International Journal of Infectious Diseases 76 (2018) 14–22

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International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Rubella virus infections and immune status among pregnant

women before the introduction of rubella vaccine in Amhara
Regional State, Ethiopia
Yitayih Wondimeneha,* , Moges Tiruneha , Getachew Feredea , Birhanu Aberab ,
Meseret Workinehc , Meseret Birhanied , Belay Tessemaa
a
Department of Medical Microbiology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, P.O.
Box 196, Gondar, Ethiopia
b
Department of Gynecology and Obstetrics, School of Medicine, College of Medicine and Health Sciences, University of Gondar, P.O. Box 196, Gondar, Ethiopia
c
Department of Immunology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, P.O. Box 196,
Gondar, Ethiopia
d
Department of Medical Parasitology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, P.O.
Box 196, Gondar, Ethiopia

A R T I C L E I N F O A B S T R A C T

Article history: Background: Rubella and its associated congenital anomalies have been greatly reduced in most
Received 9 June 2018 developed countries through use of the rubella vaccine. However, the magnitude of the problem is
Received in revised form 24 July 2018 underestimated and there are no well-established rubella/congenital rubella syndrome prevention and
Accepted 27 July 2018
control strategies in many developing countries, including Ethiopia. The aim of this study was to
Corresponding Editor: Eskild Petersen,
Aarhus, Denmark
determine the prevalence of rubella virus infections among pregnant women and their immune status
before the introduction of rubella vaccine in Amhara Regional State, Ethiopia.
Methods: A prospective cross-sectional study was conducted among pregnant women in Dessie, Felege-
Keywords:
Rubella virus
Hiwot, and University of Gondar referral hospitals, from December 2015 to February 2017. After obtaining
Pregnant women written informed consent, socio-demographic data, reproductive history, clinical manifestations, and the
Immune status possible risk factors for rubella virus infections were collected using a structured questionnaire. The
laboratory analysis of rubella-specific antibodies was done using an enzyme-linked immunoassay
method on venous blood samples. Data were entered and analyzed using IBM SPSS Statistics version 20.
Binary logistic regression was used to determine the strength of association between the dependent
variables and covariates.
Results: A total of 600 pregnant women were included in the study. Their mean age was 26.4  5 years
(range 16–40 years). The overall seroprevalence of rubella infection was 89%. Of the total study
participants, 9.5% were positive for rubella-specific IgM antibody, which indicates acute/recent rubella
virus infection. In contrast, 79.5% of them had protective levels of rubella-specific IgG antibody and were
immune as a result of previous wild-type rubella infection. However, 11% of the pregnant women were
negative for both rubella-specific antibodies; these women represent the susceptible group.
Conclusions: A large number of pregnant women had acute/recent rubella virus infections at the time of
data collection, indicating that the virus is endemic in the study area. More than a tenth of pregnant
women were found to be susceptible to acquiring the infection in future pregnancies, with the possible
risk of rubella-associated congenital anomalies. Hence screening of all women of child-bearing age
before conception and during pregnancy might reduce the devastating effects of the virus on the
developing fetus.
© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

* Corresponding author.
E-mail addresses: yitayihlab@gmail.com (Y. Wondimeneh), mogest4@gmail.com (M. Tiruneh), get29f@gmail.com (G. Ferede), birahanua31@gmail.com (B. Abera),
mwesi@gmail.com (M. Workineh), meseretbirhanie@yahoo.com (M. Birhanie), bt1488@yahoo.com (B. Tessema).

