Clin. Exp. Obstet. Gynecol. 2023; 50(12): 279
https://doi.org/10.31083/j.ceog5012279

Original Research

Impact of COVID-19 on Cytomegalovirus Immunoglobulin M
Antibody Index
Masatoki Kaneko1,2, *,† , Junsuke Muraoka1,† , Li Yang1 , Shuichi Tokunaga1 ,Toshio Minematsu3
1 Department of Obstetrics and Gynecology, Faculty of Medicine, University of Miyazaki, 889-1692 Miyazaki, Japan
2 Graduate School of Nursing Science, University of Miyazaki, 889-1692 Miyazaki, Japan
3 Research Institute for Disease Control, Aisenkai Nichinan Hospital, 887-0034 Nichinan, Japan*Correspondence: mkaneko@med.miyazaki-u.ac.jp (Masatoki Kaneko)† These authors contributed equally.
Academic Editor: Michael H. Dahan
Submitted: 30 June 2023 Revised: 27 August 2023 Accepted: 7 September 2023

Published: 29 December 2023

Abstract
Background: Coronavirus disease 2019 (COVID-19) influenced the prevalence of other infectious diseases, including congenital cytomegalovirus (CMV) infection. However, the effect of COVID-19 on antibody titers has not been reported. This study aimed to explore
the influence of COVID-19 on levels of CMV immunoglobulin M (IgM) in pregnant women. Methods: This cross-sectional study
included pregnant women who visited the University Hospital due to CMV IgM positivity during the 7th and 8th waves of COVID-19.
Data, including maternal characteristics, history of COVID-19, CMV immunoglobulin G (IgG) and IgM index, and IgG avidity index(AI) were collected. Chemiluminescent immunoassay was performed to measure levels of IgG and IgM. Polymerase chain reaction using
neonatal urine was performed to confirm congenital infection. Results: Of the 89 pregnant women, 36 (40%) (low IgG AI: n = 10; high
IgG AI: n = 26) contracted COVID-19. Among 21 women with low IgG AI, 9 (false IgM positive: n = 8; primary infection: n = 1)
had an IgG AI of 0. Among the eight women with false IgM positivity, six (75%) contracted COVID-19. The IgM index of pregnant
women with false IgM positivity was 12.6 ± 10.9. Meanwhile, the CMV IgM index of pregnant women with false IgM positivity in the
non-COVID-19-infected group was 1.7 ± 0.5. When the IgM indices of women who contracted (n = 36) and did not contract (n = 53)
COVID-19 were compared, the IgM index of infected women (4.4 ± 5.7) was higher than those of non-infected women (2.7 ± 3.0) (p= 0.01). Regarding IgM and IgG AI, multiple logistic regression analysis revealed that there were no significantly different variables
between the two groups. Conclusions: High prevalence of false IgM positivity was observed among women who contracted COVID-19.
The IgM index of pregnant women with false IgM positivity was high. Caution should be exercised in interpreting CMV IgM indices inpregnant women with a history of COVID-19.
Keywords: COVID-19; cytomegalovirus; chemiluminescent immunoassay; immunoglobulin M; pregnancy

1. Introduction
In 2019, a severe outbreak of coronavirus disease2019 (COVID-19) caused by the severe acute respiratory
syndrome-coronavirus 2 (SARS-CoV-2) occurred worldwide. During the outbreak, long-term quarantine and distancing were recommended to protect vulnerable individuals and prevent infection [1]. Preventive measures led tosocial isolation and impaired interpersonal communication,
thereby resulting in feelings of discomfort, anxiety, panic,
anger, resentment, and despair as well as an increase in therates of domestic violence [2]. Moreover, infection control measures impacted not only mental health but also the
spread of other infectious disease. In 2020–2022, usual outbreaks of seasonal influenza and rubella did not occur inJapan [3]. Moreover, respiratory syncytial virus infection
was not prevalent among infants in 2020 in Japan; however,it was reported in 2021 and 2022 [3].

