Rev. Med. Virol. 2014; 24: 420–433.

Published online 14 October 2014 in Wiley Online Library

(wileyonlinelibrary.com)
Reviews in Medical Virology DOI: 10.1002/rmv.1814

REVIEW
Prevention of congenital cytomegalovirus
complications by maternal and neonatal
treatments: a systematic review
Stuart T. Hamilton1,2, Wendy van Zuylen1,3, Antonia Shand4,
Gillian M. Scott5, Zin Naing1,3, Beverley Hall1, Maria E. Craig1,6,7 and
William D. Rawlinson1,2,3*
1
Virology Division, SEALS Microbiology, Prince of Wales Hospital, Sydney, Australia
2
School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia
3
School of Medical Sciences, University of New South Wales, Sydney, Australia
4
Department of Maternal Fetal Medicine, Royal Hospital for Women, Sydney, Australia
5
Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
6
School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
7
Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, Australia

S U M M A RY
Human cytomegalovirus is the leading non-genetic cause of congenital malformation in developed countries. Congen-
ital CMV may result in fetal and neonatal death or development of serious clinical sequelae. In this review, we identi-
fied evidence-based interventions for prevention of congenital CMV at the primary level (prevention of maternal
infection), secondary level (risk reduction of fetal infection and disease) and tertiary level (risk reduction of infected ne-
onates being affected by CMV). A systematic review of existing literature revealed 24 eligible studies that met the in-
clusion criteria. Prevention of maternal infection using hygiene and behavioural interventions reduced maternal
seroconversion rates during pregnancy. However, evidence suggested maternal adherence to education on preventative
behaviours was a limiting factor. Treatment of maternal CMV infection with hyperimmune globulin (HIG) showed
some evidence for efficacy in prevention of fetal infection and fetal/neonatal morbidity with a reasonable safety profile.
However, more robust clinical evidence is required before HIG therapy can be routinely recommended. Limited evi-
dence also existed for the safety and efficacy of established CMV antivirals (valaciclovir, ganciclovir and valganciclovir)
to treat neonatal consequences of CMV infection, but toxicity and lack of randomised clinical trial data remain major
issues. In the absence of a licensed CMV vaccine or robust clinical evidence for anti-CMV therapeutics, patient educa-
tion and behavioural interventions that emphasise adherence remain the best preventative strategies for congenital
CMV. There is a strong need for further data on the use of HIG and other antivirals in pregnancy, as well as the devel-
opment of less toxic, novel, antiviral agents. Copyright © 2014 John Wiley & Sons, Ltd.
Received: 4 July 2014; Revised: 29 August 2014; Accepted: 2 September 2014

INTRODUCTION clinical sequelae, prematurity, intrauterine death

Human CMV is the leading non-genetic cause of or neonatal death in hundreds of thousands of in-
congenital malformation in developed countries. fants every year globally [1,2]. In practice, most
Congenital infection with CMV causes serious congenital infections remain undiagnosed [3]. Ma-
ternal CMV infection with materno-fetal transmis-
*Corresponding author: Prof. W.D. Rawlinson, Virology Division, sion occurs in approximately 0.64% of pregnancies
Prince of Wales Hospital, Level 3, Clinical Sciences Building, in developed countries [2–4]. Although cCMV re-
Randwick, New South Wales, 2031, Australia. mains relatively rare compared with preterm birth
E-mail: [email protected]
(9.6% of all births worldwide) [5], CMV infection
Abbreviations used is an unrecognised cause of prematurity, with the
bid, twice per day; cCMV, congenital cytomegalovirus; CT, computed true rate as yet undefined [6]. The rate of
tomography; HIG, hyperimmune globulin; IUGR, intrauterine growth
restriction; MRI, magnetic resonance imaging; OR, odds ratio; SNHL, materno-fetal transmission is higher in primary in-
sensorineural hearing loss; U, units. fections (14.2–52.4%, mean 32.4%) compared with

Copyright © 2014 John Wiley & Sons, Ltd.

