A case of congenital rubella syndrome and epidemiology of related cases in China, 2014–2023

ABSTRACT

Rubella is a major cause of congenital defects, and the presence of rubella infection in a pregnant woman may lead to fetal death or congenital defects known as congenital rubella syndrome(CRS). Since China has not yet established a national CRS surveillance system, the true incidence cannot be determined. To understand the disease burden and epidemiological characteristics of CRS cases in China, the article reports the first case of CRS in Quzhou, China, and conducts a retrospective analysis of related cases that have been reported in China over the past decade. Because the availability of rubella-containing vaccines (RCV) was not widespread in China before 2008, women of childbearing age born before 2008 are generally unvaccinated against RCV. Due to the lack of routine CRS monitoring and screening, CRS is underreported in China. Vaccination of nonimmune women of childbearing age with RCV and establishing a sensitive and timely case-based CRS surveillance system can accelerate the elimination of rubella and CRS.

KEYWORDS:

• Rubella
• congenital rubella syndrome
• rubella-containing vaccine
• surveillance system
• China

Rubella is a self-limiting disease with mild symptoms,^1–3 with the most important and serious consequence being congenital rubella infection. When pregnant women are infected with the rubella virus (RV), the virus can affect the placenta and infect the fetus during viremia. The adverse consequences of rubella infection during pregnancy include spontaneous abortion, stillbirth and postnatal death, congenital rubella syndrome (CRS), and neonatal rubella infection without congenital defects.^4,5 A case of CRS was first reported in Quzhou, China in 2022. To understand the disease burden and epidemiological characteristics of CRS cases in China, all laboratory-confirmed CRS cases reported since 2014 were retrospectively analyzed, which were retrieved from the China Knowledge Network (CNKI) and Boku Database Platform.

Patients and methods

According to the World Health Organization(WHO) CRS diagnostic criteria, clinically-confirmed CRS case: An infant in whom a qualified physician detects two of the complications listed in ① below or one in ① and one in ②: ① Cataract, congenital glaucoma, congenital heart disease, loss of hearing, pigmentary retinopathy. ②Purpura, splenomegaly, microcephaly, mental retardation, meningoencephalitis, radiolucent bone disease, jaundice that begins within 24 hours after birth. Laboratory-confirmed CRS case: An infant with clinically-confirmed CRS who has a positive blood test for rubella immunoglobulin M (IgM). Where special laboratory resources are available, detection of rubella virus in specimens from the pharynx or urine of an infant with suspected CRS provides laboratory confirmation of CRS.⁶

The patient was from a hospital in Quzhou. Others were retrieved from CNKI and Boku databases. Cases that also met the following criteria were included in the epidemiologic analysis: ① cases reported in 2014–2023, ② laboratory-confirmed cases, and ③ cases from China.

Case description

The patient was a male, born vaginally at full term at 38 weeks of gestation, with a birth weight of 2.3 kg. No history of resuscitation for asphyxia, and an Apgar score of 10 points at 10 minutes. He was discharged from the hospital 4 d after birth. After being discharged from the hospital, his crying and feeding were normal at home, and his skin color was normal without rash or bleeding spots. He was hospitalized due to a “respiratory tract infection” on the 16th day after birth. Physical examination on admission showed a body temperature of 37.4°C. The crying sound was loud, the skin color was rosy, the anterior fontanel was flat and soft, and the three concave signs were not present. The breath sounds in both lungs were clear and symmetrical, and no rales were heard. The heart rhythm was regular, the heart sounds were moderate, and no pathological murmur was heard. The abdomen was soft, the umbilicus was dry, and the liver and spleen were not abnormally enlarged below the ribs. The distal limbs were warm. The capillary refill time was <3 seconds and no mottling was seen. Routine blood count: white blood cell count 12.9 × 10 * 9/L, lymphocyte percentage 59.2%, monocyte percentage 13.1%, and neutrophil percentage 22.1%. The hemoglobin was 142 g/L, the red blood cell count was 4.35 × 10 * 12/L, and the platelet count was 556 × 10 * 9/L. Coagulation function, thyroid function routine, and blood biochemistry tests were normal. The results of two serum collections to detect rubella IgM and immunoglobulin G (IgG) antibodies were respectively: IgM① 5.010Index, IgG① 45.60IU/ mL; IgM②4.440Index, IgG②39.20IU/ mL. Cytomegalovirus IgM antibody was negative. Auxiliary examination: Color Doppler ultrasonography of the heart in a newborn infant showed a patent foramen ovale and a small atrial septal defect. The pediatric head color ultrasound and abdominal color ultrasound showed no obvious abnormalities, the liver, spleen, and kidneys showed no obvious abnormalities, and the cardiopulmonary diaphragm showed no abnormal X-ray signs. Hearing screening otoacoustic emissions failed in both ears, and a follow-up visit at 3 months of age confirmed the presence of hearing impairment.

