Active surveillance for congenital rubella syndrome in Yangon, Myanmar.

12 Bulletin of the World Health Organization | January 2006, 84 (1) Objective Rubella vaccine is not included in the immunization schedule in Myanmar. Although surveillance for outbreaks of measles and rubella is conducted nationwide, there is no routine surveillance for congenital rubella syndrome (CRS). Therefore, we organized a study to assess the burden of CRS. Methods From 1 December 2000 to 31 December 2002 active surveillance for CRS was conducted among children aged 0–17 months at 13 hospitals and 2 private clinics in Yangon, the capital city. Children with suspected CRS had a standard examination and a blood sample was obtained. All serum samples were tested for rubella-specific IgM; selected samples were tested for rubella- specific IgG and for rubella RNA by reverse transcriptase–polymerase chain reaction (RT–PCR). Findings A total of 81 children aged 0–17 months were suspected of having CRS. Of these, 18 children had laboratory-confirmed CRS (7 were IgM positive; 7 were RT–PCR positive; and 10 were IgG positive at > 6 months of age). One additional child who tested positive by RT–PCR and whose mother had had rubella during pregnancy but who had a normal clinical examination was classified as having congenital rubella infection. During 2001–02 no rubella outbreaks were detected in Yangon Division. In the 31 urban townships of Yangon Division, the annual incidence was 0.1 laboratory-confirmed cases of CRS per 1000 live births. Conclusion This is the first population-based study of CRS incidence from a developing country during a rubella-endemic period; the incidence of CRS is similar to endemic rates found in industrialized countries during the pre-vaccine era. Rubella-specific IgG tests proved practical for diagnosing CRS in children aged > 6 months. This is one of the first studies to report on the use of rubella- specific RT–PCR directly on serum samples; further studies are warranted to confirm the utility of this method as an additional means of diagnosing CRS. Keywords Rubella syndrome, Congenital/epidemiology/diagnosis; Epidemiologic surveillance; Reverse transcriptase polymerase chain reaction; Infant; Cohort studies; Myanmar (source: MeSH, NLM). Mots clés Rubéole congénitale/épidémiologie/diagnostic; Surveillance épidémiologique; Réaction polymérisation en chaîne par transcriptase inverse; Nourrisson; Etude cohorte; Myanmar (source: MeSH, INSERM). Palabras clave Síndrome de rubéola congénita/epidemiología/diagnóstico; Vigilancia epidemiológica; Reacción en cadena de la polimerasa de transcriptasa reversa; Lactante; Estudios de cohortes; Myanmar (fuente: DeCS, BIREME). Bulletin of the World Health Organization 2006;84:12-20. Voir page 18 le résumé en français. En la página 18 figura un resumen en español. Introduction Rubella is a common cause of rash and fever during childhood. However, its public health importance relates to the teratogenic effects of primary rubella infection occurring in pregnant women, a Virology Research Division, Department of Medical Research (Lower Myanmar), Yangon, Myanmar. b Yangon Children’s Hospital, Yangon, Myanmar. c Department of Medical Research (Lower Myanmar), Yangon, Myanmar. d Department of Immunization, Vaccines and Biologicals, World Health Organization, 1211 Geneva 27, Switzerland. Correspondence to this author (email: robertsons@who.int). Ref. No. 05-022814 (Submitted: 4 April 2005 – Final revised version received: 31 August 2005 – Accepted: 1 September 2005) Active surveillance for congenital rubella syndrome in Yangon, Myanmar Kyaw-Zin-Thant,a Win-Mar-Oo,a Thein-Thein-Myint,b Than-Nu-Shwe,b Aye-Maung-Han,b Khin-Mar-Aye,a Kay-Thi-Aye,a Kyaw-Moe,a Soe-Thein,c & Susan E Robertsond .19 Research which can lead to fetal death with spon- taneous abortion or to congenital defects in surviving infants. The association be- tween birth defects and rubella infection during pregnancy was first reported in 1941 by Gregg, an Australian ophthal- mologist.1 A later prospective study in the United Kingdom found that 85% of infants born to women who had had rubella during the first 11 weeks of preg- nancy had birth defects.2 Manifestations of congenital rubella syndrome (CRS) in surviving infants may be transient (e.g., low birth weight, purpura), may 13Bulletin of the World Health Organization | January 2006, 84 (1) Research Kyaw-Zin-Thant et al. Surveillance for congenital rubella syndrome in Myanmar be permanent structural