Prevention and treatment of congenital CMV 421

non-primary reactivation or reinfection (1.1–1.7%, more than one-third of 246 practitioners involved
mean 1.4%) [7,8]. However, larger numbers of af- in care of mothers and infants assumed treatment
fected babies are born to seropositive women than was readily available for cCMV [33]
to those experiencing primary infection [9,10]. Following recent new data on interventions for
CMV infection causes the intrauterine death of an preventing cCMV [39], we systematically reviewed
unknown number of babies, possibly ~0.5% strategies to prevent infection of seronegative preg-
[3,11,12]. nant women, fetuses or neonates and therapies to
Many (~10%) CMV-infected babies will be symp- reduce risk of symptomatic disease in CMV-
tomatic at birth with unilateral or bilateral SNHL, infected neonates.
vision loss, microcephaly, hepatomegaly, spleno-
megaly, thrombocytopenia, jaundice, petechiae, METHODS
motor defects, mental disability, chorioretinitis, We performed a systematic review of interventions
strabismus, optic atrophy and dental defects, with for prevention of cCMV, classified as follows: (i)
~5% (~10% of most severely affected) dying of primary prevention of maternal infection during
multiorgan dysfunction [13]. A significant propor- pregnancy; (ii) secondary prevention, or reduction
tion (~15%) of initially asymptomatic CMV- of risk of fetal infection and disease once primary
infected babies develop disease between birth and maternal CMV infection has been acquired in preg-
5 years age [3,12,14]. Fetal injury results from direct nancy; and (iii) tertiary prevention, defined as re-
viral cytopathic damage to the fetus, although pla- duction in the risk of neonates being affected by
cental infection alone may cause fetal injury via CMV once infected.
CMV-induced immunomodulation, placental dys-
regulation and placental dysfunction [11,15–19].
Literature search strategy
The health economic costs of cCMV sequelae are
Electronic databases, including PubMed, MEDLINE,
high—estimated at over $US2bn annually in the
Embase and ClinicalTrials.gov, were searched from
USA [20].
January 1968 to June 2014 for relevant studies using
Maternal prenatal screening for CMV is not cur-
the terms ‘congenital cytomegalovirus’ and ‘treat-
rently recommended in Australia, the UK nor the
ment’, ‘prophylaxis’, ‘therapeutic’, ‘prevention’, ‘in-
USA. Maternal screening is routinely performed
tervention’, ‘antiviral’ or ‘hyperimmune globulin’.
in some European countries [21,22] but is done so
without recommendations or guidelines from any
governmental agencies, authorities or medical soci- Selection criteria
eties [23]. A recent review outlined the continuing Studies were eligible for inclusion if (i) participants
controversy around screening for CMV and pro- were human pregnant women or neonates; (ii) de-
posed screening and diagnostic algorithms [24]. sign was a randomised controlled trial (RCT), con-
The saliva and urine of CMV-infected children trolled trial, observational study or case series; (iii)
are the primary sources of transmission among they reported data on primary, secondary or ter-
pregnant women [8]. Transmission may occur often tiary interventions for CMV infection with fetal or
from older siblings in day care, with particular risk neonatal clinical outcomes; (iv) full text was avail-
for the seronegative woman bearing her second able; and (iv) the report was in English. Exclusion
child [25–30]. Knowledge and awareness of CMV criteria were as follows: (i) interventions to prevent
is frequently limited among both healthcare practi- CMV infection via other routes of maternal trans-
tioners and women of childbearing age [31–36]. mission (e.g. transfusion) and (ii) review articles,
Health professionals are the main source of infor- abstracts, letters or conference proceedings.
mation on CMV for women, with 12.5–54% of
women only having heard of CMV from a health Study selection
professional [31,32,37]. However, a survey of prac- Two reviewers independently screened the title and
tising obstetricians and gynaecologists in the USA abstract of retrieved records. This was supple-
reported that only 44% counselled women in the mented by hand searching the reference lists of
prevention of CMV infection and 28% had limited key reviews and all included studies. Full-text pub-
knowledge regarding CMV transmission risks lications were sought and reviewed for studies
[38]. Another survey in the Netherlands found that identified by either reviewer as being potentially

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv
422 S. T. Hamilton et al.

eligible. Disagreements about final study inclusion Primary prevention of congenital CMV—
were resolved by consensus between reviewers. prevention of maternal primary CMV
infection
Data extraction Vaccine (one study). Pass [78] reported results from a
The extracted data included information on study phase II placebo-controlled, randomised, double-
design, participants (number and age), description blinded trial in seronegative women within 1 year
and duration of intervention, nature of control of giving birth. The test group of 225 women
group, method of outcome assessment and inci- received one-to-three intramuscular vaccinations
dence of cCMV infection or disease in each group. of glycoprotein B adjuvanted with MF59 at 0, 1
and 6 months, and 216 control women received
one-to-three doses of placebo. Infection occurred
Critical appraisal in 8% (18/225) or 3.3 per 100 person-years of the
Assessment of risk of bias was performed using the vaccine group and 14% (31/216) or 6.6 per 100
most updated Oxford Centre for Evidence-based person-years of the placebo group (p = 0.02), for
Medicine (OCEBM) 2011 Levels of Evidence (Treat- overall vaccine efficacy of 50% (95% confidence
ment Benefits) quality scale [40]. Two reviewers in- interval (CI), 7–73). Of seronegative women who
dependently assessed the quality of the study became pregnant during the trial, infection
according to the OCEBM guidelines, and the level occurred in 1% (1/81) of infants of mothers in the
of evidence attributed was decided by consensus. vaccine group and 3% (3/97) of infants of mothers
in the placebo group (p = 0.41).

