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Silasi M, Azzi M, Potchileev S, Burns L, Rana S. Placental Biomarker Testing for Evaluation of Suspected Preeclampsia. Clin Chem 2025; 71:548-558. [PMID: 40129181 DOI: 10.1093/clinchem/hvaf024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 01/21/2025] [Indexed: 03/26/2025]
Abstract
BACKGROUND Worldwide, hypertensive disorders of pregnancy (HDP) are a leading cause of maternal and neonatal morbidity and mortality (Semin Perinatol 2009;33:130-7). This is especially true in the United States where preeclampsia is a leading cause of premature births (Hypertens Pregnancy 2016;35:510-9 and Lancet 2008;371:164-75). Moreover, this disorder is costly due to the financial burden of the health services needed to care for mothers with preeclampsia and their very often preterm infants (Am J Obstet Gynecol 2017;217:235-6). Recently, placental biomarkers have been shown to aid in assessment of the risk of severe preeclampsia. In 2023, the FDA approved the use of soluble feline McDonough sarcoma (fms)-like tyrosine kinase-1 to placental growth factor ratio (sFlt-1/PlGF) as an additional tool for preeclampsia risk assessment between 23 and 35 weeks' gestation in high-risk patients in the United States. Use of these biomarkers will improve maternal and fetal/neonatal outcomes and may assist in decreasing the healthcare burden of these patients by adding to risk assessment and the current diagnosis and management of pregnancies with HDP. CONTENT The pathophysiology of preeclampsia stems from abnormal placentation that results in an imbalance of pro- and antiangiogenic factors leading to endothelial and vascular dysfunction and the clinical syndrome of preeclampsia (J Clin Invest 2003;111:649-58). The role of the sFlt-1/PlGF in the prediction of progression to preeclampsia has been demonstrated in multiple studies. SUMMARY The goal of this review is to demonstrate the role of placental biomarkers (sFlt-1 and PlGF) in the pathophysiology of preeclampsia, with an emphasis on clinical applications and cost-effectiveness in the United States, using real-world applications as examples.
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Affiliation(s)
- Michelle Silasi
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, Mercy Hospital St. Louis, St. Louis, MO, United States
| | - Marly Azzi
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, United States
| | - Sanela Potchileev
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, United States
| | - Luke Burns
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, United States
| | - Sarosh Rana
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, United States
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Alipova G, Ablakimova N, Tussupkaliyeva K, Bermagambetova S, Kosmuratova S, Karimsakova B, Gaiday A, Gaiday A, Dinets A, Tussupkaliyev A. Prevention of Pre-Eclampsia: Modern Strategies and the Role of Early Screening. J Clin Med 2025; 14:2970. [PMID: 40364001 PMCID: PMC12072587 DOI: 10.3390/jcm14092970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 04/13/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
Background: Pre-eclampsia (PE) remains a leading cause of maternal and perinatal morbidity and mortality worldwide. Early detection and risk stratification are critical for improving pregnancy outcomes. This review aims to summarize current advancements in PE screening, including clinical risk factors, biomarkers, imaging techniques, and predictive models. Methods: A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, and Google Scholar to identify relevant studies on PE screening and prediction. Peer-reviewed original studies, systematic reviews, and meta-analyses published in English were included, while case reports and conference abstracts were excluded. Results: Traditional screening methods rely on maternal history and clinical risk factors, while emerging approaches incorporate biochemical markers and ultrasound parameters to enhance predictive accuracy. Machine learning models and artificial intelligence (AI)-driven algorithms are being explored for improved risk stratification. However, challenges such as data heterogeneity, lack of external validation, and integration into clinical practice remain. Conclusions: Advances in PE screening hold promise for early identification and targeted prevention strategies. Future research should focus on validating predictive models in diverse populations, integrating AI with traditional screening methods, and developing personalized approaches to reduce PE-associated complications.
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Affiliation(s)
- Gulzhaina Alipova
- Department of Obstetrics and Gynecology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Nurgul Ablakimova
- Department of Pharmacology, Clinical Pharmacology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
- Department of Hospital Pharmacy, Regional Perinatal Center, Aktobe 030006, Kazakhstan
| | - Kymbat Tussupkaliyeva
- Department of Epidemiology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Saule Bermagambetova
- Department of Hygienic Disciplines and Occupational Diseases, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Sholpan Kosmuratova
- Department of Normal Physiology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Bibigul Karimsakova
- Department of General Medical Practice №1, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Andrey Gaiday
- Department of Obstetrics and Gynecology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Assel Gaiday
- Department of Radiology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
| | - Andrii Dinets
- Institute of Biology and Medicine, Taras Shevchenko National University of Kiyv, Kyiv 01033, Ukraine
| | - Akylbek Tussupkaliyev
- Department of Obstetrics and Gynecology, West Kazakhstan Marat Ospanov Medical University, Aktobe 030012, Kazakhstan
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Azzi M, Silasi M, Potchileev S, Woodham PC, Brawley A, Mueller A, Duque TB, Rana S. Neonatal cost savings in hypertensive disorders of pregnancy: Economic evaluation of the sFlt-1/PlGF test with real world implementation of biomarkers. Pregnancy Hypertens 2025; 39:101190. [PMID: 39826331 DOI: 10.1016/j.preghy.2025.101190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 01/11/2025] [Accepted: 01/11/2025] [Indexed: 01/22/2025]
Abstract
BACKGROUND Preeclampsia is a key cause of prematurity in the U.S. and incurs significant healthcare costs. An imbalance between soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) predicts severe preeclampsia and aids in its management. OBJECTIVE This study aimed to assess the cost-effectiveness of the sFlt-1/PlGF test as an addition to standard care for patients at risk of developing preeclampsia. STUDY DESIGN A decision tree analysis was conducted to assess the cost effectiveness of the ratio test in the United States, using data from Preeclampsia Risk Assessment: Evaluation of Cut-offs to Improve Stratification [PRAECIS] and from a real-world evidence study conducted after the implementation of sFlt-1/PlGF testing into routine clinical practice (Biomarker Examination and Analysis for Clinical Obstetrical Navigation Study [BEACON]). The model compared standard of care alone versus a biomarker-based approach utilizing the sFlt-1/PlGF test for managing patients at risk of preeclampsia with severe features. Published data was used to estimate theoretical cost values of infants for their first six months of life. RESULTS The analysis indicated potential total neonatal cost savings of nearly $10,595,332 (95% CI: $6,555,439 to $14,730,536) per 1,000 patients using the sFlt-1/PlGF ratio test, translating to about $10,595 saved per patient. The incremental cost-effectiveness ratio (ICER) analysis showed a mean cost savings of $62,572 for each pregnancy prolonged by two weeks. CONCLUSION The sFlt-1/PlGF test, when used alongside standard care, enhances risk stratification for severe preeclampsia and may lead to significant neonatal cost savings by reducing preterm deliveries and neonatal intensive care admissions.
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Affiliation(s)
- Marly Azzi
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, USA
| | - Michelle Silasi
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, Mercy Hospital, St. Louis, MO, USA
| | - Sanela Potchileev
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, USA
| | - Padmashree C Woodham
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, Medical College of Georgia, Wellstar MCG Health, Augusta, GA, USA
| | - Amalia Brawley
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, Medical College of Georgia, Wellstar MCG Health, Augusta, GA, USA
| | - Ariel Mueller
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, USA; Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA
| | | | - Sarosh Rana
- Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, University of Chicago Medical Center, Chicago, IL, USA.
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Guiñazú G, Tomasso G, Vitureira G, Rey G, Fio V, Sosa L, Garay OU. Economic analysis of the use of the Flt-1/PlGF preeclampsia ratio compared to the standard of care in Uruguay. REVISTA COLOMBIANA DE OBSTETRICIA Y GINECOLOGIA 2024; 75:4148. [PMID: 39530873 PMCID: PMC11655075 DOI: 10.18597/rcog.4148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 08/20/2024] [Indexed: 11/16/2024]
Abstract
Objectives Preeclampsia (PE) is a pregnancyrelated hypertensive disorder that can lead to severe complications and adverse maternal and fetal outcomes. This study aimed to estimate the economic impact of integrating the sFlt-1/PlGF ratio into Uruguay's healthcare system as part of routine clinical practice for diagnosing. Material and methods A decision tree model was used to estimate the annual economic impact on the Uruguayan healthcare system for a hypothetical cohort of women with suspected PE. This included relevant costs associated with diagnosis, monitoring, and treatment from the initial presentation of suspected PE until childbirth. The study analyzed the annual costs under two scenarios: the standard of care and a scenario incorporating the sFlt-1/PlGF ratio for PE, using 2022 as the reference year. Various deterministic and probabilistic sensitivity analyses were performed. Results The economic model estimated that the implementation of the sFlt-1/PlGF ratio could save the Uruguayan healthcare system $95,432,678 Uruguayan pesos (2,320,269 United States Dollars [USD]) annually, representing a 5 % reduction in costs compared with the standard of care. These savings were primarily due to a reduction in hospitalizations of women with suspected PE. The estimated economic impact equated to an annual net saving of approximately $10,602 Uruguayan pesos (258 USD) per patient. Conclusions The introduction of the sFlt-1/PlGF ratio into the Uruguayan healthcare system is likely to generate savings due to the optimization of the management of hospitalizations for women with suspected preeclampsia (PE). However, the potential for savings will primarily depend on the current hospitalization rate of these women (the efficiency of managing high-risk PE pregnancies) and the length of stay for hospitalized women.
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Affiliation(s)
- Gonzalo Guiñazú
- Roche Diagnostics Argentina, Buenos Aires (Argentina).Roche Diagnostics ArgentinaBuenos AiresArgentina
| | - Giselle Tomasso
- Unidad Clínica y Epidemiológica Montevideo (Unicem), Montevideo (Uruguay). Unidad Clínica y Epidemiológica MontevideoMontevideoUruguay
| | - Gerardo Vitureira
- Centro Hospitalario Pereira Rossell, Montevideo (Uruguay). Centro Hospitalario Pereira RossellMontevideoUruguay
| | - Grazzia Rey
- Hospital de Clínicas Dr. Manuel Quintela, Universidad de la República, Montevideo (Uruguay). Universidad de la RepúblicaUniversidad de la RepúblicaMontevideoUruguay
| | - Veronica Fio
- Clínica Ginecotocológica A, Facultad de Medicina UdelaR, Montevideo (Uruguay). Clínica Ginecotocológica AMontevideoUruguay
| | - Leonardo Sosa
- Hospital de Clínicas Dr. Manuel Quintela, Universidad de la República, Montevideo (Uruguay). Universidad de la RepúblicaUniversidad de la RepúblicaMontevideoUruguay
| | - Osvaldo Ulises Garay
- Roche Diagnostics International Ltd., Rotkreuz (Switzerland). International LtdRotkreuzSwitzerland
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Rosenberg EA, Seely EW. Update on Preeclampsia and Hypertensive Disorders of Pregnancy. Endocrinol Metab Clin North Am 2024; 53:377-389. [PMID: 39084814 DOI: 10.1016/j.ecl.2024.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/02/2024]
Abstract
There have been recent advances in the prevention, diagnosis, and management of hypertensive disorders of pregnancy which complicate approximately 16% of pregnancies in the United States. Initiation of low-dose aspirin by 16 weeks' gestation reduces preeclampsia in high-risk women. The Food and Drug Administration approved the use of the soluble fms-like tyrosine kinase 1/placental growth factor ratio for the short-term prediction of preeclampsia. Pregnancy outcomes are improved in women with chronic hypertension when antihypertensives are initiated at a threshold blood pressure of 140/90 mm Hg. Women with prior preeclampsia have increased cardiovascular disease risk and should receive risk reduction counseling.
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Affiliation(s)
- Emily A Rosenberg
- Division of Endocrinology, Diabetes, and Metabolic Diseases, Medical University of South Carolina, 96 Jonathan Lucas Street, CSB 822, Charleston, SC 29425, USA
| | - Ellen W Seely
- Department of Medicine, Division of Endocrinology, Diabetes, and Hypertension, Brigham & Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA.
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Patel E, Suresh S, Mueller A, Bisson C, Zhu K, Verlohren S, von Dadelszen P, Magee L, Rana S. sFlt1/PlGF among patients with suspected preeclampsia when considering hypertensive status. AJOG GLOBAL REPORTS 2024; 4:100359. [PMID: 39005612 PMCID: PMC11239699 DOI: 10.1016/j.xagr.2024.100359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/16/2024] Open
Abstract
BACKGROUND In high-resource settings, biomarkers of angiogenic balance, such as the soluble fms-like tyrosine kinase-1 (sFlt1)/placental growth factor (PlGF) ratio, have been studied extensively to aid in evaluation of patients with suspected preeclampsia (PE), and have been incorporated into the 2021 International Society for the Study of Hypertension in Pregnancy definition of PE. The utility in under-resourced settings has not been as well characterized. OBJECTIVE This analysis sought to identify the role of the sFlt1/PlGF ratio in the evaluation of patients with or without hypertension who are suspected of having PE without other diagnostic information. STUDY DESIGN This is a secondary analysis of a prior prospective study of patients who were presented with suspected PE at ≥20+0 weeks' gestation at a single academic tertiary care center. Patients were recruited in the parent study from July 2009 to June 2012. In the original study, clinicians were masked to biomarker results, and patients were followed by chart review. In this analysis, the performance of the sFlt1/PlGF ratio (≤38, >38, or >85) was assessed alone in identifying both hypertensive and non-hypertensive patients at risk of evolving into PE with severe features (PE-SF; American College of Obstetricians and Gynecologists' definition) within two weeks of the triage visit (PE-SF2). Hypertension was defined as a blood pressure (BP)≥140/90 mmHg. RESULTS There were 1043 patients included in the analysis; of whom, 579 (55.5%) and 464 (44.5%) presented with or without hypertension, respectively. In triage, 332 (75.4%) of hypertensive patients presented due to BP concerns, and the remainder were evaluated due to other features (new-onset headache, proteinuria, or edema). On triage evaluation, 66.8% of all patients had a normal sFlt1/PlGF ratio ≤38, and 17.0% had an elevated ratio >85. Among hypertensive patients, a sFlt1/PlGF ratio ≤38 was a good rule-out test for PE-SF2 (negative likelihood ratio [LR-] of 0.15), and a ratio >85 was a good rule-in test (positive likelihood ratio [LR+] of 5.75). Among normotensive patients, sFlt1/PlGF was useful as a rule-in test for ratio >38 (LR+ 5.13) and >85 (LR+ 12.80). Stratified by gestational age, sFlt1/PlGF continued to be a good rule in and good rule out test at <35 weeks among those with hypertension but did not have good test performance ≥35 weeks. sFlt1/PlGF had a good test performance as a rule in test for >85 regardless of gestational age. In triage, 4.3% (30/693) of patients with sFlt1/PlGF ratio <38 had concurrent laboratory evidence of PE, compared with 15.9% (28/176) patients with ratio >85. CONCLUSION These findings support the potential for the use of sFlt1/PlGF and BP measurement alone in resource-limited settings where other laboratory tests or clinical expertise are unavailable for risk stratification. Performance of the biomarker varied by the presence of hypertension and gestational age.
