Untreated vitamin B12 (B12) deficiency may cause delayed development in infants. Several newborn screening (NBS) programs have reported an increased detection rate of B12 deficiency when second-tier dried blood spot (DBS) analyses of total homocysteine (tHcy) and methylmalonic acid (MMA) are included. This is a retrospective study of newborns reported from NBS during 2012−2021 with confirmed B12 deficiency. DBSs were retrieved from the NBS biobank for second-tier MMA and tHcy analysis. Thirty-one newborns were diagnosed with B12 deficiency out of 552970 screened. Twenty-five were ascertained from sixty-one false positive (FP) cases of methylmalonic acidemia and propionic acidemia (PA), and six infants screened positive for other NBS metabolic diseases with propionylcarnitine (C3) in the normal range. In the original DBS, 7/23 (30%) and 12/23 (52%) of B12-deficient newborns with FP methylmalonic acidemia/PA had MMA and tHcy > 99th percentile. B12 deficiency was a common differential diagnosis of screening positive for methylmalonic and PA. C3 failed to identify a subset of newborns with B12 deficiency. Second-tier MMA and tHcy analyses in the DBS showed suboptimal sensitivity for identifying infants with B12 deficiency. The shortcomings of NBS should be acknowledged when considering B12 deficiency as a primary target of NBS panels.
Keywords: B12 deficiency; dried blood spot; methylmalonic acidemia; newborn screening; propionic acidemia; sensitivity; specificity.