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Congenital Rubella Syndrome Surveillance After Measles Rubella Vaccination Introduction in Yogyakarta, Indonesia

Herini, Elisabeth Siti MD, PhD*; Triono, Agung MD*; Iskandar, Kristy MD, MSc, PhD*,†; Prasetyo, Ashadi MD, MSc; Nugrahanto, Andika Priamas MD*; Gunadi, MD, PhD†,§

Author Information
The Pediatric Infectious Disease Journal: December 2021 - Volume 40 - Issue 12 - p 1144-1150
doi: 10.1097/INF.0000000000003290

Abstract

Rubella infection is a generally mild disease caused by the RV in children and young adults. Rubella infection in children frequently causes mild symptoms, including low-grade fever, erythematous rash, lymphadenopathy, sore throat, red eyes, headache, malaise, and anorexia.1 Additionally, rubella infection in pregnant women, especially during the first trimester, may cause miscarriage, stillbirth, and congenital abnormalities known as congenital rubella syndrome (CRS).2 Rubella infection during pregnancy mostly goes undetected because it often occurs without a rash.3

Globally between 1996 and 2010, it was estimated that around 105,000 babies were born with CRS each year, and half of them were reported in Southeast Asia caused by the absence of routine vaccination programs.4 Surveillance conducted by South East Asia Regional Office-World Health Organization (SEARO-WHO) from 2010 to 2015 showed an estimated 30,463 rubella cases worldwide. This estimate is assumed to be lower than the actual number, considering that the cases were often underreported. In 2016, the number of CRS in Indonesia became the highest in the world.5

Before introducing the rubella vaccination program, the incidence of CRS was 0.1–0.2 per 1000 live births.6 Meanwhile, the estimated incidence of CRS is 0.05–0.25 per 1000 live births based on a study conducted in Yogyakarta, Indonesia. The most common defects found in CRS cases are hearing loss (100%), congenital cataracts (72.7%), microcephaly (72.7%), and congenital heart disease (45.5%).7 No antiviral therapy is available, and diagnosis is made in the newborn when tissue damage has already occurred during intrauterine life [3]. CRS is estimated to cost $4200–140,000 for lifetime care in developed countries.6 A study in the United States found that the two-dose MMR program would save $231 per case of rubella prevented and $683,813 per case of CRS avoided.8

Rubella vaccines are safe and very effective.9 More than 95% of seroconvert recipients older than 11 months with 1 dose of vaccine and responses to the antibody are detectable over a long period.9,10 Several countries have eliminated rubella or significantly reduced the burden of CRS through successful vaccination programs.11

In 2016, Bangladesh, Bhutan, Myanmar, Nepal, Sri Lanka, Thailand, and Timor-Leste had introduced routine vaccination programs against rubella, while Indonesia and India had introduced it in 2017.12 The measles rubella (MR) vaccination campaigns in Indonesia were conducted from August to September 2017 in Java and from August to September 2018 for other regions. The MR vaccination campaigns in Indonesia were targeted to all children 9 months to <15 years of age regardless of vaccination status or previous measles and rubella infection history. The MR campaign coverage rate for phase I was 100.98%, and phase II was 72.99%, with national coverage at 87.33%. These simultaneous vaccinations had a significant impact on reducing rubella infection by 85% in 6 provinces of Java. However, it is necessary to be aware of some regions with <85% vaccination coverage in 201 of 514 districts/cities in Indonesia. To reduce the incidence of the disease, the threshold of herd immunity is >85%; therefore, some regions with <85% vaccination coverage may potentially be the source of rubella transmission in Indonesia.13

Studies concerned with the impact of the national vaccination campaign have not been done often. An effective surveillance system and promotion of vaccination programs in Indonesia as an endemic country are essential for eliminating rubella in the world.

MATERIALS AND METHODS

Patients

This study was conducted at the tertiary referral hospital, Dr Sardjito General Hospital, Yogyakarta, Indonesia, from July 2015 to July 2020. A total of 229 patients with suspected case definition for CRS case finding were enrolled. Patients were recruited from child health (cardiology, growth and development, neurology, and perinatology division), ophthalmology, and otolaryngology departments.

