Increased Plasma Pro-B-Type Natriuretic Peptide in Infants of Women with Type 1 Diabetes Karen G. Halse, 1,2 Marie L.S. Lindegaard, 1 Jens P. Goetze, 1 Peter Damm, 2 Elisabeth R. Mathiesen, 3 and Lars B. Nielsen 1* Background: Up to 40% of newborn infants of women with type 1 diabetes have echocardiographic signs of cardiomyopathy. Increased plasma concentrations of B-type natriuretic peptide (BNP) and its precursor (proBNP) are markers of cardiac failure and hypoxia in adults. In this study, we investigated whether plasma concentrations of proBNP and/or BNP are increased in infants of women with type 1 diabetes. Methods: Plasma BNP and proBNP were measured with RIAs. The proBNP assay measures both intact proBNP and NH 2 -terminal fragments derived from this precur- sor, whereas the BNP assay measures only BNP-32 and not proBNP. Results: Infants of women with diabetes and hemoglo- bin A 1c (Hb A 1c ) >6.2% before delivery had a higher median plasma proBNP concentration (31 pmol/L; inter- quartile range, 21– 47 pmol/L; n  16) than infants of healthy women [16 (9 –32) pmol/L; n  21; P  0.01]. Infants of women with diabetes and Hb A 1c <6.2% (n  15) had intermediate values. The plasma BNP and proBNP concentrations were closely associated (r 2  0.80; P <0.0001); within the group of infants of women with diabetes and Hb A 1c >6.2%, both correlated with the degree of fetal stress during labor. Conclusions: Maternal diabetes and suboptimal meta- bolic control may affect the fetal heart and may predom- inantly stimulate proBNP secretion in conjunction with perinatal stress. © 2005 American Association for Clinical Chemistry Maternal diabetes is associated with increased risk of stillbirth (1), but the causes are not fully clarified. Up to 40% of newborn infants of women with type 1 diabetes have echocardiographic signs of cardiomyopathy with cardiac enlargement and asymmetric septal hypertrophy. Most often, these changes are asymptomatic and disap- pear within the first 6 months of life, but they can also lead to severe morbidity and mortality (2–4). It is thus conceivable that cardiac dysfunction could be a cause of stillbirths in pregnancies complicated by diabetes. During fetal life, infants of women with diabetes often have hyperglycemia, hyperinsulinemia (5, 6), and increased concentrations of markers of hypoxic stress, e.g., plasma erythropoietin (5, 7). These factors could all have negative effects on the fetal heart in utero (8, 9). It is well estab- lished that optimal metabolic control at conception and during the first trimester is essential to minimize the risk of congenital malformations in the offspring (10 ). In addition, suboptimal metabolic control in women with type 1 diabetes is associated with the risk of stillbirth (10 ). Nevertheless, the strength of a putative association be- tween metabolic control in the mother and the extent of neonatal hypertrophic cardiomyopathy is not known (11, 12). At this stage, the diagnosis of neonatal diabetic cardiomyopathy is based on clinical observations and echocardiography. B-Type natriuretic peptide (BNP) 4 is a 32-amino acid peptide produced in excess by cardiac myocytes during cardiac stress (13 ). BNP is released as a 108-amino acid propeptide (proBNP), which is then cleaved into the active BNP (32 amino acids) and an N-terminal fragment (14 ). The biological roles of BNP include regulation of the extracellular fluid volume and blood pressure by increas- ing natriuresis and inhibiting the renin-angiotensin-aldo- sterone axis. In the fetus, BNP functions as a vasodilator in the placental circulation (15 ). BNP probably also has important protective autocrine effects in the heart by inhibiting fibrosis and hypertrophy (16 ). Plasma measurements of proBNP and BNP are now used to diagnose cardiac dysfunction in adults. The Departments of 1 Clinical Biochemistry, 2 Obstetrics, and 3 Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. * Address correspondence to this author at: Department of Clinical Bio- chemistry, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Fax 45-35452524; e-mail Larsbo@rh.dk. Received June 14, 2005; accepted August 22, 2005. Previously published online at DOI: 10.1373/clinchem.2005.056077 4 Nonstandard abbreviations: BNP, B-type natriuretic peptide; proBNP, pro-B-type natriuretic peptide; and Hb A 1c , hemoglobin A 1c . Clinical Chemistry 51:12 000 – 000 (2005) Endocrinology and Metabolism 1 Papers in Press. First published September 22, 2005 as doi:10.1373/clinchem.2005.056077 Copyright © 2005 by The American Association for Clinical Chemistry