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Affiliation(s)
- Easha Patel
- Division of Maternal Fetal Medicine, Department of
Obstetrics and Gynecology, University of Chicago Medicine, Chicago, IL (Dr
Patel, Ms Mueller, Drs Bisson, Zhu, Rana)
| | - Sunitha Suresh
- Division of Maternal Fetal Medicine, Department of
Obstetrics and Gynecology, NorthShore University Health System, Evanston, IL (Dr
Suresh)
| | - Ariel Mueller
- Division of Maternal Fetal Medicine, Department of
Obstetrics and Gynecology, University of Chicago Medicine, Chicago, IL (Dr
Patel, Ms Mueller, Drs Bisson, Zhu, Rana)
- Department of Anesthesia, Critical Care and Pain
Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA (Ms
Mueller)
| | - Courtney Bisson
- Division of Maternal Fetal Medicine, Department of
Obstetrics and Gynecology, University of Chicago Medicine, Chicago, IL (Dr
Patel, Ms Mueller, Drs Bisson, Zhu, Rana)
| | - Katherine Zhu
- Division of Maternal Fetal Medicine, Department of
Obstetrics and Gynecology, University of Chicago Medicine, Chicago, IL (Dr
Patel, Ms Mueller, Drs Bisson, Zhu, Rana)
| | - Stefan Verlohren
- Charité - Universitätsmedizin Berlin, Berlin, Germany
(Dr Verlohren)
| | - Peter von Dadelszen
- Institute of Women and Children's Health, Department of
Women and Children's Health, School of Life Course and Population Sciences,
King's College London, London, United Kingdom (Drs Dadelszen, Magee)
| | - Laura Magee
- Institute of Women and Children's Health, Department of
Women and Children's Health, School of Life Course and Population Sciences,
King's College London, London, United Kingdom (Drs Dadelszen, Magee)
| | - Sarosh Rana
- Division of Maternal Fetal Medicine, Department of
Obstetrics and Gynecology, University of Chicago Medicine, Chicago, IL (Dr
Patel, Ms Mueller, Drs Bisson, Zhu, Rana)
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Burwick RM, Rodriguez MH. Angiogenic Biomarkers in Preeclampsia. Obstet Gynecol 2024; 143:515-523. [PMID: 38350106 DOI: 10.1097/aog.0000000000005532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/04/2024] [Indexed: 02/15/2024]
Abstract
Preeclampsia contributes disproportionately to maternal and neonatal morbidity and mortality throughout the world. A critical driver of preeclampsia is angiogenic imbalance, which is often present weeks to months before overt disease. Two placenta-derived angiogenic biomarkers, soluble fms-like tyrosine kinase 1 (sFlt-1) and placental growth factor (PlGF), have proved useful as diagnostic and prognostic tests for preeclampsia. Recently, the U.S. Food and Drug Administration approved the sFlt-1/PlGF assay to aid in the prediction of preeclampsia with severe features among women with hypertensive disorders of pregnancy at 24-34 weeks of gestation. In this narrative review, we summarize the body of work leading to this approval and describe how the sFlt-1/PlGF ratio may be implemented in clinical practice as an adjunctive measure to help optimize care and to reduce adverse outcomes in preeclampsia.
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Affiliation(s)
- Richard M Burwick
- Division of Maternal Fetal Medicine, San Gabriel Valley Perinatal Medical Group, Pomona Valley Hospital Medical Center, Pomona, California
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Thadhani R, Cerdeira AS, Karumanchi SA. Translation of mechanistic advances in preeclampsia to the clinic: Long and winding road. FASEB J 2024; 38:e23441. [PMID: 38300220 DOI: 10.1096/fj.202301808r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 12/30/2023] [Accepted: 01/09/2024] [Indexed: 02/02/2024]
Abstract
As one of the leading causes of premature birth and maternal and infant mortality worldwide, preeclampsia remains a major unmet public health challenge. Preeclampsia and related hypertensive disorders of pregnancy are estimated to cause >75 000 maternal and 500 000 infant deaths globally each year. Because of rising rates of risk factors such as obesity, in vitro fertilization and advanced maternal age, the incidence of preeclampsia is going up with rates ranging from 5% to 10% of all pregnancies worldwide. A major discovery in the field was the realization that the clinical phenotypes related to preeclampsia, such as hypertension, proteinuria, and other adverse maternal/fetal events, are due to excess circulating soluble fms-like tyrosine kinase-1 (sFlt-1, also referred to as sVEGFR-1). sFlt-1 is an endogenous anti-angiogenic protein that is made by the placenta and acts by neutralizing the pro-angiogenic proteins vascular endothelial growth factor (VEGF) and placental growth factor (PlGF). During the last decade, this work has spawned a new era of molecular diagnostics for early detection of this condition. Antagonizing sFlt-1 either by reducing production or blocking its actions has shown salutary effects in animal models. Further, in early-stage human studies, the therapeutic removal of sFlt-1 from maternal circulation has shown promise in delaying disease progression and improving outcomes. Recently, the FDA approved the first molecular test for preterm preeclampsia (sFlt-1/PlGF ratio) for clinical use in the United States. Measuring serum sFlt-1/PlGF ratio in the acute hospital setting may aid short-term management, particularly regarding step-up or step-down of care, decision to transfer to settings better equipped to manage both the mother and the preterm neonate, appropriate timing of administration of steroids and magnesium sulfate, and in expectant management decisions. The test itself has the potential to save lives. Furthermore, the availability of a molecular test that correlates with adverse outcomes has set the stage for interventional clinical trials testing treatments for this disorder. In this review, we will discuss the role of circulating sFlt-1 and related factors in the pathogenesis of preeclampsia and specifically how this discovery is leading to concrete advances in the care of women with preeclampsia.
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Affiliation(s)
- Ravi Thadhani
- Woodruff Health Sciences Center, Emory University School of Medicine, Atlanta, Georgia, USA
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Ana Sofia Cerdeira
- Nuffield Department of Women's Health and Reproductive Research, University of Oxford, Oxford, UK
- Fetal Maternal Medicine Unit, Queen Charlotte's and Chelsea Hospital, London, UK
| | - S Ananth Karumanchi
- Departments of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA
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9
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Lee NMW, Chaemsaithong P, Poon LC. Prediction of preeclampsia in asymptomatic women. Best Pract Res Clin Obstet Gynaecol 2024; 92:102436. [PMID: 38056380 DOI: 10.1016/j.bpobgyn.2023.102436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 07/21/2023] [Accepted: 11/18/2023] [Indexed: 12/08/2023]
Abstract
Preeclampsia is a major cause of maternal and perinatal morbidity and mortality. It is important to identify women who are at high risk of developing this disorder in their first trimester of pregnancy to allow timely therapeutic intervention. The use of low-dose aspirin initiated before 16 weeks of gestation can significantly reduce the rate of preterm preeclampsia by 62 %. Effective screening recommended by the Fetal Medicine Foundation (FMF) consists of a combination of maternal risk factors, mean arterial pressure, uterine artery pulsatility index (UtA-PI) and placental growth factor (PLGF). The current model has detection rates of 90 %, 75 %, and 41 % for early, preterm, and term preeclampsia, respectively at 10 % false-positive rate. Similar risk assessment can be performed during the second trimester in all pregnant women irrespective of first trimester screening results. The use of PLGF, UtA-PI, sFlt-1 combined with other investigative tools are part of risk assessment.
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Affiliation(s)
- Nikki M W Lee
- Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China.
| | - Piya Chaemsaithong
- Department of Obstetrics and Gynecology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
| | - Liona C Poon
- Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region of China.
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10
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Hackelöer M, Schmidt L, Verlohren S. New advances in prediction and surveillance of preeclampsia: role of machine learning approaches and remote monitoring. Arch Gynecol Obstet 2023; 308:1663-1677. [PMID: 36566477 PMCID: PMC9790089 DOI: 10.1007/s00404-022-06864-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 11/18/2022] [Indexed: 12/26/2022]
Abstract
Preeclampsia, a multisystem disorder in pregnancy, is still one of the main causes of maternal morbidity and mortality. Due to a lack of a causative therapy, an accurate prediction of women at risk for the disease and its associated adverse outcomes is of utmost importance to tailor care. In the past two decades, there have been successful improvements in screening as well as in the prediction of the disease in high-risk women. This is due to, among other things, the introduction of biomarkers such as the sFlt-1/PlGF ratio. Recently, the traditional definition of preeclampsia has been expanded based on new insights into the pathophysiology and conclusive evidence on the ability of angiogenic biomarkers to improve detection of preeclampsia-associated maternal and fetal adverse events.However, with the widespread availability of digital solutions, such as decision support algorithms and remote monitoring devices, a chance for a further improvement of care arises. Two lines of research and application are promising: First, on the patient side, home monitoring has the potential to transform the traditional care pathway. The importance of the ability to input and access data remotely is a key learning from the COVID-19 pandemic. Second, on the physician side, machine-learning-based decision support algorithms have been shown to improve precision in clinical decision-making. The integration of signals from patient-side remote monitoring devices into predictive algorithms that power physician-side decision support tools offers a chance to further improve care.The purpose of this review is to summarize the recent advances in prediction, diagnosis and monitoring of preeclampsia and its associated adverse outcomes. We will review the potential impact of the ability to access to clinical data via remote monitoring. In the combination of advanced, machine learning-based risk calculation and remote monitoring lies an unused potential that allows for a truly patient-centered care.
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Affiliation(s)
- Max Hackelöer
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität Zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Leon Schmidt
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität Zu Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Stefan Verlohren
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität Zu Berlin, Charitéplatz 1, 10117, Berlin, Germany.
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Beernink RHJ, Scherjon SA, Cremers TIFH, van Asselt ADI. Cost-effectiveness analysis of a first-trimester screening test for preterm preeclampsia in the Netherlands. J Reprod Immunol 2023; 160:104141. [PMID: 37708725 DOI: 10.1016/j.jri.2023.104141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 07/07/2023] [Accepted: 08/29/2023] [Indexed: 09/16/2023]
Abstract
OBJECTIVES The risk of preterm preeclampsia (PT PE) can significantly be reduced by starting acetylsalicylic acid ≤ 16 weeks of gestational age. First trimester predictive models based on maternal risk factors to effectively start this therapy lacked sufficient power, but recent studies showed that these models can be improved by including test results of biochemical and/or -physical markers. To investigate whether testing a biochemical marker in the first trimester is cost-effective in the Netherlands, a cost-effectiveness analysis was performed in this study. STUDY DESIGN The outcome of this study was expressed as an incremental cost-effectiveness ratio (ICER) with as effect prevented PT PE cases. To evaluate the impact of each model parameter and to determine model uncertainties, both univariate and probabilistic sensitivity analyses were performed. RESULTS When compared to the baseline strategy, the test strategy is estimated to save almost 4 million euros per year on a national scale and at the same time this would prevent an additional 228 PT PE cases. The sensitivity analyses showed that the major drivers of the result are the costs to monitor a high-risk pregnancy and the specificity and that most of the model simulations were in the southeast quadrant: cost saving and more prevented complications. CONCLUSIONS This study showed that a first-trimester test strategy to screen for PT PE in the first trimester is potentially cost-effective in the Dutch healthcare setting. The fact that the specificity is a major driver of the ICER indicates the importance for a (new) screening model to correctly classify low-risk pregnancies.
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Affiliation(s)
- Rik H J Beernink
- Dept. Analytical Biochemistry, University of Groningen, Groningen, the Netherlands; Research & Development, IQ Products BV., Groningen, the Netherlands.
| | - Sicco A Scherjon
- Dept. of Obstetrics and Gynaecology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Thomas I F H Cremers
- Dept. Analytical Biochemistry, University of Groningen, Groningen, the Netherlands
| | - Antoinette D I van Asselt
- Dept. of Health Sciences, University of Groningen, University Medical Center, Groningen, the Netherlands; Dept. of Epidemiology, University of Groningen, University Medical Center, Groningen, the Netherlands
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Strijbos LTM, Hendrix MLE, Al-Nasiry S, Smits LJM, Scheepers HCJ. Which first-trimester risk assessment method for preeclampsia is most suitable? A model-based impact study. Am J Obstet Gynecol MFM 2023; 5:100974. [PMID: 37062507 DOI: 10.1016/j.ajogmf.2023.100974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/09/2023] [Accepted: 04/10/2023] [Indexed: 04/18/2023]
Abstract
BACKGROUND Low-dose aspirin treatment reduces the risk of preeclampsia among high-risk pregnant women. Internationally, several first-trimester risk-calculation methods are applied. OBJECTIVE This study aimed to assess the costs and benefits of different first-trimester preeclampsia risk estimation algorithms: EXPECT (an algorithmic prediction model based on maternal characteristics), National Institute for Health and Care Excellence (a checklist of risk factors), and the Fetal Medicine Foundation (a prediction model using additional uterine artery Doppler measurement and laboratory testing) models, coupled with low-dose aspirin treatment, in comparison with no risk assessment. STUDY DESIGN We constructed a decision analytical model estimating the number of cases of preeclampsia with each strategy and the costs of risk assessment for preeclampsia and early aspirin treatment, expressed in euros (€) in a hypothetical population of 100,000 women. We performed 1-way sensitivity analyses to assess the impact of adherence rates on model outcomes. RESULTS Application of the EXPECT, National Institute for Health and Care Excellence, and Fetal Medicine Foundation models results in respectively 1.98%, 2.55%, and 1.90% of the women developing preeclampsia, as opposed to 3.00% of women in the case of no risk assessment. Overall, the net financial benefits of the EXPECT, National Institute for Health and Care Excellence, and Fetal Medicine Foundation models relative to no risk assessment are €144, €43, and €38 per patient, respectively. The respective percentages of women receiving aspirin treatment are 18.6%, 10.2%, and 6.0% for the 3 risk assessment methods. CONCLUSION The EXPECT and Fetal Medicine Foundation model are comparable with regard to numbers of prevented preeclampsia cases, and both are superior to the National Institute for Health and Care Excellence model and to no risk assessment. EXPECT is less resource-demanding and results in the highest cost savings, but also requires the highest number of women to be treated with aspirin. When deciding which strategy is preferable, cost savings and easier use have to be weighed against the degree of overtreatment, although low-dose aspirin has no clear disadvantages during pregnancy.