RESULTS Hygiene and behavioural interventions (three studies).

The search yielded 360 non-duplicated articles with Adler et al. [79] reported a cluster RCT examining
336 articles excluded for not meeting the selection the effectiveness of a behavioural prevention
criteria, leaving 24 eligible studies (Figure 1). Of the approach on reducing child-to-parent CMV
24 articles, four were RCTs, two were randomised transmission. Mothers in the education group
cluster control trials, three were non-randomised were given information about CMV infection and
phase I/II trials, six were observational studies, three its complications. Instructions were provided
were case–control studies and six were case series orally and in writing and included protective
(Table 1). Thirty-seven case reports were also identi- behaviours (frequent hand washing after exposure
fied and not included in this review [41–77] but were to a child’s bodily fluids or a child’s objects and
detailed elsewhere (Supplementary Table 1). wearing latex gloves during diaper changes and
handling the child’s dirty laundry) and behaviours
to avoid (intimate contact with the child such as
kissing on the mouth, sleeping together, sharing
towels/washcloths and sharing food or drink). Of
28 non-pregnant seronegative mothers whose
children were under 36 months of age, attending
child care and shedding CMV, 37% (4/11)
seroconverted in the education group compared
with 47% (8/17) in controls. A second education
group (third arm) receiving additional social
reinforcement for adherence and problem solving
had a further reduced seroconversion rate (25%,
2/8). None of the pregnant women in the fourth
arm who received an intervention equivalent to that
of the education group seroconverted (0%, 0/14).
Adler et al. [80] reported a subsequent cluster
Figure 1. Results of the search strategy for interventions for the
prevention and treatment of congenital cytomegalovirus infection
RCT of 166 seronegative mothers who were either
and disease pregnant or attempting pregnancy and had a child

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv
 Table 1. Summary of types of studies, study characteristics and quality of interventions for the prevention and treatment of
congenital cytomegalovirus infection in mothers and infants
Intervention Prevention Country n Study type Treatment benefitsa

Vaccine
Pass et al. 2009 [78] Primary USA 225 Phase II RCT 2
Behavioural intervention
Adler et al. 1996 [79] Primary USA 50 Cluster control 3
Adler et al. 2004 [80] Primary USA 166 Cluster control 2
Prevention and treatment of congenital CMV

Vauloup-Fellous et al. 2009 [81] Primary France 5312 Case series 4

Hyperimmune globulin
Prophylaxis

Copyright © 2014 John Wiley & Sons, Ltd.

Nigro et al. 2005 [82]b Secondary Italy 84 Phase I/II NRT 4
Revello et al. 2014 [39] Secondary Italy 122 Phase II RCT 2
Nigro et al. 2014 [83] Secondary Italy 358 Observational 4
Buxmann et al. 2012 [85]b Secondary Europe 39 Observational 4
Treatment
Nigro et al. 2005 [82]b Secondary Italy 45 Phase I/II NRT 4
Visentin et al. 2012 [88] Secondary Italy 68 Case–control 4
Nigro et al. 2012 [84] Secondary Italy 64 Case–control 4
Buxmann et al. 2012 [85]b Secondary Europe 4 Observational 4
JCISG 2012 [89] Secondary Japan 12 Case series 4
Nigro 2012 [90] Secondary Italy 17 Case–control 4
Valaciclovir
Jacquemard et al. 2007 [91] Secondary France 45 Observational 4
Roxby et al. 2014 [92] Secondary USA 141 Phase II RCT 2
Ganciclovir
Nigro et al. 1994 [93] Tertiary Italy/Germany 12 Observational 4
Whitley et al. 1997 [94] Tertiary 42 Phase II NRT 4
Michaels et al. 2003 [95] Tertiary USA 9 Case series 4
Kimberlin et al. 2003 [96] Tertiary USA 43 Phase III RCT 2

Continues

DOI: 10.1002/rmv
Rev. Med. Virol. 2014; 24: 420–433.
423
424 S. T. Hamilton et al.

