Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy: Gestational Hypertension, Preeclampsia, Eclampsia, Chronic Hypertension, and HELLP Syndrome

Chapter 8

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy: Gestational Hypertension, Preeclampsia, Eclampsia, Chronic Hypertension, and HELLP Syndrome James N. Martin, Jr. and Rachael F. Morris Obstetrics, Gynecology & Maternal-Fetal Medicine, The University of Mississippi Medical Center, Jackson, MS, United States

INTRODUCTION Although the earliest references to eclampsia as a complication of human pregnancy appear centuries ago in the Hippocratic literature, these were largely limited to convulsive attacks or fits that occurred at the end of pregnancy usually in association with headache and drowsiness [1]. Until relatively recently, pregnant women were not evaluated medically until labor and delivery occurred. The concept of prenatal care as conceived by Pinard, Ferguson, and Ballantyne was not implemented in the United States until Putnam advanced the concept early in the 20th century in Boston [1]. Recognition that edema with weight increase, elevation of blood pressure, and albuminuria/proteinuria often preceded eclamptic convulsion led to the recognition of preeclampsia (abbreviated as “PE” throughout this review) as an at-risk pregnancy complication which could often be detected before a convulsive, eclamptic fit occurred, thereby potentially impacting management with a lessening of maternal morbidity and mortality. In addition, recognition that other conditions involving renal and vascular disease could present clinically like preeclampsia/eclampsia followed. The concept of preeclampsia/ eclampsia as a syndromic condition rather than a single entity evolved over time. Building upon early monographs on eclampsia by Hinselmann, Stander, and Kosmak that were published between 1924 and 1931, Dieckmann in 1941 compiled the state of the knowledge in this field and called the spectrum of preeclampsia/ eclampsia-like disorders the “Toxemias of Pregnancy” [1]. The syndromic picture of this pregnancy-specific, female-only condition as well as our imperfect understanding of its pathophysiologic component pieces continues to challenge our efforts to classify and manage patients exhibiting features of this fascinating, enigmatic, and often dangerous group of gestational disorders [2]. Because hypertension is a frequent feature of these disorders, often they are considered within the umbrella term “hypertensive disorders of pregnancy” with an emphasis on plural forms of presentation similar to that of Dieckmann’s plural term for what he termed “the toxemias.” Since Dieckmann’s monumental work was published in 1941, there have been substantial advances in our understanding of preeclampsia/eclampsia as well a growing body of evidence to guide therapy. This is incredibly important because this common spectrum of disorders continues to affect 3%–7% of all pregnancies in the United States, accounts for 18% of our maternal deaths, and is a leading cause for preterm birth. Indeed its prevalence in the United States has increased over the past two decades [3] and the rates of severe preeclampsia also increased [4]. For 2012 the cost of preeclampsia to the US health system was estimated at $2.18 billion [5]. As a global health problem, the spectrum of preeclampsia/eclampsia disorders continues to be a leading cause of maternal and perinatal morbidity and mortality [6]. The World Health Organization (WHO) estimates that PE is directly responsible for 70,000 maternal deaths and 500,000 infant deaths annually worldwide [7, 8]. In the United Kingdom, PE is responsible for approximately 15% of all direct maternal deaths; 15% of preterm births; and between 9% and 26% of maternal deaths worldwide are attributed to preeclampsia [9].

Sex Differences in Cardiovascular Physiology and Pathophysiology. https://doi.org/10.1016/B978-0-12-813197-8.00008-7 © 2019 Elsevier Inc. All rights reserved.

121

122

PART

III Preeclampsia and Long-Term Consequences

Beyond the numbing significance of these large numbers of affected mothers, PE is a risk to maternal health beyond pregnancy itself since mothers who exhibit this syndromic disorder during pregnancy demonstrate throughout their subsequent lives an increased risk for cardiovascular disease including stroke [10–13]. In addition, children from PE pregnancies are more likely to develop cardiovascular disease, hypertension, and metabolic syndrome at earlier ages compared to others [14]. Given its national and global health significance as a threat to population health, the American College of Obstetricians and Gynecologists (ACOG) between 2011 and 2013 convened a task force to review critically the world’s obstetric literature on this topic in order to update the state of knowledge as a platform upon which to recommend evidence-based guidelines for patient care in the United States [2]. First published in late 2013, the findings of the Hypertension in Pregnancy ACOG Task Force Report are foundational to what is presented in the chapter to follow, supplemented by subsequently published literature and a comprehensive algorithm developed to illustrate the ACOG guidelines in action. Other national bodies and international professional organizations have been similarly engaged in the effort to optimize management of hypertensive disorders of pregnancy as an important step toward improving global women’s health [15]. In this modern overview of the “toxemias of pregnancy” as preeclampsia-spectrum disorders, we will briefly consider selected aspects such as pathophysiology, risk factors, classification, treatment, postpartum care, and prevention. Selected major concept areas will be emphasized. How this impacts practice at the Mayo Clinic in Rochester will be illustrated by the comprehensive algorithm developed by Drs. Mary Catherine Tolcher, Kyle Traynor, and Carl Rose [16]. Use of this model will enable the reader to understand more graphically how important correct classification of these disorders is since that impacts practice and outcomes. Three chapters to follow will more fully address the topics of cardiovascular and renal risk during and after pregnancy, how the maternal brain responds to pregnancy and preeclampsia-spectrum disorders, and how maternal health is impacted beyond the end of a PE pregnancy.

