Newborn Screening Expands – Inviting Collaboration on Clinical Trials

Soon, the screening will be expanded to include two new diseases and two disease groups, making it one of the most comprehensive newborn screening programs in Europe.

“The most important resource we have is the trust of the population. We have nearly 100% participation – only 15-20 parents per year decline to have their infant included in the screening program. Each year, we receive blood samples from around 55,000 newborns,” says Olve Moldestad.

Moldestad is the head of the Department of Newborn Screening at the Pediatric and Adolescent Clinic at Oslo University Hospital (OUS) and is highly dedicated to his work. In addition, to his role as department head, he co-leads the Partnership for Rare Diseases with Anne Bee Hegge, who works at Roche and serves on LMI’s Innovation Committee. Recently, Moldestad invited industry representatives from the Partnership to visit the newborn screening department to demonstrate how modern newborn screening works and discuss how they can help make Norway a more attractive country for clinical trials.

Timing of Sampling is Crucial

 “We only take one sample from the infants, and the timing of the sample is therefore very important: the biomarkers for the diseases are different and develop differently over time. We have to choose a time after birth when it’s possible to distinguish abnormal values from normal ones for all biomarkers. Therefore, it is ideal to collect the sample between 48 to 72 hours after birth,” explains Moldestad.

He shows the so-called filter cards, where the blood drops are placed in five separate spots. Once the sample is ready, the card is filled out with details like the mother’s name, ID number, address, and phone number, pregnancy duration, the baby’s birth date, weight, and gender. The filter cards are sent to all maternity wards in Norway, along with secured return envelope.

Receiving Samples Four Times a Day

“The test cards come are returned through a couple different ways: from Ullevål and Rikshospitalet via internal transport, from many hospitals in Health South-East by the Health Express, and from the rest of the country by secured transport via Bring. We receive test card deliveries here four times a day, these routines are a part of our daily workflow,” says Moldestad.

Using an advanced punching machine, small (Ø 3.2 mm) round blood samples are extracted from each test card. The samples are then analyzed with various instruments: mass spectrometry, immunohistochemistry, and quantitative PCR. As many as 20 diseases are first analyzed using mass spectrometry.

“We have a national mandate to conduct genetic mass screening of newborns, but the tests are primarily carried out through biochemical analyses,” Moldestad says.

Modern newborn screening consists of at least two levels: the first for high sensitivity and the second for high specificity. Following the first analyses, a small number of samples will show abnormal levels of one or more biomarkers and will undergo further, more advanced analyses at the second level. Second-level screening includes advanced mass spectrometry methods, single-gene testing, and broader sequencing with gene panel analysis.

“We use the methods that best suit the specific condition and ensure the integrity of the child. The analyses must also be done quickly because some diseases manifest right after birth, and treatment should begin as soon as possible to save the child’s life and ensure optimal cognitive development,” Moldestad explains.

Newborns are Initially Assumed Healthy

Further, he explains that the team primarily focuses on biochemistry and targeted genetics, operating within the framework of the regulation on genetic mass screening. The samples are taken from all newborns are used for healthcare, quality control, and method development.

“Since this is a screening, the infants are initially presumed healthy. From our standpoint, we are assuming everything is normal until results give us reason to look a bit closer into abnormalities. Consequence of reporting a false positive is significant; as such, a message can worry parents for years, even if they are later informed that results were not as serious as first thought. Fortunately, we are wrong only 1 out of 10 times, which often involves another rare disease,” says Moldestad.

After the medical assessment is, complete at the Newborn Screening Department the abnormal results are then communicated to the respective pediatric departments.

“Many think of newborn screening as just one test, but in reality, it’s a complex system for risk assessment, conditions and for future diseases,” says Moldestad.

Long-Term Storage at -20 Degrees Celsius

After the samples are analyzed, they are essentially a “waste product,” but in 2018, the government decided to store the blood samples permanently so they can also be used for method development and research. When considering a new screening condition, it’s crucial to have old filter cards available to test the method on both healthy children and those who had the disease. Today, the newborn screening program at OUS has about 800,000 samples stored in its biobank. They are stored in freezers at -20 degrees Celsius in a unique automated storage unit.