Oxford Centre for Evidence-based Medicine 2011 Levels of Evidence (treatment benefits) [40]; 2 = Randomized trial or observational study with dramatic effect,
Treatment benefitsa

JCISG, Japanese Congenital Cytomegalovirus Infection Immunoglobulin Fetal Therapy Study Group; RCT, randomised clinical trial; NRT, non-randomised
in day care aged <36 months. The intervention
group received identical information and behav-
ioural instructions as mothers in the Adler et al.
4 1996 study [79]. Those who received the interven-
4

4
4
tion (education in measures to prevent CMV trans-
mission) had identical seroconversion rates of 7.8%
(9/115) compared with controls (4/51). However,
the seroconversion rate for women with a child
shedding CMV who were already pregnant before
enrolment was 5.8% (1/17) compared with 42%

3 = Non-randomized controlled cohort/ follow-up study, 4 = Case series, case–control studies or historically controlled studies.
(10/24) for women attempting conception
Observational
Study type

(p = 0.008).
Case series

Case series
Case series

Vauloup-Fellous et al. [81] reported a single-

arm study where hygiene counselling on CMV
prevention at 12 weeks’ gestation reduced sero-
conversion rates. Detailed hygiene information
was given to parents orally and in writing simi-
lar to the Adler et al. 1996 study [79], except
wearing protective gloves was not recom-
23

13
6

mended. The maternal seroconversion rate was

n

0.19% (5/2595) at 36 weeks’ gestation compared

with 0.42% (11/2595) rate of seroconversion of
women prior to counselling in the first trimester
of pregnancy. Of the 16 seroconversions, 15/16
women were at high risk of infection, 12/16
had a child under 3 years of age at home and
Country

7/16 were doctors or nurses.

Austria
Japan

Spain
USA

Italy

Secondary prevention of congenital CMV—

prophylaxis prevention and treatment of
fetal CMV infection during pregnancy
Same study reported both prophylaxis and treatment arms.

CMV HIG therapy. HIG prophylaxis (four studies).

Prevention

Nigro et al. [82], in a prospective, non-randomised,

Tertiary
Tertiary

Tertiary
Tertiary

controlled phase I and II study, investigated

passive immunisation for prevention of fetal infection
and treatment of infected fetuses in women who
seroconverted during pregnancy. In the prophylaxis
arm of the study, women with a primary CMV
infection during pregnancy (<21 weeks’ gestation)
Tanaka-Kitajima et al. 2005 [97]

with unknown fetal infection status were given

100 U/kg iv HIG monthly from diagnosis until
Del Rosal et al. 2012 [100]
Lombardi et al. 2009 [99]
Table 1. (Continued)

delivery. Infants of these women had reduced rates

Lackner et al. 2009 [98]

of infection, 16% (6/37), compared with 40% (19/

47) in untreated controls (absolute risk reduction of
24%). The only predictor associated with a
Valganciclovir
Intervention

significant reduction in the risk of congenital

infection was receipt of HIG with an OR of 0.32
(95% CI, 0.10–0.94; p = 0.04).
Revello et al. [39], in a double-blinded,
trial.

randomised, placebo-controlled study, investigated

b
a

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv
Prevention and treatment of congenital CMV 425