manifestations (e.g., deafness, congenital heart disease, cataracts, mental retardation) or may be late-emerging conditions (e.g., diabetes, thyroid disorders).3 WHO estimates that worldwide more than 100 000 children are born with CRS each year, mostly in developing countries.4, 5 Studies of CRS have been conducted in many parts of the world, including several south-east Asian countries.6 In Myanmar, several rubella sero- prevalence studies from the 1970s that were conducted in urban settings showed high immunity (> 92%) among women of childbearing age, although one study showed only 80% immunity among women aged 15–19 years.7, 8 While this suggests that rubella infections occurred mostly prior to childbearing age in the 1970s, a case series of children with con- genital anomalies seen at a tertiary referral centre that has Yangon’s largest neonatal intensive care unit during 1975–78 found that 21 (11%) of 196 children had signs clinically compatible with CRS.8 The National Immunization Pro- gramme in Myanmar provides one dose of measles vaccine to all children when they are aged 9 months; however, the routine immunization schedule does not include rubella vaccine. Measles– mumps–rubella vaccine is available privately but uptake is limited because of the cost. In 2000, Myanmar imple- mented enhanced surveillance procedures for measles and rubella; these consist of investigating outbreaks of febrile illnesses with maculopapular rash in people of all ages. The National Health Laboratory tests serum specimens from 5–10 cases for each outbreak: specimens are tested for measles-specific IgM and if they are nega- tive, they are tested for rubella-specific IgM.9 Given the lack of information on the burden of CRS in Myanmar, a prospective surveillance study was under- taken, using both molecular and serologi- cal tests to confirm the diagnosis. Methods Active surveillance From 1 December 2000 to 31 December 2002, active surveillance for CRS occur- ring in children aged 0–17 months was conducted in Yangon, Myanmar, at all 13 hospitals providing paediatric ser- vices, including: specialist ophthalmol- ogy; ear, nose and throat; and obstetric hospitals, and at two private clinics. Meetings were held with administrators and physicians at each study site, and a study coordinator (usually a paediatri- cian) was appointed. The coordinators were provided with posters that displayed the definitions of CRS cases, study forms, information on the availability of labo- ratory tests, and details on how to con- tact the study laboratory. Each month the study coordinators were contacted to ensure that all suspected CRS cases had been reported. In August 2001 and July 2002, one-day workshops on CRS were held for physicians at participating hos- pitals. In addition, information on CRS was presented at national and regional medical conferences, and a briefing on rubella and CRS was included in con- tinuing education materials for physi- cians provided by the National Medical Association. Ethical procedures The study protocol was reviewed and approved by the Ethical Committee on Medical Research Involving Human Sub- jects, Department of Medical Research (Lower Myanmar), Yangon, and the WHO Secretariat Committee on Re- search Involving Human Subjects, Geneva, Switzerland. Parents of children meeting the case definition for suspected CRS were provided with information about the study. If parents provided in- formed consent, children were enrolled. Each child enrolled had a standard clini- cal examination and a 1 ml blood sample was obtained. A questionnaire was ad- ministered to the mother asking about the child’s medical history as well as her pregnancy history, including whether rubella had been diagnosed during the first trimester of pregnancy. Case definitions Case definitions were modified from WHO guidelines.10 Suspected CRS A child aged 0–17 months was defined as having suspected CRS if there was a maternal history of suspected or con- firmed rubella during pregnancy and/or a physician detected at least one of the following clinical signs: congenital heart disease, suspicion of deafness, cataract, glaucoma, pigmentary retinopathy, pur- pura, splenomegaly or microcephaly. Clinically confirmed CRS A child aged 0–17 months was defined as having clinically confirmed CRS if a physician detected two of the clinical signs in group (a) or one from group (a) and one from group (b). Group (a) consists of: cataract(s), congenital glau- coma, pigmentary retinopathy, congeni- tal