Cytomegalovirus (CMV) is the most common virusthat causes morbidity and mortality in congenitally infectedfetuses and newborns, resulting in a broad range of disabilities (e.g., sensorineural hearing loss, visual impairment,
and motor and cognitive deficits) [4]. The prevalence rateof congenital CMV infection ranges from 0.2% to 2.0% in
newborns. However, 10%–15% of newborns with CMV infection are symptomatic [4,5]. In Japan, the prevalence ofcongenital CMV infection in newborns is 0.31% [6]. However, the prevalence of congenital CMV infection during
the COVID-19 outbreak significantly decreased in several
areas [7,8].
The number of patients who contracted COVID-19 remarkably increased during the 7th and 8th waves of the
COVID-19 pandemic (i.e., between July 6, 2022 and January 24, 2023) in Japan compared with other waves. Similarly, several pregnant women contracted COVID-19 during these periods. Along with the number of pregnant
women who contracted the disease, we experienced an in-

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crease in the number of pregnant women referred due to
CMV immunoglobulin M (IgM) positivity during the 7th
and 8th waves. Acute and chronic viral infections can induce long-term immunological effects. After recovery fromnatural acute measles infection, there is a marked reduction in humoral immunity and increased susceptibility tononmeasles infections [9]. The Bacillus Calmette–Guérin(BCG) live vaccine can reduce allcause mortality in infants
due to its pathogen nonspecific effect [10,11]. Hence, itis thought that BCG “train” innate immune cells such as
monocytes and their progenitors [10,11]. However, the effect of COVID-19 on the immune response to CMV has notbeen reported. Thus, this study aimed to clarify the influence of COVID-19 on CMV IgM levels in pregnant women.

2. Patients and Methods
Pregnant women who underwent routine maternal
serum screening at primary clinics during the first maternal health checkup were enrolled to the study. Blood samples to detect CMV IgM and immunoglobulin G (IgG) wereobtained and subjected to routine maternal serum screening. Blood samples for anti-CMV antibody screening were
centrifuged at 10,000 rpm for 15 min and analyzed bychemiluminescent immunoassay (CLIA) using Architect®
i2000SR (Abbott Diagnostics, Chicago, IL, USA) analyzer
in SRL laboratory. The Architect™ CMV IgM and IgG(Abbott Medical Japan LCC, Tokyo, Japan) were used tomeasure levels of antibodies. In CLIA, specimens are reacted with magnetic particles on which the CMV antigen
was immobilized. After washing off the unreacted material, hydrogen peroxide water and sodium hydroxide wereadded, and the chemiluminescence of acridinium was measured as emission intensity; the validity of CLIA has been
confirmed [12,13]. Cutoff values for CMV IgG and IgMlevels were 6.0 AU/mL and 1.0 (index), respectively, andwere interpreted according to the manufacturer’s instructions. The CMV IgM index was automatically calculatedby the instrument as the ratio of the luminescence intensityof the sample to the cutoff value (average luminescence intensity of calibrator × 1.00) from the measurement resultsof the sample and control. The cutoff value was stored as acalibration result for each reagent lot. Maternal serum samples were routinely stored in a refrigerator for 1 week prior
to further use.
After evaluating CMV IgM positivity, pregnant
women were referred to the University Hospital between
July 6, 2022 and January 24, 2023 for clinical consultation;
those who provided informed consent were enrolled in thisstudy. The same maternal sera used to measure CMV IgG
and IgM levels were used to measure the CMV IgG avidity index (AI) at Aisenkai Nichinan Hospital (Miyazaki,
Japan). IgG avidity assay was conducted as previously described [4], with slight modifications. The Enzygnost antiCMV enzyme-linked immunosorbent assay kit (Siemens
Healthcare Diagnosis, Tokyo, Japan) was used for the anal2

ysis. Maternal information, including age, medical complications, obstetrical history, history of COVID-19 before
routine maternal serum screening, and severity of COVID19, were obtained from medical charts. COVID-19 was diagnosed by SARS-CoV-2 polymerase chain reaction (PCR)
on nasopharyngeal swabs performed at the health center.
Patients were judged to be severely ill when they received
respiratory management.
Amniocentesis at approximately 20 weeks of gestation was offered to pregnant women to confirm fetal infection using PCR, which was performed within 2 weeks for
all neonates born to pregnant women who were CMV IgM
positive.
Negativity for IgG, positivity for IgM, and an IgG AI
of 0 after repeated serological tests at appropriate intervals
represented nonspecific immunoreactions to CMV IgM.
Statistical Analysis
Between-group differences were assessed using theMann–Whitney U-test, χ2 analysis, or Fisher’s exact test.
Differences among four groups were assessed using the
Kruskal–Wallis test. A p < 0.05 indicated statistical significance.
Multivariable logistic regression analysis was performed to identify independent predictive factors. Only
predictive variables with a p < 0.2 in the univariate analysis
were entered into a logistic regression model. A stepwise
forward procedure using the likelihood ratio test was usedin the multivariable logistic regression analysis. Variables
with p < 0.05 in multivariable logistic regression were determined as independent predicative factors.
Statistical analysis was performed using SPSS software program for Windows, version 22 (IBM SPSS Statistics, Tokyo, Japan). Data are presented as the mean ± standard deviation.