an HIG prophylaxis treatment regimen similar to with HIG treatment of 23%. The CMV transmission
the Nigro study of 2005, and this study was rate after HIG treatment was 21% (5/24) following
powered to replicate the difference observed in periconceptional or first-trimester infection and
the Nigro study (an absolute risk reduction of 27% (4/15) after second-trimester infection. With-
24%) [68]. Mothers with confirmed primary infec- out HIG treatment, after first-trimester and
tion acquired between 5 and 26 weeks’ gestation second-trimester CMV infections, respectively,
were given 100 U/kg iv HIG or placebo monthly Bodéus et al. [86] reported transmission rates of
starting within 6 weeks of presumed onset of infec- 34.5% (39/113) and 44.1% (60/136) and Enders
tion until 36 weeks’ gestation or a CMV-positive et al. [87] transmission rates of 30% (25/83) and of
amniocentesis. There was a non-statistically signifi- 38% (29/76).
cant reduction in the rate of fetal infection with 30%
(18/61) congenital infections in the HIG-treated HIG treatment (six studies). Nigro et al. [82], in the
group compared with 44% (27/62) in the placebo treatment arm of their study, gave pregnant
control group (absolute risk reduction of 14%) women with CMV detected in amniotic fluid (indi-
(95% CI, 3 to 31; p = 0.13). The rate of obstetric cating fetal infection) iv HIG at 200 U/kg maternal
complications (preterm delivery, preeclampsia and weight. Some mothers (9/31) were given follow-up
fetal growth restriction) in women who remained iv intraumbilical or intra-amniotic fluid doses of
in the study until the time of delivery was higher HIG if ultrasound indicated persistent fetal in-
in the HIG group (13%, 7/53) than in the placebo volvement (400 U/kg fetal weight). Women receiv-
group (2%, 1/51; p = 0.06). ing HIG gave birth to infants with a reduced rate of
Nigro et al. [83] recently reported an observa- symptomatic disease (3%, 1/31) compared with
tional study from a number of different centres women who declined HIG treatment (50%, 7/14).
and study designs investigating the effects of HIG The only predictor associated with a significant re-
administration on birth weight and duration of duction in the risk of congenital infection was re-
gestation. The study comprised 358 women who ceipt of HIG (OR 0.02 [95% CI, ∞ to 0.15,
had primary CMV infection during pregnancy, p < 0.001]). Symptomatic cCMV disease was de-
221 of whom were included in previous studies fined by fetal or infant death, neurologic involve-
[82,84]. Of the 162 women receiving at least one ment, mental disability (IQ below 70) or motor
dose of HIG (one to eight doses, 100–200 U/kg or delay.
150–200 mg/kg of maternal weight), 64% (103/ Visentin et al. [88], in a partly randomised case–
162) delivered an infected newborn compared with control study, used similar criteria to those used
85% (164/194) of women who did not receive HIG by the 2005 Nigro study [82]. Women with
(OR 0.32 [95% CI, 0.19–0.53, p < 0.001]). In contrast primary CMV prior to 17 weeks’ gestation with
to the Revello et al. study [39], the receipt of HIG congenitally infected fetuses, determined on
was not associated with either diminished birth amniocentesis at >20 weeks, were offered a single
weight or reduced duration of pregnancy, although dose of iv HIG treatment (200 U/kg of maternal
losses to follow-up and completeness of data were weight) at 20–24 weeks’ gestation. The untreated
not stated. infants were from women who refused treatment
Buxmann et al. [85], in a retrospective observa- or who had CMV infection prior to HIG avail-
tional study, investigated the efficacy of HIG pro- ability. Fewer infants in the HIG-treated arm
phylaxis and treatment for cCMV. The prevention (13% or 4/31) had poor outcomes at 1 year of age
group consisted of 38 women and their 39 infants compared with 43% (16/37) in untreated mothers
with maternal primary infection during the first (p < 0.01). Poor outcome was defined as infants
or second trimester of pregnancy, where amniotic with neurological or audiological involvement,
fluid testing was not undertaken prior to HIG ther- necrotising haemorrhagic enterocolitis or chronic
apy. HIG was intravenously administered to 37/38 liver disease.
mothers (one to five doses, median dose 200 U/kg), Nigro et al. [84], in a case–control study, re-
and to 2/39 infants via the umbilical vein (two to evaluated infants from the 2005 study [82]. The
four doses, 500–800 U). In total, 9/39 infants were study comprised 64 congenitally infected infants
congenitally infected (including one terminated from pregnancies with confirmed primary maternal
pregnancy), giving an overall transmission rate infection at ≤20 weeks’ gestation. The cases (n = 32)

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv
426 S. T. Hamilton et al.