heart disease or hearing loss. Group (b) consists of: purpura, splenomegaly, microcephaly, mental retardation, me- ningoencephalitis, radiolucent bone disease, or jaundice occurring within 24 hours after birth. Laboratory-confirmed CRS A child aged 0–17 months was defined as having laboratory-confirmed CRS if the child was suspected of having CRS and a serum sample was positive for rubella-specific IgM; and/or positive for rubella-specific IgG at age 6–17 months (only if the child had not received rubella vaccine and had no history of febrile rash illness); and/or positive for rubella RNA by reverse transcriptase–polymerase chain reaction (RT–PCR). Congenital rubella infection A child aged 0–17 months was defined as having congenital rubella infection if there was a positive serum test for rubella but there were no clinical signs of CRS. Clinical examination Each child was examined clinically by the attending paediatrician; this examina- tion was based on a standard protocol. At Yangon Children’s Hospital all children with suspected congenital heart disease had echocardiography. Hearing was tested by determining whether the child responded to sound; otoacoustic hearing testing equipment was not available. Laboratory methods Blood samples were kept at the study hospitals for a few hours at 4–8 °C before being transferred to the Virology Re- search Division, Department of Medical Research (Lower Myanmar), Yangon. Serum samples were separated and stored at –70 °C until further procedures were performed. All 81 serum samples from sus- pected cases were tested for rubella IgM with a commercially available ELISA kit (Human GmbH, Germany), which was used according to the manufacturer’s instructions. A subset of 57 specimens (70%) that had sufficient serum was tested for ru- bella IgG using a commercially available ELISA kit (bioMérieux, Netherlands). A subset of 39 specimens (48%) that had serum remaining was tested for the pres- ence of rubella virus genome using the 14 Bulletin of the World Health Organization | January 2006, 84 (1) Research Surveillance for congenital rubella syndrome in Myanmar Kyaw-Zin-Thant et al. Table 1. Sources reporting 81 suspected cases of congenital rubella syndrome, Yangon, Myanmar, December 2000–December 2002 Source No. (%) of suspected cases No. (%) of cases confirmed by laboratory testing Yangon Children’s Hospital 37 (46) 7 (39) Central Women’s Hospital 17 (21) 4 (22) Private clinics 6 (7) 1 (6) Thingangyun Sanpya General Hospital 5 (6) 2 (11) North Okkalapa General Hospital 4 (5) 1 (6) Eye Hospital (Yangon) 3 (4) 1 (6) South Okkalapa Women and Children’s Hospital 3 (4) 0 No.2 Military Hospital 2 (3) 0 Ear, Nose and Throat Hospital (Yangon) 1 (1) 0 Insein General Hospital 1 (1) 1 (6) Defence Services Obstetrics, Gynaecological and Children’s Hospital 1 (1) 1 (6) East Yangon General Hospital 1 (1) 0 West Yangon General Hospital 0 0 Yangon General Hospital 0 0 Total 81 18 reverse transcription–nested polymerase chain reaction method at the National Institute of Infectious Diseases, Tokyo, Japan.11 Specimens were shipped from Yangon packed in dry ice and stored at –70 °C in Tokyo prior to testing. DNA fragments covering the whole E1 gene of the rubella virus genome were synthesized using RT–PCR. The resulting products were purified and directly sequenced, and the phylogenetic tree constructed. Data analysis Data were entered and analysed using Epi Info software, version 6.04b (United States Centers for Disease Control and Prevention, Atlanta, GA, USA, and WHO, Geneva, Switzerland). Yangon is the capital of Myanmar and the capital of Yangon Division, one of 14 administrative states/divisions in the country. Yangon Division had a population of approximately 5.7 million in 1999.12 Yangon Division is adminis- tratively divided into 45 townships; the 33 urban townships of Yangon Division were included in the active surveillance system since residents in these town- ships had easy access to one or more hospitals participating in the study. We calculated the incidence of suspected and laboratory-confirmed CRS cases among children aged 0–11 months occurring per 1000 live births. Findings From 1 December 2000 to 31 December 2002, active surveillance for CRS de- tected 81 children aged 0–17 months who were suspected of having CRS; all were enrolled in the study. Of these, 37 (46%) were reported by the Yangon Children’s Hospital, the tertiary referral centre for paediatrics (Table 1). Seventeen of the suspected cases (21%) were reported by the Central Women’s Hospital, a tertiary referral centre with the largest neonatal intensive care unit in Yangon. Six sus- pected cases (7%) were reported by the private clinics. Among the 81 children with suspected CRS, 54 (67%) were aged 0–5 months at enrolment; 20 children (25%) were aged 6–11 months; and 7 children (9%) were aged 12–17 months. Three sets of twins were enrolled. Laboratory-confirmed cases There were 18 laboratory-confirmed cases: 7 tested positive for rubella IgM; 10 tested positive for rubella IgG when they were aged > 6 months, and 7 tested positive by RT–PCR (Table 2). The seven children who tested positive for ru- bella IgM were aged 1, 2, 3 (2 children), 6, 8 and 17 months, respectively. Among the 10 children who had IgG present when they were aged > 6 months, only one child (aged 6 months) tested positive for IgM. Four of the children who tested positive by RT–PCR also tested positive for IgM and had unique rubella virus sequences. The remaining three children who tested positive by RT–PCR tested negative for IgM: one child was positive for rubella IgG at the age of 10 months; the other two children had unique ru- bella virus sequences. Of the 18 laboratory-confirmed cases of CRS, 11 met the definition for a clinically confirmed case (Fig. 1). Seven laboratory-confirmed cases did not meet the definition of a clinically confirmed case: two children with con- genital heart disease (one had a maternal history of rubella), two children with bilateral cataracts (only one of whom had a maternal history of rubella), one child with hearing impairment (and a maternal history of rubella), one child with microcephaly and cleft palate, and one child with splenomegaly. There were three pairs of twins with suspected CRS (Table 3). In the first pair, one child was classified as having con- genital rubella infection; this twin had no clinical signs but had a positive maternal history, negative IgM, positive RT–PCR test and a unique virus sequence. The sibling had clinically-confirmed CRS with a negative IgM test; the RT–PCR test was not done. In the second pair of twins, one child had clinically-confirmed and laboratory-confirmed CRS while the sibling was asymptomatic and labora- tory tests were negative. The third pair of twins presented with splenomegaly alone and CRS was not confirmed by laboratory tests. Congenital rubella infection One child with congenital infection tested positive by RT–PCR but had no obvious signs of CRS, although there was a positive maternal history of rubella. This child was classified as having con- genital rubella infection. 15Bulletin of the World Health Organization | January 2006, 84 (1) Research Kyaw-Zin-Thant et al. Surveillance for congenital rubella syndrome in Myanmar Table 2. Clinical presentation of children with laboratory confirmation of congenital rubella syndrome (n = 18) or congenital rubella infection (n = 1), Yangon, Myanmar, December 2000–December 2002 Clinical signs Maternal Age Laboratory results history of (months) IgM RT–PCRa Virus IgG at rubella sequenceb > 6 months Hearing impairment, mental retardation Yes 3 Positive Positive AY 280706 NDc VSD,d cataract (bilateral) No 2 Positive Positive AB 080199 ND PDA,e splenomegaly, microcephaly Yes 8 Positive Positive AB 080200 ND VSD, cataract, splenomegaly, purpura Yes 1 Positive Positive AB 080198 ND CHD,f purpura, microcephaly, mental retardation No 15 Negative Positive AB 080197 ND PDA, splenomegaly, hepatomegaly No 0 Negative Positive AY 280707 Negative PDA, cataract, purpura No 10 Negative Positive ND Positive No abnormalities identifiedg Yes 0 Negative Positive ND ND Cataract (bilateral) No 17 Positive Negative ND ND Splenomegaly No 3 Positive Negative ND ND PDA, cataract and microphthalmos (right eye), No 6 Positive Negative ND Positive nystagmus, splenomegaly, hepatomegaly Cataract (bilateral) Yes 6 Negative ND ND Positive VSD, cataract, pigmentary retinopathy, purpura, No 7 Negative ND ND Positive splenomegaly, mental retardation Microcephaly, cleft palate No 9 Negative ND ND Positive VSD Yes 10 Negative ND ND Positive CHD, hearing impairment,cataract (bilateral), Yes 10 Negative Negative ND Positive microcephaly, purpura, possible mental retardation, syndactyly (left) VSD, PS,h purpura, microcephaly No 11 Negative Negative ND Positive Hearing impairment Yes 14 Negative Negative ND Positive VSD No 17 Negative ND ND Positive a RT–PCR = reverse transcriptase–polymerase chain reaction. b Each rubella virus