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Maternal and neonatal screening methods for congenitalcytomegalovirus infect ion

著者Author(s) Tanimura, Kenji / Yamada, Hideto

掲載誌・巻号・ページCitat ion Journal of Obstetrics and Gynaecology Research,45(3):514-521

刊行日Issue date 2019-03

資源タイプResource Type Journal Art icle / 学術雑誌論文

版区分Resource Version author

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© 2018 Japan Society of Obstetrics and Gynecology. This is the peerreviewed version of the following art icle: [Journal of Obstetrics andGynaecology Research, 45(3):514-521, 2019], which has beenpublished in final form at ht tps://doi.org/10.1111/jog.13889. This art iclemay be used for non-commercial purposes in accordance with WileyTerms and Condit ions for Use of Self-Archived Versions.

DOI 10.1111/jog.13889

JaLCDOI

URL http://www.lib.kobe-u.ac.jp/handle_kernel/90005799

PDF issue: 2021-07-01

1

Maternal and Neonatal Screening Methods for

Congenital Cytomegalovirus Infection

Kenji Tanimura, and Hideto Yamada

Department of Obstetrics and Gynecology, Kobe University Graduate School of

Medicine, Kobe, Japan

Corresponding author: Hideto Yamada, Professor & Chairman

Department of Obstetrics and Gynecology, Kobe University Graduate School of

Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan

Phone: +81-78-382-6000; fax: +81-78-382-6019

E-mail: yhideto@med.kobe-u.ac.jp

Running title: Screening for congenital CMV infection

2

Abstract

Human cytomegalovirus is a common cause of congenital infection that may lead to

severe long-term sequelae. Because there are no established vaccines, fetal interventions,

or neonatal treatments, neither maternal nor neonatal screening is recommended.

However, recent studies have indicated that early antiviral treatment may improve

neurological outcomes in symptomatic infants with congenital infection. Therefore,

prenatal detection may be important in newborns at high risk of such infection.

Polymerase chain reaction for cytomegalovirus DNA in the amniotic fluid is considered

the gold standard for diagnosis of intrauterine infection, but its use is limited because

amniocentesis is an invasive procedure. In a prospective cohort study, we have reported

that the presence of cytomegalovirus DNA in secretions of the maternal uterine cervix

were predictive of congenital infection in groups at high risk. However, we also recently

demonstrated that maternal serological screening for primary cytomegalovirus infection

using specific immunoglobulin G, the immunoglobulin G avidity index, or specific

immunoglobulin M can overlook many cases. Previous research has indicated that the

combination of early detection by universal neonatal screening of urinary

cytomegalovirus DNA combined with early antiviral therapy can improve outcomes in

infants with symptomatic congenital infection. In this article, we review the current state

of maternal and neonatal screening for congenital cytomegalovirus infection.

Keywords: Congenital infection, Cytomegalovirus, Polymerase chain reaction,

Screening, Serological tests

3

Introduction

Human cytomegalovirus (CMV) is a common cause of mother-to-child infection

that may lead to severe long-term sequelae in affected infants. The prevalence of

congenital CMV infection is 0.2%–2.4% in newborns in developed countries,1-3 and

10%–15% of infected fetuses have symptomatic infection at birth. The clinical

manifestations include fetal growth restriction, low birth weight, and central nervous

system and multiple organ involvement; they can be so severe that they cause major

neurological sequelae in approximately 90% of surviving infants. In addition, 10%–15%

of infants with asymptomatic congenital CMV infection develop long-term sequelae,

including progressive sensorineural hearing difficulty and mental retardation.4

In the United States, an estimated 40,000 children are born annually with

congenital CMV infection, and an estimated 8000 children develop long-term sequelae.5

The annual economic costs of caring for these affected children was estimated at $1–2

billion in the 1990s, but in recent years, those costs are estimated to exceed $3 billion.5-7

Therefore, we must develop effective strategies to reduce or prevent adverse sequelae

associated with congenital CMV infection. At present, universal screening for

congenital CMV infection is not recommended for either mothers or neonates because

of a lack of suitable vaccines or treatments. Recently, however, it was demonstrated that

early diagnosis and intervention with antiviral drugs can improve neurological outcomes

in children with symptomatic infection.8-10 Thus, prenatal detection in newborns at high

risk of congenital infection could ensure accurate diagnosis, early treatment, and

prevent the personal and economic costs of the complications of infection.

