A new paradigm for preeclampsia

That preeclampsia is a growing problem, and one of the most significant causes of maternal-fetal morbidity and mortality today, is what drove the American College of Obstetricians and Gynecologists (ACOG) to convene a task force on hypertension in pregnancy in 2011. Indeed, the incidence of preeclampsia has increased approximately 10% over the last 3 decades in the United States, such that approximately 5%-7% of all pregnant women will develop the disorder.

The specific etiology of preeclampsia remains unclear, but the reasons for the increased incidence likely include the rise in delayed childbearing, the increased use of assisted reproductive technology, a rise in the number of twins, and the obesity pandemic.

Epidemiologically, older women with their first pregnancy are at higher risk of developing preeclampsia, whether or not they use assisted reproductive technology (ART). The not-infrequent use of ART among older women, namely IVF, has a compounding effect. So too, does the incidence of twinning. While we fortunately are seeing a lower rate of higher-order multiple gestations associated with IVF than we did in the 1990s, the incidence of twinning has increased dramatically. Women with multiple gestations of any order are at higher risk of developing preeclampsia.

The obesity pandemic is widely believed to be the most modifiable risk factor for preeclampsia. If we can help women to achieve a body mass index (BMI) that is as close to optimal as possible prior to conception, we will likely see significant reductions in the incidence of hypertensive disorders.

Prompt diagnosis of preeclampsia is critical, and on this front, ACOG\'s Task Force on Hypertension in Pregnancy report of 2013 sets forth an important new paradigm for thinking about the disorder and establishing its presence.

Managing preeclampsia remains challenging, however, as there are many areas in which evidence for guiding therapy and management is still insufficient. ACOG’s task force set out to review available data and to attempt to provide clarity on the management of preeclampsia as well as its diagnosis. This was no easy task, and in their culminating report, which lists 60 distinct recommendations, the task force clearly acknowledges the weak evidence base, giving relatively few of their recommendations top marks for both the quality of evidence and their strength of recommendation.

The report appropriately reminds us that there are few if any prescriptions or protocols when it comes to managing preeclampsia. My main concern with the task force’s coverage of management involves their recommendations that magnesium sulfate be used to treat patients with eclampsia and those with preeclampsia with severe features, but not necessarily those without severe features. Patients can progress so rapidly that unless every woman with preeclampsia is vigilantly scrutinized during labor and post delivery – a difficult, if not impossible, task – the window of opportunity to prevent convulsions through the use of magnesium sulfate may well be missed.

ACOG’s new terminology, definitions

Importantly, ACOG’s Task Force on Hypertension in Pregnancy report emphasizes that preeclampsia is an evolving, dynamic, and multisystemic process. It recommends elimination of the terms "mild" and "severe" preeclampsia and encourages the use of new terminology, pushing us to think instead of preeclampsia as being a disorder with or without "severe features." According to the report, a diagnosis of "mild preeclampsia" applies only at the moment at which the diagnosis is established, making the phrase misleading.

Physicians and other providers who have long been in practice will have a hard time ridding their vocabulary of the terms mild and severe preeclampsia, but the intent of the recommendation – to foster appreciation of preeclampsia as an evolving disease – is important and should become entrenched in our approach to hypertension in pregnancy.

The report also downgrades the role of proteinuria in the diagnosis of preeclampsia. Proteinuria is defined as the excretion of 300 mg or more of protein in a 24-hour urine collection or a urine protein/creatinine ratio of at least 0.3 mg/dL. Although proteinuria may indeed be a primary diagnostic finding, it should not be required in order to make the diagnosis of preeclampsia if other severe features are present.

As described in the report, severe features of preeclampsia may include thrombocytopenia (platelet count less than 100,000/microliter), impaired liver function, a rise in serum creatinine indicating progressive renal insufficiency (a serum creatinine concentration greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease), central nervous system disturbances, pulmonary edema, and persistently high elevations in blood pressure (a systolic blood pressure of 160 mm Hg or higher or a diastolic reading of 110 mm Hg or higher on two occasions at least 4 hours apart).

The document states, in other words, that to establish preeclampsia, equal weight should be given to any of these so-called severe features – even in the absence of proteinuria – when they occur along with new-onset hypertension at 20 weeks’ gestation or beyond. (The blood pressure criteria stipulate hypertension as a systolic blood pressure of 140 mm Hg or higher and a diastolic of 90 mm Hg or higher, taken on at least two occasions 4 hours apart.)

