Jose Galaz1,2,3, Roberto Romero1,4,5,6,7,8, Marcia Arenas-Hernandez1,2, Bogdan Panaitescu1,2, Robert Para1,2, Nardhy Gomez-Lopez1,2,9. 1. Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U. S. Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA. 2. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA. 3. Department of Obstetrics and Gynecology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. 4. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA. 5. Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA. 6. Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA. 7. Detroit Medical Center, Detroit, MI, USA. 8. Department of Obstetrics and Gynecology, Florida International University, Miami, FL, USA. 9. Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA.
Abstract
OBJECTIVES: Preterm birth remains the leading cause of perinatal morbidity and mortality worldwide. Preterm birth is preceded by spontaneous preterm labor, which is commonly associated with sterile intra-amniotic inflammation; yet, no approved treatment exists for this clinical condition. Corticosteroids are the standard of care to improve neonatal outcomes in women at risk of preterm birth. Herein, we first validated our model of alarmin-induced preterm birth. Next, we investigated whether treatment with betamethasone could prevent preterm birth resulting from sterile intra-amniotic inflammation in mice. METHODS: Under ultrasound guidance, the first cohort of dams received an intra-amniotic injection of the alarmin high-mobility group box-1 (HMGB1, n=10) or phosphate-buffered saline (PBS, n=9) as controls. A second cohort of dams received HMGB1 intra-amniotically and were subcutaneously treated with betamethasone (n=15) or vehicle (n=15). Dams were observed until delivery, and perinatal outcomes were observed. RESULTS: Intra-amniotic HMGB1 reduced gestational length (p=0.04), inducing preterm birth in 40% (4/10) of cases, of which 100% (4/4) were categorized as late preterm births. Importantly, treatment with betamethasone extended the gestational length (p=0.02), thereby reducing the rate of preterm birth by 26.6% (from 33.3% [5/15] to 6.7% [1/15]). Treatment with betamethasone did not worsen the rate of neonatal mortality induced by HMGB1 or alter weight gain in the first three weeks of life. CONCLUSIONS: Treatment with betamethasone prevents preterm birth induced by the alarmin HMGB1. This study supports the potential utility of betamethasone for treating women with sterile intra-amniotic inflammation.
OBJECTIVES: Preterm birth remains the leading cause of perinatal morbidity and mortality worldwide. Preterm birth is preceded by spontaneous preterm labor, which is commonly associated with sterile intra-amniotic inflammation; yet, no approved treatment exists for this clinical condition. Corticosteroids are the standard of care to improve neonatal outcomes in women at risk of preterm birth. Herein, we first validated our model of alarmin-induced preterm birth. Next, we investigated whether treatment with betamethasone could prevent preterm birth resulting from sterile intra-amniotic inflammation in mice. METHODS: Under ultrasound guidance, the first cohort of dams received an intra-amniotic injection of the alarmin high-mobility group box-1 (HMGB1, n=10) or phosphate-buffered saline (PBS, n=9) as controls. A second cohort of dams received HMGB1 intra-amniotically and were subcutaneously treated with betamethasone (n=15) or vehicle (n=15). Dams were observed until delivery, and perinatal outcomes were observed. RESULTS: Intra-amniotic HMGB1 reduced gestational length (p=0.04), inducing preterm birth in 40% (4/10) of cases, of which 100% (4/4) were categorized as late preterm births. Importantly, treatment with betamethasone extended the gestational length (p=0.02), thereby reducing the rate of preterm birth by 26.6% (from 33.3% [5/15] to 6.7% [1/15]). Treatment with betamethasone did not worsen the rate of neonatal mortality induced by HMGB1 or alter weight gain in the first three weeks of life. CONCLUSIONS: Treatment with betamethasone prevents preterm birth induced by the alarmin HMGB1. This study supports the potential utility of betamethasone for treating women with sterile intra-amniotic inflammation.
Authors: Y Liu; J M Cousin; J Hughes; J Van Damme; J R Seckl; C Haslett; I Dransfield; J Savill; A G Rossi Journal: J Immunol Date: 1999-03-15 Impact factor: 5.422
Authors: Elke Kuypers; Jennifer J P Collins; Boris W Kramer; Gaston Ofman; Ilias Nitsos; J Jane Pillow; Graeme R Polglase; Matthew W Kemp; John P Newnham; Antonio W D Gavilanes; Relana Nowacki; Machiko Ikegami; Alan H Jobe; Suhas G Kallapur Journal: Am J Physiol Lung Cell Mol Physiol Date: 2011-12-09 Impact factor: 5.464
Authors: A J Thomson; J F Telfer; A Young; S Campbell; C J Stewart; I T Cameron; I A Greer; J E Norman Journal: Hum Reprod Date: 1999-01 Impact factor: 6.918