https://doi.org/10.1016/j.ijid.2018.07.024
1201-9712/© 2018 The Author(s). Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 Y. Wondimeneh et al. / International Journal of Infectious Diseases 76 (2018) 14–22
Introduction
Rubella virus is an important human pathogen that causes an
acute and contagious disease known as rubella, little red, 3-day
measles, or German measles (Fokunang et al., 2010). Humans are
the only reservoir for this virus (Mounerou et al., 2015). The virus
has an incubation period of 2–3 weeks. The route of transmission is
air-borne in postnatal cases and transplacental during pregnancy
(Kolawole et al., 2014). The disease caused by this virus commonly
occurs in childhood and is characterized by a maculopapular rash
associated with a low-grade fever, lymphadenopathy, and malaise
(Al-Rubai et al., 2010). It can also cause joint pains, headache, and
conjunctivitis in adults (Lezan, 2015). Transient arthralgia or
arthritis may also occur (Heggie and Robbins, 1969). It is also a rare
cause of thrombocytopenic purpura and encephalitis (Sherman
et al., 1965). However, up to 50% of rubella cases are subclinical
(Horstmann et al., 1965).
Rubella infection is considered relatively benign, and in the
absence of pregnancy, the infection is usually mild and self-limiting
(CDC, 2001). However, during pregnancy, it has a devastating effect
on the developing fetus (Adam et al., 2013; Cradock-Watson et al.,
1981) and this represents a major health concern worldwide
(Mirambo et al., 2015). Currently, there is no specific treatment
for the virus (Olajide et al., 2015). However, its burden can be
minimized through use of the live attenuated rubella vaccine
(Alleman et al., 2016; Demicheli et al., 2012; WHO, 2014). The control
of rubella and congenital rubella syndrome (CRS) relies on a high
population level of immunity (Gilbert et al., 2017).
The World Health Organization (WHO) proposed the introduc-
tion of rubella vaccine in each country in the year 2000 (Robertson
et al., 2003) and different efforts are undergoing in different WHO
regions (Martínez-Quintana et al., 2015; CDC, 2010; WHO, 2008).
As a result, the burden has declined, although mostly in
industrialized countries (Adewumi et al., 2014). However, rubella
vaccine is still not available in many developing countries (Njeru
et al., 2015) and it is not included in their immunization programs
(WHO, 2012). Rubella is an under-recognized public health
problem (Cutts and Vynnycky, 1999; Mamvura et al., 2015). In
Africa, few countries have included rubella vaccine in their national
immunization programs and data on the seroprevalence of the
virus are very limited (Martínez-Quintana et al., 2015).
Although Ethiopia has planned to introduce the rubella vaccine
(WHO, 2015), it is currently not included in the national
immunization program (Getahun et al., 2016). There are only a
few reports on rubella in the country (Cutts et al., 2000a;
Gebreselassie and Almaz, 1985), with most containing very old
information (Gebreselassie and Almaz, 1985; Sandow et al., 1982)
or reporting on suspected cases of measles among children (Mitiku
et al., 2011; Getahun et al., 2016; Shiferaw et al., 2016). There is only
one recently published report on rubella among pregnant women
(Tamirat et al., 2017) and one case report on CRS (Mekonnen, 2017)
in the country. All of these indicate that there is scarcity of data and
that the magnitude of rubella and its consequences is largely
unknown. Hence, the aim of this study was to determine rubella
virus infections and immune status among pregnant women
before the introduction of rubella vaccine in Amhara Regional
State, Ethiopia.
Materials and methods
Study design, area, and period
A prospective cross-sectional study was conducted in three
referral hospitals in Amhara Regional State, namely Dessie, Felege-
Hiwot, and University of Gondar referral hospitals, from December
2015 to February 2017.
15
Study participants
The study participants were pregnant women who visited the
respective antenatal care clinics of the referral hospitals during the
study period and gave informed consent and the required amount
of blood sample for laboratory analysis.
Sample size and sampling technique
The study participants were selected using a simple random
sampling technique and the sample size was calculated using a
single population proportion formula by considering a 95%
confidence interval, 4% margin of error, and 50% proportion.
The sample size was proportionally allocated to the selected
referral hospitals based on the previous flow of pregnant women
visiting the antenatal care clinics of the respective referral
hospitals. Pregnant women who gave informed consent and the
required amount of blood sample were included in the study.
Pregnant women who were seriously sick at the time of data
collection and those who visited the respective referral hospitals
for the second time during the study period were excluded from
the study.
Data collection
After obtaining written informed consent from each study
participant, socio-demographic data, clinical information, and
information on reproductive history and possible risk factors of the
pregnant women were collected using a structured and pre-tested
questionnaire.
Blood collection and handling
Using a plain tube, 5 ml of venous blood was collected
aseptically from each pregnant woman for the determination of
rubella antibodies. Blood was allowed to clot for an hour at room
temperature, centrifuged at 3500 rpm for 5 min, and then serum
was separated and collected in sterile storage vials to be stored at
70  C until laboratory analysis.
Laboratory analysis and interpretation of results
Rubella IgM and IgG antibodies were determined using an
enzyme-linked immunoassay (ELIA) method as per the manufac-
turer’s instructions (Linear Chemicals SL, Spain). The results were
read in a micro-well reader at 450 nm and compared in a parallel
manner with calibrators and controls. For rubella-specific IgM, the
qualitative result was interpreted as positive if the rubella IgM
index was >1.1, negative when the index was <0.9, and equivocal
when the index was 0.9 and 1.1. The quantitative rubella IgG
result was expressed in international units per milliliter (IU/ml). In
accordance with the manufacturer’s instructions, the IgG result
was interpreted as positive when the IgG index value was >10 IU/
ml, as equivocal at 5–10 IU/ml, and as negative at <5 IU/ml.
Quality assurance mechanisms
The rubella test kits (IgM and IgG EIA kits) have their own
quality control materials that can be run in parallel with patient
samples, and all test procedures were done strictly following the
manufacturer’s instructions. In addition, standard operational
procedures were strictly followed and the questionnaire was pre-
tested in non-selected health institutions. Training was given for
data collectors and they were also regularly supervised by the
research team. In addition, the inclusion and exclusion criteria
were given to the data collectors.
16 Y. Wondimeneh et al. / International Journal of Infectious Diseases 76 (2018) 14–22