The patient was detected positive for rubella IgM antibody twice in the neonatal period. Combined with his clinical symptoms, he met the WHO diagnostic criteria for CRS as a laboratory-confirmed case. On the 23rd day after birth, throat swabs, urine, and tears were collected from the children, and RV nucleic acid was detected by reverse transcriptase polymerase chain reaction. The results were all negative. On the same day, the sera of parents were collected to test for rubella IgM antibodies, and the results were all negative. Epidemic history of mother: a 24-year-old rural woman with a history of immunization the against hepatitis B vaccine, Bacille Calmette-Guerin vaccine, Diphtheria, and tetanus toxoid with whole cell pertussis vaccine, measles vaccine, and Meningococcal polysaccharide vaccine. She had not received rubella-containing vaccines (RCV), had no history of fever and rash during pregnancy, and had no contact with rubella patients. The prenatal examination was unremarkable and negative for Syphilis tolulized red unheated serum test and Human Immunodeficiency Virus.

Epidemiology of CRS cases

A search of the literature database yielded 5 articles reporting laboratory-confirmed CRS since 2014, yielding 15 confirmed cases of CRS. Except for 11 cases reported in Fujian in 2019, all of them were reported as individual cases, and the reported provinces and years were: Beijing in 2014, Zhejiang in 2015, Liaoning in 2016, and Jilin in 2018. Including Quzhou’s reported case, there are a total of 16 confirmed cases of CRS. The serum rubella IgM test of all children was positive, and the 1E genotype rubella virus was isolated from the Liaoning case.

Among the 16 cases, 9 were male, 6 were female, and 1 case had no gender information. 87.50% (14/16) were admitted to the neonatal department immediately after birth. 31.25% (5/16) were premature infants, and 43.75% (7/16) were small for gestational age infants. 18.75% (3/16) had a history of RV infection or fever or rash during pregnancy. 50.00% (8/16) had abnormal prenatal examinations, including intrauterine growth retardation and abnormal cardiac color ultrasound. 62.50% (10/16) had cardiac defects, including patent ductus arteriosus, patent foramen ovale, atrial septal defect, and mild pulmonary hypertension. 31.25% (5/16) of the children had hearing impairment. 12.50% (2/16) had congenital cataracts, 31.25% (5/16) developed jaundice within 24 hours, and 31.25% (5/16) had thrombocytopenia. 6.25% (1/16) were combined with long bone damage, and 6.25% (1/16) were combined with Dandy-Walker syndrome, cerebral palsy, microcephaly, and epilepsy. 6.25% (1/16) were complicated by other intrauterine viral infections and died due to hemophagocytosis syndrome.