sequence has been registered with GenBank. The GenBank accession number is listed in the table. c ND= not done. d VSD = ventricular septal defect. e PDA = patent ductus arteriosus. f CHD = congenital heart disease. g This child was classified as having congenital rubella infection. h PS = pulmonary stenosis. Fig. 2 shows the distribution of 18 laboratory-confirmed cases of CRS and the case of congenital infection by month of birth. Nearly half of these chil- dren were born during the cool season (October–December) but there was no obvious clustering of cases. Virus sequencing For six of the RT–PCR products, rubella virus strains were identified (manuscript in preparation). Five strains were geno- type I, and all of these were from children living in central Yangon. One strain was genotype II, and this came from a child whose mother had lived in western Myanmar during the first trimester of pregnancy. The six strains differed from each other by 0.2–6.4% in their nucleo- tide sequences. Population-based incidence among children A total of 66 000 births occurred an- nually in the 33 urban townships of Yangon Division. During the 25-month surveillance period there were 59 sus- pected cases of CRS and 11 laboratory- confirmed cases among children aged 0–11 months in central Yangon. Thus, the annual incidence per 1000 live births was 0.4 suspected cases and 0.1 labora- tory-confirmed cases. Measles and rubella surveillance The nationwide surveillance of measles and rubella outbreaks was conducted by the National Immunization Programme in collaboration with the National Health Laboratory. The surveillance showed that most outbreaks of febrile rash illnesses during 2001–02 were caused by measles. In only one outbreak were 4/6 specimens found to be positive for rubella IgM. This small rubella outbreak occurred in the Southern Shan State (in the eastern part of Myanmar, more than 450 km from Yangon) during mid-2001, and there was no evidence of spread to other areas of the country. The active laboratory- linked surveillance for febrile rash illness did not detect any rubella outbreaks in Yangon during the study period. Discussion This is the first report from a developing country to implement active surveillance for congenital rubella syndrome during a rubella-endemic period. The annual incidence of 0.1 confirmed cases of CRS per 1000 live births found in central 16 Bulletin of the World Health Organization | January 2006, 84 (1) Research Surveillance for congenital rubella syndrome in Myanmar Kyaw-Zin-Thant et al. Table 3. Clinical signs and results of laboratory tests from twins suspected of having congenital rubella syndrome during a period of active surveillance, Yangon, Myanmar, December 2000–December 2002 Twin (sex) Age Clinical signs Laboratory results Twin 1A (male) 4 days No obvious signs; maternal history of rubella IgM negative, RT–PCRa positive, genotype I sequenced Twin 1B (female) 4 days Patent ductus arteriosus, splenomegaly; maternal IgM negative, RT–PCR not done history of rubella Twin 2A (female) 12 days No obvious signs IgM negative, RT–PCR negative, IgG positive at age 12 days, IgG negative at age 9 months Twin 2B (male) 12 days Patent ductus arteriosus, splenomegaly, hepatomegaly IgM negative, RT–PCR positive, genotype I sequenced, IgG positive at age 12 days, IgG negative at age 9 months Twin 3A (female) 4 days Splenomegaly; died in hospital aged 51 days IgM negative, RT–PCR negative Twin 3B (female) 4 days Splenomegaly; died at home aged 54 days IgM negative, RT–PCR negative a RT–PCR = reverse transcriptase–polymerase chain reaction. Yangon is similar to the annual incidence of 0.1/1000 reported in Canada13 and 0.2/1000 reported in Norway14 during endemic periods prior to the introduc- tion of rubella vaccine. Rubella is an en- demic disease with epidemics occurring every 5–9 years. Most population-based assessments of the incidence of CRS occurred after large-scale outbreaks of rubella, and the annual incidence has ranged from 1–4 cases per 1000 live births in the epidemic setting.4 CRS surveillance is difficult during endemic periods because it is a relatively rare disease. The success of this study re- flects the ongoing efforts that were made to keep clinicians alert to the disease us- ing a variety of strategies, such as making monthly inquiries about suspected cases at each participating hospital, presenting information on the disease at medical conferences and preparing a briefing on rubella and CRS as part of continuing