Data analysis procedure
Data were checked for completeness, cleaned manually, and
entered into and analyzed using IBM SPSS Statistics version 20.0
(IBM Corp., Armonk, NY, USA). Data were summarized using
frequency tables and graphs. For continuous variables, the range
and mean  standard deviation (SD) were used. In the case of two
categorical variables, univariate and multivariate analysis with a
95% confidence interval (CI) was performed to measure the
association, and p-value of less than 0.05 was considered
statistically significant.
Results
Socio-demographic characteristics of the pregnant women
A total of 600 pregnant women were included in the study. The
mean age of the participants was 26.4  5 years (range 16–40
years). Approximately a third of the study participants were in the
age group of 25–29 years (n = 224, 37.3%), the majority were
married (n = 587, 97.8%), and approximately two-thirds lived in an
urban area (n = 386, 64.3%). One hundred and seventy (28.3%) of
the study participants had a certificate and above level of
education and 317 (53.0%) had an occupation of housewife
(Table 1).
Overall prevalence of rubella IgM and IgG antibodies
(79.5%, 95% CI 76.3–82.5%) were positive only for rubella IgG
antibodies. This indicates that the overall number of rubella-
specific IgM-positive pregnant women at the time of data
collection was 57 (9.5%, 95% CI 7.3–11.7%). According to the
present study, 66 (11.0%, 95% CI 8.7–13.7%) of the pregnant women
were negative for both rubella IgM and IgG antibodies; these
women represent the susceptible group (Figure 1).
Rubella IgM and IgG antibodies in relation to socio-demographic
characteristics
In the present study, eight (12.9%) of the IgM-positive study
participants were in the age group of 35 years (p = 0.688), one
(20.0%) was divorced (p = 0.433), 18 (10.8%) had a high school level
of educational attainment (p = 0.417), and 34 (10.7%) had an
occupation of housewife (p = 0.591). Similarly, 51 (82.3%) of the
IgG-positive pregnant women were in the age group of 35 years
(p = 0.100), 468 (79.7%) were married (p = 0.294), 313 (81.1%) lived
in an urban area (p = 0.196), 17 (89.5%) had an occupation of student
(p = 0.209), and 120 (82.2%) had no formal education (p = 0.922).
There was no significant association for any of these socio-
demographic factors. However, the pregnant women living in
urban settings had IgM positivity two times (95% CI 1.05–3.78) that
of the women living in rural settings (p = 0.036) (Table 1).
Rubella IgM and IgG antibodies in relation to reproductive
characteristics

The overall seroprevalence of rubella was 89.0% (n = 534) (95%
CI 86.3–91.3%). Of the total study participants, 49 (8.2%, 95% CI 6.2–
10.2%) were positive for both IgM and IgG antibodies at the same
time. However, eight (1.3%, 95% CI 0.5–2.2%) of the pregnant
women were positive only for rubella IgM antibodies and 477
At the time of data collection, 211 (35.2%) of the women were in
the first trimester of pregnancy, 191 (31.8%) in the second trimester,
and 198 (33.0%) in the third trimester. With regard to the
relationship of rubella antibodies with the study participants’
reproductive characteristics, 26 (13.1%) of the IgM-positive

Table 1
Rubella-specific IgM and IgG antibodies in relation to socio-demographic characteristics and trimesters of pregnancy of women in Amhara Regional State referral hospitals,
Ethiopia, December 2015 to February 2017.

Socio-demographic characteristics Number tested IgM-positive Only IgG-positive

Positive, n (%) COR (95% CI) p-Value Positive, n (%) COR (95% CI) p-Value
Age group
<20 years 30 3 (10.0) 1 20 (66.7) 1
20–24 years 186 13 (7.0) 0.7 (0.18–2.53) 0.561 149 (80.1) 2.0 (0.87–4.67) 0.103
25–29 years 224 22 (9.8) 1.0 (0.28–3.50) 0.975 178 (79.5) 1.9 (0.85–4.42) 0.117
30–34 years 98 11 (11.2) 1.1 (0.30–4.4) 0.851 79 (80.6) 2.1 (0.84–5.16) 0.115
35 years 62 8 (12.9) 1.3 (0.33–5.43) 0.688 51 (82.3) 2.3 (0.85–6.30) 0.100

Marital status
Married 587 55 (9.4) 1 468 (79.7) 2.6 (0.43–15.87) 0.294
Single 8 1 (12.5) 1.4 (0.17–11.44) 0.764 6 (75.0) 2.0 (0.18–22.06) 0.571
Divorced 5 1 (20.0) 2.4 (0.27–22.02) 0.433 3 (60.0) 1

Residence
Urban 386 44 (11.4) 2.0 (1.05–3.78) 0.036 313 (81.1) 1.3 (0.87–1.96) 0.196
Rural 214 13 (6.1) 1 164 (76.6) 1

Educational status
No formal education 146 14 (9.6) 1.2 (0.54–2.57) 0.673 120 (82.2) 1.0 (0.58–1.83) 0.922
Elementary school 118 11 (9.3) 1.2 (0.50–2.62) 0.747 93 (78.8) 0.8 (0.46–1.50) 0.534
High school 166 18 (10.8) 1.4 (0.65–2.82) 0.417 125 (75.3) 0.7 (0.40–1.15) 0.150
Certificate and above 170 14 (8.2) 1 139 (81.8) 1

Occupation
Civil servant 135 13 (9.6) 1.3 (0.28–6.27) 0.717 105 (77.8) 1.2 (0.47–3.17) 0.676
Merchant 67 6 (9.0) 1.2 (0.23–6.51) 0.808 59 (88.1) 2.6 (0.83–8.02) 0.101
Farmer 35 1 (2.9) 0.4 (0.03–4.28) 0.424 31 (88.6) 2.7 (0.70–10.47) 0.148
Student 19 1 (5.3) 0.7 (0.06–8.26) 0.773 17 (89.5) 3.0 (0.54–16.27) 0.209
Housewife 317 34 (10.7) 1.5 (0.34–6.62) 0.591 245 (77.3) 1.2 (0.48–2.93) 0.703
Daily laborer 27 2 (9.1) 1 20 (74.0) 1

COR, crude odds ratio; CI, confidence interval.