PATHOGENESIS AND PATHOPHYSIOLOGY A failure of normal development of the maternal-fetal placental interface is considered to be pivotal in the pathogenesis of preeclampsia [17–21]. Given the syndromic nature of the preeclampsia’s or “toxemias,” a number of aberrations from normal human pregnancy development may be operative with varying and variable contributions from more than one origin. The placenta is central to the etiology of preeclampsia since its removal begins the process of recovery after delivery [22]. Residual components and effects of the abnormal placenta and its supporting membranes and tissues presumably remain active for a short time following its removal at the time of delivery in order to explain how postpartum PE/eclampsia can occur. As developed by Roberts and coworkers, two stages of pathophysiology are proposed in which very early in gestation the blood supply to the placenta is reduced by defective implantation or preexisting vascular disease. This in turn initiates a second stage characterized by the release into the maternal circulation of humoral factors causing endothelial dysfunction which can persist for days to a few weeks postpartum [17, 18, 22]. The prevalence of placental villous and vascular histological lesions is four- to sevenfold higher in mothers with PE compared to those with normal pregnancies although less than 50% of PE pregnancies are affected—placental lesions are not specific to the diagnosis of PE [23]. That defective trophoblastic invasion with associated uteroplacental hypoperfusion can lead to preeclampsia is supported by animal and human studies [24]. Incomplete spiral artery remodeling during early gestation may contribute to placental underperfusion, ischemia, and oxidative stress, causing the release of antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sEng) into the maternal circulation which damages the maternal endothelium [25]. However, the phenomenon of abnormal spiral artery remodeling is not specific to preeclampsia since it can be seen in pregnancies complicated by intrauterine fetoplacental growth restriction [24]. Thus the search has continued to seek preeclampsia-specific aberrations in immune mediators and inflammation, the heme oxygenase pathway, hydrogen sulfide pathway, nitric oxide pathway, autoantibodies to angiotensin receptor 1 (AT1-AAs), misfolded proteins, and others as summarized recently [19, 22]. The possible plurality of preeclampsia pathogenesis is illustrated by the proposed separation of PE into two broad categories based on gestational age at presentation, specifically early (<34 weeks’ gestation) versus late (34 weeks’ gestation) onset preeclampsia [22, 26–28]. Early onset PE patients exhibit an abnormally high impedance to blood flow in the uterine arteries which has been associated with failure of the spiral arteries to transform normally resulting in higher levels of sFLt-1, lower platelet growth factor (PlGF), and higher sFlt-1/PlGF ratios than seen in patients with late-onset PE. Maternal mortality rates are 24 times higher when preeclampsia onset occurs prior to 28 weeks’ gestation [29]; the implications for future pregnancy for the early onset group include a fourfold increased risk of stillbirth in a subsequent pregnancy [30] and higher risks of recurrent preeclampsia than the later onset group [31]. The late PE group, comprising the majority of patients with PE, exhibits signs of endothelial dysfunction, defective vasoregulation, generalized

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy Chapter

8

123

vasoconstriction, loss of intravascular volume, and reduced blood flow to various maternal organs. However, the separation into these two categories is artificial since most PE patients demonstrate much overlap by exhibiting features of early and late disease. It is the early group which contributes most to the high maternal and perinatal morbidity and mortality rates attributed to PE. Although it is convenient epidemiologically to consider patients as early or late preeclampsia, there is significant crossover and the potential for confusion if applied to practice. Thus ACOG guidelines and classification systems do not label patients as either early or late PE.

RISK FACTORS FOR PREECLAMPSIA The patient at greatest risk to develop preeclampsia/eclampsia in one of its forms is a mother who has in a prior pregnancy suffered from the condition (1 in 7 risk, relative risk of 8.4) [32]. A metaanalysis of individual patient data from almost 100,000 pregnancies revealed an overall recurrence rate for all hypertensive disorders of pregnancy to be 20.7% [33]. Mothers with underlying chronic vascular disease due to chronic hypertension (1 in 4 risk of developing superimposed preeclampsia), diabetes mellitus (relative risk 3.7), or collagen vascular disease (relative risk 2.5–2.8) are at high risk as well. Others at some risk are mothers who are obese (BMI > 30), have a multiple gestation, are 40 years of age, underwent assisted reproductive therapy to achieve pregnancy, have a history of prior stillbirth or placental abruption, develop trophoblastic disease or fetal aneuploidy, or have chronic renal disease. A first pregnancy (nulliparity) or a first baby with a new partner (primipaternity) completes the list of important risk factors for the development of PE [2, 34, 35]. More than half of all PE cases develop in healthy nulliparous women. North and colleagues found that the ability to predict PE in this patient group using clinical phenotype was modest [36]. Clinical risk factors at 14–16 weeks’ gestation were age, mean arterial blood pressure, body mass index, family history of PE and/or coronary heart disease, maternal birthweight, and vaginal bleeding for at least 5 days [36]. Combining multiple biomarkers and clinical data as reported in the Screening for Pregnancy Endpoint (SCOPE) study revealed similarly modest prediction [37]. Only when placental growth factor and cystatin C were combined with mean arterial pressure, body mass index at 14–16 weeks’ gestation and maternal Doppler scans did the predictive ability for early onset PE (but not term PE) improve to a point where prospective clinical trials using a multivariate, two-stage screening approach could be considered and undertaken. A competing risks model was recently proposed which adds Afro-Caribbean and South Asian origins to the present risk criteria recommended by ACOG [2, 38, 39]. Very exciting PE prediction findings have been reported by Santillan and colleagues at the University of Iowa [40]. Plasma arginine vasopressin (AVP) secretion as assessed by measurement of copeptin, its more stable precursor protein, was found to be significantly elevated as early as the sixth week of gestation and thereafter throughout PE pregnancies compared to control gestations [40, 41]. Moreover, increased levels of copeptin appear to be specific to PE; they are not altered in patients with gestational hypertension (GH), for instance [42]. Thus AVP may have a role in the pathogenesis of PE [43].

