Tinnakorn Chaiworapongsa1, Roberto Romero2, Offer Erez3, Adi L Tarca1, Agustin Conde-Agudelo4, Piya Chaemsaithong1, Chong Jai Kim5, Yeon Mee Kim6, Jung-Sun Kim7, Bo Hyun Yoon8, Sonia S Hassan1, Lami Yeo1, Steven J Korzeniewski9. 1. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI. 2. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, 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. Electronic address: prbchiefstaff@med.wayne.edu. 3. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Department of Obstetrics and Gynecology, Soroka University Medical Center, School of Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel. 4. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI. 5. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 6. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea. 7. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. 8. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea. 9. Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health/Department of Health and Human Services, Bethesda, MD, and Detroit, MI; Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI; Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI.
Abstract
BACKGROUND: Fetal death is an obstetrical syndrome that annually affects 2.4 to 3 million pregnancies worldwide, including more than 20,000 in the United States each year. Currently, there is no test available to identify patients at risk for this pregnancy complication. OBJECTIVE: We sought to determine if maternal plasma concentrations of angiogenic and antiangiogenic factors measured at 24-28 weeks of gestation can predict subsequent fetal death. STUDY DESIGN: A case-cohort study was designed to include 1000 randomly selected subjects and all remaining fetal deaths (cases) from a cohort of 4006 women with a singleton pregnancy, enrolled at 6-22 weeks of gestation, in a pregnancy biomarker cohort study. The placentas of all fetal deaths were histologically examined by pathologists who used a standardized protocol and were blinded to patient outcomes. Placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor-1 concentrations were measured by enzyme-linked immunosorbent assays. Quantiles of the analyte concentrations (or concentration ratios) were estimated as a function of gestational age among women who delivered a live neonate but did not develop preeclampsia or deliver a small-for-gestational-age newborn. A positive test was defined as analyte concentrations (or ratios) <2.5th and 10th centiles (placental growth factor, placental growth factor/soluble vascular endothelial growth factor receptor-1 [angiogenic index-1] and placental growth factor/soluble endoglin) or >90th and 97.5th centiles (soluble vascular endothelial growth factor receptor-1 and soluble endoglin). Inverse probability weighting was used to reflect the parent cohort when estimating the relative risk. RESULTS: There were 11 fetal deaths and 829 controls with samples available for analysis between 24-28 weeks of gestation. Three fetal deaths occurred <28 weeks and 8 occurred ≥28 weeks of gestation. The rate of placental lesions consistent with maternal vascular underperfusion was 33.3% (1/3) among those who had a fetal death <28 weeks and 87.5% (7/8) of those who had this complication ≥28 weeks of gestation. The maternal plasma angiogenic index-1 value was <10th centile in 63.6% (7/11) of the fetal death group and in 11.1% (92/829) of the controls. The angiogenic index-1 value was <2.5th centile in 54.5% (6/11) of the fetal death group and in 3.7% (31/829) of the controls. An angiogenic index-1 value <2.5th centile had the largest positive likelihood ratio for predicting fetal death >24 weeks (14.6; 95% confidence interval, 7.7-27.7) and a relative risk of 29.1 (95% confidence interval, 8.8-97.1), followed by soluble endoglin >97.5th centile and placental growth factor/soluble endoglin <2.5th, both with a positive likelihood ratio of 13.7 (95% confidence interval, 7.3-25.8) and a relative risk of 27.4 (95% confidence interval, 8.2-91.2). Among women without a fetal death whose plasma angiogenic index-1 concentration ratio was <2.5th centile, 61% (19/31) developed preeclampsia or delivered a small-for-gestational-age neonate; when the 10th centile was used as the cut-off, 37% (34/92) of women had these adverse outcomes. CONCLUSION: (1) A maternal plasma angiogenic index-1 value <2.5th centile (0.126) at 24-28 weeks of gestation carries a 29-fold increase in the risk of subsequent fetal death and identifies 55% of subsequent fetal deaths with a false-positive rate of 3.5%; and (2) 61% of women who have a false-positive test result will subsequently experience adverse pregnancy outcomes. Published by Elsevier Inc.