 Y. Wondimeneh et al. / International Journal of Infectious Diseases 76 (2018) 14–22 17

those without a history of spontaneous abortion (p = 0.005). In

477 (79.5%)
[95% CI: 76.3-82.5] contrast, pregnant women without a previous history of sponta-
neous abortion had 1.7 times (95% CI 1.04–2.87) the IgG positivity
rate of those who had a previous history of spontaneous abortion
(p = 0.034) (Table 2).

Rubella IgM and IgG antibodies in relation to the clinical

49 (8.2%) 66 (11.0%)
[95% CI: 6.2-10.2]
[95% CI: 8.7-13.7] manifestations
8 (1.3%)
[95% CI: 0.5-2.2]

A B C D
Immune status of the pregnant women
Figure 1. The overall prevalence of rubella specific IgM and IgG antibodies among
pregnant women in Amhara Regional Sate Referral Hospitals, Ethiopia, December
2015-February 2017. The letter “A”: indicates the number of pregnant women who
were positive for both rubella specific IgM and IgG antibodies at a time, “B”: Positive
only for rubella IgM antibody, “C”: Positive only for rubella IgG antibody, “D”:
Negative for both rubella IgM and IgG antibodies.
pregnant women were in the third trimester of their current
pregnancy (p = 0.136). In addition, six (17.1%) of the IgM-positive
study participants had a previous history of more than three live
births (p = 0.191), one (33.3%) had a previous history of more than
three still births (p = 0.205), and six were grand multigravidae
(16.2%) (p = 0.175) (Table 2).
One hundred and seventy-four (82.5%) of the IgG-positive
women were in the third trimester of their current pregnancy
(p = 0.096), 29 (83.0%) had a history of more than three previous
live births (p = 0.972), 40 (83.3%) had a history of one to three still
births (p = 0.434), and 248 (80.8%) were multigravidae (p = 0.346).
None of these reproductive history factors was significantly
associated with IgM and IgG positivity. However, the pregnant
women with a history of one to three previous spontaneous
abortions had 2.5 times (95% CI 1.32–4.63) the IgM positivity of
In this study, four (26.7%) of the IgM-positive pregnant women
had lymphadenopathy (p = 0.082), four (14.3%) had a runny nose
(p = 0.381), and six (17.1%) had a sore throat (p = 0.119) at the time of
data collection. In addition, 19 (12.2%) had a headache (p = 0.187),
five (20.8%) had an inflamed eye (p = 0.062), and three (17.6%) had
jaundice (p = 0.255). In contrast, 471 (79.8%) of the IgG-positive
pregnant women had no arthralgia/arthritis (p = 0.138) and 467
(79.8%) had no lymphadenopathy (p = 0.124). In addition, 458
(80.1%) of the IgG-positive pregnant women had no runny/stuffy
nose (p = 0.124) and 403 (80.9%) had no malaise (p = 0.058).
Furthermore, 361 (81.3%) of the IgG-positive pregnant women
had no headache (p = 0.066) and 465 (79.8%) had no jaundice
(p = 0.360). However, none of them had significant association
(Table 3).
There was a significant association between the presence of a
maculopapular rash and rubella-specific IgM positivity in the
multivariate logistic regression analysis. The pregnant women
with a maculopapular rash had 3.5 times (95% CI 1.464–8.649) the
IgM positivity of those without a maculopapular rash (p = 0.005).
There was also a significant association between the presence or
absence of a maculopapular rash and rubella-specific IgG positivity
in the multivariate logistic regression analysis. The pregnant
women without a maculopapular rash had 2.5 times (95% CI 1.120–
5.691) the protective antibody of those who had a maculopapular
rash at the time of data collection (p = 0.026) (Table 3).

Table 2
Rubella IgM and IgG antibodies in relation to the reproductive history of the pregnant women in Amhara Regional State referral hospitals, Ethiopia, December 2015 to
February 2017.

Reproductive characteristics Number tested IgM-positive Only IgG-positive

Positive, n (%) COR (95% CI) p-Value Positive, n (%) COR (95% CI) p-Value
Trimester at the time of data collection
First trimester 211 18 (8.5) 1 174 (82.5) 1.5 (0.93–2.44) 0.096
Second trimester 191 13 (6.8) 0.8 (0.37–1.64) 0.518 153 (80.1) 1.3 (0.80–2.10) 0.302
Third trimester 198 26 (13.1) 1.6 (0.86–3.10) 0.136 150 (75.8) 1

History of live births

None 256 25 (9.8) 1 197 (77.0) 1
1–3 309 26 (8.4) 0.9 (0.48–1.51) 0.577 251 (81.2) 1.3 (0.86–1.95) 0.212
>3 35 6 (17.1) 1.9 (0.72–5.05) 0.191 29 (83.0) 1.5 (0.57–3.65) 0.434