PREVENTION An important component of PE management is its prevention when possible. The utility of some form of aspirin for the prevention of PE has been known for almost 40 years [44]. Variable findings have been reported depending upon the trials and datasets utilized for analysis. A systematic review by the US Preventive Services Task Force in 2014 reported that the daily use of low-dose aspirin (LDA) which begins as early as the second trimester of pregnancy resulted in a 15% reduction in preterm birth, a 20% reduction in fetal growth restriction, and a 24% reduction in PE [45]. In response to these findings, ACOG issued a Practice Advisory in July 2016 to expand its prior 2013 guidelines and recommend the initiation of daily LDA (81 mg) after 12 weeks’ gestation in patients with one or more of the following risk factors: history of preeclampsia (especially if accompanied by an adverse outcome), multifetal gestation, chronic hypertension, diabetes types 1 or 2, renal disease, and/or autoimmune disease such as systemic lupus erythematosus and antiphospholipid syndrome [46]. The effectiveness of LDA to effect severe PE reduction in patients with multiple gestations appears to be less than singleton gestation [47]. Smokers versus nonsmokers appear to be less protected [48]. Because of the significant risk for PE that being overweight or obese encumbers pregnancy, it is likely that this will be added as a risk factor in the future [49]. The National Institute for Health and Care Excellence (NICE) in the United Kingdom has similar recommendations, recommending that LDA therapy begin before 12 weeks’ gestation and continue until 36 weeks’ gestation [50]. Different results have been reported for prevention effectiveness based on time of prophylaxis initiation during pregnancy—several investigators have provided data demonstrating better prevention of PE and fetal growth restriction when daily LDA (50–150 mg of aspirin daily) is begun by 16 weeks’ gestation; best results appear to occur when higher

124

PART

III Preeclampsia and Long-Term Consequences

dosages of LDA are used up to 150 mg daily [51–53]. Otherwise Meher and colleagues utilized individual patient data from the Perinatal Antiplatelet Review of International Studies Collaboration to show benefit to daily LDA administration in patients at risk of PE even if begun after 16 weeks’ gestation [54]. Another benefit of early initiation of low-dose aspirin for PE prevention is the beneficial effect it also has to reduce spontaneous preterm birth [55, 56]. The addition of daily antepartum prophylactic enoxaparin to LDA (or enoxaparin alone) for women with prior severe PE <34 weeks’ gestation does not add benefit in the form of fewer placenta-mediated complications [57, 58]. LDA can be continued postpartum for the prevention of cardiovascular disease in women considered to be at high risk [59]. Other agents and interventions under consideration to lower the risk for PE include calcium supplementation (1 g/day) in patient populations with low-calcium diets [60–62], metformin [63], pravastatin [64–67], and diet/lifestyle changes [68, 69].

CLASSIFICATION OF HYPERTENSIVE DISORDERS OF PREGNANCY ACOG classification of the various hypertensive disorders of pregnancy has remained constant since its creation in 1972 with some modifications made in 1990 and 2000 based upon recommendations of the Working Group of the National High Blood Pressure Education Program (NHBPEP Working Group Report) [70]. Although ACOG very recently in 2013 modified some of the components of its classification scheme, the four principal categories created in 1972 were sustained for the newest guidelines. These include (1) preeclampsia-eclampsia, (2) chronic hypertension (of any cause), (3) chronic hypertension with superimposed preeclampsia, and (4) GH. Each of these will be considered in separate sections to follow that will each focus upon diagnosis and management issues pertinent to each specific category of hypertensive pregnancy disorder.

Preeclampsia-Eclampsia [2] Preeclampsia (PE) is a pregnancy-specific syndrome that includes the development of new-onset hypertension in the second half of pregnancy or postpartum. Criteria for hypertension include a systolic blood pressure 140 mmHg OR diastolic blood pressure 90 mmHg measured correctly on two occasions at least 4 hours apart after 20 weeks’ gestation or in the first weeks postpartum in a woman with previously normal blood pressure. If the systolic OR diastolic pressures are severely elevated (160 mmHg OR 90 mmHg, respectively) on repeated measurements usually within 15–30 minutes, the diagnosis is confirmed and timely antihypertensive therapy is indicated (see Fig. 1 algorithm). Proteinuria usually accompanies hypertension in a patient with preeclampsia, but not always. Proteinuria is defined either as a urine protein (mg/dL) to creatinine (mg/dL) ratio 0.3 OR the excretion of 300 mg of protein in a 24-hour urine collection; in the absence of these quantitative measures, a qualitative urine dipstick protein reading of 1 + is suggestive of proteinuria. A metaanalysis of data from 24 trials revealed that a random protein/creatinine (P/C) ratio result of < 0.30 provides useful evidence to rule out the presence of significant proteinuria; a sensitivity of 91.0% and specificity of 86.3% was determined for the >0.30 threshold to reflect significant proteinuria [71, 72]. Cade’s Australian study reported a positive predictive value of 94% and a sensitivity of 95% for predicting proteinuria [73]. In the absence of proteinuria, the diagnosis of preeclampsia can be made in the presence of new-onset hypertension in association with any of the following: thrombocytopenia (platelets <100,000/mL), renal insufficiency (serum creatinine >1.1 mg/dL or doubling of serum creatinine in the absence of other renal disease), impaired liver function (transaminases at twice normal concentrations in IU/L), evidence of pulmonary edema or the presence of cerebral (new onset headache) or visual symptoms/disturbances. For diagnostic purposes, preeclampsia is correctly termed as either with or without severe features; severe features include any one or more of the following: (1) severe systolic or diastolic hypertension ranging above >160/110; (2) moderate to severe thrombocytopenia (platelets <50,000 or <100,000/mL, respectively); (3) impaired liver function reflected either by twice normal concentrations of transaminases or severe persistent right upper quadrant abdominal/epigastric pain; or (4) other evidence of maternal organ compromise including either renal insufficiency, cardiopulmonary compromise/pulmonary edema, and/or central nervous system/visual disturbance reflective of maternal brain compromise. The presence and not the amount of proteinuria is relevant to management—once demonstrated, repeated testing is unnecessary to guide or impact therapy [2].