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Affiliation(s)
- Lynn T M Strijbos
- Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands (Drs. Strijbos).
| | - Manouk L E Hendrix
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center+, Maastricht, The Netherlands (Dr. Hendrix, Dr. Al-Nasiry, and Dr Scheepers)
| | - Salwan Al-Nasiry
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center+, Maastricht, The Netherlands (Dr. Hendrix, Dr. Al-Nasiry, and Dr Scheepers); GROW School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands (XX Al-Nasiry and XX Scheepers)
| | - Luc J M Smits
- Department of Epidemiology, Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands (Prof. Smits)
| | - Hubertina C J Scheepers
- Department of Obstetrics and Gynaecology, Maastricht University Medical Center+, Maastricht, The Netherlands (Dr. Hendrix, Dr. Al-Nasiry, and Dr Scheepers); GROW School for Oncology and Reproduction, Maastricht University, Maastricht, The Netherlands (XX Al-Nasiry and XX Scheepers)
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Placental Growth Factor (PlGF)- Based Biomarker Testing to Help Diagnose Pre-eclampsia in People With Suspected Pre-eclampsia: A Health Technology Assessment. ONTARIO HEALTH TECHNOLOGY ASSESSMENT SERIES 2023; 23:1-146. [PMID: 37284279 PMCID: PMC10241193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Background Pre-eclampsia is a potentially serious condition affecting up to 5% of pregnancies, most frequently after 20 weeks' gestation. Placental growth factor (PlGF)-based tests measure either the blood level of PlGF or the ratio of soluble fms-like tyrosine kinase-1 (sFlt-1) to PlGF. They are intended to complement standard clinical assessment to help diagnose pre-eclampsia in people with suspected pre-eclampsia. We conducted a health technology assessment of PlGF-based biomarker testing as an adjunct to standard clinical assessment to help diagnose pre-eclampsia in pregnant people with suspected pre-eclampsia, which included an evaluation of diagnostic accuracy, clinical utility, cost-effectiveness, the budget impact of publicly funding PlGF-based biomarker testing, and an assessment of preferences and values. Methods We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using AMSTAR 2, Cochrane Risk of Bias tool, the Quality of Diagnostic Accuracy Studies 2 (QUADAS-2) tool, and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic literature search of the economic evidence. We did not conduct a primary economic evaluation as the impact of the test on maternal and neonatal outcomes is uncertain. We also analyzed the budget impact of publicly funding PlGF-based biomarker testing in pregnant people with suspected pre-eclampsia in Ontario. To contextualize the potential value of PlGF-based biomarker testing, we spoke with people whose pregnancies had been impacted by pre-eclampsia as well as their family members. Results We included one systematic review and one diagnostic accuracy study in the clinical evidence review. The Elecsys sFlt-1/PlGF ratio test using a test cut-off of less than 38 for ruling out pre-eclampsia within 1 week yielded a negative predictive value (NPV) of 99.2% and the DELFIA Xpress PlGF 1-2-3 test using a cut-off of 150 pg/mL or greater for ruling out pre-eclampsia within 1 week yielded a NPV of 94.8% (diagnostic GRADE: Moderate for both tests). All clinical utility outcomes were associated with uncertainties (GRADE: Low).We included 13 studies in the economic evidence review, most of which concluded that the use of PlGF-based biomarker testing resulted in cost savings. Seven studies were partially applicable to the Ontario health care setting but have some important limitations; the remaining 6 studies were not applicable. We estimated that publicly funding PlGF-based biomarker testing for people with suspected pre-eclampsia in Ontario would lead to an additional annual cost of $0.27 million in year 1 to $0.46 million in year 5, for a total additional cost of $1.83 million over 5 years.Direct engagement included 24 people who had been impacted by pre-eclampsia during their pregnancies as well as one family member. Participants described the emotional and physical impacts of having suspected pre-eclampsia and subsequent treatments. Those that we spoke with valued shared decision-making and identified potential gaps in patient education, specifically as it relates to symptom management for suspected pre-eclampsia. Overall, the participants viewed PlGF-based biomarker testing positively for its perceived medical benefits and minimal invasiveness. They felt that access to PlGF-based biomarker testing may also improve health outcomes through improved patient education, care coordination, and patient-centred care (e.g., prompting more frequent prenatal monitoring, when needed). In addition, PlGF-based biomarker testing was perceived to be equally beneficial for family members who may act as the health care proxy in an emergency. Lastly, participants emphasized that there should be equitable access to PlGF-based biomarker testing and support from a care provider should be offered when trying to interpret the results, particularly if the results are accessible through an online patient portal. Conclusions Compared with standard clinical assessment alone in people with suspected pre-eclampsia (gestational age between 20 and 36 weeks + 6 days), PlGF-based biomarker testing as an adjunct to standard clinical assessment likely improves prediction of pre-eclampsia. It may also reduce time to pre-eclampsia diagnosis, severe adverse maternal outcomes, and length of stay in the neonatal intensive care unit, although the evidence is uncertain. PlGF-based biomarker testing may result in little to no difference in other clinical outcomes such as maternal admission to hospital and perinatal adverse outcomes.The economic literature review showed that PlGF-based biomarker testing was cost-effective for use in people with suspected pre-eclampsia, but with some uncertainties. A primary economic evaluation was not done for this health technology assessment because the impact of the test on maternal and neonatal outcomes is uncertain. Publicly funding PlGF-based biomarker testing for people with suspected pre-eclampsia would lead to an additional cost of $1.83 million over 5 years.Publicly funding PlGF-based biomarker testing was viewed favourably by people directly impacted by pre-eclampsia as well as their family members. Those with whom we spoke valued testing to help diagnose suspected pre-eclampsia and valued the potential medical benefits. Participants emphasized that patient education, and equitable access to PlGF-based biomarker testing should be requirements for implementation in Ontario.
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Economic Impact Analysis of Incorporation of Elecsys sFlt-1/PlGF Ratio Into Routine Practice for the Diagnosis and Follow-Up of Pregnant Women With Suspected Preeclampsia in Argentina. Value Health Reg Issues 2023; 34:1-8. [PMID: 36335800 DOI: 10.1016/j.vhri.2022.09.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 07/01/2022] [Accepted: 09/13/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVES Preeclampsia (PE) is a hypertensive disorder of pregnancy that can cause severe complications and adverse fetal/maternal outcomes. We aimed to estimate the annual economic impact of incorporating Elecsys® sFlt-1/PlGF PE ratio, which measures soluble fms-like tyrosine kinase-1 and placental growth factor, into routine clinical practice in Argentina to aid diagnosis of PE and hemolysis, elevated liver enzymes, and low platelets syndrome from second trimester onward in pregnancies with clinical suspicion of PE. METHODS A decision tree was used to estimate annual economic impact on the Argentine health system as a whole, including relevant costs associated with diagnosis, follow-up, and treatment from initial presentation of clinically suspected PE to delivery. Annual costs of a standard-of-care scenario and a scenario including PE ratio (reference year 2021) were analyzed. RESULTS The economic model estimated that using the sFlt-1/PlGF ratio would enable the overall health system to save ∼$6987 million Argentine pesos annually (95% confidence interval $12 045-$2952 million), a 39.1% reduction in costs versus standard of care, mainly due to reduced hospitalizations of women with suspected PE. The economic impact calculation estimated net annual savings of approximately $80 504 Argentine pesos per patient with suspected PE. Based on the assumed uncertainty of the parameters, the likelihood the intervention would be cost saving was 100% for the considered scenarios. CONCLUSION Our analysis suggests that the implementation of the sFlt-1/PlGF ratio in women with suspected PE in Argentina will enable the health system to achieve significant savings, contributing to more efficient clinical management through the likely reduction of unnecessary hospitalizations, depending on assumptions. Results rest on the payers' ability to recover savings generated by the intervention.
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Hughes RCE, Phillips I, Florkowski CM, Gullam J. The predictive value of the sFlt-1/PlGF ratio in suspected preeclampsia in a New Zealand population: A prospective cohort study. Aust N Z J Obstet Gynaecol 2023; 63:34-41. [PMID: 35670085 DOI: 10.1111/ajo.13549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 05/08/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Internationally, placental growth factor (PlGF)-based tests are used as prognostic markers in suspected preeclampsia. However, Ministry of Health guidelines do not currently endorse PlGF-based tests in New Zealand (NZ). AIMS To investigate the predictive value of soluble fms-like tyrosine kinase 1 (sFlt-1)/PlGF ratio in suspected preeclampsia in a NZ population. MATERIALS AND METHODS A prospective cohort study of singleton pregnancies at 20+0 -36+6 weeks gestation with suspected preeclampsia as defined by Society of Obstetric Medicine Australia and NZ (SOMANZ) criteria. PRIMARY OBJECTIVE to evaluate a sFlt-1/PlGF ratio >38 at ≤35+0 weeks gestation to predict birth ≤14 days. SECONDARY OBJECTIVES to assess a sFlt-1/PlGF ratio cut-off of 38 at ≤37+0 weeks gestation, to rule out preeclampsia ≤1 week, rule in preeclampsia ≤4 weeks, and to predict perinatal outcome. Clinicians were blinded to sFlt-1/PlGF ratio results. RESULTS Included were 222 participants, 19.4% Māori and 10.4% Pasifika. A sFlt-1/PlGF >38 predicted birth ≤14 days, positive predictive value (PPV) 51.4% (95% CI, 39.6-63.0) and negative predictive value (NPV) 95.9% (95% CI, 91.4-98.1), median (interquartile range) days to birth 14 (2-27) vs 49 (33-70), P < 0.000. A sFlt-1/PlGF cut-off of 38 ruled out preeclampsia ≤1 week (NPV 96.2% (95% CI, 92.3-98.2)) and ruled in preeclampsia ≤4 weeks (PPV 75.0% (95% CI, 65.0-82.9)). A sFlt-1/PlGF >38 was associated with greater perinatal morbidity. CONCLUSIONS The predictive value of the sFlt-1/PlGF ratio in NZ is comparable to that reported in international trials. Used in clinical practice the sFlt-1/PlGF ratio may aid risk stratification in suspected preeclampsia, directing limited resources to those pregnancies at highest risk.
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Affiliation(s)
- Ruth C E Hughes
- Christchurch Women's Hospital, Canterbury District Health Board, Christchurch, New Zealand.,Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand
| | - Ian Phillips
- Head of Endocrine and Steroid Laboratory, Canterbury Health Laboratories, Christchurch, New Zealand
| | - Chris M Florkowski
- Consultant in Chemical Pathology: Canterbury Health Laboratories, Christchurch, New Zealand
| | - Joanna Gullam
- Christchurch Women's Hospital, Canterbury District Health Board, Christchurch, New Zealand.,Department of Obstetrics and Gynaecology, University of Otago, Christchurch, New Zealand
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16
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Chaiworapongsa T, Romero R, Gotsch F, Gomez-Lopez N, Suksai M, Gallo DM, Jung E, Levenson D, Tarca AL. One-third of patients with eclampsia at term do not have an abnormal angiogenic profile. J Perinat Med 2022:jpm-2022-0474. [PMID: 36567427 DOI: 10.1515/jpm-2022-0474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/04/2022] [Indexed: 12/27/2022]
Abstract
OBJECTIVES An abnormal angiogenic profile is present in about one-half of women with preeclampsia at term. Few studies examined the roles of angiogenic biomarkers in eclampsia. The aims of this study were to determine (1) whether the degree of an anti-angiogenic state, reflected by a low placental growth factor (PlGF) to soluble fms-like tyrosine kinase-1 (sFlt-1) ratio, in women with eclampsia differed from that of women with severe preeclampsia; and (2) the prevalence of women who had an abnormal angiogenic profile at the diagnoses of preterm and term eclampsia. METHODS A cross-sectional study was conducted to include women in the following groups: (1) uncomplicated pregnancy (n=40); (2) severe preeclampsia (n=50); and (3) eclampsia (n=35). Maternal serum concentrations of PlGF and sFlt-1 were determined by immunoassays. RESULTS Women with preterm, but not term, eclampsia had a more severe anti-angiogenic state than those with severe preeclampsia (lower PlGF and PlGF/sFlt-1 ratio, each p<0.05). However, the difference diminished in magnitude with increasing gestational age (interaction, p=0.005). An abnormal angiogenic profile was present in 95% (19/20) of women with preterm eclampsia but in only 67% (10/15) of women with eclampsia at term. CONCLUSIONS Angiogenic biomarkers can be used for risk assessment of preterm eclampsia. By contrast, a normal profile of angiogenic biomarkers cannot reliably exclude patients at risk for eclampsia at term. This observation has major clinical implications given that angiogenic biomarkers are frequently used in the triage area as a test to rule out preeclampsia.