History of spontaneous abortion

None 510 41 (8.0) 1 413 (81.0) 1.7 (1.04–2.87) 0.034
1–3 90 16 (17.8) 2.5 (1.32–4.63) 0.005 64 (71.1) 1

History of stillbirth
None 549 52 (9.5) 1 435 (79.2) 1.9 (0.17–21.23) 0.599
1–3 48 4 (8.3) 0.9 (0.30–2.52) 0.795 40 (83.3) 2.5 (0.20–31.0) 0.434
>3 3 1 (33.3) 4. 8 (0.43–53.6) 0.205 2 (66.7) 1

Having malformed children

None 576 55 (9.5) 1.2 (0.27–5.07) 0.842 459 (79.7) 1.3 (0.51–3.37) 0.578
1–3 24 2 (8.3) 1 18 (75.0) 1

Gravidity
Primigravida 256 23 (9.0) 1 200 (78.1) 1
Multigravida 307 28 (9.1) 1.0 (0.57–1.83) 0.955 248 (80.8) 1.18 (0.78–1.77) 0.346
Grand multigravida 37 6 (16.2) 1.96 (0.74–5.19) 0.175 29 (78.4) 1.0 (0.44–2.34) 0.972

COR, crude odds ratio; CI, confidence interval.

18 Y. Wondimeneh et al. / International Journal of Infectious Diseases 76 (2018) 14–22

Table 3
Rubella IgM and IgG antibodies in relation to the clinical information of the pregnant women in Amhara Regional State referral hospitals, Ethiopia, December 2015 to February
2017.

Clinical information Number tested IgM-positive Only IgG-positive

Positive, n (%) COR (95% CI) AOR (95% CI) p-Value Positive, n (%) COR (95% CI) AOR (95% CI) p-Value
Mild fever
Yes 162 11 (6.8) 1 130 (80.2) 1.1 (0.68–1.67)
No 438 46 (10.5) 1.6 (0.81–3.19) 347 (79.2) 1

Maculopapular rash
Yes 30 8 (26.7) 3.9 (1.64–9.14)a 3.5 (1.46–8.65) 0.005 17 (56.7) 1 0.026
No 570 49 (8.6) 1 460 (80.7) 3.2 (1.51–6.78)a 2.5 (1.12–5.69)

Arthralgia/arthritis
Yes 10 1 (10.0) 1.1 (0.13–8.52) 6 (60.0) 1
No 590 56 (9.5) 1 471 (79.8) 2.6 (0.73–9.50)

Lymphadenopathy
Yes 15 4 (26.7) 3.7 (1.12–11.86)a 3.0 (0.87–10.1) 0.082 10 (66.7) 1
No 585 53 (9.1) 1 467 (79.8) 2.0 (0.66–5.90)

Runny or stuffy nose

Yes 28 4 (14.3) 1.6 (0.55–4.88) 19 (67.9) 1
No 572 53 (9.3) 1 458 (80.1) 1.9 (0.84–4.32)

Sore throat
Yes 35 6 (17.1) 2.1 (0.83–5.26) 23 (65.7) 1 0.315
No 565 51 (9.0) 1 454 (80.4) 2.1 (1.03–4.42)a 1.5 (0.68–3.33)

General malaise
Yes 102 10 (9.8) 1.0 (0.51–2.14) 74 (72.5) 1
No 498 47 (9.4) 1 403 (80.9) 1.6 (0.98–2.62)

Headache
Yes 156 19 (12.2) 1.5 (0.83–2.67) 116 (74.4) 1
No 444 38 (8.6) 1 361 (81.3) 1.5 (0.97–2.31)

Inflamed/red eyes
Yes 24 5 (20.8) 2.7 (0.95–7.40) 15 (62.5) 1 0.170
No 576 52 (9.0) 1 462 (80.2) 2.4 (1.04–5.70)a 1.9 (0.77–4.58)

Jaundice
Yes 17 3 (17.6) 2.1 (0.59–7.54) 12 (70.6) 1
No 583 54 (9.3) 1 465 (79.8) 1.6 (0.57–4.75)

COR, crude odds ratio; AOR, adjusted odds ratio; CI, confidence interval.
a
Significant association (p < 0.05).