sFlt-1/PlGF Ratio Recent reports have raised the probability that, following further testing and validation, the automated measurement of the sFlt-1/PlGF ratio from mid-trimester on may soon be used in some venues to identify if a woman with a singleton gestation

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy Chapter

8

125

is developing PE (“diagnosis”) and likely to require delivery within the subsequent four weeks’ span [74–82]. In the PROGNOSIS study, a single sFlt-1/PlGF ratio cutoff of <38 using the Elecsys assay was validated to reliably rule out the presence of PE within 1 week with a negative predictive value of >96% when undertaken between the gestational ages of 20– 34 weeks [80]. On the other hand, very elevated values were increasingly suggestive of PE with the patient in need of corticosteroids and delivery. An easily performed, rapidly available, affordable, and highly reliable test to assure PE diagnosis and reflect its disease severity could be very extremely helpful to clinicians in order to risk assess patients and identify those who would benefit from increased surveillance and/or intervention with magnesium sulfate before, during, and after labor.

Treatment Considerations: Preeclampsia Without Severe Features Comprehensive and specific details for guiding initial and ongoing management of these patients are summarized in the ACOG 2013 guidelines [2]. The Mayo Clinic algorithm as adapted from these guidelines is shown in Fig. 1 for illustration purposes [16]. Gestational age in addition to findings from a thorough assessment of the maternal (rule out criteria to indicate the presence of severe features) and fetal status (absence of fetal growth restriction, oligohydramnios, presence of reactive nonstress testing/normal biophysical profile) principally impact management decisions. Delivery is accomplished once 37 0/7ths weeks of gestational age is achieved or at any time that abruptio placenta is suspected. Delivery is also accomplished 34 0/7th weeks of gestation in circumstances of progressive labor, amnion rupture, severe fetal growth restriction (fetal weight estimated < 5th centile), severe/persistent oligohydramnios (amniotic fluid index (AFI) < 5 cm), and/or signs of fetal compromise such as abnormal fetal umbilical Doppler findings or a biophysical profile of 6/10 or less. Preeclampsia absent evidence of severe features is monitored twice weekly; a course of corticosteroids for fetal lung maturation is administered. Brief (24–48 hours) inpatient observation to document maternal and fetal status and to New-onset hypertension (≥140 mmHg systolic OR ≥90 mmHg diastolic) after 20 weeks gestation (in a previously normotensive patient)

Transfer to Triage for serial blood pressure (BP) measurements every 30 minutes Note: Only blood pressure measurements recorded in Triage are utilized for diagnostic purposes

In first 2 hours of observation:

In first 2 hours of observation:

Only a single BP ≥140 mmHg systolic OR ≥ 90 diastolic AND <160 mmHg systolic AND <110 mmHg diastolic

Two or more BPs ≥140 mmHg systolic OR ≥ 90 mmHg diastolic AND <160 mmHg systolic AND <110 mmHg diastolic

AND

AND

Asymptomatic (*see “Symptoms” box on page 128)

Asymptomatic (*see “Symptoms” box on page 128)

Dismiss to home Outpatient follow-up within 1 week Note: does not meet formal diagnostic criteria for gestational hypertension or preeclampsia at this time

Order HELLP labs: CBC, AST, creatinine, LDH, uric acid, protein/creatinine (P/C) ratio AND Continue observation for full 4 hours

Any BP ≥ 160 mmHg systolic OR ≥ 110 mmHg diastolic OR One or more BP >140 mmHg systolic or 90 mmHg diastolic AND Symptomatic (*see “Symptoms” box on page 128)

Order HELLP labs: CBC, AST, creatinine, LDH, uric acid, protein/creatinine (P/C) ratio AND Admit for observation; repeat BP check in 15 minutes AND Treat BP if ≥160 mmHg systolic OR ≥110 mmHg diastolic on recheck after 15 minutes (*see box on Antihypertensives page 128)

See page 126

See page 127

FIG. 1 Evaluation of new-onset hypertension in pregnancy based on the algorithm developed by Dr. Carl Rose and colleagues at the Mayo Clinic. Continued

126

PART

III Preeclampsia and Long-Term Consequences

administer corticosteroids can be followed by inpatient or outpatient surveillance per clinician judgment. Reduced activity and a regular diet without salt restriction are advised. Transition from absent to present severe features, decreased fetal movement, amnion rupture, or labor requires physician notification and timely evaluation. Antihypertensive therapy is not indicated in the absence of severe hypertension. Universal use of magnesium sulfate is not recommended in patients with preeclampsia without severe features.

