The Women’s Health Diagnostic Gap

The Women’s Health Diagnostic Gap Abstract Pregnancy remains a significant health risk to women in both developed and underdeveloped countries. Worldwide, 10 to 20 million women have pregnancy complications including ectopic pregnancy, preterm birth, gestational diabetes mellitus, and hypertensive states, including preeclampsia. Despite advancements in women’s health research, there is a large gap in the diagnostic tools available to screen, diagnose, and monitor these conditions. Herein, we examine existing diagnostic tools, such as the human chorionic gonadotropin discriminatory zone, cervicovaginal fetal fibronectin, sFlt-1:PlGF ratio, and glucose tolerance testing. We suggest specific objectives to improve diagnostic testing during pregnancy, including (1) developing high-quality biospecimen banks; (2) educating professionals on performance characteristics of screening tests for low prevalence diseases; (3) funding studies that address diseases unique to pregnancy; and (4) establishing trimester-specific reference intervals. Meeting these objectives could begin to narrow the diagnostic gap in women’s health. The National Institutes of Health (NIH) Revitalization Act celebrates its 15-year anniversary in 2018. This landmark law mandated that NIH-funded phase 3 clinical trials include women and minorities. Today, there are numerous studies, such as the NIH Women’s Health Initiative, that focus exclusively on women. Despite advancements in women’s health research, gaps remain. One major gap overlooked in women’s health is in vitro diagnostics, the biochemical markers used for the screening, diagnosis, prognosis, and monitoring of conditions unique to women. Pregnancy is one major area in which there is a particularly large gap in diagnostic tools. Herein, we highlight several pregnancy-related conditions with a dearth of reliable diagnostic tools and offer insight into how these unmet needs should be addressed. Despite great strides in advancing obstetrical care, pregnancy still presents a substantial health risk to women, even in developed countries. Worldwide, ~350,000 women die each year from pregnancy-related causes, and 10 to 20 million suffer complications, which commonly include ectopic pregnancy, preterm birth, gestational diabetes mellitus (GDM), and hypertensive states including preeclampsia. Despite this shocking toll, reliable biomarkers to screen or diagnose these conditions are not available. Diagnosis of ectopic pregnancy is achieved with a combination of transvaginal ultrasound, serial human chorionic gonadotropin (hCG) measurements, and an hCG “discriminatory zone,” the concentration of hCG above which a gestational sac in the uterus should be readily observed. However, the use of an hCG discriminatory zone lacks clinical utility (1). In the absence of a gestational sac on ultrasound, following serial hCG measurements may lead to a delay in diagnosis in ~40% of patients, leaving women susceptible to tubal rupture and death. Numerous candidate biomarkers such as activin A, pregnancy-associated plasma protein A, and even microRNAs have been explored, but none have proven useful. Preterm labor occurs in ~12% of all pregnancies, yet there are no available biomarkers to reliably predict which of the 4% of women in preterm labor will go on to deliver within 7 to 14 days. Cervicovaginal fetal fibronectin (fFN) is marketed to predict preterm delivery, but an understanding of the performance parameters of the fFN test illustrates why this marker is of little value. In general, a condition with low prevalence has a low pretest probability of having the condition. Thus, a screening test for a low-prevalence condition must demonstrate high positive predictive value (PPV) to be useful. The negative predictive value of fFN is 99.5% (2), meaning a negative result strongly predicts that a woman will not deliver soon. However, the PPV of fFNA is only 17%, meaning that <1 in 5 women with a positive test result will proceed to delivery with 7 to 14 days. For comparison, the PPV of flipping a coin in this population is 4%. Meta-analyses have further supported this lack of utility (3). The ability to predict normal term delivery in itself could lead to better maternal and neonatal health outcomes. However, there are currently no urine, serum, or salivary diagnostic markers to accurately predict the onset of normal term labor. Cervicovaginal fFN is known to increase at 37 to 40 weeks, but to our knowledge no attempts have been made to correlate concentrations with delivery in normal term pregnancies. An easy-to-use home device that uses urine or saliva and has a high PPV for delivery within 