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      Sequelae of Congenital Cytomegalovirus Following Maternal Primary Infections Are Limited to Those Acquired in the First Trimester of Pregnancy

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          Abstract

          Background

          The known relationship between the gestational age at maternal primary infection an the outcome of congenital CMV is based on small, retrospective studies conducted between 1980 and 2011. They reported that 32% and 15% of cases had sequelae following a maternal primary infection in the first and second or the third trimester, respectively. We aimed to revisit this relationship prospectively between 2011 and 2017, using accurate virological tools.

          Methods

          We collected data on women with a primary infection and an infected child aged at least 1 year at the time of analysis. An accurate determination of the timing of the primary infection was based upon serial measurements of immunoglobulin (Ig) M and IgG and on IgG avidity in sera collected at each trimester. The case outcome was assessed according to a structured follow-up between birth and 48 months.

          Results

          We included 255 women and their 260 fetuses/neonates. The dating of the maternal infection was prospective in 86% of cases and retrospective in 14%. At a median follow-up of 24 months, the proportion of sensorineural hearing loss and/or neurologic sequelae were 32.4% (95% confidence interval [CI] 23.72–42.09) after a maternal primary infection in the first trimester, 0 (95% CI 0–6.49) after an infection in the second trimester, and 0 (95% CI 0–11.95) after an infection in the third trimester (P < .0001).

          Conclusions

          These results suggest that a cytomegalovirus infection can be severe only when the virus hits the fetus in the embryonic or early fetal period. Recent guidelines recommend auditory follow-ups for at least 5 years for all infected children. This raises parental anxiety and generates significant costs. We suggest that auditory and specialized neurologic follow-ups may be recommended only in cases of a maternal infection in the first trimester.

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          Most cited references15

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          Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome.

          The relationship between gestational age at time of maternal cytomegalovirus (CMV) infection and outcome of fetal infection is not well defined because the timing of maternal infection is usually not known. To determine whether congenital cytomegalovirus (CMV) infection following primary maternal infection during the first trimester of pregnancy is more likely to lead to central nervous system (CNS) sequelae than fetal infection due to maternal infection later in pregnancy. Using serum collected during pregnancy from mothers of newborns with congenital CMV infection, maternal infection was categorized as first trimester (<13 weeks) or later based on dates and results of IgG and IgM assays for CMV antibody. Outcome of congenital CMV infection was assessed by longitudinal fotlow-up of the infected cohort. Sensorineural hearing loss was found in 8/34 (24%) of children in the first trimester group, compared with 1/40 (2.5%) in the later infection group (P=0.01, relative risk, 9.6). Considering any CNS sequela (hearing loss, mental retardation, cerebral palsy, seizures, chorioretinitis) 11/34 (32%) first trimester cases were affected compared with 6/40 (15%) in the later infection group (P=0.07, relative risk 2.2). None of the later group had more than one sequela, compared with 4 (12%) of the first trimester group (P=0.04). Children with congenital CMV infection following first trimester maternal infection are more likely to have CNS sequelae, especially sensorineural hearing loss, than are those whose mothers were infected later in pregnancy. However, some degree of CNS impairment can follow even late gestational infection.
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            Long-term outcomes of congenital cytomegalovirus infection in Sweden and the United Kingdom.

            Congenital cytomegalovirus (CMV) is an important cause of neurological problems, particularly sensorineural hearing loss, but data on long-term sequelae and the impact of nonprimary maternal infection are limited. We report updated findings on childhood outcomes from 2 large prospective studies. Pregnant women in Malmö, Sweden, and London, United Kingdom, were included between 1977 and 1986, and newborns were screened for CMV (virus culture of urine or saliva). Cases and matched controls underwent regular, detailed developmental assessments up to at least age 5 years. One hundred seventy-six congenitally infected infants were identified among >50 000 screened (Malmö: 76 [4.6/1000 births]; London: 100 [3.2/1000 births]); 214 controls were selected. Symptoms were recorded in 11% of CMV-infected neonates (19/176) and were mostly mild; only 1 neonate had neurological symptoms. At follow-up, 7% of infants (11/154) were classified as having mild, 5% (7/154) moderate, and 6% (9/154) severe neurological sequelae. Four of 161 controls (2%) had mild impairment. Among children symptomatic at birth, 42% (8/19) had sequelae, versus 14% (19/135) of the asymptomatic infants (P = .006). All moderate/severe outcomes were identified by age 1; mild sequelae were first identified at age 2-5 years in 6 children, and age 6-7 years in 3. Among the 16 children with moderate/severe outcomes, 2 had mothers with confirmed and 7 with presumed nonprimary infection. Moderate or severe outcomes were reported in 11% of children with congenital CMV identified through population screening, all by 1 year; all impairment detected after this age was mild. Nonprimary infections contributed substantially to the burden of childhood congenital CMV disease.
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              Using Seroprevalence and Immunisation Coverage Data to Estimate the Global Burden of Congenital Rubella Syndrome, 1996-2010: A Systematic Review