This study was approved by the Medical and Health Research Ethics Committee Faculty of Medicine, Public Health and Nursing of Universitas Gadjah Mada (KE/0475/04/2019). The purpose and methods of the research, the expected effects, the possibility of adverse events, and patients’ confidentiality were explained before signing the informed consent form.

Surveillance Study

Initial assessments, including primary sociodemographic data such as age, sex, age at the time of diagnosis, gestational age, the residence was collected. Moreover, information on maternal infection symptoms such as maculopapular rash, fever, conjunctivitis, rhinitis, cough, swollen lymph nodes, joint pain was also collected. Physical examination on the infants, including birth weight, head circumference, significant neonatal problem, complete cardiovascular examination, ophthalmic examination, and assessment for hearing impairment (using otoacoustic emissions and/or brainstem evoked response audiometry) and other supporting examinations were done for each patient.

Our CRS surveillance system was based on the clinical manifestation of the patient. If we find a suspected patient with 1 symptom of the CRS case definition from WHO, the patient will undergo a complete clinical examination to determine another affected organ.

According to the WHO, the inclusion criteria were infants with <12 months of age who fulfilled the case definition according to the WHO, had a complete set of clinical data, maternal history data, and handed the required amount of blood sample for serology testing. The case definition and final classification of CRS were adapted from the WHO CRS Surveillance Standard (see Table, Supplemental Digital Content 1, https://links.lww.com/INF/E504).5 The patients who had incomplete clinical data set and whose blood is not collected were excluded. Blood samples were not collected caused by technical problems (related to the time of collection), the patient died before the samples were collected, and the patient’s residence. Some patients from outside Yogyakarta province were unable to take the blood test because of the distance from their home.

ELISA Assays

Whole blood collection was performed aseptically from the vein by trained health care professionals with a withdrawal volume of around 1 mL for each patient if possible. In smaller infants, a draw volume of 0.5 mL blood could be tolerated. Whole blood was stored at 4−8°C for up to 24 hours or at 20–25°C for 6 hours before centrifuged at 3500 rpm for 5 minutes to separate the blood serum from the clotted blood. After that, the collected serum was stored in aliquots at −20°C until transferred. Additional blood samples were obtained after 4 weeks of collection of the first specimen from (a) infants <1 month of age at the time of first blood collection and whose first blood sample was negative for immunoglobulin M (IgM) antibodies against rubella, since IgM seropositivity may be postponed until after the first month of existence, (b) infants 6–11 months of age whose first blood sample was negative for rubella IgM antibodies but positive for rubella immunoglobulin G (IgG) antibodies, and (c) infants with inconclusive IgM or IgG antibodies resulting in first blood sample testing.

Analysis for specific IgM and IgG antibodies were completed by using rubella enzyme-linked immunosorbent assay (ELISA) kits. Results of serologic tests were classified as positive (rubella IgM and IgG optical density [OD] > 0.20 IU/mL), negative (rubella IgM and IgG OD < 0.10 IU/mL), or equivocal (0.10 < rubella IgM and IgG OD ≤ 0.20 IU/mL). These laboratory tests were performed at the Health Laboratory Center in Yogyakarta.

The examination diagram is differentiated for infants less than 6 months and more or equal to 6 months to 12 months of age (see Figures, Supplemental Digital Content 2 and 3, https://links.lww.com/INF/E504).

Statistical Analysis

Data were analyzed descriptively using the SPPS version 22 statistical package (IBM Corp., Chicago, IL) and STATA version 14. Data were presented and summarized using frequency tables, graphs, and charts.

RESULTS

The study involved 229 infants who were suspected of CRS from July 2015 to July 2020. We found that 47 of them (20.52%) were classified as laboratory-confirmed CRS cases. Sixty-nine per cent of the suspected cases (159 of 229) were classified as discarded, 9 per cent (21 of 229) were clinically compatible, and none of the infants was congenital rubella infection.