Discussion

CRS is a series of serious birth defects^3,7,8 caused by rubella infection during pregnancy. Disabilities caused by CRS include congenital heart defects, congenital cataracts, hearing impairment, and developmental delays,^9,10 which bring a severe burden to the patient’s families and society. The cause of CRS is the infection of RV during pregnancy. Epidemiologic investigation of the mothers of 16 cases of CRS showed that only 18.75% had a history of RV infection or fever or rash during pregnancy. It indicates that most CRS mothers had mild or no symptoms when they were infected with RV during pregnancy. However, the consequences of RV infection during pregnancy are serious. Of the 16 confirmed cases, 62.50% had heart defects, 31.25% had hearing impairment, 12.50% had congenital cataracts, 31.25% developed jaundice within 24 hours, and 31.25% had thrombocytopenia. These clinical conditions are costly to treat and care for, demonstrating a high CRS disease burden. CRS is a vaccine-preventable disease.¹¹ The fundamental measure to prevent CRS is vaccination with RCV. China has included RCV in its immunization program since 2008 and routinely provides free vaccination to children at 8 and 18 months of age. RCV was not widely available and vaccination rates were low before 2008, and women of childbearing age born before then generally lacked immunity to rubella. The mother in this case was born in 1998 and had an identifiable history of vaccination with other vaccines, with no history of rubella vaccination, which is consistent with the low immunization status of RCV vaccination in China during this period. Rubella-specific IgG antibodies are associated with immunity, and the concentration of antibodies in the blood above a threshold is considered to have a protective effect against infection or disease. Introducing prenatal screening for rubella susceptibility based on rubella IgG detection and vaccinating nonimmune women of childbearing age with RCV to prevent RV infection during pregnancy can reduce CRS cases.³

Approximately 100,000 babies are born with CRS each year worldwide.¹² Vynnycky et al estimated that the WHO African region had the highest incidence (64 [95% confidence interval (CI):24–123] of CRS in 2019, while the Western Pacific region, where China is located, had a lower estimated incidence(<1 per 100,000 live births [95% CI: 1–12]).¹³ China has not carried out case-based national CRS monitoring. Only 16 cases were reported in the decade from 2014 to 2023, which shows that there are very few reports of CRS in China. The lack of a nationwide CRS surveillance system makes it impossible to determine the true incidence. This paper investigates the CRS cases reported over the past decade. Four provinces including Beijing reported one CRS case each during the decade, while Fujian reported 11 cases in 2019 alone. Cases in Fujian were relatively concentrated. One of the reasons is that Fujian Province introduced screening for congenital intrauterine disorders in 2019, leading to an increase in diagnostic reports. In the past 10 y before 2019, Fujian’s CRS report was blank. The diagnosis of CRS cases relies on experienced clinicians, and the reporting of cases is related to the reporting sensitivity of the hospital. Due to the lack of routine monitoring and screening， the sensitivity of CRS reports varies among hospitals or different periods within the same hospital, resulting in significant differences in the number of reports. It also shows that China’s CRS report is underestimated. It is necessary to build a national CRS monitoring system and carry out routine monitoring systematically to understand the incidence of CRS in China. Another reason for the concentrated reporting of cases in Fujian may be related to the high incidence of rubella nationwide in China from 2018 to 2019.¹⁴ The rubella epidemic will greatly increase the burden of CRS. The peak of CRS cases is between 6–8 months after the peak of the rubella outbreak,¹⁵ which was consistent with the time of Fujian’s centralized report in 2019.

Early identification and diagnosis of CRS is a challenge. CRS is easy to miss and misdiagnose. CRS symptoms are not very specific. On the one hand, there are many causes of birth defects such as congenital heart disease, such as genetic factors, environmental factors, chemical drugs, and various viral infections. On the other hand, the clinical manifestations of CRS cases are complex and diverse, and it is difficult to identify and diagnose by symptoms. Confirmation of the diagnosis of CRS is based on laboratory evidence of congenital rubella infection i.e. serum rubella antibody test or RV test. The case is a full-term infant, normal at birth with no acute lesions detected, CRS was incidentally diagnosed 16 d after birth due to a positive rubella IgM antibody test during hospitalization for respiratory infection in combination with congenital heart disease and a failed hearing screening. This means that without lab tests for rubella IgM antibodies, CRS is easily missed. Rubella IgM antibodies in the serum cannot cross the placenta, so a positive serum rubella IgM antibody in an infant is diagnostic of rubella infection. All 16 children in this study were positive for rubella IgM antibodies, and the diagnoses were clear when combined with clinical. Rubella IgM antibody titers peak 3 ~ 4 months after birth and disappear around 1 year of age. Rubella IgG antibodies are transmitted from the mother to the fetus and will diminish from 2 to 3 months after birth. Fetus infected with rubella, autologous production of specific IgG antibody within 1 month after birth, antibody titer increases gradually and reaches the peak at 1 year of age. In this case, rubella IgM and IgG antibodies were detected twice after 16 d of life, and the results were consistent with the antibody profile of children with CRS.

