Newborn Spinal Muscular Atrophy Screening in Australia: A Non-Randomized Cohort Study
Background
In light of a new therapeutic era for spinal muscular atrophy (SMA), neonatal screening has been proposed as a gateway to facilitate timely diagnosis and access to therapy. However, there is a paucity of evidence on health outcomes outside of homogeneous populations in clinical trials to justify broader implementation of newborn screening for SMA. In this real-world study, we aimed to investigate the effectiveness of newborn screening along with access to disease-modifying therapies, as an intervention for SMA.
Methods
In this prospective, non-randomized cohort study , conducted at Sydney Children’s Hospital Network (NSW, Australia), children under 16 years of age with homozygous deletions in exon 7 mutations in the survival motor neuron 1 (SMN1) gene were included. ), non-selectively assigned to a screening group (incident population diagnosed by newborn screening) from August 1, 2018 to August 1, 2020, or a comparison group (incident population diagnosed by clinical referral) from 1 from August 2016 to July 31, 2018.
We excluded infants with compound heterozygous SMN1 mutations and those participating in ongoing and unpublished clinical trials. The effectiveness of SMA screening in newborns was compared using achievement of the motor developmental milestone defined by the WHO Multicenter Growth Reference Study at 2 years post-diagnosis. Secondary outcomes included mortality and change in Hammersmith Infant Neurological Examination-2 (HINE-2) score, ventilation requirements, and enteral requirements 2 years from the time of diagnosis.
Results
Thirty-four children met the study inclusion criteria, but 33 children were included in the study population after one neonate was excluded due to participation in an ongoing unpublished clinical trial.
Fifteen children were included in the screening group (seven [47%] males and eight [53%] females; median age 2.1 weeks [IQR 1.9–2.7]) and 18 children (nine [50%] ] men and nine [50%] women) were included in the comparison group (median age 47·8 weeks [13·0–99·9]).
The 2-year survival rate was 93% (14 of 15 children) in the screening group and 89% (16 of 18) in the comparison group. Among survivors, 11 (79%) of 14 walked independently or with assistance in the screening group, compared with one (6%) of 16 children in the comparison group (χ2=16·27; p<0 ·0001). A significantly greater change in motor function was observed in the screening group compared with the comparison group over 2 years (HINE-2 score group difference, 12.32; p<0.0001).
The requirement for respiratory support or non-intensive feeding at follow-up was higher in the comparison group than in the screening group (odds ratio 7.1 [95% CI 0.7–70.2]). Significant predictors of functional motor outcomes as determined by the HINE-2 score at 2 years after diagnosis were HINE-2 score (p=0·0022), CHOP-INTEND (p=0·0001), potential compound muscle action index (CMAP; p =0·0006), and disease status (p=0·023) at the time of diagnosis.
Interpretation Screening for SMA in newborns, coupled with early access to disease-modifying therapies, effectively improves functional burden and associated comorbidities for affected children. For children diagnosed through newborn screening, the motor score, CMAP, and disease status at diagnosis have clinical utility in determining functional independence. |
Comments
New study finds that 11/14 of children with spinal muscular atrophy (SMA) diagnosed through newborn screening and who had early access to treatment walked independently or with assistance two years after diagnosis, compared with 1/16 of children diagnosed with SMA based on clinical symptoms, presenting on average around 4 months of age.
This is the first study to provide evidence of the clinical effectiveness of newborn screening for SMA in direct comparison with traditional diagnostic and management pathways. The authors call for consideration of broader implementation of newborn screening for SMA.
Newborn Spinal Muscular Atrophy (SMA) Screening (NBS), when combined with early treatment, results in improved movement ability in affected children, including the ability to walk, in compared to children diagnosed once symptoms develop, suggests a new study published in the journal The Lancet Child & Adolescent Health .
