This introductory Chapter is devoted to the recognition of Leon Chesley’s immense impact on the study of preeclampsia and hypertensive diseases in pregnancy. In the 43 years following his epic first edition, major advances and giant strides in research have led to new insights regarding the pathophysiology of preeclampsia. Cutting-edge tools in aspects of genetics, cell imaging, immunology, molecular biology, -omics and bioinformatics have facilitated these findings. These advances, particularly in the basic sciences, are a true reflection of the influence of Leon Chesley, a PhD who did not practice medicine. However, he espoused and established the translation of scientific observations to the clinic, hospital, labor and delivery unit, and importantly, to long-term follow-up of women found to be hypertensive during pregnancy. His legacy, application of keen scientific knowledge to improve the practice of clinical obstetrics, is what Dr. Chesley so well communicated in his words and deeds. In this chapter we reproduce Dr. Chesley’s original chapter entitled “History” in its entirety (with minor edits for clarity) and conclude by republishing Dr. Chesley’s 1975 workshop banquet address titled “False Steps in the Study of Preeclampsia.” That workshop begot the establishment of the International Society for the Study of Hypertension in Pregnancy in 1976, an organization that remains committed “to stimulate research in the field of hypertension in pregnancy, disseminate the useful results of such research, and advance education in the field.” Dr. Chesley’s wisdom about how to study preeclampsia remains entirely valid today.

Qualitative and quantitative measurement of urine protein excretion is one of the most common tests performed during pregnancy. For more than 100 years, proteinuria was necessary for the diagnosis of preeclampsia, but recent guidelines recommend that proteinuria is sufficient but not necessary for the diagnosis. Still, in clinical practice, most patients with gestational hypertension will be diagnosed as having preeclampsia based on the presence of proteinuria. Although the reference standard for measuring urinary protein excretion is a 24-hour urine collection, spot urine protein-to-creatinine ratio is a reasonable "rule-out" test for proteinuria. Urine dipstick screening for proteinuria does not provide any clinical benefit and should not be used to diagnose proteinuria. The classic cutoff cited to define proteinuria during pregnancy is a value of >300 mg/24 hours or a urine protein-to-creatinine ratio of at least 0.3. Using this cutoff, the rate of isolated proteinuria in pregnancy may reach 8%, whereas preeclampsia occurs among 3% to 8% of pregnancies. Although this threshold is widely accepted, its origin is not based on evidence on adverse pregnancy outcomes but rather on expert opinion and results of small studies. After reviewing the available data, the most important factor that influences maternal and neonatal outcome is the severity of blood pressures and presence of end organ damage, rather than the excess protein excretion. Because the management of gestational hypertension and preeclampsia without severe features is almost identical in frequency of surveillance and timing of delivery, the separation into 2 disorders is unnecessary. If the management of women with gestational hypertension with a positive assessment of proteinuria will not change, we believe that urine assessment for proteinuria is unnecessary in women who develop new-onset blood pressure at or after 20 weeks' gestation. Furthermore, we do not recommend repeated measurement of proteinuria for women with preeclampsia, the amount of proteinuria does not seem to be related to poor maternal and neonatal outcomes, and monitoring proteinuria may lead to unindicated preterm deliveries and related neonatal complications. Our current diagnosis of preeclampsia in women with chronic kidney disease may be based on a change in protein excretion, a baseline protein excretion evaluation is critical in certain conditions such as chronic hypertension, diabetes, and autoimmune or other renal disorders. The current definition of superimposed preeclampsia possesses a diagnostic dilemma, and it is unclear whether a change in the baseline proteinuria reflects another systemic disease such as preeclampsia or whether women with chronic disease such as chronic hypertension or diabetes will experience a different "normal" pattern of protein excretion during pregnancy. Finally, limited data are available regarding angiogenic and other biomarkers in women with chronic kidney disease as a potential aid in distinguishing the worsening of baseline chronic kidney disease and chronic hypertension from superimposed preeclampsia.

OBJECTIVE:To assess the accuracy of angiogenic biomarkers to predict pre-eclampsia. DESIGN:Prospective multicentre study. From 2006 to 2009, 5121 pregnant women with risk factors for pre-eclampsia (nulliparity, diabetes, previous pre-eclampsia, chronic hypertension) from Argentina, Colombia, Peru, India, Italy, Kenya, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ⩽20, 23-27 and 32-35weeks' gestation (index tests, results blinded from carers). Women were monitored for signs of pre-eclampsia, diagnosed by systolic blood pressure ⩾140mmHg and/or diastolic blood pressure ⩾90mmHg, and proteinuria (protein/creatinine ratio ⩾0.3, protein ⩾1g/l, or one dipstick measurement ⩾2+) appearing after 20weeks' gestation. Early pre-eclampsia was defined when these signs appeared ⩽34weeks' gestation. MAIN OUTCOME MEASURE:Pre-eclampsia. RESULTS:Pre-eclampsia was diagnosed in 198 of 5121 women tested (3.9%) of whom 47 (0.9%) developed it early. The median maternal serum concentrations of index tests were significantly altered in women who subsequently developed pre-eclampsia than in those who did not. However, the area under receiver operating characteristics curve at ⩽20weeks' gestation were closer to 0.5 than to 1.0 for all biomarkers both for predicting any pre-eclampsia or at ⩽34weeks' gestation. The corresponding sensitivity, specificity and likelihood ratios were poor. Multivariable models combining sEng with clinical features slightly improved the prediction capability. CONCLUSIONS:Angiogenic biomarkers in first half of pregnancy do not perform well enough in predicting the later development of pre-eclampsia.