This new approach to diagnosing preeclampsia is a major change. It reflects what the ACOG document rightly calls a "minimal relationship" between the quantity of urinary protein and maternal and fetal outcomes in preeclampsia, as well as the fact that preeclampsia may quickly evolve. We need these broader criteria and lower thresholds so that we will not miss patients who might present atypically, with proteinuria not yet a significant finding, but with disease quickly developing.

Another helpful change is the removal of significant fetal growth restriction (less than the fifth percentile) as a diagnostic feature for traditionally coined "severe preeclampsia." Fetal growth restriction is not included in ACOG’s recommended list of severe features of preeclampsia. This is a helpful clarification that should prevent potentially unnecessary deliveries. The problems of fetal growth restriction (FGR) and preeclampsia should be considered and managed separately, with the option of expectant management considered with respect to each entity alone, as opposed to the finding of FGR driving a diagnosis of severe preeclampsia and thus delivery within 48 hours.

Where evidence is strongest

ACOG’s report contains 60 distinct recommendations covering hypertensive disorders in pregnancy, but only 6 of these recommendations are graded as both "strong" and based on "high-quality" evidence. (A "strong" recommendation is one that the task force considered so well supported by the literature that it is applicable to "virtually all patients.")

The remaining recommendations are either graded as "qualified" or are based on evidence that is rated as "very low," "low," or "moderate," or some combination of the "qualified" grade and a quality-of-evidence ranking below "high."

The task force utilized a strategy developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group that rates the quality of evidence based largely on what’s called "confidence in estimates of effect." Under this approach, randomized, controlled trials are important but may still be considered flawed and observational studies are usually but not necessarily classified as low quality.

The small number of strong, high-quality recommendations in the ACOG report reflects the fact that, despite advances in our understanding of preeclampsia, there are many areas in which we lack good evidence from randomized, controlled trials. Importantly, the task force emphasizes that it offers recommendations and not prescriptions, and that sound clinical judgment remains a key part of patient management.

The six strong recommendations in the report that are based on high-quality evidence are as follows:

• The administration of vitamin C or vitamin E to prevent preeclampsia is not recommended.

• Women with severe preeclampsia who are being expectantly managed at 34 weeks’ or less of gestation should receive corticosteroids for the benefit of accelerating fetal lung maturation.

• Women who have chronic hypertension with superimposed preeclampsia and are being expectantly managed at 34 weeks’ or less of gestation also should have corticosteroids administered for the purpose of accelerating fetal lung maturation.

• For women with eclampsia, the administration of parenteral magnesium sulfate is recommended.

• For women with severe preeclampsia, the administration of intrapartum-postpartum magnesium sulfate to prevent eclampsia is recommended.

• For women with HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome who are before the gestational age of fetal viability, delivery should be undertaken shortly after initial maternal stabilization.

My take

Contrary to former recommendations, the task force’s new recommendations suggest that use of magnesium sulfate for preeclampsia without severe features (formerly called "mild preeclampsia") may not be needed. Although magnesium sulfate may not be warranted in every case, patients can progress so rapidly from having no severe symptoms to developing severe symptoms that it is difficult if not impossible to parse out who would or would not benefit from treatment. If we try to do so, we run the great risk of not providing the necessary medication to our patients, thereby increasing the chances of maternal morbidity and mortality.

In our institution, we continue to use magnesium sulfate intrapartum and post partum for every patient with a diagnosis of preeclampsia, whether or not she has severe features. Without high-quality evidence to the contrary, I do not believe that we should alter the former recommendation that magnesium sulfate be used in all cases of preeclampsia. We administer the agent for 24 hours post partum because studies looking at a 48-hour window have shown that most patients who have an eclamptic seizure within 48 hours after delivery will actually experience it within the first 24 hours.

There is a remaining conundrum. We know that approximately 50% of postpartum seizures occur more than 48 hours post delivery. It is vital, therefore, that patients who have hypertensive disorders during pregnancy be educated about the signs and symptoms of postpartum preeclampsia and be given clear directions about how to contact their provider if any signs or symptoms – such as headache, visual disturbances, and right-upper-quadrant pain – are noticed. Patients who are discharged with blood pressures that are still elevated (but not enough to require hospitalization) should be seen again within 72 hours or a week for an evaluation of their blood pressure. The threshold in our practices for arranging earlier postpartum visits, moreover, should be set very low for these women.

The need for patient education is mentioned in the ACOG report, which says, "It is suggested that health care providers convey information about preeclampsia in the context of prenatal care and postpartum care using proven health care communication practices."

