Roberto Romero1, Eunjung Jung2, Tinnakorn Chaiworapongsa2, Offer Erez3, Dereje W Gudicha2, Yeon Mee Kim4, Jung-Sun Kim5, Bomi Kim4, Juan Pedro Kusanovic6, Francesca Gotsch2, Andreea B Taran2, Bo Hyun Yoon7, Sonia S Hassan8, Chaur-Dong Hsu9, Piya Chaemsaithong10, Nardhy Gomez-Lopez11, Lami Yeo2, Chong Jai Kim12, Adi L Tarca13. 1. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI; Detroit Medical Center, Detroit, MI. Electronic address: prbchiefstaff@med.wayne.edu. 2. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI. 3. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Faculty of Health Sciences, Division of Obstetrics and Gynecology, Maternity Department "D," Soroka University Medical Center, School of Medicine, Ben-Gurion University of the Negev, Beersheba, Israel; Department of Obstetrics and Gynecology, HaEmek Medical Center, Afula, Israel. 4. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Pathology, Wayne State University School of Medicine, Detroit, MI; Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea. 5. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Pathology, Wayne State University School of Medicine, Detroit, MI; Department of Pathology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Republic of Korea. 6. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; División de Obstetricia y Ginecología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile; Centro de Investigación e Innovación en Medicina Materno-Fetal, Unidad de Alto Riesgo Obstétrico, Hospital Sotero Del Rio, Santiago, Chile. 7. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea. 8. Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Office of Women's Health, Integrative Biosciences Center, Wayne State University, Detroit, MI; Department of Physiology, Wayne State University School of Medicine, Detroit, MI. 9. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Physiology, Wayne State University School of Medicine, Detroit, MI; Department of Obstetrics and Gynecology, University of Arizona, College of Medicine - Tucson, Tucson, AZ. 10. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Faculty of Medicine, Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 11. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI. 12. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Pathology, Wayne State University School of Medicine, Detroit, MI; Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea. 13. Perinatology Research Branch, Divisions of Obstetrics and Maternal-Fetal Medicine and Intramural Research, US Department of Health and Human Services, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Department of Computer Science, Wayne State University College of Engineering, Detroit, MI.
Abstract
BACKGROUND: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. OBJECTIVE: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. STUDY DESIGN: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. RESULTS: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. CONCLUSION: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders. Published by Elsevier Inc.
BACKGROUND: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known. OBJECTIVE: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion. STUDY DESIGN: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion. RESULTS: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions. CONCLUSION: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders. Published by Elsevier Inc.
Entities:
Keywords:
angiogenic index-1; classification of disease; fetal death; liquid biopsy; omics; placental growth factor; placental lesions of maternal vascular malperfusion; preeclampsia; pregnancy; preterm birth; preterm labor; preterm premature rupture of the membranes; small for gestational age; soluble fms-like tyrosine kinase-1; soluble vascular endothelial growth factor receptor-1
Authors: Wendy E Heywood; Rhian-Lauren Preece; Jeremy Pryce; Jenny Hallqvist; Robert Clayton; Alex Virasami; Kevin Mills; Neil J Sebire Journal: Placenta Date: 2017-09-29 Impact factor: 3.481