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Immunization Update

“Rubella seroprevalence of the 9e15 years oldfemale children with congenital heart anomalies:Is vaccination necessary at puberty?’’

Aysu Turkmen Karaa�gac a,*, Ays‚e _Inci Yıldırım b

a Pediatry, Kartal Kos‚uyolu Research and Training Hospital, Denizer Cad. Cevizli Kavs‚a�gı, No.2 Kartal, Istanbul,

Turkeyb Pediatric Cardiology, Kartal Kos‚uyolu Research and Training Hospital, Denizer Cad. Cevizli Kavs‚a�gı, No.2 Kartal,

Istanbul, Turkey

a r t i c l e i n f o

Article history:

Received 25 April 2014

Accepted 8 October 2014

Available online 4 November 2014

Keywords:

Rubella antibody

Female children

Congenital rubella syndrome

Vaccination

Cardiac defect

* Corresponding author.E-mail address: aysukaraagac@gmail.com

http://dx.doi.org/10.1016/j.pid.2014.10.0012212-8328/Copyright © 2014, Indian Academ

a b s t r a c t

Background: The risk of getting baby with congenital rubella syndrome (CRS) increases 10

folds for a rubella seronegative female if she has an accompanying congenital anomaly

(cardiac defect, deafness, cataract etc.) and infected during pregnancy.

Aim: To define the rubella seroprevalence of the female children with congenital anomaly

(cardiac anomalies) and vaccinate them before reaching the childbearing age due to the

increased risk of CRS.

Methods: 9e15 years old 240 female children followed in our hospital between 15th March,

2013e15th March, 2014 were included. They were non vaccinated against rubella. The

correlations between the rubella seroprevalences and the age, maternal educational status,

socioeconomic levels, accompanying cardiac diseases of these children and their parents

were analyzed statistically.

Results: The mean age was 11.5 ± 1.87 years. 38 female children out of 240 were rubella IgG

negative, so the seronegativitiy and seropositivity ratios were 15.8% and 84.2% respectively

(9e10 years group 20%e80% and 14e15 years 12.5%e87.5%) at 95% confidence interval(0.60

e1.19).However, the correlations between sociodemographic factors and the rubella sero-

prevalences were statistically insignificant (p > 0.05).

Conclusion: Our seronegativity ratio is low, but not negligable.We recommend the rubella

vaccination of the female children at puberty to prevent the CRS especially for those with

accompanying congenital anomalies.

Copyright © 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights

reserved.

(A. Turkmen Karaa�gac).

y of Pediatrics, Infectious Disease Chapter. All rights reserved.

p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 1 0 5e1 0 9106

1. Introduction

Congenital infections are acquired by a fetus either via the

placenta during pregnancy or via the birth canal of the

infectedmother during delivery. One of the first investigations

performed in the congenitally infected neonates is TORCH

(Toxoplasmosis, Rubella, Cytomegalo and Herpes viruses)

serology.1 From these agents, rubella virus causes a mild

infection with macular rash, fever, conjunctivitis and lym-

phadenomegaly in children.2 However, it creates a major risk

of infection in fetuses if acquired in the first trimester of

pregnancy.3,4 25e30% of these infected fetuses get congenital

rubella syndrome (CRS) characterized by intrauterine growth

retardation, irreversible deafness, cataract, spleen, liver or

bone marrow problems and hazardous cardiac, hematologic

and neurologic complications.1,4 Moreover, the risk of getting

a baby with CRS increases 10 folds for a female with any

congenital anomaly (cataract, deafness, cardiac anomaly etc.)

if she is rubella seronegative and infected with rubella during

pregnancy.5 For the rubella immunization MMR vaccine is

widely used. MMR vaccine was first developed by Maurice

Hilleman in 1971 as a mixture of live attenuated mumps,

measles and rubella viruses.1,2

2. Methods

240 female children in pubertal period, between 9 and 15 years

old, followed inpatient/outpatient in the Kartal Kos‚uyolu

Research and Training Hospital for their congenital cardiac

anomalies between March, 15th 2013eMarch, 15th 2014 were

included in the study if they had not been vaccinated for

rubella previously. Their MMR vaccination histories were ob-

tained from theirmothers and vaccination cards. The children

were divided into 6 age groups each containing 40 female

children. In addition to their age and accompanying cardiac

diseases, sociodemographic factors such as the educational

status of their mothers, cardiac disease histories and the so-

cioeconomic status of their parents were inquired. The fam-

ilies were informed about the study. Their written concents

were received. The telephone numbers were recorded to

inform the families whose children were rubella IgG antibody

negative about the MMR vaccination. The study was approved

by the Ethics Committee.

