IMPE Abstracts

Background: Perinatal stress, fetal growth restriction (FGR) or being small for gestational age (SGA) poses a high risk for neonatal hypoglycemia. The exact pathomechanism is unknown. In an animal model, increased levels of catecholamines were found in FGR sheep, causing β-cell adaptation with suppressed intrauterine insulin secretion, subsequently resulting in a hyper-responsive insulin secretion once the adrenergic stimulus subsides, e.g. after birth. We here examine for the first time if human neonates with different risk factors for hypoglycemia have higher levels of catecholamines in arterial umbilical cord blood (UCB) compared to controls, and if higher levels of catecholamines correlate with lower postnatal blood glucose levels.

Methods: Recruitment of 328 neonates >35+0 weeks of gestation (94 controls, 234 with risk factors for hypoglycemia). Catecholamines/metabolites in UCB were measured using LC-MS/MS. Insulin in UCB and C-peptide in amniotic fluid (AF) were determined. Neonates at risk for hypoglycemia received standardized blood glucose screenings, controls received two blood glucose measurements (age 2-3h and 36-72h). Median (interquartile range) is shown.

Results: SGA/FGR neonates had higher levels of norepinephrine (21.10 (33.18) vs. 10.88 (12.25) nmol/l, P<0.001), metanephrine (0.37 (1.23) vs. 0.12 (0.2) nmol/l, P<0.001) and 3-methoxytyramine (0.149 (0.11) vs. 0.091 (0.086) nmol/l, P=0.001) in UCB than control neonates. Neonates with perinatal stress had increased norepinephrine (24.29 (201.62) vs. 10.88 (12.25) nmol/l, P<0.001), normetanephrine (2.60 (5.26) vs. 1.25 (1.7) nmol/l, P=0.007) and epinephrine levels (2.61 (15.35) vs. 1.30 (2.01), P=0.002) in UCB compared to controls. Norepinephrine, metanephrine and 3-methoxytyramine correlated positively with the number of postnatal hypoglycemic episodes between 30-45 mg/dl per neonate (correlation coefficient (CC) 0.146, P=0.012; CC 0.151, P=0.0093; CC 0.18, P=0.002). Metanephrine and 3-methoxytyramine correlated negatively with the lowest measured blood glucose (CC -0.149, P=0.01; CC -0.153, P=0.0084). Metanephrine correlated negatively with UCB insulin (CC -0.193, P=0.001), and UCB norepinephrine, metanephrine and 3-methoxytyramine correlated negatively with AF C-peptide (CC -0.212, P=0.005; CC -0.182, P=0.016; CC -0.183, P=0.016).

Conclusion: Neonates born SGA/FGR or with perinatal stress have significantly higher levels of catecholamines in UCB at the time of birth. Higher levels of catecholamines correlate with a higher number of hypoglycemic episodes and lower blood glucose levels. In line with the experimental data from sheep models, our data strongly suggest that increased fetal catecholamines directly affect neonatal beta cell physiology, thus being the mechanistic link between pre-/perinatal stress or FGR and subsequent neonatal hyperinsulinemic hypoglycemia.