The impact of the MR vaccination campaign on CRS cases will be seen 9 months postcampaign, which is related to the gestational age of a mother with rubella infection. Therefore, to compare the impact of the MR campaign on the reduction in CRS cases, a cutoff was taken 9 months after the MR campaign was implemented. The CRS incidence was 0.39 per 1000 live births in precampaign and 0.08 in postcampaign. Figure 1 and Table 1 show that 1 year after introducing the MR vaccine campaign confirmed cases of CRS were significantly decreased (P = 0.00).

TABLE 1. - Incidence Rates of CRS Before and After Measles Rubella Vaccination Campaign in August–September 2017 in Java, 2015–2020
CRS Cases (n) Person-years at Risk Standardized IR (per 1000 PY) Adjusted IRR (95% CI)
2015 second 3 21,852 0.14 1.00
2016 first 1 22,410 0.04 0.33
2016 second 17 20,616 0.82 6.01
2017 first 4 21,138 0.19 1.38
2017 second 1 21,220 0.05 0.34
2018 first 11 21,549 0.51 3.72
2018 second 5 21,456 0.23 1.70
2019 first 1 20,475 0.05 0.36
2019 second 3 21,976 0.14 0.99
2020 first 1 26,785 0.04 0.27
CI indicates confidence intervals; CRS, congenital rubella syndrome; IR, incidence rate per 1000 person years; IRR, incidence rate ratio; PY, person years.

FIGURE 1.
FIGURE 1.:
Suspected and laboratory-confirmed CRS cases per semester. CRS indicates congenital rubella syndrome.

Sociodemographic data of the subjects are shown in Table 2. Most of the laboratory-confirmed cases were diagnosed among 1–5 months of age in 26 (55.3%) infants, while the remaining 7 (14.9%) and 14 (29.8%) infants were 0–<1 month and 6–11 months, respectively. According to gender, the laboratory-confirmed cases showed similar numbers. The number of female infants was 26 (55.3%), while the male ones were 21 (44.7%).

TABLE 2. - Sociodemographic Data
Sociodemographic Data Laboratory-confirmed CRS (n = 47) (%)
Age at diagnosis
 0–<1 mo 7 (14.9)
 1–5 mo 26 (55.3)
 6–11 mo 14 (29.8)
Sex
 Male 21 (44.7)
 Female 26 (55.3)
Gestational age
 Preterm 8 (17.0)
 Term 35 (74.5)
 Postterm 0 (0)
 Unknown 4 (8.5)
Parity
 Primipara 33 (70.2)
 Multipara 13 (27.7)
 Unknown 1 (2.1)
Birthplace
 Referral hospital 24 (51.1)
 Public health center 7 (14.9)
 Private health facilities 8 (17.0)
 Midwife clinic 4 (8.5)
Unknown 4 (8.5)
Birth weight
 Normal birth weight 16 (34.1)
 Large birth weight 1 (2.1)
 Low birth weight 22 (46.8)
 Very low birth weight 4 (8.5)
 Unknown 4 (8.5)
Growth discrepancy
 Appropriate for gestational age 18 (38.3)
 Small for gestational age 25 (53.2)
 Large for gestational age 0 (0)
 Unknown 4 (8.5)
Residence
Special Region of Yogyakarta (n = 16)
 Yogyakarta 1 (2.1)
 Sleman 3 (6.4)
 Bantul 6 (12.8)
 Gunung Kidul 4 (8.5)
 Kulon Progo 2 (4.3)
Outside Special Region of Yogyakarta (n = 31)
 Jawa Tengah 22 (46.8)
 Outside Jawa Tengah 9 (19.1)
CRS indicates congenital rubella syndrome.

The maternal age had a median of 30 years, which ranged from 20–40 years. Concerning obstetric history, most pregnancies were in term (74.5%), and most mothers were primipara (70.2%). Among all the mothers who had children with laboratory-confirmed CRS, there was only 1 (2.2%) who had rubella vaccination during her pregnancy. Besides that, according to birth history, there were 4 infants born in midwifery clinics, 8 in private health facilities, 7 in public health centers, and most of them in referral hospitals. The median birth weight of all the laboratory-confirmed cases was 2300 g (range: 1300–4100). Most of the infants were born with low birth weight (46.8%) and small for gestational age (53.2%) (see Supplemental Digital Content 4, https://links.lww.com/INF/E504).