2 ml intravenous blood was taken from each child. These

blood samples were dried at the room temperature and their

Table 1 e Rubella seronegativity and positivity ratios of all age

Ages Number of females Seropositivity ratio (%) (95% C

9e10 years 40 80.0 (79.4e81.1)

10e11 years 40 82.5 (81.9e83.6)

11e12years 40 85.0 (84.4e86.1)

12e13years 40 82.5 (81.9e83.6)

13e14 years 40 87.5 (86.9e88.6)

14e15 years 40 87.5 (86.9e88.6)

Total 240 84.2 (83.6e85.3)

p > 0.05

sera were separated after centrifugation. The sera were put

into the plastic tubes and kept at �20 centigrade degree.

Rubella IgG antibodies were analyzed by using the Captia

Rubella IgG (Biotech Medical Devices) assay with micro ELISA

(Enzyme Linked Immunosorbent Assay) technique. The

absorbance values of the blood sera were evaluated quanti-

tatively by the optic reader (Organon Teknika 230 S version

1.22) at 450 nm wavelength. The cut off value was calculated

and the immune status ratio (ISR) was found according to the

instructions. The rubella IgG was accepted as positive if the

ISR of the blood sample was above 1.25 (9.6 IU/ml), the ISR

value of the calibration solution, and negative if the ISR is

below 1.20 (9.1 IU/ml). The ISR values of the three cases were

between 1.20 and 1.25 IU/ml, so they were reanalyzed. As the

repeated values were below 1.20, rubella seronegative, the

cases were included in the study.

2.1. Statistical analysis

The collected data were analyzed by the SPSS for Windows

16.0 statistical program. The correlations between the socio-

demographic factors (the age, maternal educational status,

socioeconomic status and cardiac disease histories of the

parents) and the rubella seroprevalence of the children were

analyzed by the chi-square test. A p-value less than 0.05 was

accepted as statistically significant.

The percentages, geometrical means and the standard

deviations of the rubella antibody titers and the seropreva-

lence ratios were calculated by Microsoft Excel Program. The

results were reported at the 95% confidence interval (95% CI).

3. Results

Themean age of the 240 female children included in our study

was 11.5 ± 1.87 years (9e15). The rubella IgG antibody results

were positive in 202 females and negative in 38 females with

the seropositivity and negativity ratios of 84.2% (83.6e85.3)

and 15.8% (15.2e16.9) respectively at 95% confidence interval

(95% CI). The numbers of rubella IgG antibody positive and

negative females in these groups were as follows: 32 positive

(80%), 8 negative (20%) in the 9e10 years old group; 33 positive

(82.5%), 7 negative (17.5%) in the 10e11 years old group; 34

positive (85%), 6 negative (15%) in the 11e12 years old group;

33 positive (82.5%) and 7 negative (17.5%) in the 12e13 years

old group; and finally 35 positive (87.5%) and 5 negative(12.5%)

both in the 13e14 and 14e15 years old groups (Table 1).

groups at 95% confidence interval (p > 0.05).

I) Borderline(%) (95% CI) Seronegativity ratio (%) (95% CI)

0 (0.6e1.1) 20.0 (19.4e21.1)

2,5 (1.9e3.6) 17.5 (16.9e18.6)

2.5 (1.9e3.6) 15.0 (14.4e16.1)

0 (0.6e1.1) 17.5 (16.9e18.6)

2.5 (1.9e3.6) 12.5 (11.9e13.6)

0 (0.6e1.1) 12.5 (11.9e13.6)

1.2 (0.6e2.4) 15.8 (15.2e16.9)

p > 0.05 p > 0.05

Table 2 e Sociodemographic factors of the evaluatedchildren and their correlations with the rubellaseroprevalence (n ¼ 240).

Variables No % Correlationwith rubellaseropositivity

Maternal educational status p > 0.05

Illiterate 40 16.7

Elementary school graduates 100 41.6

High school graduates 80 33.3

University graduates 20 8.4

Socioeconomic status of the families p > 0.05

Living on the minimum wage 108 45.0

Below the minimum wage 46 19.2

Above the minimum wage 86 35.8

Accompanying cardiac disease p > 0.05

Aortic anomalies 26 10.8

PFO, PDA 64 26.6

MVP 58 24.2

ASD 52 21.6

VSD 36 15.0

DORV 4 1.8

Cardiac disease history

of the parents

p > 0.05

Present 60 25.0

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There was no statistically significant difference between

the increasing ages and the rubella seronegativity ratios

(p > 0.05) (Fig. 1).