This review focuses on our current knowledge of maternal and neonatal screening

methods for congenital CMV infection.

4

1. Maternal screening for predicting congenital CMV infection

Serological tests and imaging examinations are commonly used as screening

methods to help predict congenital CMV infection during pregnancy. A summary of the

available screening modalities is outlined in Table 1.

1-1. CMV-specific antibody tests

Approximately 40% of fetuses whose mothers have primary CMV infection

during pregnancy will become infected. In addition, it is conventionally thought that

nearly all symptomatic congenital CMV infections are caused by primary infection

either during or just before pregnancy.11 Therefore, serological tests are widely used to

detect primary CMV infection in pregnant women, including maternal blood tests of

CMV-specific immunoglobulin G (CMV IgG) and CMV-specific immunoglobulin M

(CMV IgM). The gold standard for diagnosing primary infection by this method is the

detection of CMV IgG seroconversion. However, in many pregnant women found to be

positive for CMV IgG during pregnancy, it was unknown whether they were negative

for CMV IgG before or after pregnancy. Therefore, tests for maternal serum CMV IgM

are commonly used to identify primary infection, despite having only a 20%–25%

sensitivity12 and a 15%–20% false-positive rate for detecting primary CMV infection.13

This is because CMV IgM may persist for 6–9 months after primary infection14 and may

be detected during viral reactivation.12

1-2. CMV IgG avidity measurements

The serum CMV IgG avidity index (AI) is used as a confirmatory test to identify

primary CMV infection.15 The AI is measured by coincubating serum with and without

urea (6 M) as a dissociating agent in an immunoenzymatic assay. Because the AI

5

increases over time, a low AI indicates recent infection and a high AI indicates distant

infection. Previous studies have demonstrated that a low CMV IgG AI was a significant

predictor of congenital CMV infection.16, 17 We have also reported that the rate of

change in the CMV IgG AI per 4 weeks (defined as the AI) of >10% yielded a 100%

positive predictive value for congenital CMV infection among pregnant women with

positive or equivocal CMV IgM tests and an initial CMV IgG AI of 45% and a CMV IgM index of

6

CMV DNA in the amniotic fluid, including nested, single-round, or real-time PCR, are

sensitive (75%–100%) and specific (67%–100%) for the prenatal diagnosis of fetal

CMV infection.20-22 Because of this, CMV PCR assays are considered the gold standard

for prenatal diagnosis of congenital CMV infection. Given that CMV is excreted into

the amniotic fluid through fetal urine, amniocentesis should only be performed when

fetal urination is established after 20–21 weeks of gestation. In addition, the CMV viral

load in the amniotic fluid does not achieve detectable levels until 6–9 weeks after

maternal CMV infection. To reduce false-negative results, amniocentesis and PCR

analysis should not be performed until at least 6 weeks after the primary maternal

infection and before 21 weeks of gestation.23

Despite its clear strengths, amniocentesis is essentially an invasive procedure that

risks membrane rupture. Consequently, it is not realistic for all pregnant women

suspected of having primary CMV infection to undergo this test. Recently, we

conducted a prospective cohort study to determine factors that could effectively and

noninvasively predict congenital CMV infection. Twenty-two women delivered

newborns with congenital CMV infection among 300 pregnant women with positive

CMV IgM tests.24 We evaluated maternal serum CMV IgG AI, the antigenemia assay

(C7-HRP), prenatal ultrasound findings, and PCR assay for CMV in maternal serum,

urine, and uterine cervical secretions. A stepwise approach, using univariate and

multivariable logistic regression analyses, revealed that the presence of ultrasonic fetal

abnormalities (odds ratio [OR] 31.9, 95% confidence interval [CI] 8.5–120.3; p < 0.001)

and positive PCR results in uterine cervical secretions (OR 16.4, 95% CI 5.0–54.1; p <