Only 2 women (15.6%) reported being diagnosed with rubella in pregnancy by laboratory testing. The most frequently reported symptom in mothers with CRS infants was cough (45.8%), followed by a maculopapular rash (39.6%), rhinitis (39.6%), fever (33.3%), arthralgia (18.8%), swollen lymph nodes (8.3%), conjunctivitis (2.1%), and other symptoms (4.2%).

Clinical manifestations among suspected and laboratory-confirmed CRS patients are shown in Table 3. The most frequent group, a clinical sign among suspected CRS cases, was hearing impairment (n = 129/223; 57.8%), followed by congenital heart disease (n = 129/227; 56.8%) and congenital cataracts (n = 70/227; 30.8%). Among the group B clinical signs, microcephaly was found in 143/227 (62.9%) and developmental delays in 126/218 (57.8%) of the subjects.

TABLE 3. - Clinical Manifestation of All Subjects
Clinical Characteristic Suspected (n = 229) (%) Laboratory Confirmed (n = 47) % Clinically Compatible (n = 22) % Discarded Cases (n = 160) %
Group A
• Congenital heart disease 129/227 (56.8) 43/47 (91.4) 13/22 (59.1) 73/153 (47.7)
• Cataract 70/227 (30.8) 32/47 (68.1) 6/21 (28.5) 32/156 (20.5)
• Hearing impairment 129/223 (57.8) 26/46 (55.3) 12/21 (57.1) 91/154 (59.1)
• Pigmentary retinopathy 4/221 (1.8) 1/45 (2.2) 0/20 (0) 3/153 (1.9)
• Congenital glaucoma 2/223 (0.9) 0/45 (0) 0/20 (0) 2/155 (1.3)
Group B
• Microcephaly 143/227 (62.9) 33/47 (70.2) 10/19 (52.6) 100/159 (62.9)
• Developmental delay 126/218 (57.8) 23/44 (52.3) 11/18 (61.1) 103/174 (59.2)
• Jaundice in the first 24 hrs after birth 40/223 (17.9) 11/46 (23.9) 3/19 (15.7) 26/154 (16.8)
• Purpura 8/227 (3.5) 1/47 (2.1) 0/19 (0) 7/157 (4.5)
• Meningoencephalitis 17/227 (7.4) 1/47 (2.1) 3/18 (16.7) 13/159 (8.1)
• Splenomegaly 13/229 (5.6) 3/47 (6.3) 1/20 (5) 9/157 (5.7)
• Radiolucent bone disease 8/199 (4.0) 0/36 (0) 0/14 (0) 8/144 (5.5)

Among these laboratory-confirmed CRS cases, all of the infants satisfied the clinical criteria for CRS, 40 had at least 2 group A conditions, and 7 had at least 1 group A and group B conditions. None of these infants was classified as congenital rubella infection. The most common group, A clinical sign among confirmed CRS cases, was congenital heart disease (n = 43/47; 91.4%), followed by congenital cataract (n = 32/47; 68.1%) and hearing impairment (n = 26/46; 55.3%). Pigmentary retinopathy was found in only 1 infant, and none of the infants had congenital glaucoma. Among the group B clinical signs found in confirmed CRS cases, microcephaly was found in 33/47 (70.2%) and developmental delay in 23/44 (52.3%) of the subjects. Moreover, 11/46 (23.9%) of them had jaundice in the first 24 hours after birth, and 3/47 (6.3%) of them had splenomegaly. Each of the purpura and meningoencephalitis accounted for 1/47 (2.1%) in confirmed CRS cases. None of them had a radiolucent bone disease. The most multiple symptoms were found in case 34 (congenital heart disease, cataract congenital, microcephaly, jaundice in the first 24 hours after birth, splenomegaly, and developmental delay).