The mothers of the 40 children were illiterate (16.7%), 100

of them were elementary school graduates (41.6%), 80 were

high school graduates (33.3%) and 20 were university school

graduates (8.4%). There was no correlation between the

maternal education and the rubella seropositivity of the fe-

male children (p > 0.05) (Table 2).

The families of the 108 children were living on the mini-

mum wage (45%), 86 were above the minimum wage (35.8%)

and 46 were below the minimum wage (19.2%). However, the

correlation between the rubella seropositivity and the socio-

economic status was not statistically significant (p > 0.05)

(Table 2).

Among the female children in our study, 64 (26.6%) had

patent foramen ovale (PFO) or patent ductus arteriosus (PDA),

58 (24.2%) had mitral valve pathologies (MVP), 52 (21.6%) had

atriyal septal defect (ASD), 36 (15%) had ventricular septal

defect (VSD), 26 (10.8%) had aortic anomalies and 4 (1.8%) had

double outlet right ventricule (DORV). However, there was no

correlation between the accompanying cardiac diseases of the

evaluated children and the rubella seropositivity (Table 2).

0

10

20

30

40

50

60

70

80

90

100

9-10 10-11 11-12 12-13 13-14 14-15

AGES

% R

ATI

OS

seropositivity ratioseronegativity ratio

Fig. 1 e The rubella seropositivity and negativity ratios of

the females with congenital heart diseases between 9 and

15 years of ages (p > 0.05).

Not present 180 75.0

There was cardiac disease history in the parents of 60

children (25%) and the correlation between the disease history

of the parents and the rubella seropositivity was not statisti-

cally significant (p > 0.05) (Table 2).

4. Discussion

Rubella or “three daymeasles” is a mild, but highly contagious

infection which has resulted in epidemics at 6e9 year in-

tervals and major pandemics at a frequency of every 10e30

years.6 During the major rubella epidemics in the United

States between 1963 and 65, thousands of pregnant women

not vaccinated against rubella gave birth to the babies with

CRS who died of or suffered from cardiac, neurologic, hema-

tologic or ocular complications.7,8

TheWorld Health Organization (WHO) established goals to

eliminate the rubella and CRS in the WHO Region of America

by 2010, and in the WHO European Region by 2015.9,10

Although a rubella and CRS elimination programme has also

been established in Turkey, the community based rubella and

CRS prevalence studies are inadequate as to be a baseline for

the success of this programme. After a new surveillance sys-

tem for communicable diseases was put into practice in 2005,

the number of confirmed rubella cases in Turkeywas reported

as 2245with amorbidity rate of 3.1 per 100,000 people and only

1 CRS case was reported in the same year.11 The latest CRS

case from Turkey was reported by Deveci et al in 2007 as a

newborn with low birth weight, microcephaly, micro-

phtalmia, hepatosplenomegaly, cataract, ventricular septal

defect, patent ductus arteriosus, trombocytopenia and pete-

chiae with rubella IgM positivity. The mother had not been

vaccinated against rubella and got the rubella infection in the

first trimester of pregnancy.12 It has been shown that there is

p e d i a t r i c i n f e c t i o u s d i s e a s e 6 ( 2 0 1 4 ) 1 0 5e1 0 9108

no correlation between the severity of maternal rubella

infection and its teratogenic effects.11 The time of exposure is

important, that is, the earlier the gestational age at which the

fetus is affected from rubella infection, the worse the com-

plications, especially the cardiac complications, presented

after birth.13 Furthermore, as the rubella vaccine is live

attenuated, it is not possible to vaccinate the women after

getting pregnant.1,7

Among the neurological, ocular, hematological and devel-

opmental complications of CRS, the most life threatening

complication is the cardiovascular involvement.14 By

spreading through the vascular system, the first organs tar-

geted (usually receiving lethal damage) are the heart and

blood vessels. When the heart is affected, the viral damage

occurs directly to themyocardium, primarily to the left atrium

and the heart septa, leading to thrombosis, necrosis, and

hemorrhage.13,14 Otaigbe et al from Nigeria reported that

85.7% of the patients with CRS had at least one congenital

heart defect such as patent ductus arteriosus (50% of the pa-

tients), stenosis of pulmonary arteries, fallot tetrology, aort

stenosis, myocarditis and/or ventricular septal defect.15

Among the female children in our study, 64 (26.6%) had

patent foramen ovale (PFO) or patent ductus arteriosus (PDA),

58 (24.2%) had mitral valve pathologies (MVP), 52 (21.6%) had

atriyal septal defect (ASD), 36 (15%) had ventricular septal

defect (VSD), 26 (10.8%) had aortic anomalies and 4 (1.8%) had

double outlet right ventricule (DORV). It would be better to

knowwhether the cardiac anomalies of our patients were due

to the CRS or not. However, the TORCH screening of the babies

with congenital abnormalities such as cataract, deafness or

cardiac anomalies is not a routine and well documented

procedure in our country.