Rubella IgM and IgG positivity in relation to the possible factors
The majority of the IgM-positive pregnant women, nine (17.0%),
had more than three children living in the given house (p = 0.240).
Similarly, 249 (81.9%) of the IgG-positive pregnant women had one
to three children living in the house (p = 0.727) and 18 (81.8%) had a
history of blood transfusion (p = 0.639). None of these possible risk
factors showed a statistically significant association in relation to
either IgM or IgG positivity (Table 4). However, there were
statistically significant differences in IgM positivity in relation to
frequent exposure to children and study site on both univariate and
multivariate analysis. The pregnant women who had frequent
exposure to children in their daily activities had 2.8 times (95% CI
1.6–5.1) the IgM positivity of those who had no daily exposure to
children (p = 0.001). In addition, the pregnant women from Dessie
Referral Hospital had 2.8 times (95% CI 1.546–5.160) the IgM
positivity of those pregnant women from University of Gondar
Referral Hospital (Table 4) (p = 0.001).
Discussion
Rubella IgM and IgG antibodies are important immunoglobu-
lins to study when investigating the prevalence of rubella in a given
area (Olajide et al., 2015). The presence of only IgM or both IgM and
IgG antibodies at the same time indicates an acute/recent rubella
virus infection. However, the presence of IgG antibody in the
absence of IgM is a seromarker of immunity against rubella virus
(Taneja and Sharma, 2012; Peter, 2015). The absence of both IgM
and IgG antibodies indicates susceptibility to acquiring rubella
infection. In this study, both rubella-specific IgM and IgG
antibodies were analyzed among pregnant women to determine
acute/recent infections and the levels of immunity against rubella
virus infection in the pre-vaccine era in Ethiopia.
The overall seroprevalence of rubella among pregnant women
was found to be 89% (95% CI 86.3–91.3%). A similar finding has been
reported from other African countries such as Senegal (90.1%)
(Dromigny et al., 2003) and Namibia (85.0%) (Jonas et al., 2016).
However, the overall seroprevalence in this study is higher than
reports from other African countries like the Democratic Republic
of Congo (58.97%) (Zanga et al., 2017), Sudan (65%) (Hamdan et al.,
2011), and Nigeria (68%) (Bamgboye et al., 2004), and lower than
reports from Burkina Faso (95%) (Tahita et al., 2013a,b) and
Zimbabwe (92%) (Mamvura et al., 2015). This variation in different
studies might be due to the difference in the endemicity of the
virus, the variation in the sample size of the studies, the laboratory
methods used, and differences in the cut-off points of the assays
used.
 Y. Wondimeneh et al. / International Journal of Infectious Diseases 76 (2018) 14–22 19

Table 4
Rubella IgM and IgG antibodies in relation to possible factors for rubella virus infection among pregnant women in Amhara Regional State referral hospitals, Ethiopia,
December 2015 to February 2017

Possible risk factors Number tested IgM-positive Only IgG-positive

Positive, n (%) COR (95% CI) AOR (95% CI) p-Value Positive, n (%) COR (95% CI) p-Value
Frequent exposure to children
Yes 272 38 (14.0) 2.6 (1.45–4.70)a 2.8 (1.6–5.1) 0.001 216 (79.4) 1
No 328 19 (5.8) 1 261 (79.6) 1.0 (0.68–1.50) 0.961

Number of children in a house

None 243 27 (11.1) 1 189 (77.8) 1
1–3 304 21 (6.9) 0.6 (0.33–1.08) 249 (81.9) 1.1 (0.66–1.82) 0.727
>3 53 9 (17.0) 1.6 (0.72–3.72) 39 (73.6) 1.5 (0.54–3.93) 0.456

History of blood transfusion

Yes 22 2 (9.1) 1 18 (81.8) 1.4 (0.33–6.22) 0.639
No 578 55 (9.5) 1.1 (0.24–4.62) 459 (79.4) 1

Study site
University of Gondar Referral Hospital 358 26 (7.3) 1 1 288 (80.4) 1
Felege-Hiwot Referral Hospital 115 8 (7.0) 0.9 (0.42–2.17) 0.9 (0.4–2.0) 96 (83.5) 1.2 (0.60–2.23) 0.663
Dessie Referral Hospital 127 23 (18.1) 2.8 (1.55–5.16)a 2.9 (1.6–5.4) 0.001 93 (73.2) 1.1 (0.59–2.05) 0.762

COR, crude odds ratio; AOR, adjusted odds ratio; CI, confidence interval.
a
Significant association (p < 0.05).