              Background The burden of Congenital Rubella Syndrome (CRS) is typically underestimated in routine surveillance. Updated estimates are needed following the recent WHO position paper on rubella and recent GAVI initiatives, funding rubella vaccination in eligible countries. Previous estimates considered the year 1996 and only 78 (developing) countries. Methods We reviewed the literature to identify rubella seroprevalence studies conducted before countries introduced rubella-containing vaccination (RCV). These data and the estimated vaccination coverage in the routine schedule and mass campaigns were incorporated in mathematical models to estimate the CRS incidence in 1996 and 2000–2010 for each country, region and globally. Results The estimated CRS decreased in the three regions (Americas, Europe and Eastern Mediterranean) which had introduced widespread RCV by 2010, reaching <2 per 100,000 live births (the Americas and Europe) and 25 (95% CI 4–61) per 100,000 live births (the Eastern Mediterranean). The estimated incidence in 2010 ranged from 90 (95% CI: 46–195) in the Western Pacific, excluding China, to 116 (95% CI: 56–235) and 121 (95% CI: 31–238) per 100,000 live births in Africa and SE Asia respectively. Highest numbers of cases were predicted in Africa (39,000, 95% CI: 18,000–80,000) and SE Asia (49,000, 95% CI: 11,000–97,000). In 2010, 105,000 (95% CI: 54,000–158,000) CRS cases were estimated globally, compared to 119,000 (95% CI: 72,000–169,000) in 1996. Conclusions Whilst falling dramatically in the Americas, Europe and the Eastern Mediterranean after vaccination, the estimated CRS incidence remains high elsewhere. Well-conducted seroprevalence studies can help to improve the reliability of these estimates and monitor the impact of rubella vaccination.
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                Author and article information

                Journal
                Clinical Infectious Diseases
                Oxford University Press (OUP)
                1058-4838
                1537-6591
                November 01 2019
                October 15 2019
                December 31 2018
                November 01 2019
                October 15 2019
                December 31 2018
                : 69
                : 9
                : 1526-1532
                Affiliations
                [1 ]Equipe d’Accueil, Paris Descartes University, Sorbonne Paris CitéArchet, France
                [2 ]Maternity, Hospital Necker-E.M, Paris, France
                [3 ]Neonatal Intensive Care Unit, Hospital Necker-E.M, France
                [4 ]Otology Department, Assistance Publique de Paris, Hospital Necker-E.M, France
                [5 ]Maternity, Hospital Intercommunal Poissy-Saint Germain, Marseille, France
                [6 ]Neonatology and Intensive Care Department, Assistance Publique de Marseille, Hospital La Conception, Marseille, France
                [7 ]Neonatal Intensive Care Unit, Centre Hospitalier Universitaire Nice, Hospital L’Archet, Marseille, France
                [8 ]Department of Neonatalogy, Toulouse University Hospital, Saint-Etienne, France
                [9 ]Department of Neonatalogy, Rouen University Hospital, Saint-Etienne, France
                [10 ]Department of Neonatalogy, Strasbourg University Hospital, Saint-Etienne, France
                [11 ]Neonatal Intensive Care Unit, University Hospital, Saint-Etienne, France
                [12 ]Pediatric Department, Neonatology, Centre Hospitalier Universitaire Rennes and Centre d’Investigation Clinique, France
                [13 ]Maternity, Assistance Publique Hopitaux de Paris (AP-HP), Hospital Cochin, France
                [14 ]Department of Neonatalogy, Centre Hospitalier Universitaire de Caen, France
                [15 ]Medical School, Université Caen Normandie, France
                [16 ]Brest, Neonatal and Pediatric Intensive Care Unit, Centre Hospitalier Régional Universitaire, France
                [17 ]Clinical Research Unit, AP-HP, Hospital Necker-E.M., France
                [18 ]Virology Laboratory, Reference Laboratory for Cytomegalovirus Infections, AP-HP, Hospital Necker-E.M., France
                [19 ]Unité de Recherche Clinique et Département de Santé Publique, AP-HP, Hôpital Ambroise Paré, Boulogne, France
                [20 ]University Versaille-Saint-Quentin, Unité Mixte de recherche S, Université Versailles St-Quentin-en-Yvelines, Montigny, France
                Article
                10.1093/cid/ciy1128
                30596974
                57f9c740-e177-40a6-9018-bf903be3bfdf
                © 2018

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