Treatment Considerations: Preeclampsia With Severe Features The development of severe features pushes pregnancy management to a higher level of intervention and possible delivery. Once 34 weeks of gestation is achieved in the presence of any one or more severe features, abruptio placenta, disseminated intravascular coagulation, or fetal demise, discontinuation of pregnancy is indicated. Prior to 34 weeks of gestation, the development of severe features requires inpatient care at a facility with adequate maternal and neonatal intensive care resources. A course of corticosteroids to enhance fetal lung maturation is quickly initiated; recent data supports the use of corticosteroids in pregnancy up to 37 weeks of gestation [83]. Delivery is not deferred in mothers with severe disease/features developing prior to fetal viability (around 23 0/7ths weeks of gestation in most centers). After the first 48-hour period of maternal evaluation, maternal stabilization, fetal assessment, and corticosteroid administration, the possibility of “expectant management” with delivery deferred can be considered in the absence of persisting or returning severe features, labor, amnion rupture, or evidence of severe fetal compromise such as severe fetal growth restriction (<5th centile), severe oligohydramnios (AFI < 5 cm), or very abnormal fetal Doppler velocimetry findings. Cesarean delivery is usually required with progressively preterm pregnancy and minimal prior cervical change. The development of persistent

128)

128)

FIG.1, cont’d Continued

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy Chapter

8

127

severe systolic OR diastolic hypertension requires emergent intervention with antihypertensives as recommended (Fig. 1) [84, 85]. Universal use of magnesium sulfate is recommended in patients with preeclampsia exhibiting severe features. Eclampsia is defined as the presence of new-onset convulsions and/or unexplained coma in a pregnant or postpartum women usually in the setting of preeclampsia and in the absence of other known or subsequently diagnosed neurological conditions [86]. It is sometimes described or subclassified as very preterm or preterm or term eclampsia, antepartum or postpartum eclampsia, late postpartum eclampsia (48 hours to 23 days postpartum), complicated eclampsia if coma is persistent in association with cerebral hemorrhage or other encephalopathy, and associated with or without concurrent HELLP syndrome. The MRI demonstration of findings consistent with posterior reversible encephalopathy syndrome (PRES) is considered diagnostic of eclampsia when a diagnosis is uncertain and other causation of pregnancy or postpartum-related seizure is sought [87].

Treatment Considerations Patients at risk of eclamptic convulsion (those with severe forms of preeclampsia) or following eclamptic convulsion require magnesium sulfate administration as detailed in the 2013 ACOG guidelines [2, 84]. It is usually given intravenously as a bolus followed by a continuous infusion through delivery (it is not stopped for cesarean delivery, for instance) and for 24 hours postpartum or 24 hours following convulsion. Elaborate guidelines for its use have been developed by labor and delivery units as well as states using safety bundles that are based on consensus facilitated by ACOG and the National Partnership for Maternal Safety [84]. The urgent initial and continuing treatment of severe systolic OR diastolic hypertension is imperative for all patients with preeclampsia/eclampsia and/or a hypertensive disorder of pregnancy in order

126)

FIG.1, cont’d Continued

128

PART

III Preeclampsia and Long-Term Consequences

to lessen the risk of stroke [88–91]. In the undelivered patient with eclampsia, a decision to initiate delivery efforts is appropriate as soon as the patient and fetus are assessed, stabilized, magnesium sulfate is started, and a course of corticosteroids considered especially if the gestational age is 36 weeks. The latter intervention increases greatly in importance as gestational age decreases below 34 weeks. Postponement of vaginal or cesarean delivery for 24–36 hours is desirable for fetal benefit if close maternal and fetal monitoring reveal no evidence of deteriorating status [92]. Eclampsia presenting first postpartum is usually treated with 24 hours of infused magnesium sulfate, control of severe hypertension, and the utilization of neuroimaging if the patient develops complications, localizing neurologic findings, fails to show signs of improvement or if the diagnosis is in question [2]. Patients with HELLP Syndrome represent a special subgroup within the PE/eclampsia classification system [93]. The acronym “HELLP” was suggested by Weinstein in 1982 for patients with preeclampsia/eclampsia as evidenced by Hemolysis, Elevated Liver enzymes/transaminases, and Low Platelets. It is a laboratory diagnosis supported by evidence of microangiopathic hemolytic anemia (abnormal peripheral blood smear with schistocytes, burr cells, echinocytes OR unconjugated bilirubin 1.2 mg/dL OR haptoglobin  25 mg/dL), elevated liver enzymes reflecting hepatic dysfunction (twice upper limits of normal levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and/or lactate dehydrogenase (LDH)), and moderate to severe thrombocytopenia (<100,000/mL platelets) [2]. Patients that exhibit all three criteria to make the diagnosis of HELLP syndrome have Complete HELLP syndrome: class 1 disease has severe thrombocytopenia (platelets  50,000/mL); and class 2 disease has moderate thrombocytopenia (platelets >50,000 but 100,000/mL. Patients with mild thrombocytopenia (platelets >100,000 but 150,000/mL) and/or only 2 of the 3 laboratory components of complete HELLP syndrome are considered to have Partial HELLP Syndrome. The subgroup of

FIG. 1, cont’d

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy Chapter

8

129

HELLP syndrome within the larger preeclampsia/eclampsia group is clinically important because they have higher maternal and perinatal morbidity and mortality than patients which experience any of the other hypertensive disorders of pregnancy [94, 95].

Treatment Considerations With rare exceptions, the diagnosis of HELLP syndrome compels the provider to begin efforts to end pregnancy regardless of gestational age. Regardless of gestational age or whether the mother is undelivered or delivered at the time a diagnosis of HELLP syndrome is made, a three-pronged treatment approach is recommended which includes magnesium sulfate therapy, prevention/treatment of severe systolic/diastolic hypertension, and a potent glucocorticoid such as intravenous dexamethasone [94, 96]. The protocol developed and implemented at the University of Mississippi Medical Center since the mid-1990s is presented in Table 1. Mothers and fetuses/newborns benefit when possible from management conducted at a Level 3 or 4 hospital with intensive care capacity and expertise for the benefit of mothers and babies.