education materials for physicians. It was unclear whether children born at home who had CRS would be identified by hospital-based surveillance. The 1997 Fertility and Reproductive Health Survey found that 25% of births in the Yangon Division occurred at home.15 Among the 81 children classi- fied as suspected cases of CRS and iden- tified by the hospital-based surveillance, 17 (21%) had been born at home but eventually were seen by paediatricians and reported to the surveillance system. There is a strong incentive to register infants born at home because a birth certificate is required to obtain health care, including vaccinations. This study identified three pairs of twins suspected of having CRS. In one pair of twins, one sibling had CRS confirmed both clinically and by laboratory testing while the other child was not infected. This is consistent with other reports in the medical literature that have found only one twin may be affected.16–18 Among the 18 laboratory-con- firmed cases in this study, congenital heart disease was the most common sign of CRS. It was seen in 13 children (72%). Other common signs were cataract (8 children; 44%), purpura (6 children; 33%) and splenomegaly (6 children; 33%). The proportions of vari- ous CRS signs and symptoms identified in Myanmar are similar to those reported in studies from Mexico,19 Panama20 and the United States,21 although surveillance methods varied among studies (Table 4). The proportion of children who were deaf was lower in Myanmar and Mexico but this most likely relates to the younger age at which children were examined and the limited ability to assess hearing loss in very young children in most develop- ing countries. Recently, some higher- income countries have introduced new technologies to diagnose hearing loss in infants. In Singapore, for example, traditional childhood screening detected deafness at a median age of 20.8 months but during the period 2002–04 the age at detection fell to 2.7 months at hospitals that screened neonates using otoacoustic testing and other new tech- nologies.22 Given that 50–70% of infants with CRS have impaired hearing and in many children this is the only sign,2, 3 the annual incidence of CRS in Yangon may have been twice the level reported in this study. A number of modifications in the Paediatricians and specialists (ophthalmologists, ear-nose-throat doctors, cardiologists) at 13 hospitals and selected private clinics participate Fig. 1. Flow of active surveillance for congenital rubella syndrome (CRS) among children aged 0–17 months, Yangon, Myanmar, December 2000–December 2002 WHO 05.152 81 suspected cases reported through surveillance system 49 not clinically confirmed 32 clinically confirmed CRS 7 laboratory-confirmed CRS and 1 case of congenital rubella infection 11 laboratory-confirmed CRS 17Bulletin of the World Health Organization | January 2006, 84 (1) Research Kyaw-Zin-Thant et al. Surveillance for congenital rubella syndrome in Myanmar Table 4. Clinical characteristics of children with laboratory-confirmed cases of congenital rubella syndrome in Myanmar and comparison with findings and characteristics of studies in Mexico, Panama and the United States Clinical and study Place of study characteristics Yangon, Myanmar Mexico City, Mexico 19 Panama 20 USA 21 (n = 18) (n = 42) (n = 54) (n = 122) Congenital heart disease 13/18 (72)a 28/42 (67) 34/54 (69) 86/122 (70) Cataract 8/18 (44) 29/42 (69) 16/54 (30) 52/122 (43) Splenomegaly 6/18 (33) 8/42 (19) NA 42/122 (34) Purpura 6/18 (33) NAb 16/54 (30) 45/122 (37) Microcephaly 5/18 (28) 7/42 (17) 11/54 (20) 28/122 (23) Deafness 3/18 (17) 8/42 (19) 16/54 (30) 73/122 (60) Type of study Active surveillance Retrospective review Active surveillance Passive surveillance Years of study 2000–02 1991–98 1986–87 1985–96 Mean age at last examination 8.4 months 5.0 months 15 months NA a Values are numerator/denominator (percentage) unless otherwise indicated. b NA = not available. surveillance scheme in Myanmar allowed us to confirm CRS by laboratory testing for 18 patients, whereas only 6 cases would have been confirmed by labora- tory tests if we had followed the routine surveillance guidelines recommended by WHO. The WHO guidelines call for CRS surveillance of children aged < 12 months and for testing only for rubella IgM.10 IgM testing alone will underesti- mate the burden of CRS depending on the age at which infants are screened. Chantler et al. found that among chil- dren with virologically-confirmed