DISCUSSION

There has been a decreasing number of rubella infections and CRS cases in many countries due to vaccination programs. Meanwhile, there are still massive epidemics in South East Asia, mainly in Indonesia and India, which had not introduced routine immunization in 2016. Indonesia launched the MR vaccination campaign from August to September 2017 in Java and from August to September 2018 for other regions (outside Java). It is assumed that the impact of the MR vaccination campaign on the reduction of CRS cases can only be assessed at least 9 months after the campaign launched. In this study, there was a decrease (60.9%) of CRS incidence in Yogyakarta, Indonesia, from 0.39 per 1000 live birth in the precampaign era to 0.08 in the postcampaign era. Before introducing the MR immunization campaign program, the CRS incidence of our study was closely similar to previous reports, such as 0.4 per 1000 live births in Ethiopia,14 0.5 in Malaysia,15 0.69 in Congo,1 and 0.7 in Oman.16 It was inconsistent with other studies that have documented higher CRS incidence, such as 1.5 per 1000 live births in Singapore, 1.7 in Israel, and 1.7 in Panama during outbreaks.17 This disparity of CRS incidence may be due to differences in the vaccination coverage of rubella, quality of CRS surveillance and differences in the medical health system where the studies were conducted. So far, no study has compared the impact of decreasing CRS cases before and after the MR campaign.

As well-known, the WHO definition of rubella and CRS control is a 95% reduction of rubella and CRS cases as compared with the 2008 baseline nationally and for the region.18 One of the limitations of this study is that we did not have the baseline in 2008. Therefore, we could not determine whether rubella and CRS are controlled yet or not. In 2017, the number of CRS cases in our surveillance study had decreased. This finding is because this study is only centered on 1 referral hospital so that patients from other hospitals cannot be registered. Robust laboratory surveillance is mandatory for detecting CRS cases and determining vaccine effectiveness.

In this study, most of the laboratory-confirmed CRS cases were diagnosed among 0–<6 months of age in 31 infants (65.9%), which showed the same results from the previous studies.7,14,19 It differs from a study in Africa where most laboratory-confirmed CRS cases were found in the age group 6–11 months.1 To conclude, CRS cases could be detected as early as possible. However, the awareness and knowledge levels among parents in Indonesia toward this disease remain low. This could be observed through the number of vaccinated mothers, which was only 1 person among all of the cases in this study. Additionally, the mothers who consulted their rubella infection symptoms during their pregnancy and who were diagnosed were only 2 persons. Furthermore, MR vaccination has not been implemented routinely as a part of the preconception care before mothers get pregnant in Indonesia.

More than 50% of maternal rubella infection cases occur asymptomatically. In a clinical setting, the prodromal symptoms involving fever, malaise, and adenopathy, especially in postauricular lymph nodes, develop with viremia after an incubation period of 13–20 days. A maculopapular rash sometimes develops atypical, scarlatiniform, or purpuric characteristics. Notably, the clinical diagnosis of rubella is unreliable because similar rashes occur in other viral infections.20 In this study, the most frequently reported symptom in mothers with CRS infants, was cough (45.8%), followed by a maculopapular rash (39.6%) and rhinitis (39.6%). There were 7 mothers (14.8%) with no symptoms at all. It was consistent with another study that showed a clinical diagnosis of rubella in pregnancy is unreliable because only 19% of the pregnant women presented with clinical signs. Moreover, only 7.5% of IgG positive pregnant women had fever and conjunctivitis, and 4.1% had conjunctivitis.21 Because of their inconsistent and unspecific clinical signs, the clinical diagnosis of rubella infection in pregnancy is challenging and unreliable. One of the limitations of this study is recall bias, as the cases were recruited months after maternal infection. This is because most pregnant women with 1 sign of rubella infection, especially mild symptoms, will not present to health facilities. Therefore, we propose that the woman’s immunity levels in early pregnancy should be a priority to be checked. Since most women would have had acquired their infection naturally, their IgG levels would be sufficiently high for detection using standard ELISA assays. Prenatal diagnosis of fetal infection is recommended in situations where the primary rubella infection happens within the first 4 months of pregnancy.20

Previously, the rubella vaccine was not yet included in the national program. Some individuals get the MR vaccines independently. In Indonesia, the MR immunization campaign has been carried out with a target population of up to 15 years. However, vaccination for women with no history of rubella or no immunity from serology testing was not implemented yet as a national program in Indonesia. Thus, we suggest expanding the target population of the vaccination program, including women who have not had a history of rubella or no immunity from serology testing.