0.001) were independent predictors of congenital CMV infection in high risk pregnant

women. The positive CMV PCR results in cervical secretions yielded a 50.0%

7

sensitivity, 94.2% specificity, 40.7% positive predictive value, and a 96.0% negative

predictive value for predicting congenital CMV infection.24 We proposed three

hypotheses to explain why the detection of CMV DNA in uterine cervical secretions

was associated with the occurrence of congenital CMV infection. First, we hypothesized

that CMV was transmitted to the amniotic fluid and the fetus from acute ascending

CMV infection through the genital tract. Second, we proposed that CMV shedding in

uterine cervical secretions persists after primary maternal infection or after reinfection

with a different strain, and that both cause fetal CMV infection. Third, it was considered

plausible that CMV DNA in the amniotic fluid could leak into the genital tract. In

contrast to these findings, other research by our group has indicated that the prediction

of congenital CMV infection by PCR assays of uterine cervical secretions may be

inefficient in pregnant women at low risk.19 Further research in this area is clearly

warranted.

1-4. Imaging examinations

When maternal serological CMV screening is not performed, the presence of

typical fetal abnormalities on ultrasound during the second or third trimester can

indicate congenital CMV infection. Fetal ultrasound abnormalities known to be

predictive of symptomatic congenital CMV infection include ventriculomegaly (Fig.2A),

microcephaly, intracranial calcification (Fig.2B), fetal growth restriction, pleural

effusion, ascites (Fig.2C), hepatosplenomegaly (Fig.2C), and high periventricular or

intestinal echodensity (Fig.2D).16, 25

As stated, we have previously demonstrated that the presence of fetal ultrasound

abnormalities was a significant predictive factor for congenital CMV infection in

pregnant women with positive CMV IgM tests.24 We prospectively showed that the

8

presence of ultrasound fetal abnormalities yielded a 50.0% sensitivity, a 97.5%

specificity, a 61.1% positive predictive value, and a 96.1% negative predictive value for

when predicting congenital CMV infection. Of the 300 CMV IgM-positive pregnant

women, 18 (6%) had at least one ultrasound finding suggestive of congenital CMV

infection, and 11 of these were confirmed to be infected. Moreover, ultrasound findings

of ventriculomegaly, microcephaly, intracranial calcification, and hepatosplenomegaly

were shown to be specific to congenital CMV infection, whereas fetal growth restriction,

pleural effusion or ascites, and hyperechoic bowel findings were shown to be

nonspecific.24 Other investigators have suggested that only severe cranial abnormalities,

such as ventriculomegaly and microcephaly, are associated with a poor prognosis in

infants surviving symptomatic infection.25

Despite these findings, it is still thought that magnetic resonance imaging

examinations are more sensitive for detecting fetal intracranial abnormalities associated

with congenital CMV infection compared with ultrasound examinations.26 However,

because magnetic resonance images are often difficult to interpret, neuroradiologists

should evaluate the images.

1-5. Clinical factors associated with congenital CMV infection from mothers with

non-primary infection

Our prospective cohort study indicated that universal maternal screening based on

serological tests, including CMV IgG, IgG AI, and CMV IgM, in low risk pregnant

women overlooked a number of newborns with congenital infection. This was because a

larger number of congenital CMV infections were caused by maternal non-primary

infection than by primary infection.19 In addition, recent studies have demonstrated that

the number and severity of symptoms in infants with congenital CMV infection from

9

mothers with non-primary infection were not inferior to those from mothers with

primary infection.27, 28

At present, the prediction of congenital CMV infection by laboratory or biological

testing is not yet possible in mothers with non-primary infection.29 Therefore, we

conducted a nested case-control study of 1287 pregnant women with non-primary

infection to evaluate the clinical factors associated with congenital CMV infection.30 In

this study, non-primary infection was defined as a CMV IgM index of 45%; in total, seven newborns (0.5%) developed congenital infection.