3. Results
Overall, 89 pregnant women who were referred to
the University Hospital during the study period were included in this study; among them, 36 contracted COVID19. The characteristics of the women according to a historyof COVID-19 infection are shown in Table 1. CMV IgMlevels were significantly higher in the COVID-19-infectedgroup versus the noninfected group (p = 0.01). Two independent factors, namely the IgM index and IgG AI, wereentered into the multivariate model; there were no significantly different variables (IgM; p = 0.18, odds ratio: 1.095,
95% confidence interval: 0.959–1.25, IgG AI; p = 0.45,
odds ratio: 0.993, 95% confidence interval: 0.974–1.012).
The number of pregnant women with a low IgG AI was
similar in both groups. One case of congenital CMV infection was observed in the noninfected group. The characteristics of pregnant women with a low IgG AI according
to a history of COVID-19 infection are shown in Table 2.
There were no significant differences in CMV IgG levels,

Table 1. Characteristics of pregnant women according to COVID-19 history.
Age (years)
Primipara (n)Timing of serological test (weeks)
CMV IgG (AU/mL)
CMV IgM (index)
IgG avidity index
Low IgG avidity index (n)High IgG avidity index (n)Congenital CMV infection (n)COVID-19-infected group (n = 36)

non-COVID-19-infected group (n = 53)

p value31.5 ± 4.5
1212.5 ± 4.2
145.0 ± 86.6
4.4 ± 5.7
42.4 ± 24.5
10
27
0

30.4 ± 5.7
2012.7 ± 4.6
143.1 ± 74.5
2.7 ± 3.0
49.2 ± 24.2
11
42
1

0.37
0.67
0.71
0.66
0.01
0.10
n.s.
n.s.
n.s.

COVID-19, coronavirus disease 2019; n.s., not significant; CMV, cytomegalovirus; IgG, immunoglobulin G; IgM, immunoglobulin M.

Table 2. Characteristics of pregnant women with low avidity index according to COVID-19 history.
Age (years)
Primipara (n)Timing of serological test (weeks)
CMV IgG (AU/mL)
CMV IgM (index)
IgG avidity index
CMV IgM false positivity (n)COVID-19-infected group (n = 10)

non-COVID-19-infected group (n = 11)

p value

29.8 ± 3.5
414.1 ± 7.4
32.9 ± 44.7
8.4 ± 9.8
10.3 ± 14.1
6

29.5 ± 5.5
418.0 ± 7.5
52.7 ± 54.7
3.2 ± 4.1
11.0 ± 14.6
2

0.65
1
0.06
0.31
0.09
0.76

IgM indices, and IgG AI between the groups. Nine pregnant women had an IgG AI of 0. Among them, eight had
false-positive CMV IgM results; six (75%) and two (25%)
in the COVID-19-infected and noninfected groups, respectively. The remaining case in the noninfected group wasconsidered as primary maternal infection (CMV IgG, 37.1
AU/mL; IgM, 2.58). Overall, there was no significant difference in the frequency of false IgM positivity between the
COVID-19-infected (6/36) and noninfected (2/53) groups(p = 0.06). In pregnant women with low IgG AI, there wasno significant difference in the frequency of false IgM positivity between the COVID-19-infected (6/10) and noninfected (2/11) groups (p = 0.08). The CMV IgM index inpregnant women with false IgM positivity in the COVID19 infected group was 12.6 ± 10.9, whereas that in the noninfected group was 1.7 ± 0.5.
The characteristics of pregnant women with a high
IgG AI according to a history of COVID-19 infection are
shown in Table 3. There were no significant differencesin CMV IgG levels, IgM levels, and IgG AI between thegroups.
Among the four groups (i.e., COVID-19-infected withlow IgG AI, noninfected with low IgG AI, COVID-19infected with high IgG AI, and noninfected with high IgGAI), the IgM index was not significantly different (p = 0.06).
There was a case of an infant with a congenital CMV
infection in the noninfection group. In this case, primarymaternal CMV infection was suspected due to CMV IgM
positivity (12.4) and low IgG AI (18%) at 12 weeks of gestation. Notably, the patient did not contract COVID-19. At

38 weeks of gestation, the patient delivered a male newbornthat weighed 2770 g. The neonate had signs of CMV infection (liver dysfunction and thrombocytopenia) at birth anddeveloped mild hearing impairment in the left ear.