Although there is some variation among countries in terms of
the concentration of IgG antibodies considered to be protective
(WHO, 2011b), based on the previous recommendations of the US
National Committee for Clinical Laboratory Standards (NCCLS)
(Skendzel, 1996), international agreements and guidelines (Cutts
and Vynnycky, 1999; Dimech et al., 2008), in the absence of IgM,
pregnant women who had rubella IgG levels 10 IU/ml were
classified as immune and those with IgG levels <10 IU/ml were
classified as susceptible. In the present study, 79.5% (95% CI
76.3–82.5%) of the pregnant women had IgG levels of >10 IU/ml.
None of these pregnant women had a previous history of rubella
vaccination and they were immune from wild-type rubella
infections. This might be due to the endemicity of the virus in
the study area and sustained previous infections of the study
participants before conception or during their childhood, as rubella
infection is common among children and teenagers in the country
(Shiferaw et al., 2016).
The prevalence of rubella IgG in this study was also comparable
to that reported in Burkina Faso (77%) (Tahita et al., 2013a), but it
was higher than the prevalence reported in Niger (53%) (Onake-
whor and Chiwuzie, 2011) and southern India (65%) (Padmaja et al.,
2010). However, the IgG positivity rate in this study was lower than
that found in studies conducted in other countries like Nigeria
(97.9%) (Mohammed et al., 2010), Cameroon (88.6%) (Fokunang
et al., 2010), Turkey (96.1%) (Tamer et al., 2008), Italy (85.8%)
(Calimeri et al., 2012), and Mexico (97.1%) (Alvarado-Esquivel et al.,
2016). These variations in rubella IgG positivity in different
countries might be due to the difference in the endemicity of the
rubella virus and the presence or absence of rubella vaccination in
their immunization programs.
According to the WHO, the incidence of rubella in Ethiopia was
7.27 per million inhabitants in 2017 and 5.39 per million
inhabitants in 2018 (WHO, 2018). However, due to the benign
nature of the virus and lack of independent rubella surveillance
system in the country, most of the rubella reports might be from
measles-suspected cases, as discussed earlier. The existing burden
of the virus among women of child-bearing age might therefore be
underestimated. In the present study, 9.5% of the pregnant women
were positive for rubella IgM. As rubella IgM mostly declines
quickly and is usually undetectable at 2–3 months after the
infection (Vardas, 2011), the present result indicates the presence
of acute rubella virus infection at 0–3 months before the blood
samples were obtained. Of the total pregnant women, 8.2% had
both rubella IgM and IgG antibodies. As rubella virus re-infection
following natural immunity is very rare (Mendelson et al., 2006),
the pregnant women who had both IgM and IgG antibodies might
have been in the resolving stages of primary rubella infections.
Since the majority of these pregnant women were in the third
trimester of pregnancy, they might have acquired the infection
during the first or second trimester of pregnancy and subsequently
developed IgG antibodies within 30 days of infection (Navigator,
2013). This indicates that these groups of pregnant women might
not be immune before becoming pregnant and their fetuses may
not be excluded from rubella-associated risks. Although there is a
scarcity of data about CRS in the country, as indicated earlier
(Mekonnen, 2017), the newborns from women infected with
rubella during early pregnancy might acquire a congenital rubella
infection and be born with rubella-associated congenital anoma-
lies or CRS. Therefore, the screening of women of child-bearing age
before conception or during pregnancy might be crucial to reduce
the consequences of acute rubella infection during pregnancy.
A similar IgM seroprevalence was also reported in Nigeria (9.2%)
(Onakewhor and Chiwuzie, 2011). However, the IgM positivity rate
in the present study was higher than those reported recently from
Southern Ethiopia (Tamirat et al., 2017) and Turkey (2%) (Tamer
et al., 2009). In contrast, the present study result was lower than
that in another report from Nigeria (38.8%) (Olajide et al., 2015).
These variations in rubella-specific IgM positivity might be due to
the difference in endemicity of the rubella virus and sustained
transmission in susceptible groups, differences in population
density, variations in temperature/humidity, and the presence or
absence of rubella vaccination, as discussed earlier.
No statistically significant difference in rubella IgM and IgG
positivity was found in relation to most socio-demographic
characteristics of the pregnant women in this study. A similar
finding was also reported in a recent study in Southern Ethiopia
(Tamirat et al., 2017), and in other studies in Nigeria (Pennap and
Egwa, 2016) and Namibia (Jonas et al., 2016). However, a
statistically significant association between IgM positivity and
area of residence was found in the present study; pregnant women
from urban settings had two times the IgM positivity of those from
rural settings. Although further study of rubella virus transmission
dynamics in rural and urban settings is needed, this difference in
IgM positivity between the two settings might be due to
20 Y. Wondimeneh et al. / International Journal of Infectious Diseases 76 (2018) 14–22
differences in population density. The high population density in
urban areas might increase the contact rate and, as discussed
earlier, pregnant women without protective levels of rubella
immunity might acquire the infections. A similar finding was also
reported in the pre-vaccine era in other countries (Goodson et al.,
2011; Assaad and Ljungars-Esteves, 1985; Hinman et al., 1998).
In this study, there was no statistically significant difference in
rubella antibody positivity according to the trimester of pregnancy
of the women, as has been reported in other studies (Agbede, 2011;
Olajide et al., 2015). However, emphasis should be placed on those
pregnant women who have had recent or acute infections due to
the teratogenic nature of the virus (Lee and Bowden, 2000). In the
present study, there was a statistically significant association
between a previous history of spontaneous abortion and IgM
positivity. Pregnant women with a history of one to three previous
spontaneous abortions had 2.5 times the IgM positivity rate of
those without a history of spontaneous abortion. An explanation
for this is that those pregnant women who have a previous bad
obstetric history (BOH) may be more vulnerable to acquiring acute
rubella infections (Priyanka et al., 2017). Although the mechanism
is not clear and further studies are needed, a similar finding has
also been reported in other studies (Noor et al., 2015; Abdolreza
et al., 2011).
With regard to the relationship between IgG positivity and
previous reproductive history, there was a statistically significant
difference in the levels of IgG according to the absence of a
previous history of spontaneous abortion. Pregnant women
without a previous history of spontaneous abortion had 1.7 times