CRS, serum IgM was positive by ELISA in 100% of those aged 0–2 months, in 57% of those aged 3–5 months and in only 29% of those aged 6–11 months.23 In the present study IgG testing of serum speci- mens from children aged > 6 months led to identification of 9 additional cases: 7 in children aged 6–11 months and 2 in children aged 12–17 months. Maternal IgG antibody is transmitted to the infant transplacentally; it decays gradually, having a half-life of about 1.3 months.24 Infants with CRS also produce their own rubella-specific IgG. A study in the United States of America undertaken during the pre-vaccine era assessed whether the persistence of neutralizing antibody could be used as a test for CRS: among 18 children with virologically-confirmed CRS, 17 had neutralizing antibody when they were aged > 6 months.25 Rubella IgG testing using commer- cially available ELISA kits is relatively inexpensive; however, there are a num- ber of practical limitations to its use in diagnosing CRS in children aged 6–17 months. First, IgG antibody in children in this age group may represent sero- conversion following receipt of rubella vaccine. In the present study, none of the children had received rubella vaccine. Second, IgG antibody in this age group may represent exposure to wild rubella virus. Active outbreak surveillance with laboratory confirmation identified no rubella outbreaks in Yangon during the study period; moreover, none of the chil- dren in the study had a history of febrile rash illness. Among the children in this age group with positive IgG in this study, 3 met the full clinical case definition for CRS, 4 had only one major sign (3 of these also had a maternal history of ru- bella occurring during the first trimester of pregnancy), and one child had one minor sign. In our study, only a single serum sample was available from each child; serial specimens demonstrating a sustained titre of IgG and low-avidity IgG would have provided further con- firmation of the diagnosis. The RT–PCR test is a well estab- lished method for diagnosing CRS and is usually performed on nasopharyngeal specimens or urine.26, 27 This is one of the first studies to report rubella testing us- ing RT–PCR on serum specimens from children. Further systematic studies in infants are warranted to confirm the utility of using serum specimens for RT–PCR as an additional means of di- agnosing CRS. Two of the children who tested positive by RT–PCR were aged < 1 month and tested negative for IgM. This finding is consistent with a statement from Dr LZ Cooper that “approximately 20% of infected infants tested for rubella IgM might not have detectable titres be- fore age 1 month” (oral communication, 1998, reported in reference.28 Fig. 2. Number of children with laboratory-confirmed congenital rubella syndrome (CRS) (n = 18) and congenital rubella infection (CRI) (n = 1), by month and year of birth, Yangon, Myanmar WHO 05.153Laboratory confirmed CRS CRI A 3 2000 N o. o f c hi ld re n M 2 1 0 M J J A S O N D M A M J J A S O N D J F M A M J Month and year of birth 2001 2002 J F J F 18 Bulletin of the World Health Organization | January 2006, 84 (1) Research Surveillance for congenital rubella syndrome in Myanmar Kyaw-Zin-Thant et al. The findings on the rubella virus sequences indicate that two genotypes of rubella virus were circulating in Myanmar during the study period. Five strains — all from children living in central Yangon — were genotype I, a universal genotype comprising rubella viruses from Europe, Japan and North America.29, 30 One strain was genotype II; this came from a child whose mother had lived in western Myanmar during her pregnancy. This genotype is an Asian prototype comprising mainly strains from China and India. Co-circulation of more than one rubella virus genotype has been reported previously.31 During 2003, a rubella serosurvey conducted among 100 schoolgirls in central Myanmar found that 16% of those aged 11–12 years and 18% of those aged 15–16 years tested negative for rubella IgG using a commercial ELISA kit (bioMérieux, Netherlands).32 These are moderately high rates of rubella sus- ceptibility, suggesting that the situation for women in Myanmar is different from the 1970s when serosurveys in various parts of the country showed that only a low proportion of women remained susceptible. Further serosurveys among schoolgirls and women of childbearing age would be helpful to demonstrate the level of risk in other parts of the country. Such data would aid health