Chronic Hypertension Chronic hypertension in pregnancy is defined as hypertension documented to be present before pregnancy. When prepregnancy blood pressure readings are not available, hypertension detected prior to 14–20 weeks of gestation is assumed to represent probable chronic hypertension. Early second trimester new-onset hypertension (14–20 weeks’ gestation) may represent GH or early PE. Hypertensive readings are considered to be mild-moderate (systolic 140–159 mmHg OR diastolic 90–109 mmHg) or severe (systolic >160 mmHg OR diastolic >110 mmHg), usually due to primary/essential hypertension in 90% of patients. The others may have hypertension secondary to underlying renal or endocrine disorders [2].

Treatment Considerations The patient with chronic hypertension in pregnancy undergoes a thorough baseline evaluation in order to assess her renal function/amount of proteinuria, serum uric acid and electrolytes, detect gestational diabetes, establish gestational age, assess maternal cardiovascular function (echocardiography if present for >4 years or severe), initiate LDA therapy, counsel about increased risk for preeclampsia and placental abruption, stop smoking and initiate antihypertensive therapy according to ACOG if treatment criteria are met (systolic 160 mmHg, diastolic 105 mmHg). The senior author’s practice preference is to start therapy when systolics remain in the 150s OR if diastolic pressures broach the 100 threshold. Treatment of mild to moderate hypertension has been shown to decrease the occurrence of severe hypertension [97, 98]. Medications to consider include nifedipine, methyldopa, or labetalol (Fig. 1). Pressures should not be lowered below 120 mmHg systolic

TABLE 1 Mississippi Protocol for HELLP Syndrome Indications   

All patients with class 1 HELLP syndrome All patients with class 2 HELLP syndrome Patients with class 3 HELLP syndrome/incomplete HELLP syndrome who are complicated by any of the following: eclampsia, severe epigastric pain, evidence of end-organ injury (brain, kidney, liver, heart, lungs), and/or placental abruption-disseminated intravascular coagulation (DIC)

Implementation 1. Magnesium sulfate: IV loading dose and continuous infusion during antepartum, intrapartum and for at least the first 24 hours postpartum. 2. Antihypertensive therapy: Labetalol, nifedipine, hydralazine and/or nifedipine administered as per ACOG guidelines to minimize or prevent sustained severe systolic hypertension (160 mmHg) or sustained severe diastolic hypertension (110 mmHg). 3. Intravenous dexamethasone: 10 mg IV initiated as soon as possible, given every 12 hours until delivery is accomplished and recovery postpartum is assured by normalization of HELLP laboratory indices at which time dosage is decreased to 5 mg IV every 12 hours for two doses and then stopped. 4. Management in appropriate level of hospital maternity care intensive care or hospital labor/delivery/postpartum setting: Meticulous medical care, OBGYN-MFM professional expertise, and 24/7 medical staff and laboratory, blood banking and operating room facilities are available.

130

PART

III Preeclampsia and Long-Term Consequences

or 80 mmHg diastolic. If there are findings suggestive of secondary hypertension such as resistant hypertension, hypokalemia (K <3.0 mEq/L), elevated serum creatinine >1.1 mg/dL, a strong family history of renal disease, or if pheochromocytoma or renovascular hypertension is suspected, consider referral for workup by an internist with special expertise in hypertensive patients. Home monitored blood pressure is advisable once it is verified that the patient can accurately measure her blood pressure with the equipment she is using at home [99]. Because the risk of fetal growth restriction is high in patients with chronic hypertension, ultrasonography to screen for this possibility should be undertaken and, if detected, fetoplacental assessment should include umbilical artery Doppler velocimetry. Antenatal fetal testing with nonstress tests and/or biophysical profiles is initiated between 28 and 32 weeks’ gestation in any chronic hypertensive pregnant patient who develops a maternal and/or fetal complication. Delivery before 38–39 weeks of gestation is not usually indicated in the absence of maternal or fetal complications.

Chronic Hypertension With Superimposed Preeclampsia The combination of preeclampsia and chronic hypertension during pregnancy constitutes superimposed preeclampsia. Pending the availability of biomarkers to accurately identify these patients, the following types of evidence can be used to support the diagnosis of superimposed preeclampsia for management purposes in a patient with chronic hypertension: l l

l

l l

New-onset proteinuria develops >20 weeks of gestation. In a patient with chronic hypertension and proteinuria detected early in gestation, there is a sudden, substantial, and sustained increase in proteinuria after 20 weeks of gestation. There is a sudden worsening of previously well-controlled hypertension with escalation of antihypertensive drug therapy. The patient develops criteria for HELLP syndrome. The patient develops any of the severe feature(s) of preeclampsia including severe systolic OR diastolic hypertension and/or signs/symptoms of liver, renal, cardiopulmonary, or brain compromise.

Treatment Considerations These patients are managed in the hospital setting in order to confirm the diagnosis, evaluate maternal-fetal status, and to monitor for disease progression (Fig. 1 Algorithm). Little data exists to support outpatient management of these mothers. A course of antenatal corticosteroids is indicated if pregnancy is preterm; if severe features are present, magnesium sulfate for seizure prophylaxis is indicated during workup and the intrapartum-postpartum period. Severe systolic and/or diastolic hypertension is aggressively controlled. Indications and timing of delivery is based on disease severity, gestational age, rate of disease progression, and the results of frequent maternal-fetal tests of well-being or compromise. Timing of delivery depends upon gestational age and whether evidence of severe features/HELLP syndrome surfaces. In the absence of severe features/HELLP syndrome and with reassuring fetal testing, mothers 34–37 weeks’ gestational age are candidates for expectant management until 37 weeks is achieved or evidence of maternal/fetal compromise is detected. In the absence of severe features/HELLP syndrome and with reassuring fetal testing, mothers <34 weeks can be managed in one of several ways: (1) delivery following maternal stabilization and a course of corticosteroids; or (2) expectant management until 34 weeks as long as there is no evidence of eclampsia, HELLP syndrome, abruptio placenta, nonreassuring fetal testing, or any severe features are detected. The continuation of pregnancy in a patient beyond 34 weeks in the presence of severe features is not justified beyond the time necessary to administer a course of corticosteroids, stabilize and then deliver the mother.