were congenitally infected symptomatic infants were CMV infected. In the HIG group, 89%
with hearing deficit and/or psychomotor retarda- (8/9) were normal at birth and during follow-
tion. Matched controls (n = 32) were asymptomatic up (3–8 years), and in the untreated group,
congenitally infected infants. The only risk factor 88% (7/8) were severely affected at 2–7 years
for affected infants was non-receipt of HIG at of age (p < 0.0004). One treated fetus had severe
200 U/kg iv of maternal weight (two to four doses persistent deafness, and one untreated neonate
weekly; p = 0.001). died soon after preterm birth.
In the treatment arm of the Buxmann et al. [85]
observational study, four women with congenitally
infected fetuses received HIG therapy starting be- Valaciclovir (two studies). Jacquemard et al. [91], in
tween 16 and 35 days after diagnosis (CMV-posi- a pilot observational study conducted from 2003 to
tive amniotic fluid) that included two or three 2005, assessed maternal oral valaciclovir (8 g/day) as
intraumbilical or intra-amniotic doses of HIG treatment for cCMV infections. Twenty pregnancies
(500–1000 U per dose). Three of the four mothers including 21 fetuses were treated at 28 weeks
also received IV HIG (one to three doses) at 180– (median, range: 22–34) for 7 weeks (median, range:
220 U/kg maternal weight. The outcome for the 1–12). Although the aim of this study was not to
three treated pregnancies receiving both fetal and demonstrate the clinical efficacy of valaciclovir,
maternal HIG was asymptomatic cCMV at 1 year results showed that 52% (10/21) of infants in the
of age. The outcome for the fourth infant was treatment arm had adverse outcomes compared with
symptomatic cCMV; however, this fetus presented 58% (14/24) in the untreated group.
with abnormal ultrasound findings prior to HIG Roxby et al. [92], in a randomised double-
treatment including IUGR, microcephaly and blind, placebo-controlled clinical trial in Kenyan
echogenic bowel. HIV-positive women evaluating the effect of
The Japanese cCMV Infection Immunoglobulin valaciclovir prophylaxis (500 mg bid) on mater-
Fetal Therapy Study Group 2012 [89] multi-centre nal HIV-1 RNA levels, recently reported results
trial consisted of 12 pregnant women whose fetuses for infant acquisition of CMV. Women also re-
were found to have symptomatic cCMV with ceived zidovudine monotherapy and perinatal
abnormalities detected by prenatal ultrasound, nevirapine. Of infants tested at birth, twice as
MRI and CT examinations. The HIG administra- many had detectable CMV in the placebo arm
tions included injection into the peritoneal cavity (6.9%, 4/58) compared with the valaciclovir
of affected fetuses (11/12, 1.0–3.7 g HIG, two to six arm (3.3%, 2/61), but this was not statistically
doses) and/or IV maternal administration (5/12, significant (p = 0.4). The cumulative total of in-
1.5–15.0 g HIG, one to five doses). After HIG fant CMV acquisition did not differ between
therapy, ultrasound examination demonstrated study arms by 1 year of age, and the median
ascites disappearance of 57.1% (4/7), decrease in time to CMV detection did not differ.
ascites volume of 14.3% (1/7), improvement in
IUGR of 54.5% (6/11) and disappearance of mild
Tertiary prevention of congenital CMV—
ventriculomegaly of 40% (2/5), and in one case,
hepatomegaly and hydronephrosis disappeared. treatment of symptomatic congenital CMV in
The survival rate of affected infants was 83.3% the neonate
(10/12). Concerning morbidity, 25% (3/12) of Ganciclovir (six studies). Nigro et al. [93], in a pilot
the infants developed normally, 42% (5/12) had observational study, investigated the efficacy of two
hearing difficulty and 33.3% (4/12) had develop- regimens of ganciclovir therapy (5 mg/kg bid for
mental delay. 2 weeks [group 1] or 7.5 mg/kg bid for 2 weeks
Nigro et al. [90] reported a case–control study and 10 mg/kg three times weekly for 3 months
investigating HIG therapy for fetal hypere- [group 2]) in 12 infants with symptomatic cCMV
chogenic bowel, with 9/17 treated with mater- infection. In group 1, 33% (2/6) had normal
nal HIG (one to three iv doses, 200 U/kg) and outcomes at 18-month follow-up. In group 2, 83%
8/17 untreated. Echogenic bowel resolved in (5/6) showed clinical improvement, one of whom
78% (7/9) treated fetuses and 38% (3/8) un- later developed mild psychomotor retardation.
treated fetuses (p = 0.15). At birth, all 17 infants After group 2 therapy cessation, one infant

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv
Prevention and treatment of congenital CMV 427