72 hours would be attractive to patients and could modify behavior. Furthermore, a reliable biochemical test that could predict delivery within 24 hours would be attractive to physicians to triage symptomatic patients. The incidence of preeclampsia is 5% to 8%, and it is a major contributor to premature delivery and neonatal morbidity in the United States and worldwide. Yet limited treatment options exist beyond magnesium, supportive care, and delivery of the placenta. Diagnosis is made by demonstrating hypertension and proteinuria. However, a reliable marker to predict which women will develop preeclampsia could help identify patients who would benefit from close monitoring and facilitate the development of preventive measures or treatment. Serum sFlt-1:PlGF ratio has been proposed as a predictor of preeclampsia in both symptomatic and asymptomatic women. Similar to fFN, this test has a low PPV. An analysis of the sFlt-1:PlGF ratio in women with suspected preeclampsia demonstrated an excellent negative predictive value to rule out preeclampsia within 1 week or 4 weeks (99% and 94%, respectively) (4). A major limitation of this study was the low prevalence of women who went on to develop preeclampsia at 1 and 4 weeks (3% and 13%, respectively), despite demonstrating symptoms. To overcome the low prevalence of this condition, a marker with high PPV is needed. Unfortunately, the PPVs of the ratio at 1 and 4 weeks in this study were only 9.2% and 36.7%, respectively. Diagnosis of GDM is a hotly contested subject. The American Diabetes Association and the International Association of Diabetes and Pregnancy Study Groups have suggested using a single 75-g glucose tolerance test (GTT) to diagnose GDM (5, 6). However, the American College of Obstetricians and Gynecologists has argued against this method, citing a lack of evidence that treatment improves outcome and endorsing stricter criteria that include a 50-g GTT screen with a 100-g 3-hour diagnostic GTT. However, blood glucose cutoffs for the 3-hour GTT are also contested (7). Current methods require a multipoint GTT. Ideally GDM would be diagnosed with a single blood test that eliminates the need for a biochemical challenge. Finally, even reliable diagnostic markers may go astray during pregnancy because the numerous changes in maternal physiology often result in altered reference intervals for commonly measured serum biomarkers. It is important to understand normal gestational changes to properly detect and diagnose disease during pregnancy. For example, even well-established biomarkers such as thyroid-stimulating hormone and free thyroxine (fT4) can be difficult to interpret during pregnancy. The American Thyroid Association has recommended use of trimester-specific reference intervals for thyroid-stimulating hormone. However, lack of well-defined gestational age-specific reference intervals for fT4 has led to the use of outdated and inferior biomarkers such as fT4 index in an attempt to properly interpret thyroid function during pregnancy (8). Acceptance of trimester-specific reference intervals (established by test manufacturers or from the literature) is needed to prevent misdiagnosis of thyroid disease in parturient women. Research on pregnancy-related disorders is difficult because pregnancy spans a period of 40 weeks during which many physiologic changes occur, subjects are often viewed as vulnerable, and many conditions have low prevalence. We propose four specific objectives to greatly improve on current diagnostic tools: (1) Develop well-characterized biospecimen banks with samples obtained throughout pregnancy from women with various outcomes; (2) educate clinicians, researchers, and the in vitro diagnostic industry on performance characteristics of screening tests for low-prevalence diseases; (3) fund studies that address diseases unique to pregnancy; and (4) establish trimester-specific reference intervals for relevant biomarkers. Meeting these objectives could begin to narrow the diagnostic gap in women’s health. Abbreviations: fFN fetal fibronectin fT4 free thyroxine GDM gestational diabetes mellitus GTT glucose tolerance test hCG human chorionic gonadotropin NIH National Institutes of Health PPV positive predictive value. Acknowledgments Disclosure Summary: A.M.G. serves on the editorial board for the journal Clinical Chemistry, serves as a consultant for Church and Dwight Co., Inc., serves on the Scientific and Medical Advisory Board for Theranos, has received research grant support in 2017 from BioRad Laboratories, and has received travel reimbursement from Roche Diagnostics. The remaining author has nothing to disclose. References 1. Doubilet PM, Benson CB, Bourne T, Blaivas M; for the Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy; Barnhart KT, Benacerraf BR, Brown DL, Filly RA, Fox JC, Goldstein SR, Kendall JL, Lyons EA, Porter MB, Pretorius DH, Timor-Tritsch IE. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med . 2013; 369: 1443– 1451. Google Scholar CrossRef Search ADS PubMed  2. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD, Coultrip L, Eriksen N, Holbrook RH, Elliott J, Ingardia C, Pietrantoni M. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol . 1997; 177( 1): 13– 18. Google Scholar CrossRef Search ADS PubMed  3. Sanchez-Ramos L, Delke I, Zamora J, Kaunitz AM. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol . 2009; 114( 3): 631– 640. Google Scholar CrossRef Search ADS PubMed  4. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med . 2016; 374( 1): 13– 22. Google Scholar CrossRef Search ADS PubMed  5. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care . 2010; 33( suppl 1): S62– S69. CrossRef Search ADS PubMed  6. International Association of Diabetes and Pregnancy Study Groups Consensus Panel; Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, Dyer AR, Leiva A, Hod M, Kitzmiler JL, Lowe LP, McIntyre HD, Oats JJ, Omori Y, Schmidt MI. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care . 2010; 33( 3): 676– 682. Google Scholar CrossRef Search ADS PubMed  7. Harper LM, Mele L, Landon MB, Carpenter MW, Ramin SM, Reddy UM, Casey B, Wapner RJ, Varner MW, Thorp JM, Jr, Sciscione A, Catalano P, Harper M, Saade G, Caritis SN, Sorokin Y, Peaceman AM, Tolosa JE; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Carpenter-Coustan compared with National Diabetes Data Group criteria for diagnosing gestational diabetes. Obstet Gynecol . 2016; 127( 5): 893– 898. Google Scholar CrossRef Search ADS PubMed  8. Gronowski A. Evaluation of thyroid function during pregnancy: have we taken a wrong turn? Clin Chem . 2017; 64( 3). Copyright © 2018 Endocrine Society http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Endocrinology Oxford University Press

The Women’s Health Diagnostic Gap

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Publisher
Endocrine Society
Copyright
Copyright © 2018 Endocrine Society
ISSN
0013-7227
eISSN
1945-7170
D.O.I.
10.1210/en.2017-03178
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Abstract

Abstract Pregnancy remains a significant health risk to women in both developed and underdeveloped countries. Worldwide, 10 to 20 million women have pregnancy complications including ectopic pregnancy, preterm birth, gestational diabetes mellitus, and hypertensive states, including preeclampsia. Despite advancements in women’s health research, there is a large gap in the diagnostic tools available to screen, diagnose, and monitor these conditions. Herein, we examine existing diagnostic tools, such as the human chorionic gonadotropin discriminatory zone, cervicovaginal fetal fibronectin, sFlt-1:PlGF ratio, and glucose tolerance testing. We suggest specific objectives to improve diagnostic testing during pregnancy, including (1) developing high-quality biospecimen banks; (2) educating professionals on performance characteristics of screening tests for low prevalence diseases; (3) funding studies that address diseases unique to pregnancy; and (4) establishing trimester-specific reference intervals. Meeting these objectives could begin to narrow the diagnostic gap in women’s health. The National Institutes of Health (NIH) Revitalization Act celebrates its 15-year anniversary in 2018. This landmark law mandated that NIH-funded phase 3 clinical trials include women and minorities. Today, there are numerous studies, such as the NIH Women’s Health Initiative, that focus exclusively on women. Despite advancements in women’s health research, gaps remain. One major gap overlooked in women’s health is in vitro diagnostics, the biochemical markers used for the screening, diagnosis, prognosis, and monitoring of conditions unique to women. Pregnancy is one major area in which there is a particularly large gap in diagnostic tools. Herein, we highlight several pregnancy-related conditions with a dearth of reliable diagnostic tools and offer insight into how these unmet needs should be addressed. Despite great strides in advancing obstetrical care, pregnancy still presents a substantial health risk to women, even in developed countries. Worldwide, ~350,000 women die each year from pregnancy-related causes, and 10 to 20 million suffer complications, which commonly include ectopic pregnancy, preterm birth, gestational diabetes mellitus (GDM), and hypertensive states including preeclampsia. Despite this shocking