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Affiliation(s)
- Tinnakorn Chaiworapongsa
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Roberto Romero
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.,Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.,Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI, USA.,Detroit Medical Center, Detroit, MI, USA
| | - Francesca Gotsch
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Nardhy Gomez-Lopez
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Manaphat Suksai
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Dahiana M Gallo
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Obstetrics and Gynecology, University of Valle, Cali, Colombia
| | - Eunjung Jung
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Dustyn Levenson
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Wayne State University School of Medicine, Detroit, MI, USA
| | - Adi L Tarca
- 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, U. S. Department of Health and Human Services, National Institutes of Health, Bethesda, MD, and Detroit, MI, USA.,Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI, USA.,Department of Computer Science, Wayne State University College of Engineering, Detroit, MI, USA
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Clinical value and cost analysis of the sFlt-1/PlGF ratio in addition to the spot urine protein/creatinine ratio in women with suspected pre-eclampsia: PREPARE cohort study. BMC Pregnancy Childbirth 2022; 22:910. [PMID: 36474150 PMCID: PMC9727903 DOI: 10.1186/s12884-022-05254-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND This study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia. METHODS This was a prospective cohort study performed in a tertiary referral centre. Based on the combination of PCr (< 30) and sFlt-1/PlGF (≤38) results, four groups were described: a double negative result, group A-/-; a negative PCr and positive sFlt-1/PlGF, group B-/+; a positive PCr and negative sFlt-1/PlGF, group C+/-; and a double positive result, group D+/+. The primary outcome was the proportion of false negatives of the combined tests in comparison with PCr alone in the first week after baseline. Secondary, a cost analysis comparing the costs and savings of adding the sFlt-1/PlGF ratio was performed for different follow-up scenarios. RESULTS A total of 199 women were included. Pre-eclampsia in the first week was observed in 2 women (2%) in group A-/-, 12 (26%) in group B-/+, 4 (27%) in group C+/-, and 12 (92%) in group D+/+. The proportion of false negatives of 8.2% [95% CI 4.9-13.3] with the PCr alone was significantly reduced to 1.6% [0.4-5.7] by adding a negative sFlt-1/PlGF ratio. Furthermore, the addition of the sFlt-1/PlGF ratio to the spot urine PCr, with telemonitoring of women at risk, could result in a reduction of 41% admissions and 36% outpatient visits, leading to a cost reduction of €46,- per patient. CONCLUSIONS Implementation of the sFlt-1/PlGF ratio in addition to the spot urine PCr, may lead to improved selection of women at low risk and a reduction of hospital care for women with suspected pre-eclampsia. TRIAL REGISTRATION Netherlands Trial Register (NL8308).
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Mtshali Z, Govender N, Naicker T. Circulating levels of transforming growth factor beta-1, 2 and 3 in HIV associated preeclamptic pregnancies. J OBSTET GYNAECOL 2022; 42:2853-2859. [PMID: 36006052 DOI: 10.1080/01443615.2022.2110458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The active role of transforming growth factor-beta in implantation, embryonic development and decidualization has driven our interest to evaluate circulating TGF-β(1-3) in the synergy of HIV associated pregnancy. Serum TGF-β(1-3) was quantified in normotensive (n = 38) and preeclamptic (n = 38) pregnant women, who were stratified by HIV status, HIV negative (n = 19) and HIV positive (n = 19), using a Bioplex immunoassay.Based on HIV status, we report no significant difference in TGF-β-1 (p = .95) and TGF-β2 (p = .80) however, TGF-β3 was significantly downregulated in HIV positive (p = .03) vs the HIV negative groups. A significant positive correlation (p < .05) was noted between TGF-β3 and gestational age (p = .03) (r = 0.51), birth weight (p = .04) (r = 0.53) and CD4 count (p = .02) (r = 0.53). Bivariate correlation between isoforms based on HIV status showed several significant positive associations. In the synergy of HIV infected PE, we demonstrate an association between TGF-β(1-3) with PE emanating from the hypoxic microenvironment that affects receptor-SMAD activity. Decreased TGF-β3 levels in HIV infected PE, may originate from ARV usage and/or the mutational/physiological dysregulation of SMAD expression. Impact StatementWhat is already known on this subject? TGF-β overexpression can convert its protective functions into pathogenic variants. It has a significant role in the oxidatively stressed and inflammatory condition of tissue fibrosis and hence may also be dysregulated in the microenvironment of PE. In HIV infection, TGF-β promotes viral replication and spreading through the induction of cellular proteins which induce TGF-β production. Also, mononuclear phagocytes infected with HIV also produce increased TGF-β mRNA and proteins.What do the results of the study add? Our results show no association of TGF-β isoforms (1-3) based on pregnancy type (PE vs normotensive pregnant) at term. The lack of association may be linked to TGF-βs dual promoter/suppresser nature or to gestational age.What are the implications of these findings for clinical practice and/or further research? Large-scale comprehensive clinical trials are warranted to elucidate the association and mechanistic role of TGF-β receptor-SMAD signalling, the effect of its inhibitors on cell invasion and angiogenesis as well as to deliver valuable data for the detection of novel therapeutic agents in pregnancies complicated by HIV infection.
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Affiliation(s)
- Zamahlabangane Mtshali
- Discipline of Optics and Imaging, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Nalini Govender
- Department of Basic Medical Sciences, Durban University of Technology, Durban, South Africa
| | - Thajasvarie Naicker
- Discipline of Optics and Imaging, Doris Duke Medical Research Institute, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
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Kifle MM, Dahal P, Vatish M, Cerdeira AS, Ohuma EO. The prognostic utility of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PIGF) biomarkers for predicting preeclampsia: a secondary analysis of data from the INSPIRE trial. BMC Pregnancy Childbirth 2022; 22:520. [PMID: 35761268 PMCID: PMC9238141 DOI: 10.1186/s12884-022-04817-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 06/07/2022] [Indexed: 11/10/2022] Open
Abstract
Objective To compare the prognostic performance of biomarkers soluble fms-like tyrosine kinase-1 (sFlt-1), Placental Growth Factor (PIGF), and sFlt-1/PIGF ratio as continuous values or as a binary cut-off of 38 for predicting preeclampsia (PE) within 7 days. Design Secondary analysis of a randomised clinical trial. Setting Oxford University Hospitals, Oxford, United Kingdom (UK). Population Pregnant women between 24+0 to 37+0 weeks of gestation with a clinical suspicion of preeclampsia. Main outcome Onset of preeclampsia within 7 days of the initial biomarker test. Methods Logistic regression model for onset of preeclampsia using: (i) sFlt-1 (ii) PIGF, (iii) sFlt-1/PIGF ratio (continuous), and (iv) sFlt-1/PIGF ratio as a cut-off above or below 38. Results Of the total 370 women, 42 (11.3%) developed PE within 7 days of screening. Models with sFlt-1 and sFlt-1/PIGF ratio (continuous) had greater overall performance than models with PIGF or with sFlt-1/PIGF ratio as a cut-off at 38 (R2: sFlt-1 = 55%, PIGF = 38%, sFlt-1/PIGF ratio = 57%, sFlt-1/PIGF ratio as cut-off at 38 model = 46%). The discrimination performance was the highest in sFlt-1 and sFlt-1/PIGF ratio (continuous) (c-statistic, sFlt-1 = 0.94, sFlt-1/PIGF ratio (continuous) = 0.94) models compared to PIGF or sFlt-1/PIGF cut-off models (c-statistic, PIGF = 0.87, sFlt-1/PIGF cut-off = 0.89). Conclusion Models using continuous values of sFlt-1 only or sFlt-1/PIGF ratio had better predictive performance compared to a PIGF only or the model with sFlt-1/PIGF ratio as a cut-off at 38. Further studies based on a larger sample size are warranted to substantiate this finding.
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Affiliation(s)
- Meron M Kifle
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Prabin Dahal
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
| | - Manu Vatish
- Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | - Ana Sofia Cerdeira
- Nuffield Department of Women's and Reproductive Health, University of Oxford, Oxford, UK
| | - Eric O Ohuma
- Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK. .,Maternal, Adolescent, Reproductive and Child Health Centre, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
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Lin W, Teng SW, Lin TY, Lovel R, Sung HY, Chang WY, Wu TBC, Chen HY, Wang LM, Shaw SW. Combinatorial Analysis of Circulating Biomarkers and Maternal Characteristics for Preeclampsia Prediction in the First and Third Trimesters in Asia. Diagnostics (Basel) 2022; 12:1533. [PMID: 35885439 PMCID: PMC9320107 DOI: 10.3390/diagnostics12071533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 06/10/2022] [Accepted: 06/18/2022] [Indexed: 11/16/2022] Open
Abstract
We aim to establish a prediction model for pregnancy outcomes through a combinatorial analysis of circulating biomarkers and maternal characteristics to effectively identify pregnant women with higher risks of preeclampsia in the first and third trimesters within the Asian population. A total of two hundred and twelve pregnant women were screened for preeclampsia through a multicenter study conducted in four recruiting centers in Taiwan from 2017 to 2020. In addition, serum levels of sFlt-1/PlGF ratio, miR-181a, miR-210 and miR-223 were measured and transformed into multiples of the median. We thus further developed statistically validated algorithmic models by designing combinations of different maternal characteristics and biomarker levels. Through the performance of the training cohort (0.848 AUC, 0.73−0.96 95% CI, 80% sensitivity, 85% specificity, p < 0.001) and the validation cohort (0.852 AUC, 0.74−0.98 95% CI, 75% sensitivity, 87% specificity, p < 0.001) from one hundred and fifty-two women with a combination of miR-210, miR-181a and BMI, we established a preeclampsia prediction model for the first trimester. We successfully identified pregnant women with higher risks of preeclampsia in the first and third trimesters in the Asian population using the established prediction models that utilized combinatorial analysis of circulating biomarkers and maternal characteristics.
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Affiliation(s)
- Willie Lin
- Meridigen Biotech Co., Ltd., Taipei 114, Taiwan; (W.L.); (T.B.-C.W.)
| | - Sen-Wen Teng
- Department of Obstetrics and Gynecology, Cardinal Tien Hospital, New Taipei 231, Taiwan;
- School of Medicine, Fu-Jen Catholic University, New Taipei 242, Taiwan
| | - Tzu-Yi Lin
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Ronald Lovel
- Meribank Biotech Co., Ltd., Taipei 114, Taiwan; (R.L.); (H.-Y.S.); (W.-Y.C.); (H.-Y.C.)
| | - Hsin-Yu Sung
- Meribank Biotech Co., Ltd., Taipei 114, Taiwan; (R.L.); (H.-Y.S.); (W.-Y.C.); (H.-Y.C.)
| | - Wen-Ying Chang
- Meribank Biotech Co., Ltd., Taipei 114, Taiwan; (R.L.); (H.-Y.S.); (W.-Y.C.); (H.-Y.C.)
| | - Tang Bo-Chung Wu
- Meridigen Biotech Co., Ltd., Taipei 114, Taiwan; (W.L.); (T.B.-C.W.)
| | - Hsuan-Yu Chen
- Meribank Biotech Co., Ltd., Taipei 114, Taiwan; (R.L.); (H.-Y.S.); (W.-Y.C.); (H.-Y.C.)
| | - Le-Ming Wang
- Department of Obstetrics and Gynecology, Wan Fang Hospital, Taipei 116, Taiwan;
- Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Steven W. Shaw
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, No. 199, Dun-Hua North Road, Taipei 105, Taiwan
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21
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Costa ML, Cavalli RDC, Korkes HA, Cunha Filho EVD, Peraçoli JC. Diagnosis and Management of Preeclampsia: Suggested Guidance on the Use of Biomarkers. REVISTA BRASILEIRA DE GINECOLOGIA E OBSTETRICIA : REVISTA DA FEDERACAO BRASILEIRA DAS SOCIEDADES DE GINECOLOGIA E OBSTETRICIA 2022; 44:878-883. [PMID: 35468644 PMCID: PMC9948147 DOI: 10.1055/s-0042-1744286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
OBJECTIVE It is a challenge to consider preeclampsia (PE) diagnosis and management in low and middle-income settings, where it represents a major public health concern. The placenta is the underlying cause of disease, and the plasma concentrations of proangiogenic and antiangiogenic factors released by the placenta can reflect the risks of disease progression. Antiangiogenic proteins, such as soluble fms-like tyrosine kinase 1 (sFlt-1), and proangiogenic, like placental growth factors (PlGF), are directly and inversely correlated with the disease onset, respectively. METHODS Narrative review on the use of biomarkers (sFlt-1 to PlGF ratio) with a suggested guidance protocol. RESULTS Key considerations on the use of biomarkers: the sFlt-1/PlGF ratio is mainly relevant to rule out PE between 20 and 36 6/7 weeks in cases of suspected PE; however, it should not replace the routine exams for the diagnosis of PE. The sFlt-1/PlGF ratio should not be performed after confirmed PE diagnosis (only in research settings). In women with suspected PE, sFlt-1/PlGF ratio < 38 can rule out the diagnosis of PE for 1 week (VPN = 99.3) and up to 4 weeks (VPN= 94.3); sFlt-1/PlGF ratio > 38 does not confirm the diagnosis of PE; however, it can assist clinical management. In cases of severe hypertension and/or symptoms (imminent eclampsia), hospitalization is imperative, regardless of the result of the sFlt-1/PlGF ratio. CONCLUSION The use of biomarkers can help support clinical decisions on the management of suspected PE cases, especially to rule out PE diagnosis, thus avoiding unnecessary interventions, especially hospitalizations and elective prematurity.
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Affiliation(s)
- Maria Laura Costa
- Department of Gynecology and Obstetrics, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Ricardo de Carvalho Cavalli
- Department of Gynecology and Obstetrics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
| | - Henri Augusto Korkes
- Department of Human Reproduction and Childhood, Pontifícia Universidade Católica de São Paulo, São Paulo, SP, Brazil
| | | | - José Carlos Peraçoli
- Department of Gynecology and Obstetrics, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista Júlio de Mesquita Filho, Botucatu, SP, Brazil
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22
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Biophysical Markers of Suspected Preeclampsia, Fetal Growth Restriction and the Two Combined—How Accurate They Are? REPRODUCTIVE MEDICINE 2022. [DOI: 10.3390/reprodmed3020007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives—To conduct a secondary analysis of prediction accuracy of biophysical markers for suspected Preeclampsia (PE), Fetal Growth Restriction (FGR) and the two combined near delivery in a Slovenian cohort. Methods—This was a secondary analysis of a database of a total 125 Slovenian pregnant women attending a high-risk pregnancy clinic due to suspected PE (n = 31), FGR (n = 16) and PE + FGR (n = 42) from 28–39 weeks gestation and their corresponding term (n = 21) and preterm (PTD, n = 15) controls. Data for Mean Arterial blood Pressure (MAP) and Uterine artery pulsatility index (UtA PI) estimated by Doppler sonography were extracted from the database of patients who were tested at admission to the high-risk clinic with the suspected complications. The reactive hyperemia index (RHI), and the Augmentation Index (AIX%) were extracted from the patient database using measured values obtained with the assistance of the Endo PAT, a device set to measure the signal of the peripheral arterial tone (PAT) from the blood vessels endothelium. Linear regression coefficients, Box and Whisker plots, Area under the Curve (AUC) of receiver Operation Characteristic (ROC) curves, and multiple regression were used to assess the marker accuracy using detection rate (DR) and false-positive rate (FPR) and previously reported cut-offs for estimating the positive and negative predictive value (NPV and PPV). The SPSS non-parametric statistics (Kruskal Wallis and Mann–Whitney) and Spearman’s regression coefficient were used to assess marker accuracy; p < 0.05 was considered significant. Results—MAP values reached diagnostic accuracy (AUC = 1.00, DR = 100%) for early PE cases delivered < 34, whereas UtA Doppler PI values yielded such results for early FGR < 34 weeks and the two combined reached such accuracy for PE + FGR. To reach diagnostic accuracy for all cases of the complications, the Endo PAT markers with values for MAP and UtA Doppler PI were required for cases near delivery. Multiple regression analyses showed added value for advanced maternal age and gestational week in risk assessment for all cases of PE, FGR, and PE + FGR. Spearman’s regression coefficient yielded r > 0.6 for UtA Doppler PI over GA for PE and FGR, whereas for RHI over BMI, the regression coefficient was r > 0.5 (p < 0.001 for each). Very high correlations were also found between UtA Doppler PI and sFlt-1/PlGF or PlGF (r = −0.495, p < 0.001), especially in cases of FGR. Conclusion—The classical biophysical markers MAP and UtA Doppler PI provided diagnostic accuracy for PE and FGR < 34 wks gestation. A multiple biophysical marker analysis was required to reach diagnostic accuracy for all cases of these complications. The UtA Doppler PI and maternal serum sFlt-1/PlGF or PlGF were equally accurate for early cases to enable the choice of the markers for the clinical use according to the more accessible method.