Most of the infants in this study were born with low birth weight (42.2%) and small for gestational age (53.3%). It has been linked that rubella virus (RV) infected cells grow and divide slowly compared with uninfected cells. Within a few passages, various cell lines infected with RV cease to grow. This condition was linked to phenomena such as chromosome breakage. The theory of the pathogenesis of rubella-induced birth defect has included viral proliferation in tissues resulting in reduced cellular growth rate and shortened lifespan.22,23

In some studies, the pattern of clinical manifestations in CRS varied widely. The most common clinical manifestation in our study was congenital heart disease (83.3%), followed by congenital cataract (68.2%) and hearing impairment (53.5%). It was consistent with other studies that have documented congenital heart disease as the most frequent manifestation.24–27 Some studies showed that hearing impairment was the most frequent manifestation of CRS,7,28 while the ocular problem was the most prevalent in other studies.15,29–31 This disparity in the clinical manifestations of CRS cases in various studies may be attributed to the medical health system, the specialty of the health establishments and economic constraints where the studies were conducted. While it is difficult to determine accurately, the disparity could also be due to the organ system involved and the gestational age at which maternal rubella infections occurred.32 Furthermore, it should be noted that the majority of the CRS cases were detected in 0–6 months, where it is difficult to establish any hearing impairment in such young infants unless specialist equipment is used.

Economic constraints, a gap of knowledge and healthcare system barriers are among the significant challenges faced by patients and medical staff in 1 of the most populated urban and upper-middle-income countries such as Indonesia. To eliminate rubella infection, several efforts need to be done in an endemic country, including (1) effective promotion of vaccination programs involving the private sector that raises public awareness about morbidity and mortality of this disease, (2) improving coverage of the vulnerable population (older children and adults who might have skipped previous vaccination programs), (3) implementation of MR vaccination as routine preconception care before the mother gets pregnant, and (4) an effective CRS surveillance system.

CONCLUSIONS

There has been a declining number of CRS cases after 1 year from the MR vaccination campaign in Yogyakarta, Indonesia. An effective surveillance system will help to monitor the number of CRS cases.