4. Discussion
In this study, we showed that the prevalence of false
positivity for CMV IgM in pregnant women with history of
COVID-19 was high. Moreover, the CMV IgM index inpregnant women with false IgM positivity was high.
The presence of CMV-specific IgM is useful in detecting pregnancies at high-risk for vertical CMV transmission.
However, there is no global consensus regarding maternal
serum screening for CMV infection due to the lack of established screening protocols for detecting congenital infection, effective measures for intrauterine treatment, and vaccine [4]. Additionally, immunoassay may potentially cause
false-positive or false-negative results, which may causeclinical problems. In CMV maternal serological screening,
pregnant women with CMV IgM positivity and low IgG AI
could be considered as being high-risk for vertical transmission. Misinterpretations can cause unnecessary anxiety topregnant women, which may potentially influence their decision to abort the fetus [14]. In this study, false CMV IgM
positivity was confirmed by IgG negativity, IgM positivity,
and an IgG AI of 0 after repeated serological tests at appropriate intervals. As a result, false CMV IgM positivity did
not cause clinical problems.

3

Table 3. Characteristics of pregnant women with high avidity index according to COVID-19 history.
Age (years)
Primipara (n)Timing of serological test (weeks)
CMV IgG (AU/mL)
CMV IgM (index)
IgG avidity index

COVID-19-infected group (n = 26)

non-COVID-19-infected group (n = 42)p value

32.1 ± 4.8
8
11.9 ± 1.9
188.1 ± 53.2
2.9 ± 1.5
54.8 ± 14.2

30.6 ± 5.9
1611.3 ± 1.7
166.8 ± 59.5
2.6 ± 2.6
59.3 ± 14.0

0.33
0.54
0.10
0.09
0.08
0.11

In this study, 60% of pregnant women with low
IgG avidity in the COVID-19-infected group showed false
CMV IgM positivity, although there was no statisticallysignificant difference in the frequency of pregnant womenwith false positivity between the infected and noninfectedgroups. Moreover, the IgM index in these pregnant womenwas extremely high. COVID-19 may activate the immune
system to produce a variety of antibodies, which may include crossreactive antibodies against CMV. Vandervore etal. [15] revealed a high prevalence of false-positive herpes simplex (HSV) IgM serology and significant elevationof HSV IgM indices as measured by a CLIA-based serology assay (Liaison® XL diagnostics platform, DiaSorin,
Salugia, Vercelli, Italy) for herpes simplex in patients with
COVID-19. Additionally, they found the presence of an interfering factor in these patients through interference elimination tests [15]. Hence, they concluded that the falsepositive results for HSV was caused by the direct binding of SARS-CoV-2 IgM antibodies to surface-modified
polystyrene microparticles [15]. COVID-19 infection reportedly produces false-positive reactions in dengue serologic immunoassays [16]. Although CLIA reported falsepositive results, the validity of this assay has been provenin a previous Japanese report. Kumada et al. [12] reported that repeatability studies using three different control and serum samples showed that simultaneous repeatability ranged from coefficient of variation (CV) 0% to 3.6%
for Architect™ CMV IgG and from 0% to 6.3% for Architect™ CMV IgM. Meanwhile, the daily difference repeatability ranged from 0% to 7.6% for Architect™ CMV IgG
and from 0% to 5.9% for Architect™ CMV IgM [12]. Ina sensitivity test for Architect™ CMV IgG or IgM using
a seroconversion panel, CMV IgG and IgM were positiveon days 33 and 29, respectively. Meanwhile, in a sensitivity test for a commercial enzyme immunoassay kit (Denka
Seiken, Tokyo, Japan), CMV IgG and IgM were positiveon days 43 and 29, respectively [12]. In a correlation test
between Architect™ CMV IgG and a commercial enzyme
immunoassay kit, the overall agreement rate was 99%, thepositive agreement rate was 100%, and the negative agreement rate was 96.7% [12].
Acute Parvovirus B19 infection may also cause antibody crossreactivity with the Epstein–Barr virus IgM or
HSV IgM in assays performed based on the Liaison platform (DiaSorin, Salugia, Vercelli, Italy) [17]. Crossreac4