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Aminuddin NA, Sutan R, Mahdy ZA, Rahman RA, Nasuruddin DN. The feasibility of soluble Fms-Like Tyrosine kinase-1 (sFLT-1) and Placental Growth Factor (PlGF) ratio biomarker in predicting preeclampsia and adverse pregnancy outcomes among medium to high risk mothers in Kuala Lumpur, Malaysia. PLoS One 2022; 17:e0265080. [PMID: 35275947 PMCID: PMC8916650 DOI: 10.1371/journal.pone.0265080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 02/23/2022] [Indexed: 11/18/2022] Open
Abstract
Background Preeclampsia significantly contributes to maternal and perinatal morbidity and mortality. It is imperative to identify women at risk of developing preeclampsia in the effort to prevent adverse pregnancy outcomes through early intervention. Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) level changes are noticeable several weeks before the onset of preeclampsia and its related complications. This study evaluated the feasibility of the sFlt-1/PlGF biomarker ratio in predicting preeclampsia and adverse pregnancy outcomes using a single cut-off point of >38. Methods This is a prospective cohort study conducted at a single tertiary centre, in an urban setting in Kuala Lumpur, Malaysia, between December 2019 and April 2021. A total of 140 medium to high risk mothers with singleton pregnancies were recruited at ≥20 weeks’ gestation. sFlt-1/PlGF ratio was measured and the participant monitored according to a research algorithm until delivery. The primary outcome measure was incidence of preeclampsia and the secondary outcome measure was incidence of other adverse pregnancy outcomes. Results The overall incidence of preeclampsia was 20.7% (29/140). The mean sFlt-1/PlGF ratio was significantly higher in preeclampsia (73.58 ± 93.49) compared to no preeclampsia (13.41 ± 21.63) (p = 0.002). The risk of preeclampsia (adjusted OR 28.996; 95% CI 7.920–106.164; p<0.001) and low Apgar score (adjusted OR 17.387; 95% CI 3.069–98.517; p = 0.028) were significantly higher among women with sFlt-1/PlGF ratio >38 compared with sFLT-1/PlGF ratio ≤38. The area under the receiver-operator characteristic curve (AUC) for a combined approach (maternal clinical characteristics and biomarker) was 86.9% (p<0.001, 95% CI 78.7–95.0) compared with AUC biomarker alone, which was 74.8% (p<0.001, 95% CI 63.3–86.3) in predicting preeclampsia. The test sensitivity(SEN) was 58.6%, specificity (SPEC) 91%,positive predictive value (PPV) 63% and negative predictive value (NPV) 89.3% for prediction of preeclampsia. For predicting a low Apgar score at 5 minutes, the SEN was 84.6%, SPEC 87.4%, PPV 40.7%, and NPV 98.2%; low birth weight with SEN 52.6%,SPEC 86.0%, PPV 37.0%, NPV 92.0%; premature delivery with SEN 48.5%, SPEC 89.5%, PPV 59.3%, NPV 84.7% and NICU admission with SEN 50.0%, SPEC 85.8%, PPV 37.0% and NPV 91.2%. Conclusions It is feasible to use single cut-off point of >38 ratio of the biomarkers sFlt-1/PlGF in combination with other parameters (maternal clinical characteristics) in predicting preeclampsia and adverse pregnancy outcomes among medium to high risk mothers without restricting outcome measurement period to 1 and 4 weeks in a single urban tertiary centre in Kuala Lumpur, Malaysia.
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Affiliation(s)
- Nurul Afzan Aminuddin
- Community Health Department, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rosnah Sutan
- Community Health Department, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
- * E-mail:
| | - Zaleha Abdullah Mahdy
- Obstetrics and Gynaecology Department, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
| | - Rahana Abd Rahman
- Obstetrics and Gynaecology Department, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
| | - Dian Nasriana Nasuruddin
- Pathology Department, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Rowson S, Reddy M, De Guingand D, Langston-Cox A, Marshall S, da Silva Costa F, Palmer K. Comparison of circulating total sFLT-1 to placental-specific sFLT-1 e15a in women with suspected preeclampsia. Placenta 2022; 120:73-78. [DOI: 10.1016/j.placenta.2022.02.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/29/2022] [Accepted: 02/22/2022] [Indexed: 10/19/2022]
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Women’s perspectives and attitudes towards the utility of angiogenic biomarkers in preeclampsia. Pregnancy Hypertens 2022; 28:109-113. [DOI: 10.1016/j.preghy.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 02/28/2022] [Accepted: 03/14/2022] [Indexed: 11/18/2022]
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Dathan-Stumpf A, Rieger A, Verlohren S, Wolf C, Stepan H. sFlt-1/PlGF ratio for prediction of preeclampsia in clinical routine: A pragmatic real-world analysis of healthcare resource utilisation. PLoS One 2022; 17:e0263443. [PMID: 35202416 PMCID: PMC8870556 DOI: 10.1371/journal.pone.0263443] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 01/19/2022] [Indexed: 11/19/2022] Open
Abstract
Background We investigated the impact of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio to predict short-term risk of preeclampsia on clinical utility and healthcare resource utilisation using real-world data (RWD), and compared findings with health economic modelling from previous studies. Methods and findings This retrospective analysis compared data from the German population of a multicentre clinical study (PROGNOSIS, n = 203; sFlt-1/PlGF ratio blinded and unavailable for decision-making) with RWD from University Hospital Leipzig, Germany (n = 281; sFlt-1/PlGF ratio used to guide clinical decision-making). A subgroup of the RWD cohort with the same inclusion criteria as the PROGNOSIS trial (RWD prediction only, n = 99) was also included. sFlt-1/PlGF ratio was measured using fully automated Elecsys® sFlt-1 and PlGF immunoassays (cobas e analyser; Roche Diagnostics). A similar proportion of women in the RWD and PROGNOSIS cohorts experienced preeclampsia (14.95% vs. 13.79%; p = 0.7938); a smaller proportion of women in the RWD prediction only cohort experienced preeclampsia versus PROGNOSIS (6.06%; p = 0.0526). In women with preeclampsia, median gestational age at delivery (weeks) was comparable in the RWD and PROGNOSIS cohorts (34.0 vs. 34.3, p = 0.5895), but significantly reduced in the RWD prediction only cohort versus PROGNOSIS (27.1, p = 0.0038). sFlt-1/PlGF ratio at baseline visit was not statistically significantly different for the RWD and PROGNOSIS cohorts, irrespective of preeclampsia outcome. Hospitalisations for confirmed preeclampsia were significantly shorter in the RWD cohort versus PROGNOSIS (median 1 vs. 4 days, p = 0.0093); there was no significant difference between RWD prediction only and PROGNOSIS (3 days, p = 0.9638). All-cause hospitalisations were significantly shorter in the RWD (median 1 day; p<0.0001) and RWD prediction only (1 day; p<0.0001) cohorts versus PROGNOSIS (3 days). Conclusions This study supports the findings of previous studies, showing that routine clinical use of the sFlt-1/PlGF ratio may result in shorter duration of hospitalisations, with potential economic benefits.
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Affiliation(s)
| | - Anna Rieger
- Biostatistics, Data Science and Digital Solutions, Roche Diagnostics GmbH, Penzberg, Germany
| | - Stefan Verlohren
- Department of Obstetrics, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Cyrill Wolf
- Market Access and Health Policy, Roche Diagnostics International Ltd, Rotkreuz, Switzerland
| | - Holger Stepan
- Department of Obstetrics, University Hospital Leipzig, Leipzig, Germany
- * E-mail:
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Schmidt LJ, Rieger O, Neznansky M, Hackelöer M, Dröge LA, Henrich W, Higgins D, Verlohren S. A machine-learning-based algorithm improves prediction of preeclampsia-associated adverse outcomes. Am J Obstet Gynecol 2022; 227:77.e1-77.e30. [PMID: 35114187 DOI: 10.1016/j.ajog.2022.01.026] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 12/31/2021] [Accepted: 01/06/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Preeclampsia presents a highly prevalent burden on pregnant women with an estimated incidence of 2% to 5%. Preeclampsia increases the maternal risk of death 20-fold and is one of the main causes of perinatal morbidity and mortality. Novel biomarkers, such as soluble fms-like tyrosine kinase-1 and placental growth factor in addition to a wide span of conventional clinical data (medical history, physical symptoms, laboratory parameters, etc.), present an excellent basis for the application of early-detection machine-learning models. OBJECTIVE This study aimed to develop, train, and test an automated machine-learning model for the prediction of adverse outcomes in patients with suspected preeclampsia. STUDY DESIGN Our real-world dataset of 1647 (2472 samples) women was retrospectively recruited from women who presented to the Department of Obstetrics at the Charité - Universitätsmedizin Berlin, Berlin, Germany, between July 2010 and March 2019. After standardization and data cleaning, we calculated additional features regarding the biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor and sonography data (umbilical artery pulsatility index, middle cerebral artery pulsatility index, mean uterine artery pulsatility index), resulting in a total of 114 features. The target metric was the occurrence of adverse outcomes throughout the remaining pregnancy and 2 weeks after delivery. We trained 2 different models, a gradient-boosted tree and a random forest classifier. Hyperparameter training was performed using a grid search approach. All results were evaluated via a 10 × 10-fold cross-validation regimen. RESULTS We obtained metrics for the 2 naive machine-learning models. A gradient-boosted tree model was performed with a positive predictive value of 88%±6%, a negative predictive value of 89%±3%, a sensitivity of 66%±5%, a specificity of 97%±2%, an overall accuracy of 89%±3%, an area under the receiver operating characteristic curve of 0.82±0.03, an F1 score of 0.76±0.04, and a threat score of 0.61±0.05. The random forest classifier returned an equal positive predictive value (88%±6%) and specificity (97%±1%) while performing slightly inferior on the other available metrics. Applying differential cutoffs instead of a naive cutoff for positive prediction at ≥0.5 for the classifier's results yielded additional increases in performance. CONCLUSION Machine-learning techniques were a valid approach to improve the prediction of adverse outcomes in pregnant women at high risk of preeclampsia vs current clinical standard techniques. Furthermore, we presented an automated system that did not rely on manual tuning or adjustments.
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Affiliation(s)
- Leon J Schmidt
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Oliver Rieger
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Mark Neznansky
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Max Hackelöer
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health at Charité -Universitätsmedizin Berlin, Berlin, Germany
| | - Lisa A Dröge
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Wolfgang Henrich
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - David Higgins
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité BIH Innovation, BIH Digital Health Accelerator Program, Berlin, Germany.
| | - Stefan Verlohren
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany; Berlin Institute of Health at Charité -Universitätsmedizin Berlin, Berlin, Germany.
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Verlohren S, Dröge LA. The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia. Am J Obstet Gynecol 2022; 226:S1048-S1058. [PMID: 33002498 DOI: 10.1016/j.ajog.2020.09.046] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/22/2020] [Accepted: 09/25/2020] [Indexed: 01/21/2023]
Abstract
The definition of preeclampsia is changing. However, with the addition of organ symptoms to the presence of hypertension in pregnancy instead of relying only on proteinuria, a more precise detection of women at risk of preeclampsia-associated adverse events has not been achieved. Instead, under the new definitions of the American College of Obstetricians and Gynecologists and of the International Society for the Study of Hypertension in Pregnancy, more women are classified as preeclamptic, with a tendency to milder disease. Furthermore, angiogenic and antiangiogenic factors have emerged as essential tools for predicting and diagnosing preeclampsia at high accuracies. Next to being rooted in the pathophysiology of the disease, they have been proven to be reliable tools for predicting and diagnosing the disease. In addition, 2 cutoffs have been evaluated for the clinical setting. As shown in the Prediction of Short-Term Outcome in Pregnant Women With Suspected Preeclampsia Study, at the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio cutoff of 38, a preeclampsia can be ruled out for 1 week with a negative predictive value of 99.3% (95% confidence interval, 97.9-99.9) and ruled in with a positive predictive value of 36.7% (95% confidence interval, 28.4-45.7). The diagnostic cutoff of 85 has been shown to accurately identify women with preeclampsia, with a sensitivity of up to 88% and a specificity of 99.5%. In this review, we highlight the central role of angiogenic and antiangiogenic factors in the differential diagnosis of women presenting at high risk of the disease, such as patients with chronic hypertension or chronic kidney disease. We will focus on their ability to predict preeclampsia-associated adverse fetal and maternal outcomes. This is only possible when critically reviewing the evolution of the definition of "preeclampsia." We show how changes in this definition shape our clinical picture of the condition and how angiogenic and antiangiogenic biomarkers might be included to better identify women destined to develop preeclampsia-related adverse outcomes.
