Rubella vaccine is usually given in combination with measles and mumps vaccines as a measles-mumps-rubella vaccination. Because it contains live attenuated virus, its use is contraindicated during pregnancy. However, since the introduction of rubella vaccine, no cases of congenital rubella syndrome have been reported following vaccination during pregnancy. We report a case of a female infant, born to a woman inadvertently vaccinated with measles-mumps-rubella vaccination early in pregnancy, who manifested a phenotype of cardiac and neurologic defects, neurodevelopmental delay, and lymphocytopenia consistent with congenital rubella syndrome.
Preventing congenital rubella infection (CRI) and particularly congenital rubella syndrome (CRS) is the principal goal of universal rubella vaccination during childhood. Since the introduction of rubella vaccines in the 1960s, vaccination strategies have eliminated CRS in many countries, including France. The most widely used rubella vaccines are based on the live attenuated RA 27/3 strain grown in human diploid cells. Japan and China use the TO-336 and BRD-2 attenuated strains, respectively. Rubella vaccine is usually administered in combination with measles and mumps vaccine as a measles-mumps-rubella vaccination (MMR), but because the rubella virus may be highly virulent to the fetus in early pregnancy, administration of even an attenuated live virus vaccine is not advised during that period. Further, women are usually warned to avoid conception for 1 month after rubella vaccination. Although existing evidence has suggested that the risk of CRS after vaccination during early pregnancy is very small,1–9 we report a case of a female infant born to a mother who received an MMR vaccination early in pregnancy who presented with a phenotype consistent with CRS. Both parents gave consent for us to describe this case.
Case Study
In 2012, a 29-year-old gravida 1 para 0 woman was referred at 34 weeks’ gestation for intrauterine growth restriction and preterm labor. Because of an abnormal fetal heart rate pattern, a caesarean section was performed.
Neonatal Findings
A female neonate was delivered at 34 1/7 weeks’ gestational age. Birth weight was 1715 g (<13th percentile), birth length was 40 cm (<4th percentile), and occipital head circumference was 30.5 cm (30th percentile). Apgar scores were recorded as 10, 10, and 10 at 1, 5, and 10 minutes, respectively. The neonate was transferred to the neonatal ICU because of prematurity. Cranial ultrasonography at 6 days of age and a brain MRI at 9 days of age revealed findings consistent with congenital infection, including bilateral ventriculomegaly, extensive bilateral thalamic calcifications, and hyperechogenicity of the thalamic vessels. Congenital cytomegalovirus, herpes simplex, parvovirus, syphilis, toxoplasma, and enterovirus infections were excluded by molecular and/or serological tests. Rubella infection was suspected because the mother had received her first dose of MMR at 5 weeks’ gestation when she was still unaware of her pregnancy. Congenital rubella infection was confirmed by a positive rubella RT-PCR10 in urine and plasma and positive rubella virus-specific immunoglobulin M in serum collected at birth and at 1 and 2 months of age. At 2 months, rubella RNA was detected in the cerebrospinal fluid (CSF). Genetic analysis of urine and CSF was also performed at 1 and 2 months of age, respectively. The coding region of the rubella virus E1 gene was amplified directly from clinical specimens by RT-PCR and the sequences of resulting DNA fragments were assigned to genotypes by phylogenetic analysis with rubella virus reference sequences. This enabled identification of the 1a genotype (vaccine genotype: RVi Pennsylvania U.S.A/0.64/VAC virus) (Fig 1).11 All molecular and serological investigations were performed in the World Health Organization Rubella National Reference Laboratory.
With respect to physical findings, the neonate was initially hypertonic and developed abnormal clonic movements on day 8. Valproic acid treatment was initiated on day 20 (10mg/kg per 24 h) and continued for 1 year (dose regularly adjusted to the child’s weight). Cutaneous rashes were absent. At 27 days of age, a retinal examination revealed pigmentary retinopathy. A transient systolic murmur was attributed to pulmonary artery stenosis. The infant was intermittently leukopenic and lymphocytopenic for a few months (nadir counts were 2.6 × 109/L and 0.82 × 109/L, respectively) but no quantitative or functional immune defects were identified. Other clinical and biological evaluations were normal (liver function tests, auditory brain response, and bone radiographs). The child was transitioned from the PICU at day 32 and discharged from the hospital on day 76.
Maternal Clinical Information
The mother was born and raised in Cameroon and had received no rubella vaccinations during childhood. She was healthy, had no known history of immune deficiency, and did not travel during her pregnancy. She was vaccinated at 5 weeks’ gestation with a first dose of MMR when she was unaware of her pregnancy. Retrospective testing performed on a serum sample collected between conception and vaccination did not detect rubella IgG by Immunoblot and ELISA assays. By 9 weeks’ gestation, rubella IgG level was 51 IU/mL. Her pregnancy was uneventful except for nausea and vomiting that developed in the second month. She reported no contact with sick individuals during her pregnancy. Routine pregnancy tests did not reveal other infections, and in particular, her serology was negative for HIV at delivery. An ultrasound performed at 22 weeks’ gestation did not detect any fetal abnormalities. She has since delivered 2 healthy term infants.