TABLE 4. - Clinical and Laboratory Findings of Confirmed CRS Cases
Cases Age (mo) Sex Setting Clinical Presentation(s) in Each Infant Serology Test
First IgM First IgG Second IgM Second IgG
Case 1 <1 M Urban congenital heart disease, hearing impairment, microcephaly, jaundice in the first 24 hours after birth, developmental delay 12.82
Case 2 <1 F Rural congenital heart disease, hearing impairment, microcephaly 11.83
Case 3 1 M Rural congenital heart disease, hearing impairment, microcephaly 6.01
Case 4 1 F Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly 13.28
Case 5 2 F Urban hearing impairment, microcephaly, jaundice in the first 24 hours after birth, developmental delay 1.87
Case 6 2 F Rural congenital heart disease, hearing impairment, microcephaly, 5.49
Case 7 <1 M Rural congenital heart disease, hearing impairment, jaundice in the first 24 hours after birth 4.66
Case 8 7 M Urban hearing impairment, microcephaly, developmental delay 12.3 286
Case 9 2 F Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly 6.6
Case 10 3 M Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly, developmental delay 21.13
Case 11 8 M Rural congenital heart disease, cataract congenital, developmental delay 0.3 246
Case 12 2 F Rural congenital heart disease, cataract congenital, microcephaly 10.24
Case 13 2 F Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly 14.74
Case 14 2 F Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly 10.69
Case 15 2 M Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly 0.688
Case 16 4 M Rural congenital heart disease, hearing impairment 0.38
Case 17 5 M Urban congenital heart disease, cataract congenital, microcephaly, developmental delay 0.738
Case 18 3 M Rural congenital heart disease, cataract congenital, developmental delay 0.32
Case 19 7 F Rural congenital heart disease, cataract congenital, microcephaly, developmental delay 0.43 2.26
Case 20 2 F Urban congenital heart disease, cataract congenital, pigmentary retinopathy, hearing impairment 1.12
Case 21 7 F Rural congenital heart disease, cataract congenital, microcephaly, developmental delay 0.27 2.59
Case 22 7 M Rural hearing impairment, microcephaly, developmental delay 1.40 2.89
Case 23 7 M Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly, developmental delay 0.21 192
Case 24 11 F Urban congenital heart disease, hearing impairment, microcephaly, splenomegaly, developmental delay 1.29 1.87
Case 25 1 F Rural congenital heart disease, cataract congenital 10.08
Case 26 6 F Urban congenital heart disease, cataract congenital, hearing impairment, microcephaly, developmental delay 0.46 2.44
Case 27 <1 M Rural congenital heart disease, developmental delay 0.32
Case 28 1 M Urban congenital heart disease, cataract congenital 0.62
Case 29 4 M Rural congenital heart disease, cataract congenital, hearing impairment 0.99
Case 30 5 M Rural congenital heart disease, cataract congenital, jaundice in the first 24 hours after birth 0.67
Case 31 3 F Rural congenital heart disease, cataract congenital, purpura, microcephaly 1.14
Case 32 10 F Urban hearing impairment, microcephaly, meningoencephalitis, developmental delay 0.79 0.93
Case 33 <1 F Urban congenital heart disease, cataract congenital 1.37
Case 34 1 M Urban congenital heart disease, cataract congenital, microcephaly, jaundice in the first 24 hours after birth, splenomegaly, developmental delay 1.42
Case 35 3 M Urban congenital heart disease, cataract congenital, microcephaly 1.37
Case 36 <1 M Rural congenital heart disease, cataract congenital, microcephaly 0.88
Case 37 4 F Rural cataract congenital, developmental delay 0,43
Case 38 3 F Rural congenital heart disease, cataract congenital, microcephaly, jaundice in the first 24 hours after birth, splenomegaly 0.83
Case 39 4 M Rural congenital heart disease, cataract congenital, microcephaly, jaundice in the first 24 hours after birth 0.99
Case 40 2 F Rural congenital heart disease, hearing impairment, microcephaly 0.608
Case 41 10 M Rural congenital heart disease, cataract congenital, hearing impairment, developmental delay 10.68 95
Case 42 9 F Rural congenital heart disease, cataract congenital, microcephaly 0.82 400
Case 43 9 F Rural congenital heart disease, microcephaly, jaundice in the first 24 hours after birth 0.047 0.94 0.008 1.95
Case 44 10 F Rural congenital heart disease, cataract congenital, microcephaly, jaundice in the first 24 hours after birth, developmental delay 0.002 1.06 0.048 2.98
Case 45 4 F Urban congenital heart disease, hearing impairment, microcephaly, developmental delay 1.173
Case 46 5 F Rural congenital heart disease, cataract congenital, hearing impairment, developmental delay 0.472
Case 47 10 F Rural congenital heart disease, cataract congenital, hearing impairment, microcephaly, jaundice in the first 24 hours after birth, developmental delay 0.443 1.829
*Range normal (IgM Positive: OD > 0.2 IU/mL; IgG Positive: OD > 0.2 IU/mL).
F indicates female; IgG, immunoglobulin G; IgM, immunoglobulin M; M, male; mo, month; OD, optical density.
The bolded one indicates a positive serology result, while the other is negative.

ACKNOWLEDGMENTS

We thank the patients and their families who have contributed in these studies. We are also grateful to a native speaker at the English Services Center, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, for editing the grammar and proofreading of our manuscript. We would like to also express our appreciation for the cooperation of the Health Laboratory Center Yogyakarta and Provincial Health Office Yogyakarta for establishing this surveillance.

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Keywords:

surveillance; congenital rubella syndrome; hospital-based study; measles rubella vaccination campaign; Indonesia

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