developed severe psychomotor retardation and in all cases. All patients developed neurologic defi-
hearing loss following transient improvement. cits including hearing loss; however, in two infants,
Whitley et al. [94] reported preliminary phase II an improvement of hearing loss was observed at
pharmacokinetic and pharmacodynamic results in 12- to 41-month follow-up.
42 infants with symptomatic cCMV treated with Lackner et al. [98], in an observational case–
daily ganciclovir doses of 8 or 12 mg/kg/day for control study, investigated iv ganciclovir therapy
up to 6 weeks. Hearing improvement or stabiliza- (5–10 mg/kg for 21 days) for SNHL on 23 asymp-
tion occurred in 16% (5/30) babies at 6 months or tomatic cCMV-infected infants over a 4- to 10-year
later. Of 13 infants (13/42) with retinitis at baseline, follow-up period. Treatment was commenced
62% (8/13) had complete normalisation, and 38% within the first 10 days of life. All 23 children had
(5/13) developed retinal detachment. Resolution normal sensorineural hearing at one year of age,
of hepatosplenomegaly occurred in 7% (3/42) in- but 5/23 children were subsequently lost to follow-
fants; however, 64% (27/42) had persistent evi- up. Of the eight infants in the untreated group,
dence of hepatosplenomegaly without significant SNHL occurred in 11% (2/8). SNHL did not develop
resolution. in any of the ganciclovir-treated neonates (0/10).
Michaels et al. [95] reported a case series of nine in-
fants aged 3 days to 11 months with symptomatic Valganciclovir (two studies). Lombardi et al. [99]
cCMV, who received iv ganciclovir for 5.5–18 months reported an open case series of 12 infants aged
followed by oral ganciclovir (550 mg/m2/dose three ≤30 days with symptomatic cCMV, who received
times a day) for 6–36 months. At the beginning of oral valganciclovir (15 mg/kg bid) for 6 weeks. At
therapy, 56% (5/9) of infants were diagnosed with baseline, 60% (8/12) of infants were diagnosed
SNHL (two moderate and three severe). At follow- with SNHL (five moderate and three severe), and
up, 60% (3/5) had unchanged SNHL, while 40% at 6-month follow-up, 75% (6/8) infants had
(2/5) had improved hearing in one ear. There was unchanged SNHL, whereas 25% (2/8) had
no deterioration in the 44% (4/9) infants with improved hearing (from moderate to mild). The
normal hearing. 4/12 infants with normal hearing at baseline and
Kimberlin et al. [96] conducted a phase III at 3 months of life preserved normal hearing at
randomised, controlled study to determine the 6 months.
efficacy of IV ganciclovir therapy (6 mg/kg bid
Del Rosal et al. [100] reported a recent retrospec-
for 6 weeks) in neonates with symptomatic CMV
tive case series of 13 infants with cCMV infection
disease involving the CNS. Of the 100 participants
and CNS involvement, who received oral
enrolled, only 42% (42/100) were evaluable for
valganciclovir (32 mg/kg/day bid) for a median
the primary end point, which may have diminished
treatment duration of 6 months (4/13 also received
effective randomisation. The study revealed 84%
intravenous ganciclovir; 12 mg/kg/day bid). Re-
(21/25) of neonates with symptomatic cCMV
sults showed 85% had hearing defects at baseline
disease in the ganciclovir treatment arm had
compared with 50% at 12 months. By ears, 18
hearing improvement or continued normal hearing
showed hearing loss at baseline (seven mild, three
at 6 weeks, compared with 59% (10/17) in the
moderate and eight severe), and at 12 months, nine
untreated group (p = 0.06). At 6-month follow-up,
remained stable, seven had improved and none
none of the ganciclovir recipients had hearing
had worsened. In eight normal ears at baseline, no
deterioration, and 41% (7/17) of control patients
deterioration was found at 12 months.
did (p < 0.01). At 1 year of age or greater, 21%
(5/24) who received ganciclovir had hearing
deterioration in the best ear, compared with 68% DISCUSSION
(13/19) of controls (p < 0.01). This is the first systematic review to examine inter-
Tanaka-Kitajima et al. [97] reported a case series of ventions for primary, secondary and tertiary pre-
six infants with symptomatic cCMV infection vention of congenital CMV. Although a number of
treated with 5–12 mg/kg bid for 2–7 weeks from case series, case–control and observational studies
days 0 to 45 (median, day 14). After ganciclovir were identified, there was a significant lack of
administration, active signs of chorioretinitis, throm- robust clinical trial data examining either prophy-
bocytopenia and anaemia disappeared or improved laxis or treatment interventions for cCMV. High-

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv
428 S. T. Hamilton et al.