Infant Follow-up
The infant was followed by a pediatrician at a medical and social center. To manage her neuro-orthopedic disorders, mainly affecting the legs, she was treated with kinesitherapy, physiotherapy, ergotherapy, psychomotor therapy, and botulinum toxin injections from the age of 3 years, which produced good results. She currently uses a wheelchair but can walk unaided for very short distances (100 m) and has an orthopedic chair and braces when seated. She suffers regularly from bladder and intestinal disorders. She has strabismus with hyperopia and myopia but no auditory impairment. Her dental enamel is abnormal. Her growth after 15 months of age was normal. Lymphocytopenia persisted that prompted more detailed immunologic work-up that was unrevealing except for isolated abnormal T-cell counts in the setting of normal B lymphocyte and natural killer cell counts and normal T-cell stimulation testing. After exclusion of a primary immunodeficiency disease, she received all childhood vaccinations consistent with French guidelines, except for MMR.
She is a very happy and sociable child. From the age of 9, she has benefited from an aide who helps her to manipulate learning tools and be mobile in class. Problems with distractibility, attention difficulties, lack of inhibitory control, and abnormal fatigability have been reported; her height and weight are normal for her age but she experienced a moderately early onset of puberty.
Discussion
We report a case of a girl, born to a rubella-seronegative woman vaccinated with MMR in early pregnancy, who presented with a phenotype consistent with CRS (peripheral pulmonic stenosis; spastic diplegia; neurodevelopmental delay; transient lymphocytopenia). CRS was confirmed by virological testing (rubella PCR, rubella IgM), and genotyping identified a vaccine-specific rubella strain.
Rubella virus can cause severe CRS if a pregnant woman is infected during the first trimester of pregnancy. Thanks to highly efficient vaccines and vaccination strategies, CRI and CRS have been eliminated in many countries.12 All European countries include MMR vaccination in their national immunization programs. By 2020, the interruption of endemic transmission was confirmed in 26 of 51 European countries, including France.
Rubella vaccine contains the Wistar RA 27/3 rubella strain that was isolated from human infected tissues and subsequently attenuated. It is produced in human diploid fibroblast cells. In adults, viremia occurs 7 to 10 days after primary immunization. The vaccine is generally well-tolerated. Transient lymphadenopathy and arthralgia are sometimes recorded.
Between 1971 and 1989, the US Centers for Disease Control and Prevention maintained a register of 321 susceptible pregnant women who inadvertently received the vaccine during pregnancy or in the 3 months before conception. They did not report any neonatal birth defects resulting from rubella, although a few neonates were positive for rubella IgM, suggesting subclinical CRI.1 Another prospective study that compared fetal malformation rates in the infants of 94 women who had mistakenly received rubella vaccinations while pregnant versus rates in infants of 94 pregnant women not vaccinated during pregnancy2 found similar rates in both groups. Further, no significant differences existed in rates of miscarriage, birth weight distributions, or developmental milestones. There were no differences in hearing test results between the 2 groups. The only significant difference was a higher rate of abortions among the women receiving vaccinations during pregnancy. Since this study, several publications reporting on hundreds of susceptible women who continued their pregnancies after inadvertent periconceptional immunization did not identify any infant with CRS3–9 (Table 1). Furthermore, no cases of CRS were reported in infants born to more than 2600 women of unknown serological status before periconceptional immunization.13
Hofmann et al were the first to describe a case of persistent fetal rubella vaccine virus infection without the development of any discernible adverse effects after inadvertent vaccination during early pregnancy.14
The mumps and measles components of the MMR vaccine are not a concern when administered inadvertently in pregnancy because there is no pattern of embryopathy that has resulted from wild type infection in pregnant women.1 Moreover, many women exposed to rubella vaccine in early pregnancy received combined vaccination against measles and rubella, and no embryo-fetal adverse effects were attributed to the measles vaccine.3–5,8,9
More generally, it is recommended that all live attenuated viral vaccines against diseases such as varicella or yellow fever should be avoided during pregnancy. However, should inadvertent immunization occur during pregnancy, for those vaccines as well as for the rubella vaccine, reassurance is usually provided and pregnancy termination is not considered.15 Indeed, no cases of congenital varicella syndrome or risk of yellow fever embryo-fetal anomalies following these vaccinations have been reported to date.15–19
Moreover, regarding yellow fever, if a woman cannot postpone travel to an endemic region, vaccination may be recommended even if she is pregnant.20–22
CRS related to rubella vaccine virus has not been previously reported. In the future, the investigation of sequences in preserved specimens should be recommended to confirm any potential adverse effects of MMR vaccines. However, an adverse effect occurring in less than 1 in 10 000 cases may not previously have been detected, which supports maintaining the contraindication of rubella vaccination during pregnancy. Given that almost 10 years have passed since the child in this case was born and CRS was suspected, we are confident that her pattern of defects had no other cause.
Although healthcare workers should screen all individuals of child-bearing age not just for known pregnancy but also a possibility of pregnancy (“is it possible you could be pregnant?”) before administering a live viral vaccine, inadvertent vaccination during pregnancy should not constitute a reason for termination. Although mothers can be reassured, specific prenatal ultrasound follow-up should be offered together with neonatal rubella screening at birth. If vaccine-related CRS is suspected, comprehensive pediatric follow-up is appropriate.
Drs Bouthry and Vauloup-Fellous performed the virological study, undertook the literature search, prepared the figures, interpreted the data, and wrote the draft manuscript; Dr Queinnec managed the patient from birth, acquired all clinical data, and reviewed and revised the manuscript; Dr Vauzelle assisted with the literature search, analysed the data, and reviewed and revised the manuscript; and all authors critically reviewed the manuscript for important intellectual content, approved the final version, and agree to be accountable for all aspects of this work.
FUNDING: No funding was secured for this study.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