This chapter contains Leon Chesley’s introduction from his sole-authored first edition, including an in-depth and scholarly review of our knowledge of preeclampsia through the ages. Also included is his lecture, “False steps in the history of preeclampsia,” presented in September 1975 at an International Workshop; both meeting and lecture considered the impetus for renewed focus on this devastating disease. The chapter also contains an “EDITORS’ UPDATE” summarizing progress made since Chesley’s single-authored first edition, including the new classification schema in the American College of Obstetricians and Gynecologists’ Hypertension Task Force 2013 recommendations.

Assess the accuracy of serum soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng) and urinary PlGF as predictors of preeclampsia in a prospective multicountry study. From 2006-9, 5121 pregnant women from centers in Argentina, Colombia, India, Italy, Kenya, Peru, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ⩽20 (index tests, results kept blind from care givers), 23–27 and 32–35 weeks’ gestation. During prenatal care, women were closely monitored for signs of preeclampsia, diagnosed by systolic blood pressure ⩾140 mmHg and/or diastolic blood pressure ⩾90 mmHg, and proteinuria with protein/creatinine ratio ⩾0.3, protein ⩾1 g/l or, one dipstick measurement ⩾2+ appearing after gestational week 20, and defined as early preeclampsia when these signs appeared before 34 weeks’ gestation. Preeclampsia was diagnosed in 3.9% (198 of the 5121 women) whom 47 (0.9%) had early disease. No test performed well at <20 weeks for either early or all preeclampsia (area under receiver operating characteristics curve, AUC ⩽0.6). Multivariable models combining biomarkers with clinical features (age, body mass index, smoking, multiple pregnancy, hypertension or treatment for it) did not improve the prediction capability before 20 weeks. Serum PlGF was the best predictor of preeclampsia at any gestation (AUC 0.82 at 32–35 weeks) and at early onset (AUC 0.82 at 23–27 weeks). Angiogenic biomarkers, alone or combined with clinical risk factors, performed poorly as predictors of preeclampsia, when measured early in pregnancy (<20 weeks). M. Widmer: None. C.B. Cuesta: None. K. Khan: None. A.M. Gülmezoglu: None. S.A. Karumanchi: Consultant: Roche, Beckman, Siemens. M.D. Lindheimer: None.

Assess the accuracy of serum soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng) and urinary PlGF as predictors of preeclampsia in a prospective multicountry study.From 2006-9, 5121 pregnant women from centers in Argentina, Colombia, India, Italy, Kenya, Peru, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ⩽20 (index tests, results kept blind from care givers), 23-27 and 32-35weeks' gestation. During prenatal care, women were closely monitored for signs of preeclampsia, diagnosed by systolic blood pressure ⩾140mmHg and/or diastolic blood pressure ⩾90mmHg, and proteinuria with protein/creatinine ratio ⩾0.3, protein ⩾1g/l or, one dipstick measurement ⩾2+ appearing after gestational week 20, and defined as early preeclampsia when these signs appeared before 34 weeks' gestation.Preeclampsia was diagnosed in 3.9% (198 of the 5121 women) whom 47 (0.9%) had early disease. No test performed well at <20 weeks for either early or all preeclampsia (area under receiver operating characteristics curve, AUC ⩽0.6). Multivariable models combining biomarkers with clinical features (age, body mass index, smoking, multiple pregnancy, hypertension or treatment for it) did not improve the prediction capability before 20weeks. Serum PlGF was the best predictor of preeclampsia at any gestation (AUC 0.82 at 32-35weeks) and at early onset (AUC 0.82 at 23-27weeks).Angiogenic biomarkers, alone or combined with clinical risk factors, performed poorly as predictors of preeclampsia, when measured early in pregnancy (<20weeks).M. Widmer: None. C.B. Cuesta: None. K. Khan: None. A.M. Gülmezoglu: None. S.A. Karumanchi: Consultant: Roche, Beckman, Siemens. M.D. Lindheimer: None.

This chapter discusses the profound alterations in renal hemodynamics and glomerular filtration of normal pregnancy and the changes that occur with preeclampsia. Also discussed are the changes in osmoregulation during gestation, which result from a decreased osmotic threshold for both thirst and vasopressin secretion leading to water retention and dilution of body fluids. Both glomerular filtration (GFR) and renal plasma flow (RPF) rise starting in the luteal phase of the last menstrual cycle, reaching their highest levels (40–65% for GFR and 50–85% for RPF) by at least mid-gestation. The chapter further discusses the possible causes of these changes, emphasizing the potential role for the ovarian hormone relaxin and nitric oxide. As for the decrease in the osmotic thresholds of thirst and vasopressin release during normal gestation, a new steady state of plasma osmolality is reached some 10 mOsm/kg H2O below nonpregnant values, which is maintained till term and manifested by a “normal” plasma sodium concentration of 5 mEq/L or so below nonpregnant norms. These changes too begin in the luteal phase and may relate to increased relaxin secretion. Finally, the physiological changes in the renal handling of uric acid and protein during normal pregnancy, and how they change with preeclampsia are also presented. Both GFR and RPF decrease with preeclampsia but values are still often above nonpregnant levels. Preeclampsia is also characterized by decreased excretion of uric acid leading to hyperuricemia, and changes in renal morphology (glomerular endotheliosis) accompanied by increased urinary protein excretion. The possible roles of antiangiogenic and other circulating factors which may impair glomerular function and structure during preeclampsia are discussed. Finally there are descriptions of preeclampsia’s renal histopathology, as well as indications and contraindications for renal biopsy in pregnant women.