Even if we don't know the real etiologies of their cardiac

anomalies, we do know that their risk of getting babies with

CRS and its lethal complications will increase 10 folds if they

get rubella infection during pregnancy.5,14 Our study showed

that there is no correlation between the type of cardiac dis-

ease of the children, the economic status or the educational

status of their parents or the cardiac disease histories of their

grand families and their rubella seropositivity ratios.

In addition, long term follow-up of newborns with CRS

have shown that they carry 50 times higher risk of late

onset chronic diseases such as insulin-dependent diabetes

or thyroid dysfunction than the general population.16

Therefore, congenital rubella should be considered as a

preventable chronic disease producing ongoing vital organ

damage throughout life. The most powerful tool to get rid of

these unwanted consequences of congenital rubella infec-

tion is vaccination.17 After performing their rubella sero-

prevalence studies, 64% of European countries and 28% of

developing countries have included rubella vaccine to their

national vaccination programmes.17,18 In our country the

rubella vaccination has being applied as mumps-measles-

rubella (MMR) vaccine at the ages of 12 months and 6

years since 2006.19 However, the rubella seropositivity ratio

we found is 84.2%, that is, below the desired level. It would

be better to revise the ages at which the MMR vaccination

should be applied because if a high vaccine coverage can

not be achieved, the risk of CRS may increase due to a shift

in rubella virus susceptibility to older age groups, including

women of child-bearing age.17,20 The highest rubella sero-

negativity was in the 9 years old group (20%) and the lowest

in the 13 and 14 years old groups (12.5%) at the 95% confi-

dence interval in our study, indicating a natural immunity

via an uncontrolled rubella virus circulation. It should not

be neglected that the rubella virus may spread via the

nasopharyngeal secretions, blood, urine, and feces of the

infected children up to one year following the clinical

illness.21,22 Therefore, these children (native or imported)

are also the potential reservoirs for the rubella seronegative

females of childbearing age and for the pregnants. Papania

et al reported that the elimination of endemic measles,

rubella and CRS from the United States was sustained

through 2011 due to the international importation.23

Therefore, all suspecected cases with febrile rush should

be reported and the seronegative females should be detec-

ted and vaccinated in the pubertal period.

Although their numbers are limited, there are studies

about the age specific rubella seroprevalences in our coun-

try. The rubella seronegativity ratio in our study was similar

to that found in the study of Aksit et al in the same age

group as 15.8% and 12.4% respectively.24 It would be better

to compare the rubella seroprevelance we found with the

similar studies performed in the same age group. However,

we could not find studies about the rubella seroprevelance

among the female children with accompanying congenital

anomalies at puberty as far as the literature searches we

carried out.

Although the rubella seronegativity ratiowe found is low, it

is not negligable. We included only 240 female children from a

single center, so it may not represent the other parts of

Turkey. The results of this studymay be used as a baseline for

community based prevalence studies to determine the female

children with increased risk of rubella infection. Despite the

ongoing efforts to eradicate the disease, some parts of the

world as well as our country still continue to be affected by

this preventable disease.

Another critical point in the management with rubella and

CRS is the economical aspect. Many European countries

realized in 1970's that vaccinating especially female children

at puberty would be more cost effective than treating the

complications of CRS.9,17,25 The cost effectiveness of a mass

vaccination campaign is estimated to be at least $2900 per

case of CRS prevented.25

As a conclusion we recommend that the rubella and the

CRS cases should bemore seriously documented as to be used

for the new community based prevalence studies. The rubella

antibodies should be screened in the pre-vaccination period

among the children with cataract, deafness or cardiac

anomalies attributable to rubella to estimate the prevalence of

CRS. Finally rubella IgG antibodies should be evaluated at

puberty and the rubella seronegative female children should

be vaccinated after planning the appropriate vaccination

strategies to reduce the incidence of CRS and its devastating

systemic consequences.

Conflicts of interest

All authors have none to declare.

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