Insulin/C-peptide interpretation in Infants with Hypoglycaemia of Unknown Origin

Hypoglycaemia is not a disease per se but a manifestation of underlying perturbations of glucose homeostasis. Among the biochemical tests commonly requested in newborns with confirmed, persistent/recurrent hypoglycaemia of unknown origin is the measurement of insulin and C-peptide in a blood sample(s) taken during the period of hypoglycaemia. Accepting an elevated insulin result with/without raised C-peptide as bona fide could trigger unnecessary investigations and/or diagnostic misapplications. The focus of this review is to highlight the significance of the "maternal-fetal-newborn" associations and the effect of transplacental transfer of two types of harmful IgG autoantibodies which could affect the measurements of insulin/C-peptide and confuse their interpretation. One is maternal insulin binding autoantibodies (IAA), a double whammy which can cause hypoglycaemia and distort insulin results due to insulin autoimmune syndrome (IAS also known as Hirata's disease). The other is non-IAA autoantibodies which if present, do not cause hypoglycaemia per se but interfere analytically causing fictitious hyperinsulinaemia if measured in infants with hypoglycaemia. IgM is not transferred but could be produced by the fetus and continue after birth. The presence of IgM in newborns' blood in substantial amounts occurs if a congenital infection is encountered in-utero or early neonatal period. IgM has also the potential to interfere in immunoassays causing fictitious results. Irrespective of insulin/C-peptide levels; maternal/obstetric history coupled with early tests for antibodies by polyethylene glycol (PEG) followed by confirmatory biochemical tests on both maternal and newborn samples would identify distorted/fictitious hyperinsulinaemia, thus helping appropriate interpretation of insulin/C-peptide results and avoids diagnostic misapplications.