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Affiliation(s)
- Stefan Verlohren
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
| | - Lisa-Antonia Dröge
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
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Li X, Liu L, Whitehead C, Li J, Thierry B, Le TD, Winter M. OUP accepted manuscript. Brief Funct Genomics 2022; 21:296-309. [PMID: 35484822 PMCID: PMC9328024 DOI: 10.1093/bfgp/elac006] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 03/11/2022] [Accepted: 03/18/2022] [Indexed: 11/24/2022] Open
Abstract
Preeclampsia is a pregnancy-specific disease that can have serious effects on the health of both mothers and their offspring. Predicting which women will develop preeclampsia in early pregnancy with high accuracy will allow for improved management. The clinical symptoms of preeclampsia are well recognized, however, the precise molecular mechanisms leading to the disorder are poorly understood. This is compounded by the heterogeneous nature of preeclampsia onset, timing and severity. Indeed a multitude of poorly defined causes including genetic components implicates etiologic factors, such as immune maladaptation, placental ischemia and increased oxidative stress. Large datasets generated by microarray and next-generation sequencing have enabled the comprehensive study of preeclampsia at the molecular level. However, computational approaches to simultaneously analyze the preeclampsia transcriptomic and network data and identify clinically relevant information are currently limited. In this paper, we proposed a control theory method to identify potential preeclampsia-associated genes based on both transcriptomic and network data. First, we built a preeclampsia gene regulatory network and analyzed its controllability. We then defined two types of critical preeclampsia-associated genes that play important roles in the constructed preeclampsia-specific network. Benchmarking against differential expression, betweenness centrality and hub analysis we demonstrated that the proposed method may offer novel insights compared with other standard approaches. Next, we investigated subtype specific genes for early and late onset preeclampsia. This control theory approach could contribute to a further understanding of the molecular mechanisms contributing to preeclampsia.
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Affiliation(s)
- Xiaomei Li
- UniSA STEM, University of South Australia, Mawson Lakes, 5095, SA, Australia
| | - Lin Liu
- UniSA STEM, University of South Australia, Mawson Lakes, 5095, SA, Australia
| | - Clare Whitehead
- Pregnancy Research Centre, Dept of Obstetrics & Gynaecology, University of Melbourne, Royal Women’s Hospital, Melbourne, 3052, VIC, Australia
| | - Jiuyong Li
- UniSA STEM, University of South Australia, Mawson Lakes, 5095, SA, Australia
| | - Benjamin Thierry
- Future Industries Institute, University of South Australia, Mawson Lakes, 5095, SA, Australia
| | - Thuc D Le
- Corresponding authors: Thuc D. Le, UniSA STEM, University of South Australia, Mawson Lakes, 5095, SA, Australia. E-mail: ; M. Winter, Future Industries Institute, University of South Australia, Mawson Lakes, 5095, SA, Australia. E-mail:
| | - Marnie Winter
- Corresponding authors: Thuc D. Le, UniSA STEM, University of South Australia, Mawson Lakes, 5095, SA, Australia. E-mail: ; M. Winter, Future Industries Institute, University of South Australia, Mawson Lakes, 5095, SA, Australia. E-mail:
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Amadi PU, Agomuo EN, Ukaga CN, Njoku UC, Amadi JA, Nwaekpe CG. Preclinical Trial of Traditional Plant Remedies for the Treatment of Complications of Gestational Malaria. MEDICINES (BASEL, SWITZERLAND) 2021; 8:79. [PMID: 34940291 PMCID: PMC8703497 DOI: 10.3390/medicines8120079] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/14/2021] [Accepted: 12/14/2021] [Indexed: 12/16/2022]
Abstract
Background: Most pregnant women living in high malaria endemic regions of Nigeria use herbal remedies for the management of malaria-in-pregnancy, rather than the commonly prescribed drugs. Remedies common to this area involve a suspension of A. indica (AI) leaves and in some cases, a suspension containing a mixture of AI and D.edulis (PS). Aim: This study examined the therapeutic efficacies of AI, PS, or a combination of AI and PS in a pregnant rat model for exoerythrocytic stages of Plasmodium falciparum parasite. Method: A predetermined sample size of 30 dams was used (for a power level and confidence interval of 95%), and divided equally into six groups made up of non-malarous dams, untreated malarous dams, and malarous dams either treated exclusively with 1 mL of 3000 mg/kg b.w AI, 1000 mg/kg b.w PS, AI + PS (50% v/v), or 25 mg/kg b.w CQ. Result: No maternal mortality was recorded. AI significantly improved maternal weight gain from 32.4 to 82.2 g and placental weight from 0.44 to 0.53 g. In the curative test, AI and AI + PS significantly reduced the average percentage parasitemia (APP) in the pregnant rats from >80% to <20%. No significant difference in the APP was found between the pregnant rats treated with any of CQ or AI during the suppressive test. Results for the prophylactic test of the study groups showed that the APP was significantly reduced from 24.69% to 3.90% when treated with AI and 3.67% when combined with PS. AI + PS reduced diastolic blood pressure from 89.0 to 81.0 mm/Hg and compared with that of the non malarous dams. AI or AI + PS significantly increased the platelet counts (103 µL) from 214.1 to 364.5 and 351.2, respectively. AI and AI + PS improved birth weight from 2.5 to 3.9 g and crown rump length from 2.6 to 4.1 cm. For biomarkers of preeclampsia, combining AI and PS led to the reversal of the altered levels of creatine kinase, lactate dehydrogenase, cardiac troponin, soluble Fms-Like Tyrosine Kinase-1, and placental growth factor. Conclusions: This study validates the use of A. indica for the treatment of gestational malaria due to its antiplasmodial and related therapeutic effects and in combination with pear seeds for the management of malaria-in-pregnancy-induced preeclampsia.
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Affiliation(s)
| | | | - Chinyere Nneka Ukaga
- Department of Animal and Environmental Biology, Imo State University, Owerri 460102, Nigeria;
| | - Uche Chinedu Njoku
- Department of Biochemistry, University of Port Harcourt, Choba 500102, Nigeria;
| | - Joy Adaku Amadi
- Department of Nutrition and Dietetics, Imo State University, Owerri 460102, Nigeria;
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DeepDRG: Performance of Artificial Intelligence Model for Real-Time Prediction of Diagnosis-Related Groups. Healthcare (Basel) 2021; 9:healthcare9121632. [PMID: 34946357 PMCID: PMC8701302 DOI: 10.3390/healthcare9121632] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/17/2021] [Accepted: 11/22/2021] [Indexed: 11/16/2022] Open
Abstract
Nowadays, the use of diagnosis-related groups (DRGs) has been increased to claim reimbursement for inpatient care. The overall benefits of using DRGs depend upon the accuracy of clinical coding to obtain reasonable reimbursement. However, the selection of appropriate codes is always challenging and requires professional expertise. The rate of incorrect DRGs is always high due to the heavy workload, poor quality of documentation, and lack of computer assistance. We therefore developed deep learning (DL) models to predict the primary diagnosis for appropriate reimbursement and improving hospital performance. A dataset consisting of 81,486 patients with 128,105 episodes was used for model training and testing. Patients' age, sex, drugs, diseases, laboratory tests, procedures, and operation history were used as inputs to our multiclass prediction model. Gated recurrent unit (GRU) and artificial neural network (ANN) models were developed to predict 200 primary diagnoses. The performance of the DL models was measured by the area under the receiver operating curve, precision, recall, and F1 score. Of the two DL models, the GRU method, had the best performance in predicting the primary diagnosis (AUC: 0.99, precision: 83.2%, and recall: 66.0%). However, the performance of ANN model for DRGs prediction achieved AUC of 0.99 with a precision of 0.82 and recall of 0.57. The findings of our study show that DL algorithms, especially GRU, can be used to develop DRGs prediction models for identifying primary diagnosis accurately. DeepDRGs would help to claim appropriate financial incentives, enable proper utilization of medical resources, and improve hospital performance.
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Khosla K, Espinoza J, Perlaza L, Gencay M, Mueller AL, Harris JM, Wolf C, Posnett JW, Woelkers DA, Rana S. Cost effectiveness of the sFlt1/PlGF ratio test as an adjunct to the current practice of evaluating suspected preeclampsia in the United States. Pregnancy Hypertens 2021; 26:121-126. [PMID: 34749060 DOI: 10.1016/j.preghy.2021.10.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 10/23/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE Preeclampsia is a major obstetric disorder that can lead to severe maternal, fetal and infant outcomes. In women with suspected preeclampsia, measurement of the soluble fms-like tyrosine kinase-1 (sFlt1) and placental growth factor (PlGF) ratio has been shown to have a high negative predictive value (>97%). Our aim was to estimate the value to the US healthcare system of adopting this test into clinical practice. STUDY DESIGN An economic model was developed for the evaluation of suspected preeclampsia from a US payer perspective using data from a US observational study of 459 women evaluated between 23 and 34.6 weeks. Test results were not available to clinicians. The model compares two strategies for managing suspected preeclampsia: standard care versus a biomarker-informed pathway utilizing the sFlt1/PlGF ratio. RESULTS Utilization of the sFlt1/PlGF ratio test reduced the number of women admitted for suspected preeclampsia by 34-49%. Despite fewer admissions, a higher proportion of women admitted to hospital subsequently developed preeclampsia, and the proportion of women not admitted who would subsequently develop preeclampsia remained low (3.2%-6.7%). Cost savings arising from a reduction in admissions are estimated to be $1050 in the base case; varying the hospitalization cost ±25% would lead to savings in the range $771 to $1330 per patient at 2020 prices. CONCLUSION Adopting the sFlt1/PlGF ratio test as an adjunct to clinical criteria improves the assessment of risk in women presenting with suspicion of preeclampsia and has the potential to safely reduce unnecessary admissions and save costs.
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Affiliation(s)
- Kavia Khosla
- University of Chicago Pritzker School of Medicine, Chicago, IL, USA
| | - Jimmy Espinoza
- Department of Obstetrics & Gynecology, Division of Fetal Therapy and Surgery, Baylor College of Medicine, Houston, TX, USA
| | | | | | - Ariel L Mueller
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Cyrill Wolf
- Roche Diagnostics International Ltd, Rotkreuz, Switzerland
| | | | - Douglas A Woelkers
- Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California at San Diego School of Medicine, San Diego, CA, USA
| | - Sarosh Rana
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, University of Chicago, Chicago, IL, USA.
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Andersen LLT, Helt A, Sperling L, Overgaard M. Decision Threshold for Kryptor sFlt-1/PlGF Ratio in Women With Suspected Preeclampsia: Retrospective Study in a Routine Clinical Setting. J Am Heart Assoc 2021; 10:e021376. [PMID: 34459248 PMCID: PMC8649230 DOI: 10.1161/jaha.120.021376] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 06/07/2021] [Indexed: 11/16/2022]
Abstract
Background The objective was to evaluate predictive performance and optimal decision threshold of the Kryptor soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio when implemented for routine management of women presenting with symptoms of preeclampsia. Methods and Results Observational retrospective study of a cohort of 501 women with suspected preeclampsia after 20 weeks of gestation. Women referred to maternity ward for observation of preeclampsia had an sFlt-1/PlGF ratio test included in routine diagnostic workup. Maternal and offspring characteristic data included maternal risk factors, outcomes, delivery mode, and indication for suspected preeclampsia. Biochemical measurements to determine sFlt-1/PlGF ratio were performed using the BRAHMS/Kryptor sFlt-1/PlGF ratio immunoassays. Results were analyzed by area under receiver-operating characteristic curve. Preeclampsia occurred in 150 of 501 (30%) of symptomatic women with an sFlt-1/PlGF ratio determined before the time of diagnosis. Area under receiver-operating characteristic curve for diagnosis of early-onset preeclampsia within 1 and 4 weeks was 0.98 (95% CI, 0.96-1.00) and 0.95 (95% CI, 0.92-0.98), respectively. For late-onset preeclampsia, predictive performance within 1 and 4 weeks was lower: 0.90 (95% CI, 0.85-0.94) and 0.85 (95% CI, 0.80-0.90), respectively. The optimal single sFlt-1/PlGF ratio threshold for all preeclampsia and late-onset preeclampsia within 1 and 4 weeks was 66. The negative and positive predictive values for ruling out and ruling in developing preeclampsia within 1 week were 96% and 70%, respectively. Conclusions The Kryptor sFlt-1/PlGF ratio is a useful clinical tool ruling out and in preeclampsia within 1 week. Prediction within 4 weeks is superior for early-onset preeclampsia. A single decision threshold of 66 is indicated for use in clinical routine.
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Affiliation(s)
| | - Annemarie Helt
- Department of Obstetrics and GynecologyOdense University HospitalOdenseDenmark
| | - Lene Sperling
- Department of Obstetrics and GynecologyOdense University HospitalOdenseDenmark
- Department of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
| | - Martin Overgaard
- Department of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
- Department of Clinical Biochemistry and PharmacologyOdense University HospitalOdenseDenmark
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Chantraine F, Van Calsteren K, Devlieger R, Gruson D, Keirsbilck JV, Dubon Garcia A, Vandeweyer K, Gucciardo L. Enhancing the value of the sFlt-1/PlGF ratio for the prediction of preeclampsia: Cost analysis from the Belgian healthcare payers' perspective. Pregnancy Hypertens 2021; 26:31-37. [PMID: 34482271 DOI: 10.1016/j.preghy.2021.08.113] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 07/28/2021] [Accepted: 08/12/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To evaluate the economic impact of introducing the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test into clinical practice in Belgium for the prediction of preeclampsia (PE). STUDY DESIGN We developed a one-year time-horizon decision tree model to evaluate the short-term costs associated with the introduction of the sFlt-1/PlGF test for guiding the management of women with suspected PE from the Belgian public healthcare payers' perspective. The model estimated the costs associated with the diagnosis and management of PE in pregnant women managed in either a test scenario, in which the sFlt-1/PlGF test is used in addition to current clinical practice, or a no test scenario, in which clinical decisions are based on current practice alone. Test characteristics were derived from PROGNOSIS, a non-interventional study in women presenting with clinical suspicion of PE. Unit costs were obtained from Belgian-specific sources. The main model outcome was the total cost per patient. RESULTS Introduction of the sFlt-1/PlGF ratio test is expected to result in a cost saving of €712 per patient compared with the no test scenario. These savings are generated mainly due to a reduction in unnecessary hospitalizations. CONCLUSIONS The sFlt-1/PlGF test is projected to result in substantial cost savings for the Belgian public healthcare payers through reduction of unnecessary hospitalization of women with clinical suspicion of PE that ultimately do not develop the condition. The test also has the potential to ensure that women at high risk of developing PE are identified and appropriately managed.