The wording of the recommendation as well as its "qualified" strength and the designation of a "low" quality of evidence should not detract from the importance of the message that patient education is a key to successful recognition and management of preeclampsia. The awareness of and knowledge about postpartum preeclampsia have been shown in recent research to be disappointingly low. We need to do better.

With respect to prevention, there are two strategies that, despite not having strong recommendations and/or the backing of high-quality evidence, are still considered to be effective. One is the use of daily low-dose aspirin (60-80 mg) in women with a history of early-onset preeclampsia and preterm delivery prior to 34 weeks’ of gestation. The other is calcium supplementation for women who have an inadequate daily intake of calcium, although this practice has less relevance in the United States than in the developing world.

The goal of low-dose aspirin is really to reduce the likelihood of severe preeclampsia recurring. Almost half of patients with a history of preeclampsia will not develop the disorder in a subsequent pregnancy (without aspirin therapy), so the reduction in the incidence of preeclampsia with low-dose aspirin is unlikely to be significant. However, as aspirin therapy is a relatively benign and inexpensive intervention, it is worth considering. Indeed, meta-analyses of women in randomized trials of low-dose aspirin for preeclampsia prevention have shown small reductions in the incidence and morbidity of preeclampsia, without any evidence of adverse effects.

[Notably, the U.S. Preventive Services Task Force said in a draft recommendation statement issued in April that it recommends low-dose aspirin use after 12 weeks of pregnancy in women who are at high risk for preeclampsia. (See accompanying story.)]

Over the years a variety of predictive strategies – for predicting early-onset preeclampsia in particular – have been proposed and researched, including various biomarkers, blood tests, and imaging studies. These are all worthwhile endeavors at the research level, but for any screening strategy to be implemented there must be an effective intervention. At the current time, our only effective intervention is delivery based on clinical findings.

On the other end of the spectrum, it is clear today that preeclampsia is associated with later-life cardiovascular disease in women. It is only in the last 5-10 years that research findings have come to the fore and that we have thought about preeclampsia as a marker for increased disease risk, just as we did starting several decades ago with gestational diabetes and the risk of future type 2 diabetes.

ACOG’s task force suggests yearly assessment of blood pressure, lipids, fasting blood glucose, and BMI in women with a medical history of preeclampsia who delivered preterm or who have a history of recurrent preeclampsia. The recommendation is "qualified," with a low quality of evidence, and contains a cautionary footnote stating that "the value and appropriate timing of assessment is not yet established."

Indeed, the next step in research will be to follow patients with preeclampsia longitudinally and determine whether or not interventional strategies can be devised to reduce the cardiovascular risk to baseline or, ideally below baseline, in these patients. Until we have such information, we should still recognize that this group of patients may be at higher risk for cardiovascular disease later in life, and, at the very least, be even more vigilant about adhering to regular health maintenance examinations.

Dr. John T. Repke is professor and chair of obstetrics and gynecology at Pennsylvania State University, Hershey, and has published extensively on hypertension in pregnancy. Dr. Repke said he has no relevant financial disclosures.

That preeclampsia is a growing problem, and one of the most significant causes of maternal-fetal morbidity and mortality today, is what drove the American College of Obstetricians and Gynecologists (ACOG) to convene a task force on hypertension in pregnancy in 2011. Indeed, the incidence of preeclampsia has increased approximately 10% over the last 3 decades in the United States, such that approximately 5%-7% of all pregnant women will develop the disorder.

The specific etiology of preeclampsia remains unclear, but the reasons for the increased incidence likely include the rise in delayed childbearing, the increased use of assisted reproductive technology, a rise in the number of twins, and the obesity pandemic.

Epidemiologically, older women with their first pregnancy are at higher risk of developing preeclampsia, whether or not they use assisted reproductive technology (ART). The not-infrequent use of ART among older women, namely IVF, has a compounding effect. So too, does the incidence of twinning. While we fortunately are seeing a lower rate of higher-order multiple gestations associated with IVF than we did in the 1990s, the incidence of twinning has increased dramatically. Women with multiple gestations of any order are at higher risk of developing preeclampsia.

The obesity pandemic is widely believed to be the most modifiable risk factor for preeclampsia. If we can help women to achieve a body mass index (BMI) that is as close to optimal as possible prior to conception, we will likely see significant reductions in the incidence of hypertensive disorders.

Prompt diagnosis of preeclampsia is critical, and on this front, ACOG\'s Task Force on Hypertension in Pregnancy report of 2013 sets forth an important new paradigm for thinking about the disorder and establishing its presence.

Managing preeclampsia remains challenging, however, as there are many areas in which evidence for guiding therapy and management is still insufficient. ACOG’s task force set out to review available data and to attempt to provide clarity on the management of preeclampsia as well as its diagnosis. This was no easy task, and in their culminating report, which lists 60 distinct recommendations, the task force clearly acknowledges the weak evidence base, giving relatively few of their recommendations top marks for both the quality of evidence and their strength of recommendation.

The report appropriately reminds us that there are few if any prescriptions or protocols when it comes to managing preeclampsia. My main concern with the task force’s coverage of management involves their recommendations that magnesium sulfate be used to treat patients with eclampsia and those with preeclampsia with severe features, but not necessarily those without severe features. Patients can progress so rapidly that unless every woman with preeclampsia is vigilantly scrutinized during labor and post delivery – a difficult, if not impossible, task – the window of opportunity to prevent convulsions through the use of magnesium sulfate may well be missed.

ACOG’s new terminology, definitions

Importantly, ACOG’s Task Force on Hypertension in Pregnancy report emphasizes that preeclampsia is an evolving, dynamic, and multisystemic process. It recommends elimination of the terms "mild" and "severe" preeclampsia and encourages the use of new terminology, pushing us to think instead of preeclampsia as being a disorder with or without "severe features." According to the report, a diagnosis of "mild preeclampsia" applies only at the moment at which the diagnosis is established, making the phrase misleading.

Physicians and other providers who have long been in practice will have a hard time ridding their vocabulary of the terms mild and severe preeclampsia, but the intent of the recommendation – to foster appreciation of preeclampsia as an evolving disease – is important and should become entrenched in our approach to hypertension in pregnancy.

The report also downgrades the role of proteinuria in the diagnosis of preeclampsia. Proteinuria is defined as the excretion of 300 mg or more of protein in a 24-hour urine collection or a urine protein/creatinine ratio of at least 0.3 mg/dL. Although proteinuria may indeed be a primary diagnostic finding, it should not be required in order to make the diagnosis of preeclampsia if other severe features are present.

As described in the report, severe features of preeclampsia may include thrombocytopenia (platelet count less than 100,000/microliter), impaired liver function, a rise in serum creatinine indicating progressive renal insufficiency (a serum creatinine concentration greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease), central nervous system disturbances, pulmonary edema, and persistently high elevations in blood pressure (a systolic blood pressure of 160 mm Hg or higher or a diastolic reading of 110 mm Hg or higher on two occasions at least 4 hours apart).

The document states, in other words, that to establish preeclampsia, equal weight should be given to any of these so-called severe features – even in the absence of proteinuria – when they occur along with new-onset hypertension at 20 weeks’ gestation or beyond. (The blood pressure criteria stipulate hypertension as a systolic blood pressure of 140 mm Hg or higher and a diastolic of 90 mm Hg or higher, taken on at least two occasions 4 hours apart.)

This new approach to diagnosing preeclampsia is a major change. It reflects what the ACOG document rightly calls a "minimal relationship" between the quantity of urinary protein and maternal and fetal outcomes in preeclampsia, as well as the fact that preeclampsia may quickly evolve. We need these broader criteria and lower thresholds so that we will not miss patients who might present atypically, with proteinuria not yet a significant finding, but with disease quickly developing.

Another helpful change is the removal of significant fetal growth restriction (less than the fifth percentile) as a diagnostic feature for traditionally coined "severe preeclampsia." Fetal growth restriction is not included in ACOG’s recommended list of severe features of preeclampsia. This is a helpful clarification that should prevent potentially unnecessary deliveries. The problems of fetal growth restriction (FGR) and preeclampsia should be considered and managed separately, with the option of expectant management considered with respect to each entity alone, as opposed to the finding of FGR driving a diagnosis of severe preeclampsia and thus delivery within 48 hours.

Where evidence is strongest

ACOG’s report contains 60 distinct recommendations covering hypertensive disorders in pregnancy, but only 6 of these recommendations are graded as both "strong" and based on "high-quality" evidence. (A "strong" recommendation is one that the task force considered so well supported by the literature that it is applicable to "virtually all patients.")

The remaining recommendations are either graded as "qualified" or are based on evidence that is rated as "very low," "low," or "moderate," or some combination of the "qualified" grade and a quality-of-evidence ranking below "high."

The task force utilized a strategy developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group that rates the quality of evidence based largely on what’s called "confidence in estimates of effect." Under this approach, randomized, controlled trials are important but may still be considered flawed and observational studies are usually but not necessarily classified as low quality.

The small number of strong, high-quality recommendations in the ACOG report reflects the fact that, despite advances in our understanding of preeclampsia, there are many areas in which we lack good evidence from randomized, controlled trials. Importantly, the task force emphasizes that it offers recommendations and not prescriptions, and that sound clinical judgment remains a key part of patient management.

The six strong recommendations in the report that are based on high-quality evidence are as follows:

• The administration of vitamin C or vitamin E to prevent preeclampsia is not recommended.

• Women with severe preeclampsia who are being expectantly managed at 34 weeks’ or less of gestation should receive corticosteroids for the benefit of accelerating fetal lung maturation.

• Women who have chronic hypertension with superimposed preeclampsia and are being expectantly managed at 34 weeks’ or less of gestation also should have corticosteroids administered for the purpose of accelerating fetal lung maturation.

• For women with eclampsia, the administration of parenteral magnesium sulfate is recommended.

• For women with severe preeclampsia, the administration of intrapartum-postpartum magnesium sulfate to prevent eclampsia is recommended.

• For women with HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome who are before the gestational age of fetal viability, delivery should be undertaken shortly after initial maternal stabilization.

My take

Contrary to former recommendations, the task force’s new recommendations suggest that use of magnesium sulfate for preeclampsia without severe features (formerly called "mild preeclampsia") may not be needed. Although magnesium sulfate may not be warranted in every case, patients can progress so rapidly from having no severe symptoms to developing severe symptoms that it is difficult if not impossible to parse out who would or would not benefit from treatment. If we try to do so, we run the great risk of not providing the necessary medication to our patients, thereby increasing the chances of maternal morbidity and mortality.

In our institution, we continue to use magnesium sulfate intrapartum and post partum for every patient with a diagnosis of preeclampsia, whether or not she has severe features. Without high-quality evidence to the contrary, I do not believe that we should alter the former recommendation that magnesium sulfate be used in all cases of preeclampsia. We administer the agent for 24 hours post partum because studies looking at a 48-hour window have shown that most patients who have an eclamptic seizure within 48 hours after delivery will actually experience it within the first 24 hours.

There is a remaining conundrum. We know that approximately 50% of postpartum seizures occur more than 48 hours post delivery. It is vital, therefore, that patients who have hypertensive disorders during pregnancy be educated about the signs and symptoms of postpartum preeclampsia and be given clear directions about how to contact their provider if any signs or symptoms – such as headache, visual disturbances, and right-upper-quadrant pain – are noticed. Patients who are discharged with blood pressures that are still elevated (but not enough to require hospitalization) should be seen again within 72 hours or a week for an evaluation of their blood pressure. The threshold in our practices for arranging earlier postpartum visits, moreover, should be set very low for these women.

The need for patient education is mentioned in the ACOG report, which says, "It is suggested that health care providers convey information about preeclampsia in the context of prenatal care and postpartum care using proven health care communication practices."

The wording of the recommendation as well as its "qualified" strength and the designation of a "low" quality of evidence should not detract from the importance of the message that patient education is a key to successful recognition and management of preeclampsia. The awareness of and knowledge about postpartum preeclampsia have been shown in recent research to be disappointingly low. We need to do better.

With respect to prevention, there are two strategies that, despite not having strong recommendations and/or the backing of high-quality evidence, are still considered to be effective. One is the use of daily low-dose aspirin (60-80 mg) in women with a history of early-onset preeclampsia and preterm delivery prior to 34 weeks’ of gestation. The other is calcium supplementation for women who have an inadequate daily intake of calcium, although this practice has less relevance in the United States than in the developing world.

The goal of low-dose aspirin is really to reduce the likelihood of severe preeclampsia recurring. Almost half of patients with a history of preeclampsia will not develop the disorder in a subsequent pregnancy (without aspirin therapy), so the reduction in the incidence of preeclampsia with low-dose aspirin is unlikely to be significant. However, as aspirin therapy is a relatively benign and inexpensive intervention, it is worth considering. Indeed, meta-analyses of women in randomized trials of low-dose aspirin for preeclampsia prevention have shown small reductions in the incidence and morbidity of preeclampsia, without any evidence of adverse effects.

[Notably, the U.S. Preventive Services Task Force said in a draft recommendation statement issued in April that it recommends low-dose aspirin use after 12 weeks of pregnancy in women who are at high risk for preeclampsia. (See accompanying story.)]

Over the years a variety of predictive strategies – for predicting early-onset preeclampsia in particular – have been proposed and researched, including various biomarkers, blood tests, and imaging studies. These are all worthwhile endeavors at the research level, but for any screening strategy to be implemented there must be an effective intervention. At the current time, our only effective intervention is delivery based on clinical findings.

On the other end of the spectrum, it is clear today that preeclampsia is associated with later-life cardiovascular disease in women. It is only in the last 5-10 years that research findings have come to the fore and that we have thought about preeclampsia as a marker for increased disease risk, just as we did starting several decades ago with gestational diabetes and the risk of future type 2 diabetes.

ACOG’s task force suggests yearly assessment of blood pressure, lipids, fasting blood glucose, and BMI in women with a medical history of preeclampsia who delivered preterm or who have a history of recurrent preeclampsia. The recommendation is "qualified," with a low quality of evidence, and contains a cautionary footnote stating that "the value and appropriate timing of assessment is not yet established."

Indeed, the next step in research will be to follow patients with preeclampsia longitudinally and determine whether or not interventional strategies can be devised to reduce the cardiovascular risk to baseline or, ideally below baseline, in these patients. Until we have such information, we should still recognize that this group of patients may be at higher risk for cardiovascular disease later in life, and, at the very least, be even more vigilant about adhering to regular health maintenance examinations.

Dr. John T. Repke is professor and chair of obstetrics and gynecology at Pennsylvania State University, Hershey, and has published extensively on hypertension in pregnancy. Dr. Repke said he has no relevant financial disclosures.

That preeclampsia is a growing problem, and one of the most significant causes of maternal-fetal morbidity and mortality today, is what drove the American College of Obstetricians and Gynecologists (ACOG) to convene a task force on hypertension in pregnancy in 2011. Indeed, the incidence of preeclampsia has increased approximately 10% over the last 3 decades in the United States, such that approximately 5%-7% of all pregnant women will develop the disorder.

The specific etiology of preeclampsia remains unclear, but the reasons for the increased incidence likely include the rise in delayed childbearing, the increased use of assisted reproductive technology, a rise in the number of twins, and the obesity pandemic.

Epidemiologically, older women with their first pregnancy are at higher risk of developing preeclampsia, whether or not they use assisted reproductive technology (ART). The not-infrequent use of ART among older women, namely IVF, has a compounding effect. So too, does the incidence of twinning. While we fortunately are seeing a lower rate of higher-order multiple gestations associated with IVF than we did in the 1990s, the incidence of twinning has increased dramatically. Women with multiple gestations of any order are at higher risk of developing preeclampsia.

The obesity pandemic is widely believed to be the most modifiable risk factor for preeclampsia. If we can help women to achieve a body mass index (BMI) that is as close to optimal as possible prior to conception, we will likely see significant reductions in the incidence of hypertensive disorders.

Prompt diagnosis of preeclampsia is critical, and on this front, ACOG\'s Task Force on Hypertension in Pregnancy report of 2013 sets forth an important new paradigm for thinking about the disorder and establishing its presence.

Managing preeclampsia remains challenging, however, as there are many areas in which evidence for guiding therapy and management is still insufficient. ACOG’s task force set out to review available data and to attempt to provide clarity on the management of preeclampsia as well as its diagnosis. This was no easy task, and in their culminating report, which lists 60 distinct recommendations, the task force clearly acknowledges the weak evidence base, giving relatively few of their recommendations top marks for both the quality of evidence and their strength of recommendation.

The report appropriately reminds us that there are few if any prescriptions or protocols when it comes to managing preeclampsia. My main concern with the task force’s coverage of management involves their recommendations that magnesium sulfate be used to treat patients with eclampsia and those with preeclampsia with severe features, but not necessarily those without severe features. Patients can progress so rapidly that unless every woman with preeclampsia is vigilantly scrutinized during labor and post delivery – a difficult, if not impossible, task – the window of opportunity to prevent convulsions through the use of magnesium sulfate may well be missed.

ACOG’s new terminology, definitions

Importantly, ACOG’s Task Force on Hypertension in Pregnancy report emphasizes that preeclampsia is an evolving, dynamic, and multisystemic process. It recommends elimination of the terms "mild" and "severe" preeclampsia and encourages the use of new terminology, pushing us to think instead of preeclampsia as being a disorder with or without "severe features." According to the report, a diagnosis of "mild preeclampsia" applies only at the moment at which the diagnosis is established, making the phrase misleading.

