Placental proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and IGF-I and IGF-II: Levels in umbilical cord blood and associations with birth weight and length Bridget DiPrisco a,b, ⁎, Ajay Kumar c , Bhanu Kalra c , Gopal V. Savjani c , Zoe Michael d , Olivia Farr a , Aimilia Eirini Papathanasiou d , Helen Christou b,d , Christos Mantzoros a,e a Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA b Division of Newborn Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA c Ansh Labs, Webster, TX, USA d Department of Pediatric Newborn Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA e Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA abstract article info Article history: Received 15 May 2019 Accepted 6 August 2019 Available online xxxx Background: A newborn's birth weight for gestational age provides important insights into his or her fetal growth and well-being. While the underlying mechanisms regulating fetal growth remain to be fully elucidated, the IGF axis plays an important role. Some components of this axis have been well-characterized in umbilical cord blood, but others have not yet been studied. We measured the proteases PAPP-A and PAPP-A2, the binding proteins they cleave (IGFBP-4 and -5), and the established molecules IGF-I and –II in umbilical cord blood to better characterize the IGF axis in relation to birth weight and length. Methods: We performed a case-control study of 180 neonates born at a tertiary teaching hospital in Boston. To maximize power, infants were recruited in a 1:3:1 ratio with 37 SGA, 111 AGA, and 37 LGA infants matched by gestational age, sex, and delivery mode. IGF-I, IGF-II, IGFBP-4, IGFBP-5, PAPP-A, and PAPP-A2 were measured in umbilical cord blood by ELISA. Associations between birth weight and birth length Z-scores and the Z-scores of the above molecules were analyzed using linear regression models and analysis of covariance. Results: Birth weight and length Z-scores were positively associated with Z-scores of IGF-I, IGF-II, total IGFBP-4, and IGFBP-5, with IGF-I having the strongest association. Birth weight and length Z-scores were negatively asso- ciated with Z-scores of intact IGFBP-4, PAPP-A, and PAPP-A2 levels. Conclusions: We confirm previous findings of significant associations between the IGFs in cord blood and new- born size and for the first time show positive associations between cord blood total IGFBP-4 and -5 and birth weight and a negative association between intact IGFBP-4 and birth weight. We also show for the first time a re- ciprocal relationship between cord blood levels of PAPP-A and PAPP-A2 and newborn size. The implications of these findings need to be further examined in large longitudinal studies and likely have diagnostic and therapeu- tic potential. © 2019 Elsevier Inc. All rights reserved. Keywords: Cord blood Fetal growth IGF axis IGF binding proteins Placental proteases 1. Introduction A newborn's birth weight for gestational age provides important in- formation about his or her fetal growth and well-being, which has con- siderable implications for postnatal health. There is an established association between birth weight for gestational age and adverse out- comes, where infants born both small for gestational age (SGA) and large for gestational age (LGA) are at risk for significant morbidity and mortality, both in the short- and long-term [1,2]. In addition to higher rates of neonatal death, SGA infants are more likely to have respiratory distress syndrome, hypoglycemia, Metabolism Clinical and Experimental 100 (2019) 153959 Abbreviations: SGA, small for gestational age; AGA, appropriate for gestational age; LGA, large for gestational age; IGF, insulin-like growth factor; IGFBP-4, insulin-like growth factor binding protein-4; IGFBP-5, insulin-like growth factor binding protein-5; PAPP-A, pregnancy-associated plasma protein-A; PAPP-A2, pregnancy-associated plasma protein-A2; ELISA, enzyme-linked immunosorbent assay. ⁎ Corresponding author at: Beth Israel Deaconess Medical Center, 330 Brookline Ave, SL-419, Boston, MA 02215, USA. E-mail address: bridget.diprisco@gmail.com (B. DiPrisco). https://doi.org/10.1016/j.metabol.2019.153959 0026-0495/© 2019 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Metabolism Clinical and Experimental journal homepage: www.metabolismjournal.com