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Affiliation(s)
- Frederic Chantraine
- Department of Obstetrics and Gynecology, Centre Hospitalier Universitaire de Liège, CHR Citadelle, Liège, Belgium.
| | - Kristel Van Calsteren
- Department of Obstetrics and Gynaecology, University Hospitals, KULeuven, Leuven, Belgium.
| | - Roland Devlieger
- Department of Obstetrics and Gynaecology, University Hospitals, KULeuven, Leuven, Belgium.
| | - Damien Gruson
- Department of Laboratory Medicine, Division of Clinical Biochemistry, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium.
| | | | | | | | - Leonardo Gucciardo
- Department of Obstetrics and Prenatal Medicine, UZ Brussel University Hospital, VUB, Brussels, Belgium.
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Poon LC, Magee LA, Verlohren S, Shennan A, von Dadelszen P, Sheiner E, Hadar E, Visser G, Da Silva Costa F, Kapur A, McAuliffe F, Nazareth A, Tahlak M, Kihara AB, Divakar H, McIntyre HD, Berghella V, Yang H, Romero R, Nicolaides KH, Melamed N, Hod M. A literature review and best practice advice for second and third trimester risk stratification, monitoring, and management of pre-eclampsia: Compiled by the Pregnancy and Non-Communicable Diseases Committee of FIGO (the International Federation of Gynecology and Obstetrics). Int J Gynaecol Obstet 2021; 154 Suppl 1:3-31. [PMID: 34327714 PMCID: PMC9290930 DOI: 10.1002/ijgo.13763] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Liona C Poon
- Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Laura A Magee
- Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | | | - Andrew Shennan
- Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Peter von Dadelszen
- Department of Women and Children's Health, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | - Eyal Sheiner
- Department of Obstetrics and Gynecology B, Soroka University Medical Center, Ben-Gurion University of the Negev, Beersheba, Israel
| | - Eran Hadar
- Helen Schneider Hospital for Women, Rabin Medical Center, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Gerard Visser
- Department of Obstetrics, University Medical Center, Utrecht, The Netherlands
| | - Fabricio Da Silva Costa
- Maternal Fetal Medicine Unit, Gold Coast University Hospital and School of Medicine, Griffith University, Gold Coast, Queensland, Australia
| | - Anil Kapur
- World Diabetes Foundation, Bagsvaerd, Denmark
| | - Fionnuala McAuliffe
- UCD Perinatal Research Centre, School of Medicine, University College Dublin, National Maternity Hospital, Dublin, Ireland
| | - Amala Nazareth
- Jumeira Prime Healthcare Group, Emirates Medical Association, Dubai, United Arab Emirates
| | - Muna Tahlak
- Latifa Hospital for Women and Children, Dubai Health Authority, Emirates Medical Association, Mohammed Bin Rashid University for Medica Sciences, Dubai, United Arab Emirates
| | - Anne B Kihara
- African Federation of Obstetricians and Gynaecologists, Khartoum, Sudan
| | | | - H David McIntyre
- University of Queensland Mater Clinical School, Brisbane, Queensland, Australia
| | - Vincenzo Berghella
- Division of Maternal-Fetal Medicine, Thomas Jefferson University, Philadelphia, USA
| | - Huixia Yang
- Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, China
| | - Roberto Romero
- 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, US Department of Health and Human Services, Bethesda, MD, and Detroit, MI, USA
| | | | - Nir Melamed
- Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Moshe Hod
- Helen Schneider Hospital for Women, Rabin Medical Center, Petach Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Use of the angiogenic biomarker profile to risk stratify patients with fetal growth restriction. Am J Obstet Gynecol MFM 2021; 3:100394. [PMID: 33991706 DOI: 10.1016/j.ajogmf.2021.100394] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/26/2021] [Accepted: 05/03/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Novel angiogenic biomarker profiles have demonstrated emerging evidence for predicting preeclampsia onset, severity, and adverse outcomes. Limited data exist in screening patients with fetal growth restriction for preeclampsia development using angiogenic biomarkers. OBJECTIVE The objective of this study was to risk stratify patients with fetal growth restriction using a soluble fms-like tyrosine kinase-1 to placental growth factor ratio. Previously published cutoff of 38 was used to predict preeclampsia development and severity as well as adverse maternal or neonatal outcomes within a 2-week time period. STUDY DESIGN This was a prospective observational cohort study performed in a single tertiary hospital. Patients with a singleton fetal growth restriction pregnancy between 24 and 37 weeks' gestation were evaluated using serial 2-week encounters from the time of enrollment to delivery. Pregnancies with proven genetic or infectious etiology of fetal growth restriction or congenital anomalies were excluded. Ultrasound growth and Doppler measurements were obtained at the start of every encounter with routine preeclampsia laboratory tests and blood pressure checks when clinically indicated. Maternal serum was collected for all serial encounters and measured for soluble fms-like tyrosine kinase-1 and placental growth factor after delivery in a double-blinded fashion. Maternal charts were reviewed for baseline demographic characteristics, pregnancy diagnoses and outcomes, and neonatal outcomes. RESULTS A total of 45 patients were enrolled for a total of 77 encounters, with the median (quartile 1, quartile 3) gestational age of the study enrolled at 31.43 (28.14-33.57) weeks. Patients were divided into low-risk (ratio of <38) and high-risk (ratio of ≥38) groups. Baseline characteristics of patients did not show any marked differences, including preeclampsia labs or ultrasound parameters, between the 2 groups. Systolic and diastolic blood pressures upon enrollment were statistically elevated when soluble fms-like tyrosine kinase-1 to placental growth factor ratio was ≥38 (P=.02 and P=.01, respectively). Compared to patients with a low ratio, patients with a high ratio had a greater proportion of preeclampsia diagnosis, higher rates of preterm delivery under 34 and 37 weeks gestation, smaller neonatal birthweight, and a shorter time to delivery from testing to delivery. CONCLUSION Among patients with fetal growth restriction, the soluble fms-like tyrosine kinase-1 to placental growth factor ratio may serve as a potential biomarker for identifying at risk patients for developing preeclampsia and subsequently preterm delivery.
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Economic evaluation of the sFlt-1/PlGF ratio for the short-term prediction of preeclampsia in a Japanese cohort of the PROGNOSIS Asia study. Hypertens Res 2021; 44:822-829. [PMID: 33594274 PMCID: PMC8255211 DOI: 10.1038/s41440-021-00624-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 11/19/2020] [Accepted: 12/16/2020] [Indexed: 11/15/2022]
Abstract
The PRediction of short-term Outcomes in preGNant wOmen with Suspected preeclampsIa Study (PROGNOSIS) Asia validated the use of the soluble fms-like tyrosine 1/placental growth factor (sFlt-1/PlGF) ratio cutoff value of ≤38 to rule out the occurrence of preeclampsia in the short term in Asian women. We assessed the economic impact of the introduction of the sFlt-1/PlGF ratio test for predicting preeclampsia in Japan using data from the Japanese cohort of PROGNOSIS Asia. The cost analysis was developed with estimates in either a no-test scenario, with clinical decisions based on standard diagnostic procedures alone, or a test scenario, in which the sFlt-1/PlGF ratio test was used in addition to standard diagnostic procedures. For both scenarios, rates of hospitalization and other test characteristics were obtained from the results for the Japanese cohort in PROGNOSIS Asia. The total cost per patient was the main outcome of this cost analysis model. Introduction of the sFlt-1/PlGF ratio test using a cutoff value of 38 resulted in a reduced hospitalization rate compared with the rate in the no-test scenario (14.4% versus 8.7%). The reduction in the rate of hospitalizations led to an estimated 16 373 JPY reduction in healthcare costs per patient. The sFlt-1/PlGF ratio test is likely to reduce the unnecessary hospitalization of women at low risk of developing preeclampsia in the short term while also identifying high-risk individuals requiring appropriate management. Reducing unnecessary hospitalizations would result in significant cost savings in the Japanese healthcare system.
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Pro- and Anti-Angiogenic Markers as Clinical Tools for Suspected Preeclampsia with and without FGR near Delivery—A Secondary Analysis. REPRODUCTIVE MEDICINE 2021. [DOI: 10.3390/reprodmed2010003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective—the objective of this study was to assess the accuracy of placental growth factor (PlGF), soluble Fms-like Tyrosine Kinase 1 (sFlt-1), and endoglin (sEng) in the diagnosis of suspected preeclampsia (PE) with and without fetal growth restriction (FGR) near delivery. Methods—this is a secondary analysis of a dataset of 125 pregnant women presenting at the high risk pregnancy clinic with suspected PE, FGR or PE + FGR in the University Medical Center of Slovenia. The dataset included 31 PE cases, 16 FGR cases, 42 PE + FGR cases, 15 cases who developed with unrelated complications before 37 weeks (wks) (PTD), and 21 unaffected controls who delivered a healthy baby at term. We also analyzed a sub-group of women who delivered early (<34 wks) including 10 PE, 12 FGR, 28 PE + FGR, and six PTD. Clinical management adhered to hospital guidelines. Marker levels were extracted from the dataset and were used to develop Receiver Operating Characteristic (ROC) curves and to calculate the area under the curve (AUC), the detection rates (DRs), and the false positive rates (FPRs). Previously published marker cutoffs for yes/no admission to hospital wards were extracted from the literature. Negative and positive predictive values (NPVs and PPVs) were evaluated for their value in determining whether hospital admission was required. Non-parametric tests were applied for statistical analysis; p < 0.05 was considered significant. Results—near delivery, all the pro-and anti-angiogenic markers provided diagnostic (ROC = 1.00) accuracy for the early (<34 wks) group of FGR. Diagnostic or near diagnostic (ROC = 0.95) accuracy was achieved by all marker for early PE + FGR but lower accuracy was achieved for early PE. For all cases, all markers, especially PlGF reached diagnostic or near diagnostic accuracy for FGR and PE + FGR. At this accuracy level, they can contribute to the clinical management of FGR, and PE + FGR. All the markers were less accurate for all PE cases. The use of published cutoffs was adequate for clinical management of FGR, whether early or for all cases, using an NPV > 90%. For PE + FGR, the PPV value approached 100%, especially for early cases, and can thus be implemented in clinical management. Neither NPV nor PPV were high enough for managing all cases of PE. There was no added value in measuring the PlGF/(sFlt-1 + sEng) ratio. Conclusion—This is the first study on a Slovenian population. It shows that near-delivery angiogenic biomarkers tests may be useful for confirming the diseases in cases where there is a diagnostic doubt. However, the clinical use of the biomarkers needs to be weighed against resources available and degree of certainty of the diagnosis made with and without them for managing suspected FGR and PE + FGR requiring delivery <34 wks, where they are very accurate, and furthermore in the management of all cases of FGR and FGR+PE. The markers were less accurate for the clinical diagnosis of PE.
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Todd N, McNally R, Alqudah A, Jerotic D, Suvakov S, Obradovic D, Hoch D, Hombrebueno JR, Campos GL, Watson CJ, Gojnic-Dugalic M, Simic TP, Krasnodembskaya A, Desoye G, Eastwood KA, Hunter AJ, Holmes VA, McCance DR, Young IS, Grieve DJ, Kenny LC, Garovic VD, Robson T, McClements L. Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment. J Clin Endocrinol Metab 2021; 106:26-41. [PMID: 32617576 PMCID: PMC7765643 DOI: 10.1210/clinem/dgaa403] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Indexed: 02/07/2023]
Abstract
CONTEXT Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. OBJECTIVE To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44. DESIGN AND INTERVENTION FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling. SETTINGS AND PARTICIPANTS Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. MAIN OUTCOME MEASURES Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. RESULTS The CD44/FKBPL ratio was reduced in placenta and plasma following clinical diagnosis of preeclampsia. At 20 weeks of gestation, a high plasma CD44/FKBPL ratio was independently associated with the 2.3-fold increased risk of preeclampsia (odds ratio = 2.3, 95% confidence interval [CI] 1.03-5.23, P = 0.04). In combination with high mean arterial blood pressure (>82.5 mmHg), the risk further increased to 3.9-fold (95% CI 1.30-11.84, P = 0.016). Both hypoxia and MSC-based therapy inhibited FKBPL-CD44 signaling, enhancing cell angiogenesis. CONCLUSIONS The FKBPL-CD44 pathway appears to have a central role in the pathogenesis of preeclampsia, showing promising utilities for early diagnostic and therapeutic purposes.
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Affiliation(s)
- Naomi Todd
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | - Ross McNally
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | - Abdelrahim Alqudah
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
- The School of Pharmacy, The Hashemite University, Amman, Jordan
| | | | - Sonja Suvakov
- Medical Faculty, University of Belgrade, Belgrade, Serbia
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, US
| | | | - Denise Hoch
- Department of Gynaecology and Obstetrics, Medical University Graz, Graz, Austria
| | - Jose R Hombrebueno
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | - Guillermo Lopez Campos
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | - Chris J Watson
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | | | | | - Anna Krasnodembskaya
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | - Gernot Desoye
- Department of Gynaecology and Obstetrics, Medical University Graz, Graz, Austria
| | - Kelly-Ann Eastwood
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
- Royal Jubilee Maternity Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
| | - Alyson J Hunter
- Royal Jubilee Maternity Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
| | - Valerie A Holmes
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | - David R McCance
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
- Royal Victoria Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
| | - Ian S Young
- Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
- Royal Victoria Hospital, Belfast Health and Social Care Trust, Northern Ireland, UK
| | - David J Grieve
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
| | - Louise C Kenny
- The Irish Centre for Foetal and Neonatal Translational Research (INFANT) and Department of Obstetrics and Gynaecology, University College Cork, Cork, Republic of Ireland
- Department of Women’s and Children’s Health, Institute of Translational Research, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
| | - Vesna D Garovic
- Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, US
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland (RCSI), Dublin, Republic of Ireland
| | - Lana McClements
- The Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Northern Ireland, UK
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW, Australia
- Correspondence and Reprint Requests: Lana McClements, School of Life Sciences, Faculty of Science, University of Technology Sydney, PO Box 123 Broadway, NSW, 2007, Australia. E-mail:
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Ohkuchi A, Kondoh E, Yamamoto T, Seki H, Saito S, Makino S, Nishida M, Kikuchi T. Expert consensus: Indication criteria and screening strategy for preeclampsia using the serum sFlt-1/PlGF ratio at 18–36 weeks of gestation in women at imminent/basal risk of preeclampsia under insurance coverage. HYPERTENSION RESEARCH IN PREGNANCY 2020. [DOI: 10.14390/jsshp.hrp2020-009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Akihide Ohkuchi
- Department of Obstetrics and Gynecology, Jichi Medical University School of Medicine
| | - Eiji Kondoh
- Department of Gynecology and Obstetrics, Kyoto University
| | - Tatsuo Yamamoto
- Department of Obstetrics and Gynecology, Kasukabe Medical Center
| | - Hiroyuki Seki
- Department of Obstetrics and Gynecology, Saitama Medical Center, Saitama Medical University
| | - Shigeru Saito
- Department of Obstetrics and Gynecology, University of Toyama
| | - Shintaro Makino
- Department of Obstetrics and Gynecology, Juntendo University
| | - Miwa Nishida
- Department of Medical, Quality and Regulatory, Roche Diagnostics K. K
| | - Takashi Kikuchi
- Department of Medical, Quality and Regulatory, Roche Diagnostics K. K
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Wu SW, Pan Q, Chen T. Research on diagnosis-related group grouping of inpatient medical expenditure in colorectal cancer patients based on a decision tree model. World J Clin Cases 2020; 8:2484-2493. [PMID: 32607325 PMCID: PMC7322429 DOI: 10.12998/wjcc.v8.i12.2484] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/25/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In 2018, the diagnosis-related groups prospective payment system (DRGs-PPS) was introduced in a trial operation in Beijing according to the requirements of medical and health reform. The implementation of the system requires that more than 300 disease types pay through the DRGs-PPS for medical insurance. Colorectal cancer (CRC), as a common malignant tumor with high prevalence in recent years, was among the 300 disease types.