toll, reliable biomarkers to screen or diagnose these conditions are not available. Diagnosis of ectopic pregnancy is achieved with a combination of transvaginal ultrasound, serial human chorionic gonadotropin (hCG) measurements, and an hCG “discriminatory zone,” the concentration of hCG above which a gestational sac in the uterus should be readily observed. However, the use of an hCG discriminatory zone lacks clinical utility (1). In the absence of a gestational sac on ultrasound, following serial hCG measurements may lead to a delay in diagnosis in ~40% of patients, leaving women susceptible to tubal rupture and death. Numerous candidate biomarkers such as activin A, pregnancy-associated plasma protein A, and even microRNAs have been explored, but none have proven useful. Preterm labor occurs in ~12% of all pregnancies, yet there are no available biomarkers to reliably predict which of the 4% of women in preterm labor will go on to deliver within 7 to 14 days. Cervicovaginal fetal fibronectin (fFN) is marketed to predict preterm delivery, but an understanding of the performance parameters of the fFN test illustrates why this marker is of little value. In general, a condition with low prevalence has a low pretest probability of having the condition. Thus, a screening test for a low-prevalence condition must demonstrate high positive predictive value (PPV) to be useful. The negative predictive value of fFN is 99.5% (2), meaning a negative result strongly predicts that a woman will not deliver soon. However, the PPV of fFNA is only 17%, meaning that <1 in 5 women with a positive test result will proceed to delivery with 7 to 14 days. For comparison, the PPV of flipping a coin in this population is 4%. Meta-analyses have further supported this lack of utility (3). The ability to predict normal term delivery in itself could lead to better maternal and neonatal health outcomes. However, there are currently no urine, serum, or salivary diagnostic markers to accurately predict the onset of normal term labor. Cervicovaginal fFN is known to increase at 37 to 40 weeks, but to our knowledge no attempts have been made to correlate concentrations with delivery in normal term pregnancies. An easy-to-use home device that uses urine or saliva and has a high PPV for delivery within 72 hours would be attractive to patients and could modify behavior. Furthermore, a reliable biochemical test that could predict delivery within 24 hours would be attractive to physicians to triage symptomatic patients. The incidence of preeclampsia is 5% to 8%, and it is a major contributor to premature delivery and neonatal morbidity in the United States and worldwide. Yet limited treatment options exist beyond magnesium, supportive care, and delivery of the placenta. Diagnosis is made by demonstrating hypertension and proteinuria. However, a reliable marker to predict which women will develop preeclampsia could help identify patients who would benefit from close monitoring and facilitate the development of preventive measures or treatment. Serum sFlt-1:PlGF ratio has been proposed as a predictor of preeclampsia in both symptomatic and asymptomatic women. Similar to fFN, this test has a low PPV. An analysis of the sFlt-1:PlGF ratio in women with suspected preeclampsia demonstrated an excellent negative predictive value to rule out preeclampsia within 1 week or 4 weeks (99% and 94%, respectively) (4). A major limitation of this study was the low prevalence of women who went on to develop preeclampsia at 1 and 4 weeks (3% and 13%, respectively), despite demonstrating symptoms. To overcome the low prevalence of this condition, a marker with high PPV is needed. Unfortunately, the PPVs of the ratio at 1 and 4 weeks in this study were only 9.2% and 36.7%, respectively. Diagnosis of GDM is a hotly contested subject. The American Diabetes Association and the International Association of Diabetes and Pregnancy Study Groups have suggested using a single 75-g glucose tolerance test (GTT) to diagnose GDM (5, 6). However, the American College of Obstetricians and Gynecologists has argued against this method, citing a lack of evidence that treatment improves outcome and endorsing stricter criteria that include a 50-g GTT screen with a 100-g 3-hour diagnostic GTT. However, blood glucose cutoffs for the 3-hour GTT are also contested (7). Current methods require a multipoint GTT. Ideally GDM would be diagnosed with a single blood test that eliminates the need for a biochemical challenge. Finally, even reliable diagnostic markers may go astray during pregnancy because the numerous changes in maternal physiology often result in altered reference intervals for commonly measured