HomeHypertensionVol. 63, No. 2Angiogenic Factors in Diagnosis, Management, and Research in Preeclampsia Free AccessBrief ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessBrief ReportPDF/EPUBAngiogenic Factors in Diagnosis, Management, and Research in Preeclampsia Sarosh Rana, S. Ananth Karumanchi and Marshall D. Lindheimer Sarosh RanaSarosh Rana From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (S.R., S.A.K.) and Division of Nephrology, Department of Medicine (S.A.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, Chevy Chase, MD (S.A.K.); and Department of Medicine and Obstetrics and Gynecology, University of Chicago School of Medicine, IL (M.D.L.). Search for more papers by this author , S. Ananth KarumanchiS. Ananth Karumanchi From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (S.R., S.A.K.) and Division of Nephrology, Department of Medicine (S.A.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, Chevy Chase, MD (S.A.K.); and Department of Medicine and Obstetrics and Gynecology, University of Chicago School of Medicine, IL (M.D.L.). Search for more papers by this author and Marshall D. LindheimerMarshall D. Lindheimer From the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology (S.R., S.A.K.) and Division of Nephrology, Department of Medicine (S.A.K.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, Chevy Chase, MD (S.A.K.); and Department of Medicine and Obstetrics and Gynecology, University of Chicago School of Medicine, IL (M.D.L.). Search for more papers by this author Originally published28 Oct 2013https://doi.org/10.1161/HYPERTENSIONAHA.113.02293Hypertension. 2014;63:198–202Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2013: Previous Version 1 Observational studies in humans and experimental studies in animals provide strong evidence that abnormalities in circulating angiogenic factors play a pathogenic role in preeclampsia.1 Numerous angiogenic factor abnormalities have been noted in preeclampsia, but the factors studied most extensively are the antiangiogenic protein, soluble fms-like protein kinase 1 (sFlt1), and the proangiogenic protein, placental growth factor (PlGF).2 Placental expression of sFlt1 is strikingly increased in preeclampsia, and this is associated with increased levels of maternal circulating sFlt1 and decreased levels of free bioactive PlGF,3 a finding confirmed by several groups.1 Alterations in these angiogenic factors occur before clinical signs and symptoms and correlate with the severity of the disease and adverse maternal/neonatal outcomes.4–7 In addition, basal sFlt1 levels are higher in women with multiple gestation, trisomy 13, and molar pregnancy conditions associated with higher preeclampsia rates.1 Other synergistic antiangiogenic proteins such as soluble endoglin have also been demonstrated to contribute to preeclampsia.8 It has therefore been hypothesized that excessive production of both antiangiogenic proteins sFlt1 (inhibiting vascular endothelial growth factor and PlGF signaling) and soluble endoglin (inhibiting transforming growth factor-β signaling) may lead to endothelial dysfunction, and the manifestations of human preeclampsia, and that phenotypic preeclampsia is attributable to an antiangiogenic state.9,10During the last decade, several clinical studies were designed to determine potential of angiogenic factors as prediction tests in preeclampsia.5,7,11–16 However, their accuracy fell far short of sensitivities and likelihood ratios required for clinical use,17–19 although prediction was much more reliable for early-onset (<34 weeks) preeclampsia.13,16,20–23 The modest results were interpreted by some as evidence that preeclampsia is a heterogeneous disease with no single pathway to explain its spectrum24 and led to a decreased interest in the importance of these measurements. However, important new roles in diagnoses, and prognosis, plus their potential regarding developing novel treatments, and improving classification schema for more meaningful immediate and remote follow-up investigations have recently emerged.1,6,25 Here, we explore dilemmas that compromise many preeclampsia studies, discuss potentially new exciting uses of these biomarkers to guide clinical care, and postulate that analysis of angiogenic profiles by improving classification will lead to better studies, particularly those designed to clarify the natural history and remote prognosis of the disorder.Problems With Clinical Studies to Predict PreeclampsiaSubstantial resources have been allocated to preeclampsia prediction studies. In most of these studies, however, the diagnostic criteria are imprecise, few using adverse outcomes other than hypertension and proteinuria in their definitions. We have known for decades that many patients diagnosed preeclamptic by clinical criteria alone are misclassified.26 This is particularly relevant when risk factors such as diabetes mellitus, chronic hypertension, and obesity are present.27–29 In a clinical study of women diagnosed with preeclampsia, renal biopsies revealed that diagnosis was incorrect in 15% of the nulliparas and almost half the multiparas, glomerulonephritis being a frequent imposter.26 Such observations are not surprising given that de novo hypertension and proteinuria are nonspecific in delineating disease. Perhaps other end points such as adverse outcomes might better define the disorder, but few studies use this approach. However, incorporating outcomes would not eliminate all errors because certain conditions that mimic preeclampsia may lead to adverse outcomes as well. Another conclusion to consider from the 1981 report26 is the lack of reliability of protocols that study multiparas.Other problems arise when studying high-risk gestations. Chronic hypertensives and the very obese frequently harbor glomerulosclerosis,30,31 the latter also demonstrating glomerulomegaly.31,32 Daily protein excretion slightly increased but still normal in early gestation may become abnormal near term, as proteinuria increases in all gravid women as gestation progresses.33 In such instances, the appearance of frank proteinuria may have nothing to do with any new pathological process but lead to an erroneous diagnosis of superimposed preeclampsia.Of interest, prediction accuracy seems far better for early than late preeclampsia because late disease often presents with mild features. With advancing gestation, production and circulating levels of sFlt1 increase in all pregnant women, including those who remain normotensive.4,15 These factors combined with the above discussed physiological increments in protein excretion make it more difficult to discriminate preeclampsia from controls using angiogenic factor measurements when the disease presents near term. However, beyond gestational week 37, such testing seems unnecessary as then hypertension, whatever the cause, is considered by most as sufficient reason to deliver.34One argument against pursuing biomarker research has been the absence of disease-modifying agents to make such pursuits useful. Critics argue that angiogenic profile use differs from those for biomarkers measured to predict aneuploidy or diabetes mellitus where pregnancy can be terminated or blood glucose controlled. It is therefore imperative that studies to predict preeclampsia focus not only on identifying the disease, but also demonstrate clinical usefulness, that is, what does the obstetrician do if disease is predicted early?Finally, most studies using angiogenic factors were performed with manual ELISA kits, methodology often displaying high interassay coefficient of variation (10%–20%). Automated assays, now available, are much more reliable, (interassay coefficients of variation <5%), report the results rapidly, and produce more robust associations with altered factor levels and preeclampsia.35–37An Improved Approach to Diagnosis and PrognosisAn emerging role for angiogenic factors is risk stratification that permits determination of the potential morbidity of the disease when women present with diagnosed or suspected preeclampsia.6,38–42 This approach resembles evaluation of suspected cardiac disease, in which use of highly sensitive cardiac troponin has revolutionized management of patients presenting with chest pain.43,44 Rather than focusing on diagnostic certainty, we have suggested that angiogenic biomarkers can predict serious imminent adverse outcomes far better than traditional laboratory and clinical criteria. For instance, our published data, although still preliminary, demonstrate that the plasma sFlt1/PlGF ratio on arrival for triage of suspected preeclampsia predicts those destined to have adverse outcomes within 2 weeks, versus those who do not, especially when women present preterm.6 The ratio alone outperformed currently relied on approaches, including blood pressure, proteinuria, uric acid, alanine aminotransferase, platelet count, and creatinine.6 Of further note is a report that measuring angiogenic proteins also permits accurate risk assessment of severe late preeclampsia, importantly identifying imminent stillbirths (the latter, if confirmed, a major breakthrough in prenatal care).45,46 Measurement of angiogenic proteins in the plasma may also serve as noninvasive surrogate of placental dysfunction.15 Circulating angiogenic factors are also useful to differentiate preeclampsia from diseases such as chronic and gestational hypertension, acute and chronic glomerulonephritis, lupus flares, and gestational thrombocytopenia.47–50Our data further suggest that clinical tests, signs, and symptoms currently used for triage lead to significant misclassification and overtesting/treating, substantial resources and costs erroneously allocated to low-risk patients.6 Thus increased specificity, using the sFlt1/PlGF ratio in triage, should by more accurately defining the population at risk, enable appropriate and reduced cost/resource expenditure.51 Most importantly this approach should permit temporization and prevent unnecessary early deliveries.25Quantitative proteinuria and liver function tests used routinely to assess preeclampsia’s severity are neither sensitive nor specific in predicting maternal and fetal complications.52–54 Similarly, headache and epigastric pain lack specificity.55 Recently, a complex model (PIERS [Preeclampsia Integrated Estimate of RiSk]) that uses clinical signs and laboratory tests to predict adverse outcomes has been advocated. However the model, not robust at presentation, is useful only after 48 hours of admission.56 Thus, it is fair to conclude that, as of 2013, protocols designed to determine risk stratification for suspected or diagnosed preeclampsia are far from ideal.57 Such assessments, too often, are directed by expert opinion–based guidelines that perform rather poorly as predictors of imminent adverse maternal or fetal outcomes.58 Needed are better approaches to predict complications and guide care. Thus, rather than relying on signs, symptoms, and nonspecific tests, biomarkers that are reproducible and quickly obtained, pathogenically linked to the disease, demonstrating high specificity to predict complications, and requiring less expertise to interpret, should have significant clinical usefulness.Accurate risk stratification will help clinicians focus on the appropriate patients whether their disease classification is definitely apparent or not when first evaluated and should also reduce unnecessary interventions on women at low risk for adverse outcomes. In fact, because the latter group did not suffer any adverse outcomes except a few iatrogenic preterm deliveries,25 we anticipate that using angiogenic biomarkers for evaluation of preeclampsia will help avoid unnecessary preterm deliveries. Thus, the compelling and promising data cited this far should be followed by larger prospective studies to confirm whether use of angiogenic factors in clinical decision making can decrease the incidence of preterm delivery and reduce resource utilization without increasing the risk of adverse maternal and neonatal outcomes.Therapeutic Studies Targeting the Angiogenic PathwayStudies of angiogenic pathways are helping devise specific therapies for preeclampsia. In a pilot study limited to 3 severe early preeclamptics (24–32 weeks of gestation), Thadhani et al59 depleted sFlt1 30% by apheresis and prolonged pregnancy by 2 to 4 weeks. If confirmed, this approach could lead to targeted therapy for a specific group of patients, those with an abnormal angiogenic profile. More recently, statin therapy that promotes PlGF expression and angiogenesis was shown to prevent or ameliorate disease in an animal model of preeclampsia.60,61 Pilot human trial to test safety and efficacy of statins in severe preeclampsia is ongoing.62 Relaxin increases production of local vascular endothelial growth factor, its therapeutic potential also being investigated.63 Finally, dietary choline supplementation, shown to reduce placental sFlt1 expression, has been suggested as a strategy to improve placental angiogenesis.64 The future for specific therapies that antagonize sFlt1’s action or reduce its production and those that enhance PlGF levels are therefore promising.Are There Multiple Causes of Phenotypic Preeclampsia?Some suggest that searching for a single biomarker to predict or diagnose preeclampsia is fruitless because the disease has multiple causes.24,65,66 If preeclampsia phenotypes were heterogeneous, both angiogenic and nonangiogenic forms24,66,67 should manifest multisystemic involvement and similar adverse maternal and perinatal outcomes. Whether this is true or not would require large prospective data, but in our studies patients diagnosed with preeclampsia, without angiogenic imbalance, showed no risk for any major preeclampsia-related adverse outcomes other than what seemed to be unnecessary decisions to deliver prematurely.25 This forms the basis of our view that preeclampsia, or at least the form of the disorder that should most concern us, is a single and specific entity whose phenotypes relate to angiogenic imbalance and that measurements of these proteins help identify the severe form of the disease, and its management, and identify the best populations for follow-up research. This does not mean that other hypertensive proteinuric diseases (at times designated suspected preeclampsia) should not be watched carefully, but that angiogenic factor measurements will by identifying what we consider “true preeclampsia” not only will help caregivers in management decisions but also improve classification, the latter improving research on causality, prediction, and epidemiological surveys of both immediate and remote outcomes.Our view of preeclampsia’s specificity, its phenotypes explained by angiogenic imbalance, and the magnitude of which influences the severity of adverse outcomes brings to mind the validity of older morphological studies in which a single pathological entity of preeclampsia seemed apparent. Sheehan and Lynch68 in a 1973 monograph discuss 677 autopsies of pregnant women, often performed within 3 hours after death, thus avoiding the confusion of postmortem changes. The text focuses on a detailed reanalysis of material from 377 cases, 159 of whom had either preeclampsia or eclampsia (Generally, eclampsia assures the clinical diagnosis of preeclampsia was correct, whereas autopsy, of course, confirms the disease’s severity!). The authors detail the gross and histological pathology of virtually every organ, the observations most unique to preeclampsia/eclampsia, greatest in liver and kidney (the latter further detailed by electron microscopy in numerous biopsy reports). These were the same lesions that investigators produced in rodents with sFlt1 overproduction several decades later and reversed the glomerular endotheliosis by administering recombinant proangiogenic proteins.3,69We suggest that the triage studies reviewed here6,37–40,42 delineate, with a high degree of success (certainly superior to current approaches), the “true preeclampsia” that is a disease with organ-specific histopathologies that lead to major adverse outcomes, including hepatic and renal disease, and fetal jeopardy, and the other outcomes classically associated with the severest forms of preeclampsia is associated with markedly elevated sFlt1/PlGF ratio in serum/plasma. We further suggest that many of the patients with sFlt1/PlGF ratios below the cutoff were misdiagnosed clinically,26 one reason they could be managed expectantly.In summary, we posit that altered angiogenic factors allow clinicians to discriminate a serious from a more benign form of hypertension and proteinuria in a manner that defines a specific and multisystemic form of preeclampsia with a definitive organ pathology or the true preeclampsia.Concluding ThoughtsThis commentary focused on newer uses of angiogenic factors, most notably for accurately diagnosing and managing preterm preeclampsia. We discussed pitfalls in preeclampsia research that may underlie disputes regarding whether preeclampsia phenotypes have heterogeneous causes, or our view that they represent angiogenic factor imbalance, alone. Thus, we conclude by suggesting that even if multiple factors lead the placenta to produce excess amounts of antiangiogenic factors, these proteins alone account for the disease’s major phenotypes and therefore are extremely specific for both diagnosis and prognosis. Also, measuring these factors whose results can be produced rapidly with automated platforms will be important for triage may prevent unnecessary early deliveries in preeclamptic women with normal angiogenic profile. Based on our data, we also suggest that future screening studies should focus on prediction of angiogenic form of preeclampsia rather than disease diagnosis based on nonspecific clinical criteria. Measurement of angiogenic factors may also aid in designing specific preventive, and therapeutic trials, and for adequate short- and long-term follow-up studies.Sources of FundingS. Rana is supported by K08HD068398-01A1 (National Institute of Child Health and Human Development) and 13CRP16130003 (American Heart Association). S.A. Karumanchi is an investigator of the Howard Hughes Medical Institute.DisclosuresS.K. Karumanchi is a coinventor on multiple patents for preeclampsia markers and reports service as a consultant to Roche, Siemens, Beckman Coulter, and has financial interest in Aggamin LLC. The other authors report no conflicts.FootnotesCorrespondence to Sarosh Rana, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Kirstein 382 Boston, MA 02215. E-mail [email protected]References1. Powe CE, Levine RJ, Karumanchi SA. Preeclampsia, a disease of the maternal endothelium: the role of antiangiogenic factors and implications for later cardiovascular disease.Circulation. 2011; 123:2856–2869.LinkGoogle Scholar2. Cerdeira AS, Karumanchi SA. Angiogenic factors in preeclampsia and related disorders.Cold Spring Harb Perspect Med. 2012; 2.CrossrefMedlineGoogle Scholar3. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann TA, Morgan JP, Sellke FW, Stillman IE, Epstein FH, Sukhatme VP, Karumanchi SA. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.J Clin Invest. 2003; 111:649–658.CrossrefMedlineGoogle Scholar4. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM, Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the risk of preeclampsia.N Engl J Med. 2004; 350:672–683.CrossrefMedlineGoogle Scholar5. Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, Bujold E, Gonçalves L, Gomez R, Edwin S, Mazor M. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia.J Matern Fetal Neonatal Med. 2005; 17:3–18.CrossrefMedlineGoogle Scholar6. Rana S, Powe CE, Salahuddin S, Verlohren S, Perschel FH, Levine RJ, Lim KH, Wenger JB, Thadhani R, Karumanchi SA. Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.Circulation. 2012; 125:911–919.LinkGoogle Scholar7. Noori M, Donald AE, Angelakopoulou A, Hingorani AD, Williams DJ. Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.Circulation. 2010; 122:478–487.LinkGoogle Scholar8. Venkatesha S, Toporsian M, Lam C, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia.Nat Med. 2006; 12:642–649.CrossrefMedlineGoogle Scholar9. Agarwal I, Karumanchi SA. Preeclampsia and the Anti-Angiogenic State.Pregnancy Hypertens. 2011; 1:17–21.CrossrefMedlineGoogle Scholar10. Romero R, Chaiworapongsa T. Preeclampsia: a link between trophoblast dysregulation and an antiangiogenic state.J Clin Invest. 2013; 123:2775–2777.CrossrefMedlineGoogle Scholar11. Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar LM, Crombleholme WR, Ness RB, Roberts JM, Hubel CA. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor.J Clin Endocrinol Metab. 2005; 90:4895–4903.CrossrefMedlineGoogle Scholar12. Rana S, Karumanchi SA, Levine RJ, Venkatesha S, Rauh-Hain JA, Tamez H, Thadhani R. Sequential changes in antiangiogenic factors in early pregnancy and risk of developing preeclampsia.Hypertension. 2007; 50:137–142.LinkGoogle Scholar13. Stepan H, Unversucht A, Wessel N, Faber R. Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion.Hypertension. 2007; 49:818–824.LinkGoogle Scholar14. Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, Gotsch F, Edwin S, Nien JK, Chaiworapongsa T, Mittal P, Mazaki-Tovi S, Than NG, Gomez R, Hassan SS. The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age.J Matern Fetal Neonatal Med. 2008; 21:279–287.CrossrefMedlineGoogle Scholar15. Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, Kusanovic JP, Gotsch F, Erez O, Mazaki-Tovi S, Gomez R, Edwin S, Chaiworapongsa T, Levine RJ, Karumanchi SA. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.J Matern Fetal Neonatal Med. 2008; 21:9–23.MedlineGoogle Scholar16. Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Mittal P, Vaisbuch E, Mazaki-Tovi S, Gotsch F, Edwin SS, Gomez R, Yeo L, Conde-Agudelo A, Hassan SS. A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.J Matern Fetal Neonatal Med. 2009; 22:1021–1038.CrossrefMedlineGoogle Scholar17. Powers RW, Jeyabalan A, Clifton RG, Van Dorsten P, Hauth JC, Klebanoff MA, Lindheimer MD, Sibai B, Landon M, Miodovnik M; Eunice Kennedy Shriver National Institute of Child Health Human Development Maternal-Fetal Medicine Units Network. Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies.PLoS One. 2010; 5:e13263.CrossrefMedlineGoogle Scholar18. McElrath TF, Lim KH, Pare E, Rich-Edwards J, Pucci D, Troisi R, Parry S. Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy.Am J Obstet Gynecol. 2012; 207:407.e1–407.e7.CrossrefGoogle Scholar19. Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van der Post JA, von Dadelszen P, Mol BW, Pajkrt E; EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: a systematic review and meta-analysis.BJOG. 2012; 119:778–787.CrossrefMedlineGoogle Scholar20. Stepan H, Geipel A, Schwarz F, Krämer T, Wessel N, Faber R. Circulatory soluble endoglin and its predictive value for preeclampsia in second-trimester pregnancies with abnormal uterine perfusion.Am J Obstet Gynecol. 2008; 198:175.e1–175.e6.CrossrefGoogle Scholar21. Diab AE, El-Behery MM, Ebrahiem MA, Shehata AE. Angiogenic factors for the prediction of pre-eclampsia in women with abnormal midtrimester uterine artery Doppler velocimetry.Int J Gynaecol Obstet. 2008; 102:146–151.CrossrefMedlineGoogle Scholar22. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. First-trimester prediction of hypertensive disorders in pregnancy.Hypertension. 2009; 53:812–818.LinkGoogle Scholar23. Myatt L, Clifton R, Roberts J, Spong C, Wapner R, Thorp J, Mercer B, Peaceman A, Ramin S, Carpenter M, Sciscione A, Tolosa J, Saade G, Sorokin Y, Anderson G; Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Can changes in angiogenic biomarkers between the first and second trimesters of pregnancy predict development of pre-eclampsia in a low-risk nulliparous patient population?BJOG. 2013; 120:1183–1191.CrossrefMedlineGoogle Scholar24. Roberts JM, Bell MJ. If we know so much about preeclampsia, why haven’t we cured the disease?J Reprod Immunol. 2013; 99:1–9.CrossrefMedlineGoogle Scholar25. Rana S, Schnettler WT, Powe C, Wenger J, Salahuddin S, Cerdeira AS, Verlohren S, Perschel FH, Arany Z, Lim KH, Thadhani R, Karumanchi SA. Clinical characterization and outcomes of preeclampsia with normal angiogenic profile.Hypertens Pregnancy. 2013; 32:189–201.CrossrefMedlineGoogle Scholar26. Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hypertension in pregnancy: clinical-pathological correlations and remote prognosis.Medicine (Baltimore). 1981; 60:267–276.CrossrefMedlineGoogle Scholar27. Germain S, Nelson-Piercy C. Lupus nephritis and renal disease in pregnancy.Lupus. 2006; 15:148–155.CrossrefMedlineGoogle Scholar28. Catalano PM. Management of obesity in pregnancy.Obstet Gynecol. 2007; 109(2 pt 1):419–433.CrossrefMedlineGoogle Scholar29. Powe CE, Thadhani R. Diabetes and the kidney in pregnancy.Semin Nephrol. 2011; 31:59–69.CrossrefMedlineGoogle Scholar30. Marcantoni C, Fogo AB. A perspective on arterionephrosclerosis: from pathology to potential pathogenesis.J Nephrol. 2007; 20:518–524.MedlineGoogle Scholar31. Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD. Obesity-related glomerulopathy: an emerging epidemic.Kidney Int. 2001; 59:1498–1509.CrossrefMedlineGoogle Scholar32. Kasiske BL, Napier J. Glomerular sclerosis in patients with massive obesity.Am J Nephrol. 1985; 5:45–50.CrossrefMedlineGoogle Scholar33. Lindheimer MD, Kanter D. Interpreting abnormal proteinuria in pregnancy: the need for a more pathophysiological approach.Obstet Gynecol. 2010; 115(2 pt 1):365–375.CrossrefMedlineGoogle Scholar34. Koopmans CM, Bijlenga D, Groen H, et al; HYPITAT study group. Induction of labour versus expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’ gestation (HYPITAT): a multicentre, open-label randomised controlled trial.Lancet. 2009; 374:979–988.CrossrefMedlineGoogle Scholar35. Sunderji S, Gaziano E, Wothe D, Rogers LC, Sibai B, Karumanchi SA, Hodges-Savola C. Automated assays for sVEGF R1 and PlGF as an aid in the diagnosis of preterm preeclampsia: a prospective clinical study.Am J Obstet Gynecol. 2010; 202:40.e1–40.e7.CrossrefGoogle Scholar36. Verlohren S, Galindo A, Schlembach D, Zeisler H, Herraiz I, Moertl MG, Pape J, Dudenhausen JW, Denk B, Stepan H. An automated method for the determination of the sFlt-1/PIGF ratio in the assessment of preeclampsia.Am J Obstet Gynecol. 2010; 202:161.e1–161.e11.CrossrefGoogle Scholar37. Gullai N, Stenczer B, Molvarec A, Fügedi G, Veresh Z, Nagy B, Rigó J. Evaluation of a rapid and simple placental growth factor test in hypertensive disorders of pregnancy.Hypertens Res. 2013; 36:457–462.CrossrefMedlineGoogle Scholar38. Chaiworapongsa T, Romero R, Savasan ZA, Kusanovic JP, Ogge G, Soto E, Dong Z, Tarca A, Gaurav B, Hassan SS. Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia.J Matern Fetal Neonatal Med. 2011; 24:1187–1207.CrossrefMedlineGoogle Scholar39. Moore AG, Young H, Keller JM, Ojo LR, Yan J, Simas TA, Maynard SE. Angiogenic biomarkers for prediction of maternal and neonatal complications in suspected preeclampsia.J Matern Fetal Neonatal Med. 2012; 25:2651–2657.CrossrefMedlineGoogle Scholar40. Sibiude J, Guibourdenche J, Dionne MD, Le Ray C, Anselem O, Serreau R, Goffinet F, Tsatsaris V. Placental growth factor for the prediction of adverse outcomes in patients with suspected preeclampsia or intrauterine growth restriction.PLoS One. 2012; 7:e50208.CrossrefMedlineGoogle Scholar41. Chaiworapongsa T, Romero R, Whitten A, Tarca AL, Bhatti G, Draghici S, Chaemsaithong P, Miranda J, Hassan SS. Differences and similariti

Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy Hypertension in Pregnancy was developed by the Task Force on Hypertension in Pregnancy: James M. Roberts, MD, Chair; Phyllis A. August, MD, MPH; George Bakris, MD; John R. Barton, MD; Ira M. Bernstein, MD; Maurice Druzin, MD; Robert R. Gaiser, MD; Joey R Granger, PhD; Arun Jeyabalan, MD, MS; Donna D. Johnson, MD; S. Ananth Karumanchi, MD; Marshall Lindheimer, MD; Michelle Y. Owens, MD, MS; George R. Saade, MD; Baha M. Sibai, MD; Catherine Y. Spong, MD; Eleni Tsigas; and the American College of Obstetricians and Gynecologists' staff: Gerald F. Joseph, MD; Nancy O'Reilly, MHS; Alyssa Politzer; Sarah Son, MPH; and Karina Ngaiza. The information in Hypertension in Pregnancy should not be viewed as a body of rigid rules. The guidelines are general and intended to be adapted to many different situations, taking into account the needs and resources particular to the locality, the institution, or the type of practice. Variations and innovations that improve the quality of patient care are to be encouraged rather than restricted. The purpose of these guidelines will be well served if they provide a firm basis on which local norms may be built.

Hypertension and/or renal disease occurring in the setting of pregnancy present a unique set of clinical challenges for the nephrologist who may be called to consult by his colleagues in obstetrics or primary care medicine. In 2004, Seminars in Nephrology published the “New Developments in Preeclampsia” 1 Davison J.M. Lindheimer M.D. New developments in preeclampsia. Semin Nephrol. 2004; 24: 537-625 Abstract Full Text Full Text PDF Scopus (2) Google Scholar issue in which we participated. It not only explored progress in this important renal and hypertensive disorder unique to pregnancy, but interestingly contained pictures of a normal and abnormal placenta on the cover of a nephrological journal. Not to be outdone, 6 years later this issue of Seminars in Nephrology reviews the status of renal disease and hypertension during pregnancy, and shows a cover picture of changes in the endothelium of the choroid plexus of an animal model of preeclampsia. 2 Maharaj A.S. Walshe T.E. Saint-Geniez M. Venkatesha S. Maldonado A.E. Himes N.C. et al. VEGF and TGF-beta are required for the maintenance of the choroid plexus and ependyma. J Exp Med. 2008; 205: 491-501 Crossref PubMed Scopus (159) Google Scholar This underscores the tremendous progress recently made in understanding the genesis of preeclampsia phenotypes, focusing on the roles of certain antiangiogenic proteins, including the very ominous convulsive complication—eclampsia.

Preeclampsia occurs more frequently in women of African ancestry. The cause of this hypertensive complication is unclear, but placental oxidative stress may play a role. Because mitochondria are the major sites of oxidative phosphorylation, we hypothesized that placentas of preeclamptic pregnancies harbor mitochondrial DNA (mtDNA) mutations. Next-generation sequencing of placental mtDNA in African American preeclamptics (N = 30) and controls (N = 38) from Chicago revealed significant excesses in preeclamptics of nonsynonymous substitutions in protein-coding genes and mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 5 gene and an increase in the substitution rate (P = .0001). Moreover, 88% of preeclamptics and 53% of controls carried at least one nonsynonymous substitution (P = .005; odds ratio [OR] = 6.36, 95% confidence interval [CI]: 1.5-39.1). These results were not replicated in a sample of African American preeclamptics (N = 162) and controls (N = 171) from Detroit. Differences in study design and heterogeneity may account for this lack of replication. Nonsynonymous substitutions in mtDNA may be risk factors for preeclampsia in some African American women, but additional studies are required to establish this relationship.

This article reviews the association of chronic renal disease and pregnancy. Included are discussions of guidelines for counseling pregnant women with underlying chronic renal disease who are considering conceiving as well as management of those already pregnant. Specifically highlighted are recent studies that question the validity of using estimated glomerular filtration rate and other formulae and questions of whether we should strive to replace the classic counseling approaches based primarily on serum creatinine levels with guidelines based on chronic kidney disease classification. The article concludes with a review as well as a critique of recent research on the prevalence of preeclampsia in women with underlying chronic renal disease, as well as if women with preeclampsia and underlying kidney disease have accelerated courses toward end-stage renal disease.

Hypertension complicates 5% to 7% of all pregnancies. A subset of preeclampsia, characterized by new-onset hypertension, proteinuria, and multisystem involvement, is responsible for substantial maternal and fetal morbidity and is a marker for future cardiac and metabolic disease. This American Society of Hypertension (ASH) position paper summarizes the clinical spectrum of hypertension in pregnancy, focusing on preeclampsia. Recent research breakthroughs relating to etiology are briefly reviewed. Topics include classification of the different forms of hypertension during pregnancy, and status of the tests available to predict preeclampsia, and strategies to prevent preeclampsia and to manage this serious disease. The use of antihypertensive drugs in pregnancy, and the prevention and treatment of the convulsive phase of preeclampsia, eclampsia, with intravenous MgSO4 is also highlighted. Of special note, this guideline article, specifically requested, reviewed, and accepted by ASH, includes solicited review advice from the American College of Obstetricians and Gynecologists. J Am

OBJECTIVE: Molar pregnancy is associated with very early-onset preeclampsia. Since excessive circulating antiangiogenic factors may play a pathogenic role in preeclampsia, we hypothesized that molar placentas produce more antiangiogenic proteins than normal placentas.STUDY DESIGN: This retrospective case-control study used a semiquantitative immunohistochemical technique to compare histologic sections of molar placentas to normal controls. Tissue slides were treated with 2 antisera: one recognized the antiangiogenic markers fms-like tyrosine kinase receptor 1 (Flt1) and its soluble form (sFlt1), while the other recognized vascular endothelial marker CD31. Stain intensity was graded from 1 + (strong focal staining) to 4 + (91-100% staining).RESULTS: Molar placentas (n = 19) showed significantly more staining than controls (n = 16) for Flt/sFlt1 (P < .0001).CONCLUSION: There was a significant difference in Flt1/sFlt1 immunostaining intensity when molar placentas were compared to controls. This supports a hypothesis that the phenotype of preeclampsia in molar pregnancy may result from trophoblasts overproducing at least 1 antiangiogenic protein.

This review and opinion article focuses on the definitions and meanings of abnormal protein excretion in pregnancy, asking the following questions: Are our tests to determine abnormal proteinuria adequately performed? Are current guidelines for diagnosis of excessive proteinuria, especially when used to identify preeclampsia, supported by adequate data? Can the magnitude of proteinuria be used as a reliable clinical biomarker of the gravity of preeclampsia? Should timed urine collections, primarily 24-hour excretions, be supplanted by the urine protein/creatinine ratio in clinical practice? The answers to most of these questions are: We are not sure, or some guidelines are poorly supported by data and may prove erroneous. We suggest a more physiologic approach to assessment of proteinuria and believe that if clinicians and investigators looked at proteinuria in terms of how the kidney handles protein in health and disease it would lead to a more rational and evidence-based approach to proteinuria in pregnancy. Finally, we recommend that current cutoff for abnormal proteinuria be used to diagnose preeclampsia, but the level of proteinuria should not guide management. Other variables, such as status of blood pressure control, evidence of increasing organ damage in the liver and hematological systems, evidence of falling glomerular filtration rate, and signs of neurological involvement, are more reliable indicators of severity of preeclampsia.