Univariate logistic regression analyses demonstrated that threatened premature delivery

(OR 10.6, 95%CI 2.0–55.0; p < 0.01) and multiple pregnancy (OR 7.1, 95%CI 1.4–

37.4; p < 0.05) were associated with congenital infection. Univariate logistic regression

analyses also indicated that maternal fever or flu-like symptoms (OR, 3.7; 95% CI 0.8–

16.9; p = 0.09) and preterm delivery (OR, 4.0; 95% CI 0.9–18.1; p = 0.07) tended to be

associated with congenital infection. Finally, multivariable logistic regression analyses

demonstrated that threatened premature delivery (OR 8.4, 95%CI 1.5–48.1; p < 0.05)

was an independent risk factor for congenital CMV infection in pregnant women with

non-primary CMV infection.30

We proposed two hypotheses to explain why threatened premature delivery was

associated with the occurrence of congenital CMV infection in women with

non-primary CMV infection. One was that intrauterine CMV infection causes

threatened premature delivery, and the other was that the inflammatory conditions

underling threatened premature delivery reactivates latent CMV via cytokine induction,

thereby leading to maternal-to-fetal transmission.

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2. Neonatal Screening for detecting congenital CMV infection

It remains controversial whether universal or targeted neonatal screening should

be performed for congenital CMV infection. Regarding universal screening, PCR assays

for CMV DNA in the saliva or urine of newborns are widely used. Because CMV

shedding into the maternal breast milk can cause false-positive results with saliva

testing, infants with positive PCR results from the saliva should receive confirmatory

testing by PCR assay of the urine. By contrast, regarding targeted CMV screening,

infants who fail neonatal hearing screening and who are referred for audiological testing

should undergo PCR testing of the urine. A problem with the targeted approach is that it

may overlook infants with asymptomatic congenital infection, which account for most

cases, or cases with a delayed onset of hearing loss.31

In a prospective multicenter clinical trial, 6348 infants underwent universal

screening by PCR assay for CMV DNA in the urine.10 A total of 32 infants (0.5%) were

positive for urinary CMV, and 16 (50%) of these were diagnosed with symptomatic

congenital CMV infection. Oral valganciclovir (16–32 mg/kg/day) was given to 12 of

the infants for 6 weeks. Among these, 4 (33%) showed severe developmental

impairment, 3 (25%) showed mild developmental impairment, and 5 (42%) showed

normal development at a median of 37 months of age.10 Previous reports have estimated

that 70%–90% of infants with symptomatic congenital CMV infection have severe

sequelae.32 Therefore, these results indicate that outcomes in infants with symptomatic

infection may be improved by the combination of early detection by universal neonatal

screening (based on urinary PCR assays) and early antiviral treatments.10

3. Maternal and neonatal screening algorithm for congenital CMV infection

11

Figure 1 shows a proposed screening algorithm for congenital CMV infection

based on the results of our prospective cohort studies.16, 19, 24, 33

For universal maternal screening, all pregnant women should undergo serum

CMV IgG measurements in the first trimester. At this stage, CMV IgG-negative women

receive educational intervention to prevent primary infection during pregnancy, and

CMV IgG levels will be measured again routinely at 34–36 weeks of gestation or if

acute CMV infection is suspected. CMV IgG seroconversion in these women during

pregnancy indicates primary infection, and all infants born to these mothers should

undergo urinary PCR analysis for CMV DNA.

As a targeted screening approach, pregnant women at risk of congenital CMV

infection e.g., women who have fetal ultrasound abnormalities associated with

congenital CMV infection, threatened premature delivery, or flu-like symptoms, should

undergo CMV IgG and IgM measurements; if they are positive for both, primary CMV

infection can be suspected. Amniocentesis followed by CMV DNA PCR analysis of the

amniotic fluid may be performed with informed consent. Pregnant women who tested

positive for CMV IgG but negative for CMV IgM are considered to have non-primary

infection, but non-primary infection also causes congenital infection. Therefore,

newborns of mothers who are at high risk for congenital CMV infection, regardless of

primary or non-primary infection, should undergo PCR assays of the urine for CMV

DNA.

Newborns with positive urinary PCR results should receive a workup to identify

symptoms of congenital CMV infection, including ophthalmoscopy, cerebral ultrasound,

physical and neurological examinations, head computed tomography, head magnetic

resonance imaging, and auditory brainstem response testing. There is no established

12

consensus regarding the efficacy of neonatal treatments for symptomatic congenital

CMV infection. However, because recent studies have suggested that early intervention

with antiviral drugs may improve neurological outcomes in symptomatic infection,

neonatal therapy with intravenous ganciclovir8, 9 or oral valganciclovir10 can be

considered.

