.
timeFrame: Within 21 days of life
Secondary outcomes:
measure: Frequency of non-primary infections during pregnancy (Nested study)
timeFrame: 10, 20, 30, 40 gestation weeks
measure: Frequency of HCMV re-infections vs re-activations during pregnancy (Nested study)
timeFrame: 10, 20, 30, 40 gestation weeks
measure: Antigen-specific IgG levels in non-primary infection during pregnancy (Nested study)
timeFrame: 10, 20, 30, 40 gestation weeks
measure: Antigen-specific IgM levels in non-primary infection during pregnancy (Nested study)
timeFrame: 10, 20, 30, 40 gestation weeks
measure: Neutralizing antibody titers in non-primary infection during pregnancy (Nested study)
timeFrame: 10, 20, 30, 40 gestation weeks
measure: Risk factors for congenital HCMV infection in pregnant women with preconception immunity. Age
timeFrame: Delivery
measure: Risk factors for congenital HCMV infection in pregnant women with preconception immunity. Country of origin
timeFrame: Delivery
measure: Risk factors for congenital HCMV infection in pregnant women with preconception immunity. Occupation
timeFrame: Delivery
measure: Risk factors for congenital HCMV infection in pregnant women with preconception immunity. Contact with young children
timeFrame: Delivery
measure: Risk factors for congenital HCMV infection in pregnant women with preconception immunity. Twin pregnancy
timeFrame: Delivery
measure: Risk factors for congenital HCMV infection in pregnant women with preconception immunity. Concomitant pathologies
timeFrame: Delivery
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
city: Brescia
country: Italy
facility: Poliambulanza Brescia
city: Carate Brianza
country: Italy
facility: ASST Vimercate (Ospedale di Carate Brianza)
city: Desio
country: Italy
facility: ASST Monza (presidio di Desio)
city: Milan
country: Italy
facility: Fondazione IRCCS Ospedale Maggiore Policlinico
city: Milan
country: Italy
facility: Ospedale Macedonio Melloni (ASST FBF-Sacco)
city: Milan
country: Italy
facility: Ospedale San Raffaele
city: Milan
country: Italy
facility: Ospedale Buzzi (ASST FBF-Sacco)
city: Milan
country: Italy
facility: Ospedale Sacco (ASST FBF-Sacco)
city: Monza
country: Italy
facility: Fondazione Monza Brianza per il Bambino e la sua Mamma
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Varese
country: Italy
facility: ASST dei Sette Laghi (Ospedale Filippo Del Ponte)
Study officials:
affiliation: Fondazione IRCCS Policlinico San Matteo
name: Daniele Lilleri, MD
role: PRINCIPAL_INVESTIGATOR
References: