Pinpointing the Perplexity of Preeclampsia

5. May 2015
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Preeclampsia, a hypertensive disorder of pregnancy (HDP), is a leading cause of maternal and perinatal mortality and morbidity. Ten million women develop preeclampsia each year but definition is difficult as it depends on an unreliable assessment of symptoms.

An insidious or fulminant clinical presentation

Preeclampsia is a multi-system disorder characterized by the new onset of elevated blood pressure and either proteinuria or end-organ dysfunction in the last half of pregnancy (after 20 weeks of gestation in a previously normotensive woman). Severe hypertension and signs/symptoms of end-organ injury are considered part of the severe spectrum of preeclampsia. As stated in an article by Wagner reviewing diagnosis and management of the disorder,

“The challenge remains that clinical presentation of preeclampsia may be insidious or fulminant. Some women may be asymptomatic at the time they are found to have hypertension and proteinuria; others may present with symptoms of severe preeclampsia, such as visual disturbances, severe headache, or upper abdominal pain”.

Among the great challenges to treatment of pregnant women with preeclampsia where access to care is not an issue is the fact that assessment of symptoms often prove unreliable for detection purposes and even the very definition of the disease remains controversial and an ongoing topic of medical debate.

A hypocritical misquote of Hippocrates

Many researchers and writers have incorrectly attributed an observation on the susceptibility of pregnant woman to convulsions to Hippocrates. According to his Aphorisms written in the 4th century BCE (Sec. VI, No. 30), “It proves fatal to a woman in a state of pregnancy, if she be seized with any of the acute diseases.” As clarified in Chesley’s Hypertensive Disorders of Pregnancy, one such quotation “In pregnancy, drowsiness and headache accompanied by heaviness and convulsions, is generally bad,” comes from the Coacae Praenotiones (Coan Prognosis), XXXI, No. 507. The Greeks of that time clearly recognized the symptomatology of preeclampsia.

Uncommonly difficult to define

As clarified in Chesley’s Hypertensive Disorders of Pregnancy, until the 1990s, literature regarding measurement of blood pressure in pregnancy was quite confusing. There was no unanimity regarding the preferable posture for testing the subject, and most important which Korotkoff sound, K4 or K5, was the appropriate measurement of diastolic pressure in pregnant women. Preeclampsia is now most commonly defined by new-onset proteinuria and, potentially, other end-organ dysfunction. Many of the current clinical practice guidelines (PRECOG, PRECOG II, WHO, NICE, NVOG) define preeclampsia as gestational hypertension with proteinuria (which is more often a mandatory criterion). The condition is typically diagnosed in the second or third trimester when clinical symptoms of hypertension and proteinuria appear.

With or without proteinuria?

While many practice guidelines maintain this as a mandatory criterion, it is important to note that the American College of Obstetricians and Gynecologists (ACOG) in a 2013 report removed proteinuria as an essential criterion for diagnosis of preeclampsia. They also removed massive proteinuria (5 grams/24 hours) and fetal growth restriction as possible features of severe disease because massive proteinuria has a poor correlation with outcome and fetal growth restriction is managed similarly whether or not preeclampsia is diagnosed. Oliguria was also removed as a characteristic of severe disease.

One of the greatest challenges, and perhaps mysteries with preeclampsia, is that it may arise de novo, or women may have a diminished (or no) nocturnal BP decrease. While hypertension is considered the one of the most accessible important clinical signs, precise measurement is required. Researchers have shown that both systolic and diastolic BP show definite reproducible circadian pattern in both preeclamptic and normotensive pregnant women but this pattern remains both quantitatively and qualitatively different in preeclamptic women. To complicate matters further, while disease severity in preeclampsia generally correlates with the degree and number of organ dysfunctions, fetal manifestations may occur before, with, or in the absence of maternal manifestations. It is important to note that preeclampsia and eclampsia are not distinct disorders but the manifestation of the spectrum of clinical symptoms of the same condition.

In an interview with Catalin Buhimschi, MD, Director of the Division of Maternal Fetal Medicine, Vice Chair for Research in The Ohio State University Department of Obstetrics and Gynecology at The Ohio State University Wexner Medical Center, he shared that “Despite the technological revolution of the 20th century, the way physicians diagnose preeclampsia has not changed within the last 100 years. The diagnosis is based on signs and symptoms that are not unique features of this condition. This leads to uncertainty in diagnosis and the best management decision for both patients and practitioners. “

Clarifying the discrepancy between severe and early-onset

The International Committee of the International Society for the Study of Hypertension in Pregnancy (ISSHP) circulated a questionnaire that focused on the thresholds for defining severe preeclampsia and the gestation at which to define early-onset preeclampsia, and on the definition and inclusion of the HELLP syndrome or other clinical features in severe preeclampsia. Their objective was to determine the definitions and clarify the discrepancy in the literature on the definitions of severe and early-onset preeclampsia. ISSHP found that there was a general agreement to define preeclampsia as severe if blood pressure was >160 mmHg systolic or 110 mmHg diastolic. There was scarce agreement on the amount of proteinuria to define severity. The HELLP syndrome, which stands for a series of symptoms that make up a syndrome that can affect pregnant women, H- hemolysis, EL- elevated liver enzymes, and LP- low platelets counts, was considered a feature to include in the severe classification. Most investigators considered early-onset preeclampsia occurs before 34 weeks. The revised statement specifying the classification, diagnosis and management of the hypertensive disorders of pregnancy from ISSHP can be accessed here.

An important and somewhat controversial issue regarding HELLP syndrome is that as many as 15% to 20% of affected patients do not have concurrent hypertension or proteinuria, leading some experts to believe that HELLP syndrome may be a separate disorder from preeclampsia. Both severe preeclampsia and HELLP syndrome may be associated with serious hepatic manifestations, including infarction, hemorrhage, and rupture.

The global impact of preeclampsia

Preeclampsia remains a significant socioeconomic, cultural, and public health burden in both developed and developing countries. According to CORDIS, the European Commission’s primary public repository and portal to disseminate information on all EU-funded research projects and their results, preeclampsia claims the lives of 50,000 mothers and almost one million babies annually. Preeclampsia and other hypertensive disorders of pregnancy remain the second most common cause of maternal death. In a recent literature review utilizing PubMed (MEDLINE), AJOL, Google Scholar, and Cochrane databases, the prevalence of preeclampsia was found to range from 1.8% to 16.7% in developing countries. Preeclampsia is associated with high maternal and perinatal morbidity and mortality; according to WHO, incidence of preeclampsia is seven times higher in developing countries (2.8% of live births) than in developed countries (0.4%) and it is the cause of 12% of maternal deaths.

The challenge of predicting and detecting preeclampsia

Across first and third world countries, there exist several challenges to predicting and detecting preeclampsia, including but not limited to the challenge of limited access and consultation with an obstetrician, obstetric internist, or other skilled provider, measuring and managing blood pressure, diagnosing proteinuria, and assessing and using edema as an indicator. Proper maintenance and recording of accurate of initial and ongoing blood pressure measurements remain an issue. For women with low literacy and/or limited quantitative proficiencies, self-monitoring and recording may also prove challenging for the reading and recording of blood pressure levels. In developing countries, device acquisition (due to cost), distribution, and technical education/instruction may also prove difficult. Patient access for proper diagnosis of proteinuria may be limited in developing countries; evaluation of urine samples may prove too expensive for initial and certainly repeated testing. Furthermore, there remains the very practical issue of implementation and the need for technician proficiency to interpret testing results. Some researchers have suggested using edema as an indicator but there remains a similar challenge to that of adequate blood measurement self-monitoring and recording – reviewing numbers and maintaining accurate written records after measuring the size of various body parts.

D’Souza and Josin state in a recent article,

“Although numerous clinical and biochemical tests have been proposed for prediction or early detection of preeclampsia, most remain unrealistic for general use in most developing countries. At present, there is not a single reliable and cost-effective screening test for preeclampsia which can be recommended for use in most developing countries. Although some studies on uterine artery Doppler studies and first-trimester maternal serum markers for early detection of preeclampsia have shown promise. There is not enough evidence to suggest their routine use in clinical practice, more so in resource poor settings”.

In an interview with Wendy L. Davis, Chief Executive Officer, GestVision, Inc., she shared that “Current diagnostic methods for preeclampsia are not specific and the need for a better test is well recognizer. Remarkably, new diagnostic approaches are all blood-based (not urine) and often run in a central laboratory, not at the point of care. Many determine the patient’s risk of preeclampsia, not if the patient actually has preeclampsia”.

The field has recognized the developed and developing market needs for better diagnostics for preeclampsia. Several companies have or are continuing to develop promising technologies that could be translated in to developing a reliable diagnostic test(s) for preeclampsia. Some have suggested that an ideal diagnostic test for preeclampsia, along with routine prenatal examination, should be should be accurate, predict preeclampsia even before the onset of clinical symptoms, simple enough to perform, cost –effective, and available at the point of care. While there is hope for the development of such a diagnostic, only one is under current investigation as a urine-based test – The GestAssured™ test from GestVision, Inc. appears to be a simple to use, intended for point of care at the doctor’s office and does not require a laboratory with specialized testing equipment. In addition to the ongoing development of this novel diagnostic for detecting preeclampsia, recent data on predicting/screening appear promising with results suggesting that a combination of both biophysical and biochemical testing at 11-13 weeks could effectively identify women at high risk for subsequent development of HDP. While we have seen little change in the detection and diagnosis of preeclampsia in the past century, interest in this research area and the evolution of diagnostics technology may soon allow for a radical departure from current practice to better address this global problem associated with pregnancy.

 

 

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