Conclusions

There are no available vaccines or established fetal/neonatal treatments for CMV

infection, which means that universal screening for congenital infection has not been

recommended to date. However, studies are now demonstrating that early intervention

with antiviral drugs may improve neurological outcomes in symptomatic infants with

congenital CMV infection. Both primary and non-primary CMV infection during

pregnancy can cause severe congenital infection, and detecting all newborns with

congenital infection will require universal neonatal screening by PCR assay for CMV

DNA in the newborn urine. Further studies are needed not only to establish fetal and

neonatal treatments for symptomatic congenital CMV infection but also to consider the

costs and benefits of universal neonatal screening.

13

Acknowledgments

We acknowledge and thank the following for supporting this and previous

research: Shinya Tairaku, Yasuhiko Ebina, Mayumi Morizane, and Masashi Deguchi at

the Department of Obstetrics and Gynecology, Kobe University Graduate School of

Medicine; Ichiro Morioka and Kazumichi Fujioka at the Department of Pediatrics, Kobe

University Graduate School of Medicine; and Toshio Minematsu at the Research Center

for Disease Control, Aisenkai Nichinan Hospital.

Disclosures

The authors have no conflicts of interest related to this article.

14

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Figure legends

Figure 1. A screening algorithm for congenital CMV infection

In a maternal universal screening method based on CMV IgG measurements or targeted

screening, newborns at high risk for congenital infection are selected to undergo PCR

assays of the urine for CMV DNA. Infants with symptomatic congenital CMV infection

may receive antiviral treatments.

Abbreviations: CMV, cytomegalovirus; Ig, immunoglobulin; GW, weeks of gestation;

PCR, polymerase chain reaction; ABR, auditory brainstem response; CT, computed

tomography.

Figure 2. Ultrasound fetal abnormalities associated with congenital CMV infection.

Ventriculomegaly (A), intracranial calcification (B), ascites and hepatomegaly (C), and

intestinal echodensity (D) on grayscale ultrasound.

1

Table 1. Screening methods used to predict congenital CMV infection during pregnancy

Method Advantage Disadvantage

CMV-specific IgG The detection of IgG seroconversion is the gold standard for diagnosing primary infection. Both baseline and follow-up serum are needed.

CMV-specific IgM Easy and time-saving method for diagnosing primary infection.

・Cross reacting antibody may cause false-positive results. ・IgM may persist long after infection.

CMV IgG avidity index A confirmatory test for identifing primay infection. Cutoff values vary among different assays.

CMV-DNA PCR assay of the amniotic fluid

Highly sensitive and highly specific methods for diagnosing fetal infection.

・Amniocentesis may increase the risk of menbrane rupture. ・Obtaining samples before 21 GW may cause false-negative results.

CMV-DNA PCR assay of the uterine servical secretion

Noninvasive and highly specific methods for predicting fetal infection in high-risk pregnant women.

・The sensitivity for predicting fetal infection may be at most 50%. ・This assay may be inefficient in low-risk pregnant women.

Fetal ultrasound Useful for predicting outcomes and severity of congenital infection.

Sensitivity may dependent on the observer's experience and the timing of examination.

MRI Highly sensitive for detecting intracranial abnormalities of the fetuses Experienced neuroradiologists should evaluate the images.

Abbreviations: CMV, cytomegalovirus; Ig, immunoglobulin; PCR, polymerase chain reaction; GW, weeks of gestation; MRI, magnetic

resonance imaging.

Negative

IgG seroconversion

CMV IgGin the first trimester

Primary infection

IgG positiveand

IgM negative

Non-primary infection

Educational intervention

Targeted screeningUniversal screening

CMV IgG at the timing of suspicion of acute CMV infection

or at 34–36 GW

CMV IgG and IgM

Pregnant women who have ultrasound fetal abnormalities, threatened premature delivery, fever or flu-like symptoms

CMV DNA PCR assay of the amniotic fluid

Workup of congenitally infected newborns: ABR, ophthalmoscopy, head CT etc.Positive

Neonatal treatment with antiviral drugs

Diagnosis of symptomatic infection

CMV-DNA PCR assay of the newborn urine

Figure 1

IgG positiveand

IgM positive

l II'

I I I I

II'

I

I I

'" II' , II'

I I

,

I I

A B

C D

Figure 2