SMA is a rare genetic neuromuscular condition that develops predominantly in childhood. It is characterized by weak muscles and problems with movement that often lead to significant disability and sometimes death. About one in 40 to 60 people carry the main gene that causes SMA, and it is estimated that one in 10,000 babies will be born with two essential genes missing, leading to the disease. The age at which symptoms appear is variable, but they may not be seen until the baby is several months old, and many people with SMA experience a delay in diagnosis. Although there is currently no cure for SMA, there are treatment options that can improve symptoms, especially when the child begins treatment before the development of clinical symptoms.
NBS is a public health program of screening infants soon after birth for conditions that are treatable, but are not always evident in the neonatal period. All newborns undergo NBS programs with parental consent, not just those with a family history of the disease.
“Neonatal screening has been proposed as the gateway to early diagnosis and more timely access to SMA treatment; However, evidence on the impact of neonatal screening for SMA beyond non-diverse populations in clinical trials was previously lacking. Our study is the first to look at real-world data on how children with SMA diagnosed through newborn screening compare to children diagnosed after symptoms develop. We believe our findings justify broader implementation of newborn screening for SMA,” says Dr Arlene D’Silva, from the University of New South Wales.
During the study, the health of 15 newborn babies diagnosed with SMA following a positive screening result was compared between August 1, 2018 and August 1, 2020 (the first two years of the Australian NBS pilot program for SMA). with that of 18 infants and children with SMA diagnosed after clinical remission with symptoms of the disease in the two years before the start of the NBS pilot program for SMA (August 1, 2016 - July 31, 2018). Of the 15 children diagnosed by NBS, nine did not show any symptoms of SMA during the first weeks of life and were therefore considered presymptomatic when they began treatment.
Two years after diagnosis, health professionals assessed the children’s ability to sit, crawl, stand, and walk, along with some other measure of movement ability. Three of the children (one diagnosed by NBS and two by symptom onset) in the trial entered palliative care within two years of diagnosis.
The researchers found that 11/14 of children diagnosed with NBS were walking independently or with assistance two years after diagnosis, compared to only 1/16 of children diagnosed before the NBS pilot program. Children diagnosed by NBS also scored higher on average on other measures of movement ability and independence in daily tasks than children diagnosed by symptoms. This is despite the fact that the children diagnosed with NBS are all younger than the other group.
“Our study suggests that screening for SMA in newborns reduces current delays in the diagnosis and treatment of SMA in children. Early detection and diagnosis are essential to providing children with SMA with better health outcomes and quality of life. "It is extremely promising that the majority of children diagnosed through newborn screening in our study were able to walk after two years, compared to children diagnosed through symptoms who were mostly only able to sit up without assistance," says Dr Didu Kariyawasam, from the University of New South Wales.
She continues: “Although we are seeing pilot programs being implemented, only a small number of countries have fully introduced newborn screening for SMA, with less than 2% of newborns worldwide currently screened for the condition. Our study provides further evidence of the value of newborn screening for SMA and encourages broader implementation. tion of this effective intervention.”
The authors acknowledge some limitations of their study, including that the trial was not randomized meaning it could be prone to selection bias, however this was mitigated by the chronological enrollment of children when they were referred to the service. Furthermore, it was not possible to match the two groups by age, due to the inherent diagnostic delays associated with a clinical diagnosis. The Australian NBS pilot study for SMA is designed to accelerate and enable equitable access to diagnosis and treatment. Therefore, these findings may not be generalizable to areas where there are delays in the screening and treatment process, including challenges in accessing appropriate health services and treatment.
Writing in a linked comment, Professor Hisahide Nishio, of Kobe Gakuin University, Japan, who was not involved in the study, says: "Newborn screening allows patients with SMA to access treatment at earlier stages, regardless of SMN2 copy number or disease status, resulting in better outcomes for individuals and for society. The cost-benefit data of newborn screening for SMA will help inform countries wishing to implement a newborn screening program for SMA. However, given the high cost of new treatments and different conditions in countries (e.g., different economies and insurance systems), it will take some time for patients with SMA all over the world benefit equally from advances in medicine.