Physicians and other providers who have long been in practice will have a hard time ridding their vocabulary of the terms mild and severe preeclampsia, but the intent of the recommendation – to foster appreciation of preeclampsia as an evolving disease – is important and should become entrenched in our approach to hypertension in pregnancy.

The report also downgrades the role of proteinuria in the diagnosis of preeclampsia. Proteinuria is defined as the excretion of 300 mg or more of protein in a 24-hour urine collection or a urine protein/creatinine ratio of at least 0.3 mg/dL. Although proteinuria may indeed be a primary diagnostic finding, it should not be required in order to make the diagnosis of preeclampsia if other severe features are present.

As described in the report, severe features of preeclampsia may include thrombocytopenia (platelet count less than 100,000/microliter), impaired liver function, a rise in serum creatinine indicating progressive renal insufficiency (a serum creatinine concentration greater than 1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease), central nervous system disturbances, pulmonary edema, and persistently high elevations in blood pressure (a systolic blood pressure of 160 mm Hg or higher or a diastolic reading of 110 mm Hg or higher on two occasions at least 4 hours apart).

The document states, in other words, that to establish preeclampsia, equal weight should be given to any of these so-called severe features – even in the absence of proteinuria – when they occur along with new-onset hypertension at 20 weeks’ gestation or beyond. (The blood pressure criteria stipulate hypertension as a systolic blood pressure of 140 mm Hg or higher and a diastolic of 90 mm Hg or higher, taken on at least two occasions 4 hours apart.)

This new approach to diagnosing preeclampsia is a major change. It reflects what the ACOG document rightly calls a "minimal relationship" between the quantity of urinary protein and maternal and fetal outcomes in preeclampsia, as well as the fact that preeclampsia may quickly evolve. We need these broader criteria and lower thresholds so that we will not miss patients who might present atypically, with proteinuria not yet a significant finding, but with disease quickly developing.

Another helpful change is the removal of significant fetal growth restriction (less than the fifth percentile) as a diagnostic feature for traditionally coined "severe preeclampsia." Fetal growth restriction is not included in ACOG’s recommended list of severe features of preeclampsia. This is a helpful clarification that should prevent potentially unnecessary deliveries. The problems of fetal growth restriction (FGR) and preeclampsia should be considered and managed separately, with the option of expectant management considered with respect to each entity alone, as opposed to the finding of FGR driving a diagnosis of severe preeclampsia and thus delivery within 48 hours.

Where evidence is strongest

ACOG’s report contains 60 distinct recommendations covering hypertensive disorders in pregnancy, but only 6 of these recommendations are graded as both "strong" and based on "high-quality" evidence. (A "strong" recommendation is one that the task force considered so well supported by the literature that it is applicable to "virtually all patients.")

The remaining recommendations are either graded as "qualified" or are based on evidence that is rated as "very low," "low," or "moderate," or some combination of the "qualified" grade and a quality-of-evidence ranking below "high."

The task force utilized a strategy developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group that rates the quality of evidence based largely on what’s called "confidence in estimates of effect." Under this approach, randomized, controlled trials are important but may still be considered flawed and observational studies are usually but not necessarily classified as low quality.

The small number of strong, high-quality recommendations in the ACOG report reflects the fact that, despite advances in our understanding of preeclampsia, there are many areas in which we lack good evidence from randomized, controlled trials. Importantly, the task force emphasizes that it offers recommendations and not prescriptions, and that sound clinical judgment remains a key part of patient management.

The six strong recommendations in the report that are based on high-quality evidence are as follows:

• The administration of vitamin C or vitamin E to prevent preeclampsia is not recommended.

• Women with severe preeclampsia who are being expectantly managed at 34 weeks’ or less of gestation should receive corticosteroids for the benefit of accelerating fetal lung maturation.

• Women who have chronic hypertension with superimposed preeclampsia and are being expectantly managed at 34 weeks’ or less of gestation also should have corticosteroids administered for the purpose of accelerating fetal lung maturation.

• For women with eclampsia, the administration of parenteral magnesium sulfate is recommended.

• For women with severe preeclampsia, the administration of intrapartum-postpartum magnesium sulfate to prevent eclampsia is recommended.

• For women with HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome who are before the gestational age of fetal viability, delivery should be undertaken shortly after initial maternal stabilization.

My take

Contrary to former recommendations, the task force’s new recommendations suggest that use of magnesium sulfate for preeclampsia without severe features (formerly called "mild preeclampsia") may not be needed. Although magnesium sulfate may not be warranted in every case, patients can progress so rapidly from having no severe symptoms to developing severe symptoms that it is difficult if not impossible to parse out who would or would not benefit from treatment. If we try to do so, we run the great risk of not providing the necessary medication to our patients, thereby increasing the chances of maternal morbidity and mortality.