tion have also been observed in other immunoassays. Gong
et al. [18] reported that Architect rubella IgM, CMV IgM,
and antihepatitis C virus (HCV) showed cross-reactivity
with other disease-specific antibodies. Thus, antibodies
from other infections may serve as interfering substances.
However, no false positives of the listed antigens were
found in this study.
Interferences in the immunoassay include rheumatoid factor or other autoantibodies, heterophilic antibodies, human antianimal antibodies, albumin, complement,
lysozyme, fibrinogen, and paraproteins [19]. As these interferences can cause nonspecific reactions, the presence orabsence of these factors should be recognized in interpreting the results. In this study, no participant had concomitantautoimmune diseases. According to the instructions of the
manufacturer, when negative and positive samples containing endogenous interfering substances were measured andcompared to each control sample, no effect was found on
the measurement results.
The limitation of this study was that we did not measure SARS-CoV-2 IgM and IgG levels due to its retrospective design. Pregnant women were diagnosed with COVID19 by SARS-CoV-2 PCR on nasopharyngeal swabs performed at the health center before maternal serological testing. Accordingly, we could not investigate which antibody
caused interference that resulted in false CMV IgM positivity and the correlation between CMV IgM index and SARSCoV-2 IgM and IgG titers. As Japanese law required a 2week quarantine period during the COVID-19 pandemic,
all pregnant women underwent serological testing at least
2 weeks after contract COVID-19. Thus, as all pregnant
women already likely experienced seroconversion at thetime of the first visit at obstetric facilities, the SARS-CoV-2
IgG was presumed to be an interfering substance.
In this study, we did not include the case of verticaltransmission among the COVID-19-infected group. Thus,
it remains unknown whether COVID-19 contributes to vertical transmission of CMV. Yamada et al. [20] showed thata threatened premature delivery was a risk factor for congenital CMV infection in pregnant women with nonprimary
CMV infection. Although there are several factors that contribute to premature delivery, the inflammatory response
can also cause premature delivery. They speculate that bacterial infection at the fetomaternal interface, such as at thedecidua and villi, activated the latent virus in the uterus

[20]. It may be possible that inflammation of the decidua
and villi due to SARS-CoV-2 could trigger vertical transmission of CMV. In such cases, CMV IgM may be positive with SARS-CoV-2 infection. However, it remains unknown whether severely affected individuals with COVID19 who develop cytokine storm are also infected with CMVor have CMV reactivation. A major primary defense mechanism of the innate immune response against viruses is thecomplement system [21,22]. Although the main functionof the complement system is to protect the host from invading viruses, its overactivation plays a role in COVID19 pathogenesis. The complement system can be activated
via three different pathways (i.e., classical, lectin, and alternative). Overactivation of the complement system via thelectin pathway caused a cytokine storm and vasculitis in patients with severe COVID-19 [23,24]. Thus, CMV, which
latently infects vascular endothelial and macrophage-based
cells, can be reactivated by COVID-19. Further investigations are warranted to elucidate this process.
The CMV IgM index was significantly higher in pregnant women with a history of COVID-19 compared withthose without a history of COVID-19. However, there
were no significantly different variables between the groups
when CMV IgM and IgG AI were included into the multivariate model. The results indicate that the IgG AI was aconfounding factor for the CMV IgM index. Moreover, thereason that the standard deviation of the CMV IgM index
was higher than the point estimate (mean) for all subgroups
was also due to a confounding factor.

nal manuscript. All authors have participated sufficiently
in the work and agreed to be accountable for all aspects of
the work.

Ethics Approval and Consent to Participate
This study was conducted in accordance with theguidelines of the Declaration of Helsinki and was approvedby the Ethics Committee of the Faculty of Medicine, University of Miyazaki, Miyazaki, Japan (approval number: 00829). Informed consent was obtained from all participants
involved in the study.

Acknowledgment
We thank Drs. Shunichi Noda, Ikuo Nakayama and
Hiroyuki Watanabe for their cooperation in collecting thedata.

Funding
This work was supported by JSPS KAKENHI, grant
number JP21K09452.

Conflict of Interest
The authors declare no conflict of interest. Masatoki
Kaneko is serving as one of the Guest editors of this journal.
Masatoki Kaneko had no involvement in the peer review ofthis article and has no access to information regarding its
peer review. Full responsibility for the editorial process forthis article was delegated to Michael H. Dahan.

5. Conclusions

References

High prevalence of false IgM positivity was observed
among women who contracted COVID-19. The IgM index of pregnant women with IgM false positivity was high.
Caution should be exercised in interpreting CMV IgM indices in pregnant women with a history of COVID-19.

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Abbreviations
AI, avidity index; COVID-19, coronavirus disease2019; CMV, cytomegalovirus; IgG, immunoglobulin G;
IgM, immunoglobulin M; SARS-CoV-2, severe acute respiratory syndrome-coronavirus 2.

Availability of Data and Materials
The datasets used and/or analyzed during the current
study are available from the corresponding author on reasonable request.

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