serum biomarkers. It is important to understand normal gestational changes to properly detect and diagnose disease during pregnancy. For example, even well-established biomarkers such as thyroid-stimulating hormone and free thyroxine (fT4) can be difficult to interpret during pregnancy. The American Thyroid Association has recommended use of trimester-specific reference intervals for thyroid-stimulating hormone. However, lack of well-defined gestational age-specific reference intervals for fT4 has led to the use of outdated and inferior biomarkers such as fT4 index in an attempt to properly interpret thyroid function during pregnancy (8). Acceptance of trimester-specific reference intervals (established by test manufacturers or from the literature) is needed to prevent misdiagnosis of thyroid disease in parturient women. Research on pregnancy-related disorders is difficult because pregnancy spans a period of 40 weeks during which many physiologic changes occur, subjects are often viewed as vulnerable, and many conditions have low prevalence. We propose four specific objectives to greatly improve on current diagnostic tools: (1) Develop well-characterized biospecimen banks with samples obtained throughout pregnancy from women with various outcomes; (2) educate clinicians, researchers, and the in vitro diagnostic industry on performance characteristics of screening tests for low-prevalence diseases; (3) fund studies that address diseases unique to pregnancy; and (4) establish trimester-specific reference intervals for relevant biomarkers. Meeting these objectives could begin to narrow the diagnostic gap in women’s health. Abbreviations: fFN fetal fibronectin fT4 free thyroxine GDM gestational diabetes mellitus GTT glucose tolerance test hCG human chorionic gonadotropin NIH National Institutes of Health PPV positive predictive value. Acknowledgments Disclosure Summary: A.M.G. serves on the editorial board for the journal Clinical Chemistry, serves as a consultant for Church and Dwight Co., Inc., serves on the Scientific and Medical Advisory Board for Theranos, has received research grant support in 2017 from BioRad Laboratories, and has received travel reimbursement from Roche Diagnostics. The remaining author has nothing to disclose. References 1. Doubilet PM, Benson CB, Bourne T, Blaivas M; for the Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy; Barnhart KT, Benacerraf BR, Brown DL, Filly RA, Fox JC, Goldstein SR, Kendall JL, Lyons EA, Porter MB, Pretorius DH, Timor-Tritsch IE. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med . 2013; 369: 1443– 1451. Google Scholar CrossRef Search ADS PubMed  2. Peaceman AM, Andrews WW, Thorp JM, Cliver SP, Lukes A, Iams JD, Coultrip L, Eriksen N, Holbrook RH, Elliott J, Ingardia C, Pietrantoni M. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol . 1997; 177( 1): 13– 18. Google Scholar CrossRef Search ADS PubMed  3. Sanchez-Ramos L, Delke I, Zamora J, Kaunitz AM. Fetal fibronectin as a short-term predictor of preterm birth in symptomatic patients: a meta-analysis. Obstet Gynecol . 2009; 114( 3): 631– 640. Google Scholar CrossRef Search ADS PubMed  4. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennström M, Olovsson M, Brennecke SP, Stepan H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren S. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N Engl J Med . 2016; 374( 1): 13– 22. Google Scholar CrossRef Search ADS PubMed  5. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care . 2010; 33( suppl 1): S62– S69. CrossRef Search ADS PubMed  6. International Association of Diabetes and Pregnancy Study Groups Consensus Panel; Metzger BE, Gabbe SG, Persson B, Buchanan TA, Catalano PA, Damm P, Dyer AR, Leiva A, Hod M, Kitzmiler JL, Lowe LP, McIntyre HD, Oats JJ, Omori Y, Schmidt MI. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care . 2010; 33( 3): 676– 682. Google Scholar CrossRef Search ADS PubMed  7. Harper LM, Mele L, Landon MB, Carpenter MW, Ramin SM, Reddy UM, Casey B, Wapner RJ, Varner MW, Thorp JM, Jr, Sciscione A, Catalano P, Harper M, Saade G, Caritis SN, Sorokin Y, Peaceman AM, Tolosa JE; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Carpenter-Coustan compared with National Diabetes Data Group criteria for diagnosing gestational diabetes. Obstet Gynecol . 2016; 127( 5): 893– 898. Google Scholar CrossRef Search ADS PubMed  8. Gronowski A. Evaluation of thyroid function during pregnancy: have we taken a wrong turn? Clin Chem . 2017; 64( 3). Copyright © 2018 Endocrine Society

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EndocrinologyOxford University Press

Published: Feb 1, 2018

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