In our institution, we continue to use magnesium sulfate intrapartum and post partum for every patient with a diagnosis of preeclampsia, whether or not she has severe features. Without high-quality evidence to the contrary, I do not believe that we should alter the former recommendation that magnesium sulfate be used in all cases of preeclampsia. We administer the agent for 24 hours post partum because studies looking at a 48-hour window have shown that most patients who have an eclamptic seizure within 48 hours after delivery will actually experience it within the first 24 hours.

There is a remaining conundrum. We know that approximately 50% of postpartum seizures occur more than 48 hours post delivery. It is vital, therefore, that patients who have hypertensive disorders during pregnancy be educated about the signs and symptoms of postpartum preeclampsia and be given clear directions about how to contact their provider if any signs or symptoms – such as headache, visual disturbances, and right-upper-quadrant pain – are noticed. Patients who are discharged with blood pressures that are still elevated (but not enough to require hospitalization) should be seen again within 72 hours or a week for an evaluation of their blood pressure. The threshold in our practices for arranging earlier postpartum visits, moreover, should be set very low for these women.

The need for patient education is mentioned in the ACOG report, which says, "It is suggested that health care providers convey information about preeclampsia in the context of prenatal care and postpartum care using proven health care communication practices."

The wording of the recommendation as well as its "qualified" strength and the designation of a "low" quality of evidence should not detract from the importance of the message that patient education is a key to successful recognition and management of preeclampsia. The awareness of and knowledge about postpartum preeclampsia have been shown in recent research to be disappointingly low. We need to do better.

With respect to prevention, there are two strategies that, despite not having strong recommendations and/or the backing of high-quality evidence, are still considered to be effective. One is the use of daily low-dose aspirin (60-80 mg) in women with a history of early-onset preeclampsia and preterm delivery prior to 34 weeks’ of gestation. The other is calcium supplementation for women who have an inadequate daily intake of calcium, although this practice has less relevance in the United States than in the developing world.

The goal of low-dose aspirin is really to reduce the likelihood of severe preeclampsia recurring. Almost half of patients with a history of preeclampsia will not develop the disorder in a subsequent pregnancy (without aspirin therapy), so the reduction in the incidence of preeclampsia with low-dose aspirin is unlikely to be significant. However, as aspirin therapy is a relatively benign and inexpensive intervention, it is worth considering. Indeed, meta-analyses of women in randomized trials of low-dose aspirin for preeclampsia prevention have shown small reductions in the incidence and morbidity of preeclampsia, without any evidence of adverse effects.

[Notably, the U.S. Preventive Services Task Force said in a draft recommendation statement issued in April that it recommends low-dose aspirin use after 12 weeks of pregnancy in women who are at high risk for preeclampsia. (See accompanying story.)]

Over the years a variety of predictive strategies – for predicting early-onset preeclampsia in particular – have been proposed and researched, including various biomarkers, blood tests, and imaging studies. These are all worthwhile endeavors at the research level, but for any screening strategy to be implemented there must be an effective intervention. At the current time, our only effective intervention is delivery based on clinical findings.

On the other end of the spectrum, it is clear today that preeclampsia is associated with later-life cardiovascular disease in women. It is only in the last 5-10 years that research findings have come to the fore and that we have thought about preeclampsia as a marker for increased disease risk, just as we did starting several decades ago with gestational diabetes and the risk of future type 2 diabetes.

ACOG’s task force suggests yearly assessment of blood pressure, lipids, fasting blood glucose, and BMI in women with a medical history of preeclampsia who delivered preterm or who have a history of recurrent preeclampsia. The recommendation is "qualified," with a low quality of evidence, and contains a cautionary footnote stating that "the value and appropriate timing of assessment is not yet established."

Indeed, the next step in research will be to follow patients with preeclampsia longitudinally and determine whether or not interventional strategies can be devised to reduce the cardiovascular risk to baseline or, ideally below baseline, in these patients. Until we have such information, we should still recognize that this group of patients may be at higher risk for cardiovascular disease later in life, and, at the very least, be even more vigilant about adhering to regular health maintenance examinations.

Dr. John T. Repke is professor and chair of obstetrics and gynecology at Pennsylvania State University, Hershey, and has published extensively on hypertension in pregnancy. Dr. Repke said he has no relevant financial disclosures.