AIM To investigate the composition and factors related to inpatient medical expenditure in CRC patients based on disease DRGs, and to provide a basis for the rational economic control of hospitalization expenses for the diagnosis and treatment of CRC.
METHODS The basic material and cost data for 1026 CRC inpatients in a Grade-A tertiary hospital in Beijing during 2014-2018 were collected using the medical record system. A variance analysis of the composition of medical expenditure was carried out, and a multivariate linear regression model was used to select influencing factors with the greatest statistical significance. A decision tree model based on the exhaustive χ2 automatic interaction detector (E-CHAID) algorithm for DRG grouping was built by setting chosen factors as separation nodes, and the payment standard of each diagnostic group and upper limit cost were calculated. The correctness and rationality of the data were re-evaluated and verified by clinical practice.
RESULTS The average hospital stay of the 1026 CRC patients investigated was 18.5 d, and the average hospitalization cost was 57872.4 RMB yuan. Factors including age, gender, length of hospital stay, diagnosis and treatment, as well as clinical operations had significant influence on inpatient expenditure (P < 0.05). By adopting age, diagnosis, treatment, and surgery as the grouping nodes, a decision tree model based on the E-CHAID algorithm was established, and the CRC patients were divided into 12 DRG cost groups. Among these 12 groups, the number of patients aged ≤ 67 years, and underwent surgery and chemotherapy or radiotherapy was largest; while patients aged > 67 years, and underwent surgery and chemotherapy or radiotherapy had the highest medical cost. In addition, the standard cost and upper limit cost in the 12 groups were calculated and re-evaluated.
CONCLUSION It is important to strengthen the control over the use of drugs and management of the hospitalization process, surgery, diagnosis and treatment to reduce the economic burden on patients. Tailored adjustments to medical payment standards should be made according to the characteristics and treatment of disease types to improve the comprehensiveness and practicability of the DRGs-PPS.
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Affiliation(s)
- Suo-Wei Wu
- Department of Medical Administration, Beijing Hospital, Beijing 100730, China
| | - Qi Pan
- Department of Medical Administration, Beijing Hospital, Beijing 100730, China
| | - Tong Chen
- Department of Medical Administration, Beijing Hospital, Beijing 100730, China
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Kapur A, Hod M. Maternal health and non-communicable disease prevention: An investment case for the post COVID-19 world and need for better health economic data. Int J Gynaecol Obstet 2020; 150:151-158. [PMID: 32401348 PMCID: PMC9087486 DOI: 10.1002/ijgo.13198] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 05/05/2020] [Indexed: 01/13/2023]
Abstract
An integrated approach to population health, disease surveillance, and preventive care will dominate the health agenda in the post COVID‐19 world. Because of their huge burden and the vulnerability imposed during a health crisis, prevention and care of non‐communicable diseases (NCDs) will need to be prioritized even further. Maternal and child health are inextricably linked with NCDs and their risk factors. The intergenerational impact of poor maternal nutrition and health conditions during pregnancy, particularly NCD‐related pregnancy complications, can be considered as a multiplier of the ongoing pandemic of NCDs. The economic cost of poor maternal health and NCD‐related pregnancy complications is likely very high, but is not adequately researched or documented in the context of long‐term population health. Interventions to address NCDs in pregnancy have beneficial effects on short‐term pregnancy outcomes; but even more importantly, identifying “at‐risk” mothers and offspring opens up the opportunity for targeted early preventive action. Preventive actions to address obesity, hypertension, type 2 diabetes, and cardiovascular diseases have a common lifestyle approach—identifying any one of these problems in pregnancy provides an opportunity to address them all. Cost–benefit analyses that only focus on the short‐term and on one condition do not capture the full value of downstream, long‐term benefits for population health. This requires urgent attention from FIGO. Integrated action on maternal health and non‐communicable disease prevention is an investment for future population health that requires more health economic data.
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Affiliation(s)
- Anil Kapur
- World Diabetes Foundation, Bagsvaerd, Denmark.,Pregnancy and Non-Communicable Diseases Committee, FIGO, London, UK
| | - Moshe Hod
- Pregnancy and Non-Communicable Diseases Committee, FIGO, London, UK.,Mor Women's Health Care Center, Tel Aviv, Israel
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Mtshali Z, Moodley J, Naicker T. An Insight into the Angiogenic and Lymphatic Interplay in Pre-eclampsia Comorbid with HIV Infection. Curr Hypertens Rep 2020; 22:35. [PMID: 32200445 DOI: 10.1007/s11906-020-01040-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW To provide insight on the imbalance of angiogenic and lymphangiogenic factors in pre-eclampsia, as well as highlight polymorphism in genes related to angiogenesis and lymphangiogenesis. RECENT FINDINGS The pregnancy-specific disorder pre-eclampsia is diagnosed by the presence of hypertension with/without proteinuria, after 20 weeks of gestation. The pathogenesis of pre-eclampsia remains ambiguous, but research over the years has identified an imbalance in maternal and foetal factors. Familial predisposition and gene variation are also linked to pre-eclampsia development. The sFlt-1/PIGF ratio has attracted great attention over the years; more recently several researchers have reported that a sFlt-1/PIGF ratio of ≤ 38 can be used to predict short-term absence of pre-eclampsia. This ratio has the potential to prevent adverse pregnancy outcomes and reduce healthcare costs significantly. Genome-wide studies have additionally identified variation in the foetal gene near Flt-1. The development of preeclampsia is not limited to the maternal interface, but foetal involvement as well as genetic interplay is associated with the disorder.
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Affiliation(s)
- Zamahlabangane Mtshali
- Optics and Imaging Centre, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.
| | - Jagidesa Moodley
- Department of Obstetrics and Gynaecology and Women's Health and HIV Research Group, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Thajasvarie Naicker
- Optics and Imaging Centre, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa
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Poon LC, Galindo A, Surbek D, Chantraine F, Stepan H, Hyett J, Tan KH, Verlohren S. From first-trimester screening to risk stratification of evolving pre-eclampsia in second and third trimesters of pregnancy: comprehensive approach. ULTRASOUND IN OBSTETRICS & GYNECOLOGY : THE OFFICIAL JOURNAL OF THE INTERNATIONAL SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY 2020; 55:5-12. [PMID: 31503374 DOI: 10.1002/uog.21869] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 08/30/2019] [Indexed: 06/10/2023]
Affiliation(s)
- L C Poon
- Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - A Galindo
- Fetal Medicine Unit - Maternal and Child Health and Development Network, Department of Obstetrics and Gynaecology, University Hospital 12 de Octubre, Instituto de Investigación Hospital 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain
| | - D Surbek
- Department of Obstetrics and Gynecology, Inselspital Bern University Hospital, University of Bern, Bern, Switzerland
| | - F Chantraine
- Department of Obstetrics and Gynecology, CHR Citadelle, CHU Liege, Liege, Belgium
| | - H Stepan
- Department of Obstetrics, University Hospital Leipzig, Leipzig, Germany
| | - J Hyett
- Department of Women and Babies, Royal Prince Alfred Hospital, Sydney, Australia
| | - K H Tan
- KK Women's and Children's Hospital, Singapore
| | - S Verlohren
- Department of Obstetrics, Charité - Universitätsmedizin Berlin, Berlin, Germany
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sFlt-1/PlGF Ratio as a Predictive Marker in Women with Suspected Preeclampsia: An Economic Evaluation from a Swiss Perspective. DISEASE MARKERS 2019; 2019:4096847. [PMID: 31485276 PMCID: PMC6710794 DOI: 10.1155/2019/4096847] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Accepted: 07/11/2019] [Indexed: 12/20/2022]
Abstract
In Switzerland, 2.3% of pregnant women develop preeclampsia. Quantification of the soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio has shown a diagnostic value in the second and third trimesters of pregnancy, in particular in ruling out preeclampsia within one week. We estimated the economic impact of implementing sFlt-1/PlGF ratio evaluation, in addition to the standard of care (SOC), for women with suspected preeclampsia from a Swiss healthcare system's perspective. A decision tree model was developed to estimate direct medical costs of diagnosis and management of a simulated cohort of Swiss pregnant women with suspected preeclampsia (median week of gestation: 32) until delivery. The model compared SOC vs. SOC plus sFlt-1/PlGF ratio, using clinical inputs from a large multicenter study (PROGNOSIS). Resource use data and unit costs were obtained from hospital records and public sources. The assumed cost for sFlt-1/PlGF evaluation was €141. Input parameters were validated by clinical experts in Switzerland. The model utilized a simulated cohort of 6084 pregnant women with suspected preeclampsia (representing 7% of all births in Switzerland in 2015, n = 86,919). In a SOC scenario, 36% of women were hospitalized, of whom 27% developed preeclampsia and remained hospitalized until birth. In a sFlt-1/PlGF test scenario, 76% of women had a sFlt-1/PlGF ratio of ≤38 (2% hospitalized), 11% had a sFlt-1/PlGF ratio of >38-<85 (55% hospitalized), and 13% had a sFlt-1/PlGF ratio of ≥85 (65% hospitalized). Total average costs/pregnant woman (including birth) were €10,925 vs. €10,579 (sFlt-1/PlGF), and total costs were €66,469,362 vs. €64,363,060 (sFlt-1/PlGF). Implementation of sFlt-1/PlGF evaluation would potentially achieve annual savings of €2,105,064 (€346/patient), mainly due to reduction in unnecessary hospitalization. sFlt-1/PlGF evaluation appears economically promising in predicting short-term absence of preeclampsia in Swiss practice. Improved diagnostic accuracy and reduction in unnecessary hospitalization could lead to significant cost savings in the Swiss healthcare system.
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Padayachee S, Moodley J, Naicker T. A Review of Angiogenic Imbalance in HIV-Infected Hypertensive Disorders of Pregnancy. Curr Hypertens Rep 2019; 21:69. [PMID: 31342170 DOI: 10.1007/s11906-019-0970-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE OF REVIEW This review provides a comprehensive insight into the angiogenic profile of hypertensive and normotensive pregnancies compromised by HIV infection. Furthermore, we evaluate the economic implementation of the sFlt-1/PlGF ratio and review the reports on therapeutic apheresis in limiting sFlt-1 production. RECENT FINDINGS In preeclampsia, an increased expression of sFlt-1 triggers angiogenic imbalance. Women of African ancestry have high levels of angiogenic factors than other racial groups. The sFlt-1/PlGF ratio shows promise in the early assessment of preeclampsia, while sFlt-1 apheresis restores angiogenic imbalance. Studies suggest antiretroviral therapy does not impact the angiogenic shift in preeclampsia development. The angiogenic profile in pregnant women of different races influences preeclampsia development. Despite the opposing immune response in HIV infection and preeclampsia, the HIV tat protein strongly mimics vascular endothelial growth factor (VEGF); hence, it is plausible to assume that HIV infection may ameliorate the angiogenic imbalance in preeclampsia.
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MESH Headings
- Angiogenic Proteins/blood
- Angiogenic Proteins/physiology
- Biomarkers/blood
- Biomarkers/metabolism
- Blood Component Removal
- Female
- HIV Infections/blood
- HIV Infections/complications
- HIV Infections/physiopathology
- Humans
- Hypertension, Pregnancy-Induced/blood
- Hypertension, Pregnancy-Induced/physiopathology
- Hypertension, Pregnancy-Induced/therapy
- Membrane Proteins/blood
- Membrane Proteins/physiology
- Neovascularization, Pathologic/blood
- Neovascularization, Pathologic/physiopathology
- Neovascularization, Physiologic/physiology
- Pre-Eclampsia/blood
- Pre-Eclampsia/physiopathology
- Pre-Eclampsia/therapy
- Pregnancy
- Pregnancy Complications, Infectious/blood
- Pregnancy Complications, Infectious/physiopathology
- Vascular Endothelial Growth Factor A/blood
- Vascular Endothelial Growth Factor A/physiology
- Vascular Endothelial Growth Factor Receptor-1/blood
- Vascular Endothelial Growth Factor Receptor-1/physiology
- tat Gene Products, Human Immunodeficiency Virus/blood
- tat Gene Products, Human Immunodeficiency Virus/physiology
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Affiliation(s)
- Sayuri Padayachee
- Optics and Imaging Centre, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Private Bag 7, Congella, Durban, KwaZulu-Natal, 4013, South Africa.
| | - Jagidesa Moodley
- Women's Health and HIV Research Group, Department of Obstetrics and Gynecology, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
| | - Thajasvarie Naicker
- Optics and Imaging Centre, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Private Bag 7, Congella, Durban, KwaZulu-Natal, 4013, South Africa
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Schlembach D, Hund M, Wolf C, Vatish M. Diagnostic utility of angiogenic biomarkers in pregnant women with suspected preeclampsia: A health economics review. Pregnancy Hypertens 2019; 17:28-35. [DOI: 10.1016/j.preghy.2019.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 03/11/2019] [Indexed: 02/09/2023]
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