quality evidence from RCTs will be required before NCT01376778) should provide more definitive evi-
any interventions can be recommended and will dence for HIG prophylaxis. The studies on HIG
likely be needed before health systems will agree therapy have similar methodological issues that
to cover the associated costs. prevent any definitive conclusions regarding effi-
For primary prevention of cCMV, the behavioural cacy of treatment. However, all studies that met
intervention studies showed reduced seroconver- the inclusion criteria of this review consistently
sion rates with education. However, both the 1996 showed a beneficial trend. Unfortunately, there
[79] and 2004 [80] studies have previously been con- are no listed randomised clinical trials investigating
sidered to have a risk of selection and detection bias efficacy of HIG treatment of cCMV at present. The
[101]. The Adler et al. 2004 study also observed evidence for valaciclovir efficacy for secondary pre-
identical seroconversion rates in the education and vention of cCMV is more limited than HIG therapy
control groups when non-pregnant and pregnant with only two studies available: one prophylactic
women were included in the analysis, despite show- RCT (where CMV acquisition was a secondary
ing some efficacy for pregnant women compared aim in a homogenous, diseased population) and
with women attempting conception. This finding one pilot pharmacokinetic study (where only a
was attributed to pregnant women being more very modest effect was observed).
motivated to alter their behaviour and adhere to For tertiary prevention of cCMV symptomatic
instructions compared with non-pregnant women, disease in the neonate, all studies that met our in-
consistent with their 1996 findings. The Vauloup- clusion criteria showed some evidence for efficacy
Fellous et al. 2009 study [81] lacked control data, of ganciclovir and valganciclovir treatment, partic-
which limits interpretation of their findings; how- ularly in stabilising or improving SNHL. However,
ever, this study also showed some evidence for of the six ganciclovir studies and two
behavioural intervention efficacy. Overall, given valganciclovir studies included, only the ganciclo-
the low cost, the trend to efficacy in pregnant vir RCT contained case–control data [96] and all
women and the positive impact of maternal control but one [97] showed some association of treatment
over these measures, the hygiene procedures in with neutropaenia.
these papers would be recommended. The major conclusions from this systematic re-
For secondary prevention of cCMV, the HIG pro- view are based on a limited number of studies,
phylaxis studies by Nigro et al. [82] and Revello which have some risk of bias. Nevertheless, in
et al. [39] should not strictly be combined as a the absence of a CMV vaccine and limited evi-
meta-analysis to produce a definitive recommenda- dence for HIG/antiviral efficacy, education and
tion, as a combination of non-randomised and behavioural interventions remain the best pre-
randomised trial data is not recommended [102]. ventative strategy for cCMV to date. Determina-
Although both studies showed some evidence of tion of a woman’s serostatus, ideally pre-
benefit, the methodological issues contained within conception, can identify seronegative women at
each mean neither was definitive. The Nigro 2005 high risk of cCMV because of exposure risk. Al-
study was provocative and hypothesis generating; though protective hygienic measures would
however, the lack of random assignment may have clearly reduce transmission rates, on the basis
led to type 1 error. Although the Revello RCT failed of the evidence currently available, maternal ad-
to replicate the difference seen in the previous herence to behavioural interventions appears to
study, the use of pilot data to determine sample be a limiting factor. Therefore, healthcare pro-
size to estimate risk reduction may have resulted viders should counsel all women planning preg-
in type 2 error [103,104]. The Revello study was nancy and pregnant women regarding the risks
powered to show an absolute reduction in CMV of cCMV and emphasise the importance of ad-
infection of 24% in treated versus untreated cases; hering to behavioural preventative measures to
as the observed non-significant rate was 14%, the reduce this risk, even when attempting concep-
power to detect this difference was small (33%). tion. The behavioural strategies recommended
However, the 95% confidence interval of 3% to by the Centres for Disease Control and Preven-
31% reported in the study does not exclude a clini- tion [105], which show some evidence of efficacy
cally relevant effect, and at least one RCT currently on the basis of the studies contained within this
underway in the USA (ClinicalTrials.gov identifier review, are shown in Table 2.

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv
Prevention and treatment of congenital CMV 429

Table 2. Behavioural strategies recommended by the Centres for Disease Control and
Prevention
Wash your hands often with soap and water for 15–20 s, especially after changing diapers, feeding a young
child, wiping a young child’s nose or drool or handling children’s toys
Do not share food, drinks or eating utensils used by young children
Do not put a child’s pacifier in your mouth
Do not share a toothbrush with a young child
Avoid contact with saliva when kissing a child
Clean toys, countertops and other surfaces that come into contact with children’s urine or saliva

In cases where primary CMV infection is August 2014, there are currently one clinical trial un-
suspected or diagnosed during pregnancy, appro- derway investigating primary prevention strategies
priate referral to an expert with experience in manag- (behavioural intervention), three investigating sec-
ing CMV infection in pregnancy is recommended. If ondary prevention strategies (two HIG prophylaxis
the patient requests intervention, after discussion of trials and one valaciclovir trial) and two investigat-
the limitations of data for treatment, HIG therapy is ing tertiary prevention of cCMV (valganciclovir;
preferred to established anti-CMV antivirals because Supplementary Table 2). These future clinical trials
of the available data and known drug toxicity. As data due over the coming years should allow proper
for the treatment of symptomatic cCMV in the statistical analysis, to better inform decision-making
neonate, ganciclovir therapy is supported by the for the prevention and treatment of cCMV.
results of a single published RCT [96]. A later
RCT of valganciclovir (available currently in ab- CONFLICT OF INTEREST
stract form) reports that 6 months’ therapy is supe- The authors have no competing interest.
rior to 6 weeks [106].
Given the available evidence to date, priority for ACKNOWLEDGEMENTS
future case–control trials should be given to primary This work was supported by National Health and
behavioural interventions, secondary HIG prophy- Medical Research Council project grant
lactic and treatment interventions and tertiary (APP1045989). We thank Dr Michael Cannon for
ganciclovir/valganciclovir interventions. As of critical review of the manuscript.

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SUPPORTING INFORMATION
Additional supporting information may be found in the online version of this article:

Table 1: Characteristics of case reports of interventions for the prevention and treatment of congenital
cytomegalovirus infection or disease.
Table 2. Characteristics of current clinical trials investigating interventions for the prevention and treat-
ment of congenital cytomegalovirus infection or disease.

Copyright © 2014 John Wiley & Sons, Ltd. Rev. Med. Virol. 2014; 24: 420–433.
DOI: 10.1002/rmv