Gestational Hypertension Gestational hypertension (GH) is defined as new-onset hypertension without proteinuria which is detected initially after 20 weeks of gestation. Most patients with GH have mild GH; the development of severe systolic OR diastolic hypertension merits the diagnosis of severe GH which has important implications for patient management [100]. If proteinuria develops in a patient with GH, her diagnosis is changed to preeclampsia. Also, if GH fails to resolve postpartum with normalization of blood pressure off antihypertensive medications, the diagnosis is changed to chronic hypertension. GH may represent latent chronic hypertension that has not been previously expressed.

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy Chapter

8

131

Treatment Considerations Once GH is first detected and maternal-fetal evaluation reveals no evidence of labor, amnion rupture, preeclampsia, HELLP syndrome, or fetal jeopardy (no evidence of fetal growth restriction or abnormal nonstress testing results), prenatal care occurs weekly inclusive of maternal testing for new-onset proteinuria, severe hypertension, and abnormal fetal surveillance testing using nonstress testings (NSTs) or biophysical profiles (BPPs) generally. Delivery is undertaken at 37–39 weeks of gestation or at any time maternal-fetal condition worsens, amnion rupture occurs or labor begins. The development of GH after 37 weeks warrants careful consideration of delivery. Magnesium sulfate is not mandated around the time of delivery if GH remains mild. If GH becomes severe at any time antepartum, intrapartum or postpartum, management changes to what would be undertaken as if the patient had preeclampsia with the severe feature of severe hypertension. The reader’s attention is directed to the Mayo Clinic algorithm for perspective.

LABOR AND DELIVERY Issues regarding the treatment considerations for each of the categories of hypertensive disorders of pregnancy have been presented including the timing of delivery, use of magnesium sulfate, and control of severe hypertension. A systematic review of international clinical practice guidelines, including those of ACOG, found that mode of delivery should be based on the clinical circumstances and usual obstetric indications if there was no evidence of fetal compromise [15]. Cervical ripening should be undertaken if a vaginal delivery is planned and the cervix is unfavorable. Active management of the third stage of labor is recommended with oxytocin.

POSTPARTUM While maternal changes with a preeclampsia-spectrum disorder pregnancy require months to develop, labor and delivery with removal of the placenta and its supporting tissues brings about a relatively abrupt change amidst disordered maternal physiology. Peak postpartum blood pressures are expected to occur between 3 and 6 days following delivery [101]. Eclampsia has become more of a postpartum problem with 32%–44% of all cases diagnosed following delivery. Because preeclampsia-related hypertension requires 2–3 weeks to resolve spontaneously, postpartum monitoring for complications is initially very intensive but can be required in some cases for several weeks [102, 103]. The major immediate postpartum categories of concern relate to hypertension, cardiac function, hemodynamics, blood-brain barrier permeability changes, vascular function related to fluid balance and colloid osmotic pressure, renal function, and the greatly increased risk of thromboembolism in these pregnancies particularly if cardiopulmonary compromise is present [104]. Hospitalization postpartum often requires 48–72 hours following delivery to manage labor and delivery sequelae and control of hypertension. To minimize adverse maternal effects, the physician and health care team must remain closely attentive to the following: 1. Severe hypertension. Prevent severe systolic and/or diastolic hypertension to reduce the risk of maternal stroke or brain injury. Blood pressure is easily measured—it serves to reflect the amount of vasospasm, increased vascular resistance and vascular injury caused by circulating antiangiogenic factors [105]. The greatest threat to maternal well-being is the degree and duration of severe hypertension that can occur in preeclampsia-spectrum disorders, a threat that can persist for several weeks into the puerperium. Severe systolic and/or diastolic hypertension therefore is considered an emergency requiring rapid detection, provider notification, and treatment [84, 85]. To lessen the likelihood of postpartum severe hypertension, antihypertensive therapy is recommended for patients at the thresholds of 150 mmHg systolic and 100 mmHg diastolic [2, 50]. Enhanced early postpartum surveillance of hypertensive postpartum patients is recommended. 2. Magnesium sulfate is recommended during labor, delivery, and the first 24 hours postpartum for any obstetric patient with a severe preeclampsia-spectrum condition. In addition to helping prevent eclamptic convulsion or its recurrence, peripartum magnesium sulfate administration functions to neuroprotect the mother with less blood-brain barrier permeability, cerebral vasogenic edema, and neuroinflammation while enhancing vascular relaxation and vasodilation [104]. 3. Close cardiopulmonary monitoring of the mother around delivery (oxygen saturation by pulse oximetry) should be undertaken since they are likely to have depressed cardiac function, high thoracic fluid content, low colloid osmotic pressure, and increased susceptibility to pulmonary edema. Thus conservative fluid administration is advised while monitoring urine output for evidence of acute kidney injury that can develop secondary to prerenal or renal factors. Diuretics (furosemide) have a place in the postpartum management of patients with severe preeclampsia-spectrum