the IgG positivity of those who had a previous history of
spontaneous abortion. An explanation for this is that these groups
of pregnant women might have acquired the rubella infection
during their childhood and developed protective immunity against
rubella virus at their reproductive age.
Even though the clinical manifestations of rubella are non-
specific and it is difficult to diagnose clinically (WHO, 2011a), the
present study found statistically significant differences in rubella
IgM or IgG positivity according to the presence or absence of
certain clinical manifestations in the pregnant women at the time
of data collection. Although it was not statistically significant in the
multivariate analysis, pregnant women with lymphadenopathy
had three times the IgM positivity rate of those without
lymphadenopathy. The pregnant women with a maculopapular
rash had 3.5 times the IgM positivity of those without a
maculopapular rash.
In contrast, pregnant women without a maculopapular rash had
2.5 times the protective IgG antibody compared to those who had a
maculopapular rash. There was, however, no statistically signifi-
cant difference in the presence or absence of other clinical
manifestations and IgM/IgG positivity. The lack of association
between IgM/IgG positivity and most clinical manifestations may
be due to the mild nature of rubella infections (Edlich et al., 2005).
Furthermore, most patients with rubella may recover without any
complications or sequelae and pass unnoticed, as rubella virus
mostly causes a self-limiting disease in postnatal infections
(Mwambe et al., 2014; Edlich et al., 2005; Forrest and Mense,
2008).
When a comparison was made of the possible risk factors and
rubella IgM positivity, the pregnant women who had frequent
exposure to children in their daily activities had 2.8 times the IgM
positivity of those who had no daily exposure. This can be
explained by the fact that rubella infection is more common in
childhood (Junaid et al., 2011) and children might harbor and
spread the infection to susceptible pregnant women. Similarly, the
pregnant women from Dessie Referral Hospital had 2.8 times the
IgM positivity rate of pregnant women from University of Gondar
Referral Hospital. This indicates that there may be epidemiological
differences in the circulation of rubella virus within the country. In
addition, there may also have been differences in temperature and
humidity between the study sites at the time of data collection.
These differences might have contributed to the differences in
active transmission of rubella virus in the study areas.
Although maternal immunity is protective against intrauterine
rubella infection (Aboudy et al., 1997), around 11% (95% CI
8.7–13.7%) of the study participants had IgG levels 10 IU/ml;
these women were classified as seronegative and represent the
susceptible group. A similar finding has also been reported in
previous studies (Yadav et al., 1995; Pooja and Piyush, 2012;
Oyinloye et al., 2013). In developing countries, about 10–25% of
women have been reported to be seronegative (Cutts et al., 2000b;
Gavin et al., 2015), and countries with high rates of susceptibility to
rubella virus among women of child-bearing age might be at risk of
CRS (Lambert et al., 2015). The susceptibility rate of 10% among
adult women could result in outbreaks of CRS (WHO, 2011b).
Therefore, attention must be paid to the susceptible group of
women in this study in order to reduce the risk of CRS in their
future pregnancies.
Limitations of the study
Due to the lack facilities, it was not possible to use advanced
laboratory techniques like RT-PCR for the diagnosis of rubella.
Furthermore, due to the nature of the study (cross-sectional study)
and reagent constraints, it was not possible to obtain convalescent
sera from each rubella IgM-positive/IgG-negative study partici-
pant. Since the study was conducted only in the selected referral
hospitals of Amhara Regional State, Ethiopia, a large-scale
community-based study might be important. However, as there
is scarcity of data about rubella among pregnant women in the
country, the information provided by this study might serve as a
baseline for the study area and increase awareness for health
decision-makers and collaborators in the country so that the long-
term health consequences can be reconsidered.
Conclusions
The seroprevalence of rubella virus was found to be high, and
many (9.5%) of the pregnant women had acute rubella virus
infections at the time of data collection. This implies that the virus
is endemic in the study areas. Despite 79.5% of pregnant women
having IgG levels >10 IU/ml and being immune to natural/wild-
type rubella virus infections, about 11% of the pregnant women
were found to be non-immune and represent the susceptible
group. These pregnant women may be at risk of developing
rubella-associated congenital anomalies in their future pregnan-
cies. Hence, the screening of women of child-bearing age before
conception, introduction of rubella vaccination, and a strong
surveillance system might be important to reduce rubella-
associated health complications in the country.
Acknowledgements
We would like to thank the University of Gondar for funding the
project. Our special thanks also go to all of the study participants,
data collectors, and other staff at the respective referral hospitals
for their cooperation during the data collection process.
Ethical approval
The study was conducted after obtaining institutional ethical
clearance from the Ethics Committee of the University of Gondar. A
letter of agreement and the cooperation of the clinical director/
chief executive officer of each referral hospital were obtained.
 Y. Wondimeneh et al. / International Journal of Infectious Diseases 76 (2018) 14–22
Informed consent was also obtained from each study participant,
as per the National Research Ethics Review Guidelines (FDRE-MST,
2014). We also obtained written consent from each study
participant to publish the findings in a peer-reviewed journal
for the scientific community.
Funding
For data collection and laboratory reagents/materials, funding
was obtained from the University of Gondar.
Conflict of interest
The authors declare that no competing interest exists with
respect to the authorship and/or publication of this research paper.
Author contributions
YW: Participated in the conception, design and proposed the
research idea, data collection, data clearance, entry, analysis and
interpretation of the findings and drafting the manuscript and
write-up. MT: Participated in the conception, design and proposed
the research idea, supervision/consultations during data collection
and interpretations of the findings. BA: Participated in consultation
during data collection and interpretations of the findings. GF, MW,
and MB: Participated in data collection and interpretations of the
findings. BT: Participated in the conception, design and proposed
the research idea, supervision/consultations during data collection
and interpretations of the findings. All authors reviewed and
approved the final manuscript.
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