The Institute for Quality and Efficiency in Health Care (IQWiG) was commissioned by the Federal Joint Committee (G-BA) to investigate whether screening for vitamin B12 deficiency and the diseases homocystinuria, propionic acidaemia and methylmalonic aciduria should be included in the German extended newborn screening (ENS) programme. After careful consideration of the comments on the preliminary report, the Institute has now concluded in the final report that the benefits outweigh the harms, at least in screening for vitamin B12 deficiency. The evidence from the available studies is insufficient to answer the question of whether this is also the case for the other three target diseases.
Metabolic diseases that cause irreversible damage
Vitamin B12 and certain enzymes are essential for the breakdown of protein in the human body. If a pregnant woman cannot absorb vitamin B12, this is dangerous for the newborn because the human body cannot produce vitamins. It can also happen that the breakdown of protein in the newborn is blocked due to a lack of certain enzymes. This is the case with the very rare congenital metabolic disorders homocystinuria, propionic acidaemia and methylmalonic aciduria. These three diseases and vitamin B12 deficiency can affect the physical and mental development of children, causing brain damage, seizures, coma and damage to the eyes, kidneys and blood vessels. The effects can be life-threatening.
The four diseases mentioned above can be diagnosed by analysing blood dropped on filter paper. In ENS, which is already performed in Germany in accordance with the Paediatric Directive of the G-BA, venous or heel blood is taken between the 36th and 72nd hour of life, dripped onto filter paper and analysed to detect a number of specified diseases. It does not yet include the target diseases that are the focus of this report.
The aim of newborn screening for vitamin B12 deficiency and the other target diseases is to identify and treat affected children at an early stage - i.e. before their metabolism becomes unbalanced and causes irreversible damage, particularly to the brain.
It is important to note that three of the target diseases are very rare: homocystinuria, propionic acidaemia and methylmalonic aciduria each affect only about 1 in 100,000 to 500,000 newborns. In contrast, maternal vitamin B12 deficiency is more common, with an incidence of less than 1 in 5000 children, although severe cases are also very rare. A vegan or strictly vegetarian diet during pregnancy can cause vitamin B12 deficiency in the newborn. And although adequate vitamin B12 intake during pregnancy is generally recommended, babies are still born with severe vitamin B12 deficiency due to maternal deficiency.
Despite little evidence: benefits of vitamin B12 screening outweigh harms
To answer the question of whether screening for vitamin B12 deficiency and other target diseases should be included in ENS, IQWiG identified three studies that compared screening with no screening and 13 studies that compared early treatment with late treatment.
The three studies that investigated the effects of screening provided hardly any meaningful data. Although these studies included several hundred thousand children in total, only about 20 children had one of the target diseases.
The 13 studies that compared early treatment with late treatment also had major shortcomings. The main problem with these observational studies was that the children in the early and late treatment groups differed in many ways: age, length of follow-up, patient selection, and disease severity. Therefore, any differences between the treatment groups could not be attributed to the timing of treatment.
Nevertheless, in its final report, IQWiG now sees a hint of a benefit of screening for acquired vitamin B12 deficiency. IQWiG took into account the results of a large pilot project in Heidelberg and a nationwide data collection on rare paediatric diseases (ESPED). New analyses were submitted to IQWiG for this purpose. Most importantly, the commenting procedure on the preliminary report confirmed that, even without study data, it is ultimately clear that early and timely administration of vitamin B12 can prevent possible irreversible damage from acquired vitamin B12 deficiency in newborns.
Treatment of acquired vitamin B12 deficiency is causal, short-term and associated with a very low risk of harm to the newborn. In newborns with vitamin B12 deficiency at birth, physical and mental development is severely jeopardized without vitamin B12 supplementation. Screening is therefore beneficial in terms of early treatment, especially as affected babies are usually asymptomatic at the time of an abnormal screening result. In terms of potential harm, three aspects are relevant: firstly, the anxiety of parents until a definitive diagnosis is made (also in the case of a false alarm), and secondly, the possible short-term overtreatment by vitamin B12 supplementation. However, there is no evidence of any relevant potential harm from an overdose of vitamin B12. Thirdly, in very rare cases, disease variants may be detected that are so mild that they would never have caused symptoms without treatment.
The assessment involved weighing the substantial benefits in rare individual cases (preventing irreversible harm from acquired vitamin B12 deficiency) against minor harms (psychological distress and administration of vitamin B12 in the event of a false-positive result). IQWiG's final evaluation concluded that the benefits of screening for vitamin B12 deficiency in newborns outweigh the harms.
Procedure of report production
The G-BA commissioned IQWiG with this project in November 2022. IQWiG published the preliminary results, the preliminary report, in September 2023 and invited comments. Following the commenting procedure, the report was revised and sent to the G-BA as a final report in February 2024. This report was published in March 2024; an English translation was published in September 2024. The written comments submitted on the preliminary report were published in a separate document at the same time as the final report. The Institute involved an external expert in the project.