The newborn screening biobank is regulated by the Biobank Act §9a.

“Sampling and storing the test cards is consentform based. From birth, parents give consent on behalf of the infants. They receive a reminder letter when the child turns 2, informing them they can withdraw consent if they wish. Before the children turn 16, they will receive a new letter allowing them to withdraw consent themselves. However, we haven’t reached that point yet, as the system was expanded in 2012. The oldest samples in the biobank – and therefore the children concerned – are 12 years old. Parents and children should feel confident that only the Newborn Screening Department handles this sensitive information,” assures Moldestad.

Expanding with Two New Diseases and Two Disease Groups

Today, the screening covers 26 diseases, including phenylketonuria, congenital hypothyroidism, cystic fibrosis, congenital adrenal hyperplasia, 19 metabolic diseases, severe combined immunodeficiency, other severe T-cell defects, 3-hydroxy 3-methylglutaryl-CoA lyase deficiency, and spinal muscular atrophy (SMA). In 2024, distal urea cycle defects, remethylation defects, sickle cell anemia, and metachromatic leukodystrophy will be added.

With this expansion, Norway’s newborn screening will cover 39 congenital diseases – making it one of the most comprehensive newborn screening programs in Europe.

Striving for Clinical Trials

One goal of the Partnership for Rare Diseases is for Norwegian patients to gain access to new advanced therapies. “Our experience shows that new advanced therapies often need to be applied early in the disease course to be effective, and newborn screening can be an important resource for this,” says Moldestad. He hopes that the biobank at the Newborn Screening Department can benefit future children and invites dialogue on how Norway’s advanced newborn screening can attract more clinical trials to the country.

Moldestad emphasizes that newborn screening is part of a complete ecosystem that includes the Clinical Research Unit, NorPedMed, NordicPedMed, the Nordic University Hospital Alliance (NUHA), the Rare Disease Registry, the National Competence Service for Rare Diagnoses (NKSD), and several other registries. Through NUHA, the largest hospitals in the Nordic countries have taken significant steps to coordinate services for patients with rare diseases, with a particular focus on platform studies, benchmarking, and rare diseases.

“This international collaboration has the potential to make the Nordic regions into a joint recruitment arena for clinical trials,” Moldestad says.

All of these elements can be connected with various resources, provided there is interest. OUS also has the infrastructure for functional investigations, which systematizes advanced methods and instruments used in research, such as RNA sequencing, structural biology, metabolomics, proteomics, cell culture methods, Nanostring, Seahorse, and photometry, as well as advanced light microscopy.

Norwegian parents want to contribute to research, both for their own children’s sake and for other children. In addition, Oslo University Hospital is one of the largest hospitals in Europe, with a vast amount of expertise under one roof. With all of this combined, there are not many that can match us, says the department head.

Will lead to new knowledge and better treatments

Anne Bee Hegge, Medical Director at Roche and Moldestad’s co-leader of the Partnership for Rare Diseases, greatly appreciated the department tour.

It is important for the industry to understand the opportunities available in Norway when we have a goal to attract more clinical research to Norway, as well as better access to new treatments. The industry can also be a key player in discussions related to potential new diseases that should be included in the newborn screening program. We research and develop new treatment options for rare diagnoses, and good cooperation around both the ethical, medical, and legal issues in this area is in the patient’s best interest. With early and accurate diagnostics, we lay the foundation for good and sustainable medical treatment, and we look forward to further collaboration, says Hegge.

Synnøve Jespersen, Medical Director at Sanofi Norway, and Tarje Bergdahl, Medical Director at Novartis Norway, were also happy to be invited to a meet-and-greet at the Newborn Screening Department.

“I greatly appreciate getting an insight into the work everyone has done around the newborn screening as a national treatment service and the development that has occurred regarding the number of diseases now included in the newborn screening program”, says Jespersen.

“The newborn screening program, along with its associated registry, is an important platform for future research collaboration with the industry. This can lead to the development of even better targeted treatments, but also increased knowledge about the drivers behind severe inherited diseases”, says Bergdahl.