Establishing a case-based CRS surveillance system and carrying out routine laboratory tests is beneficial to the early identification and diagnosis of children with CRS.¹² Birth defects in children with CRS are complex multi-organ diseases.¹⁶ In addition to common congenital heart defects, congenital cataracts, and hearing impairment,¹⁷ children with CRS may also have some delayed manifestations, including developmental delay, endocrine abnormalities, and neurological diseases. Early identification of CRS can enable early intervention and early treatment, helping patients reduce related sequelae.¹⁸ Due to the lack of routine monitoring of the CRS system, clinicians have insufficient understanding of CRS, which affects the diagnosis and treatment of CRS.

The CRS surveillance system helps to control the spread of RV.^9,12 Most children with CRS can excrete RV through secretions, and the detoxification time can last up to 1 year.^7,9 Non-immune personnel are vulnerable to rubella when caring for children with CRS who are shedding the virus. In this reported case, although the child’s RV test was negative, a single negative test is not sufficient to prove that the child is not contagious.Failure to continue RV nucleic acid sampling of the child was flawed. In addition, CRS is a multisystem disease^17,18 that requires diagnosis and treatment by a multidisciplinary team. Patients need to frequently seek medical attention from different specialists, which increases the risk of rubella infection among susceptible populations. After the diagnosis of CRS, appropriate isolation precautions can be taken to limit the spread of the virus in children with CRS during the detoxification period.¹⁸

The goal of eliminating rubella was first proposed at the 65th World Health Assembly in 2012. The initial goal was that at least five of the six WHO regions could achieve rubella elimination by 2020. The resolution was also included in the Global Vaccine Action Plan 2011–2020.¹⁹ WHO defines rubella elimination as no local spread of RV has been detected in the country or region for at least 12 months, based on a well-functioning surveillance network system. As of 2020，48% (93/194) of the countries in the world have been confirmed as having eliminated rubella and CRS. The Americas region has eliminated rubella and CRS, and the European region is nearing the end. The Western Pacific Region, where China is located, plans to accelerate rubella and CRS control to eliminate it as soon as possible.²⁰

China is making progress toward its Rubella elimination goal. The two-dose RCV for Chinese children of the appropriate age remained above 95% after 2012. The National Measles and Rubella Surveillance System (NMRSS), which conducts epidemiologic and laboratory surveillance, was launched in 2014 to monitor all cases of rash and fever. These measures have laid a solid foundation and good opportunity for the control and elimination of rubella and CRS in China. WHO recommends that one of the strategies for rubella elimination is the development and maintenance of sensitive and timely case-based rubella surveillance systems and CRS surveillance systems.²¹ 30–50% of rubella cases are usually asymptomatic or mild, and many cases may go undetected and unreported, so CRS surveillance data are a necessary complement to rubella surveillance data.^11,22 A high-quality functioning CRS surveillance system is an important step in rubella control and elimination.²³ China urgently needs to pay attention to the establishment of a CRS surveillance system and routinely carry out case-based CRS system surveillance to accelerate the elimination of rubella and CRS.

Author contributions disclaimer

Xiaoying Gong wrote the article and Zhiying Yin critically reviewed the article; Canjie Zheng, Quanjun Fang, and Wenjie Xu were involved in the epidemiological investigation and data analysis. All authors have agreed on the journal to which the article will be submitted and all agree to take responsibility for all aspects of the work.

Patient consent

The patient consented to the publication of this article.

Acknowledgments

The authors thank their families, Huashu Township Health Service Center, Quzhou People’s Hospital, and Quzhou Center for Disease Control and Prevention.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.