BACKGROUND:Fetal death is an obstetrical syndrome that annually affects 2.4 to 3 million pregnancies worldwide, including more than 20,000 in the United States each year. Currently, there is no test available to identify patients at risk for this pregnancy complication. OBJECTIVE: We sought to determine if maternal plasma concentrations of angiogenic and antiangiogenic factors measured at 24-28 weeks of gestation can predict subsequent fetal death. STUDY DESIGN: A case-cohort study was designed to include 1000 randomly selected subjects and all remaining fetal deaths (cases) from a cohort of 4006 women with a singleton pregnancy, enrolled at 6-22 weeks of gestation, in a pregnancy biomarker cohort study. The placentas of all fetal deaths were histologically examined by pathologists who used a standardized protocol and were blinded to patient outcomes. Placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor-1 concentrations were measured by enzyme-linked immunosorbent assays. Quantiles of the analyte concentrations (or concentration ratios) were estimated as a function of gestational age among women who delivered a live neonate but did not develop preeclampsia or deliver a small-for-gestational-age newborn. A positive test was defined as analyte concentrations (or ratios) <2.5th and 10th centiles (placental growth factor, placental growth factor/soluble vascular endothelial growth factor receptor-1 [angiogenic index-1] and placental growth factor/soluble endoglin) or >90th and 97.5th centiles (soluble vascular endothelial growth factor receptor-1 and soluble endoglin). Inverse probability weighting was used to reflect the parent cohort when estimating the relative risk. RESULTS: There were 11 fetal deaths and 829 controls with samples available for analysis between 24-28 weeks of gestation. Three fetal deaths occurred <28 weeks and 8 occurred ≥28 weeks of gestation. The rate of placental lesions consistent with maternal vascular underperfusion was 33.3% (1/3) among those who had a fetal death <28 weeks and 87.5% (7/8) of those who had this complication ≥28 weeks of gestation. The maternal plasma angiogenic index-1 value was <10th centile in 63.6% (7/11) of the fetal death group and in 11.1% (92/829) of the controls. The angiogenic index-1 value was <2.5th centile in 54.5% (6/11) of the fetal death group and in 3.7% (31/829) of the controls. An angiogenic index-1 value <2.5th centile had the largest positive likelihood ratio for predicting fetal death >24 weeks (14.6; 95% confidence interval, 7.7-27.7) and a relative risk of 29.1 (95% confidence interval, 8.8-97.1), followed by soluble endoglin >97.5th centile and placental growth factor/soluble endoglin <2.5th, both with a positive likelihood ratio of 13.7 (95% confidence interval, 7.3-25.8) and a relative risk of 27.4 (95% confidence interval, 8.2-91.2). Among women without a fetal death whose plasma angiogenic index-1 concentration ratio was <2.5th centile, 61% (19/31) developed preeclampsia or delivered a small-for-gestational-age neonate; when the 10th centile was used as the cut-off, 37% (34/92) of women had these adverse outcomes. CONCLUSION: (1) A maternal plasma angiogenic index-1 value <2.5th centile (0.126) at 24-28 weeks of gestation carries a 29-fold increase in the risk of subsequent fetal death and identifies 55% of subsequent fetal deaths with a false-positive rate of 3.5%; and (2) 61% of women who have a false-positive test result will subsequently experience adverse pregnancy outcomes. Published by Elsevier Inc.
Authors: Robert M Silver; Michael W Varner; Uma Reddy; Robert Goldenberg; Halit Pinar; Deborah Conway; Radek Bukowski; Marshall Carpenter; Carol Hogue; Marian Willinger; Donald Dudley; George Saade; Barbara Stoll Journal: Am J Obstet Gynecol Date: 2007-05 Impact factor: 8.661
Authors: Hannah Blencowe; Simon Cousens; Fiorella Bianchi Jassir; Lale Say; Doris Chou; Colin Mathers; Dan Hogan; Suhail Shiekh; Zeshan U Qureshi; Danzhen You; Joy E Lawn Journal: Lancet Glob Health Date: 2016-01-19 Impact factor: 26.763
Authors: Joanna Gent; Sian Bullough; Jane Harrold; Richard Jackson; Kerry Woolfall; Lazaros Andronis; Louise Kenny; Christine Cornforth; Alexander E P Heazell; Emily Benbow; Zarko Alfirevic; Andrew Sharp Journal: Pilot Feasibility Stud Date: 2020-11-19