administra- tors in selecting an appropriate vaccine strategy to prevent rubella infection and CRS in Myanmar. If resources permit, it may be advisable to start immunizing adolescent girls and women of childbear- ing age, or both, against rubella as an initial step towards preventing CRS in Myanmar.33 O Acknowledgements Thanks to Professor Mya Oo, Deputy Minister, Ministry of Health; Professor Dr Paing Soe, Director General, De- Résumé Surveillance active du syndrome de rubéole congénitale à Yangon (Myanmar) Objectif Le vaccin antirubéoleux ne fait pas partie du programme de vaccination du Myanmar. Les flambées de rougeole et de rubéole font l’objet d’une surveillance au niveau national, mais il n’y a aucune surveillance systématique du syndrome rubéoleux congénital (SRC). Une étude a donc été organisée pour évaluer la charge de SRC. Méthodes Du 1er décembre 2000 au 31 décembre 2002, le SRC a fait l’objet d’une surveillance active chez les enfants de 0 à 17 mois dans 13 hôpitaux et 2 établissements privés de Yangon. Les enfants suspectés de SRC ont été soumis à un examen standard et à un prélèvement sanguin. Tous les échantillons de sérum ont été analysés à la recherche des IgM spécifiques de la rubéole ; on a recherché les IgG spécifiques de la rubéole et l’ARN du virus rubéoleux par RT-PCR dans des échantillons sélectionnés. Résultats Au total, 81 enfants âgés de 0 à 17 mois étaient suspectés de SRC; 18 de ces cas ont été confirmés en laboratoire (7 cas de positivité des IgM, 7 de positivité de la RT-PCR et 10 de positivité des IgG touchant des enfants de 6 mois ou plus). Un autre enfant présentant un test RT-PCR positif, dont la mère avait eu la rubéole pendant sa grossesse mais dont l’examen clinique s’était révélé normal, a été classé comme atteint d’une infection rubéoleuse congénitale. Au cours de la période 2001-2002, aucune flambée de rubéole n’a été détectée dans la Division de Yangon. Dans les 31 arrondissements urbains de la Division de Yangon, l’incidence annuelle était de 0,1 cas de SRC confirmé en laboratoire pour 1000 naissances vivantes. Conclusion Il s’agit de la première étude en population de l’incidence du SRC menée dans un pays en développement au cours d’une période d’endémie rubéoleuse ; l’incidence du SRC est proche des taux d’endémie rencontrés dans les pays industrialisés avant l’introduction de la vaccination systématique. Les tests reposant sur la détection des IgG spécifiques de la rubéole se sont avérés pratiques pour diagnostiquer le SRC chez les enfants de 6 mois et plus. Cette étude est l’une des premières à présenter des données sur l’utilisation de la RT-PCR spécifique du virus rubéoleux directement sur des échantillons de sérum ; d’autres études sont nécessaires pour confirmer l’utilité de cette méthode comme moyen supplémentaire pour diagnostiquer le SRC. Resumen Vigilancia activa del síndrome de rubéola congénita en Yangon, Myanmar Objetivo La vacuna contra la rubéola no figura en el calendario de vacunación en Myanmar. Aunque la vigilancia de los brotes de sarampión y rubéola se realiza a nivel nacional, no existe un sistema de vigilancia sistemática del síndrome de rubéola congénita (SRC), lo cual nos llevó a organizar un estudio para evaluar la carga de esa enfermedad. Métodos Entre el 1 de diciembre de 2000 y el 31 de diciembre de 2002 se implantó un sistema de vigilancia activa del SRC entre los niños de 0 a 17 meses de edad en 13 hospitales y 2 consultorios privados de Yangon, capital del país. Los niños con presunto SRC fueron sometidos a una exploración ordinaria, incluida la extracción de una muestra de sangre. Todas las muestras séricas fueron analizadas para determinar las IgM específicas de la rubéola; y en algunos casos se determinaron las IgG de rubéola y el ARN de rubéola mediante la reacción en cadena de la polimerasa dirigida por ARN (transcriptasa inversa) (RT–RCP). partment of Medical Research (Lower Myanmar); Dr Mon Mon, Statistician, Department of Medical Research (Lower Myanmar); the hospital study coordina- tors; and all study participants. Thanks to Dr Shigetaka Katow, National Institute of Infectious Disease, Tokyo, Japan, for inviting the principal investigator to Japan as a Visiting Research Fellow to perform PCR tests. Scientific oversight was provided by the WHO/IVB Steer- ing Committee on Epidemiology and Field Research (Professor Timo Vesikari, Chair). Also thanks to two anonymous reviewers for their insightful comments. 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