132

PART

III Preeclampsia and Long-Term Consequences

disorders in order to promote natriuresis, decrease cardiac output and stroke volume, off-load fluid, reduce venous tone, and lessen the need for antihypertensive therapy [106–109]. 4. Corticosteroids as maternal therapy are particularly efficacious in mothers with HELLP syndrome. These potent glucocorticoids (usually dexamethasone given intravenously) positively impact the maternal microcirculation and negate the actions of antiangiogenic factors, improving the function of capillaries, venules, and arterioles. As reported in two recent systematic reviews and metaanalyses, these drugs dramatically lessen maternal brain and liver morbidity, result in fewer ICU admissions, less need for blood transfusion, and facilitate a more rapid normalization of laboratory abnormalities reflective of the HELLP disease state [110, 111]. 5. Prevent Thromboembolism. Attention to increased risk for peripartum venous thromboembolism with universal thromboprophylaxis using pneumatic compression devices is recommended. Particularly at-risk severe preeclampsiaspectrum disorder patients who are obese (BMI > 30 kg/m2), undergo cesarean delivery or develop other morbidities may benefit from more aggressive therapy using low molecular weight heparin. The national consensus bundle on this issue is comprehensive and useful [112].

PERINATAL CONSIDERATIONS Adverse perinatal outcomes associated with severe preeclampsia-spectrum disorders increase with disease severity, particularly in relation to abnormality of laboratory abnormalities and clinical signs [113]. A decision to deliver early due to severity of maternal disease is heavily impactful on perinatal outcome. In a recent study of more than four million individual patient datasets, preeclampsia/eclampsia and related hypertensive disorders of pregnancy were the second leading cause for preterm birth [114]. PE is associated with a 35% increase in stillbirth [115], a fourfold increase in low birthweight delivery and a twofold increase in neonatal mortality [116, 117]. Prevention of preeclampsia therefore holds a major role in the prevention of prematurity.

DIFFERENTIAL DIAGNOSIS Not every patient that fits diagnostic criteria for one of the severe preeclampsia-spectrum disorders is accurately diagnosed. Other disorders can occur concurrently with preeclampsia/eclampsia. Many other conditions are also associated with hypertension, organ dysfunction, and findings suggestive of PE or HELLP syndrome which can render the correct diagnosis extremely challenging. Some of the more likely candidates for confusion include thrombotic thrombocytopenic purpura, acute fatty liver of pregnancy, systemic lupus erythematosus, and hemolytic uremic syndrome. The reader is referred to some of the many excellent reviews which review the complexities surrounding the differential diagnosis of severe preeclampsia [9, 118–120]. The use of biomarkers highly suggestive of PE may be shown to be very helpful in this regard when the diagnosis is obfuscated [121].

LONG-TERM CARDIOVASCULAR CONSEQUENCES Preeclampsia/eclampsia is a risk to long-term maternal health for which the patient must be counseled following delivery [10–13]. The likelihood of developing future hypertension is three to four times increased. Women with early onset preeclampsia are at increased risk to develop early onset cardiovascular disease including coronary artery disease and stroke [122–124] particularly in the presence of underlying metabolic disorders. Previously preeclamptic patients are also at risk to develop renal failure later in life [125, 126]. Patients need to be informed of these risks and encouraged to optimize their diet with healthy eating, exercise, control of lipids and blood sugar with weight reduction to achieve ideal body weight. More frequent health checks are needed to monitor these patients for the early detection of hypertension so that it can be adequately and aggressively treated.

REFERENCES [1] Dieckmann WJ. The toxemias of pregnancy. The C. V. Mosby Company: St. Louis, MO; 1941. [2] American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologists’ Task Force on Hypertension in Pregnancy, Obstet Gynecol 2013;122:1122–31. full report available at:https://www.acog.org/ Resources-and-publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy. Accessed 25 July 2017. [3] Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in the rates of preeclampsia, eclampsia and gestational hypertension, United States 19872004. Am J Hypertens 2008;21:521–6.

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy Chapter

8

133

[4] Ananth CV, Keyes KM, Wapner RJ. Preeclampsia rates in the United States 1980-2010: age-period-cohort analysis. BMJ 2013;347:f6564. [5] Stevens W, Shih T, Incerti D, Ton TGN, Lee HC, Peneva D, Macones GA, Sibai BM, Jena AB. Short-term costs of preeclampsia to the United States health care system. AJOG 2017;217(3):237–248.e16. [6] Duley L. The global impact of preeclampsia and eclampsia. Semin Perinatol 2009;33(3):130–7. [7] Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PFA. WHO analysis of maternal death: a systematic review. Lancet 2006;367 (9516):1066–74. [8] McClure JH, Cooper GM, Clutton-Brock TH, Centre for Maternal and Child Enquiries. Saving mothers’ lives: reviewing maternal deaths to make motherhood safer: 2006-8 a review. Br J Anaesth 2011;107(2):127–32. [9] Steegers EA, von Dadelszen P, Duvekot JJ, Pijnenborg R. Preeclampsia. Lancet 2010;376(9741):631–44. [10] Wenger NK. Recognizing pregnancy-associated cardiovascular risk factors. Am J Cardiol 2014;113:406–9. [11] Amaral LM, Cunningham Jr. MW, Cornelius D, LaMarca B. Preeclampsia: long-term consequences for vascular health. Vasc Health Risk Manag 2015;11:403–15. [12] Alsnes IV, Janszky I, Forman MR, Vatten LJ, Okland I. A population-based study of associations between preeclampsia and later cardiovascular risk factors. Am J Obstet Gynecol 2014;211: 657.e1–7. [13] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in late life: systematic review and meta-analysis. BMJ 2007;335:974. [14] Wu CS, Nohr EA, Bech BH, Vestergaard M, Catov JM, Olsen J. Health of children born to mothers who had preeclampsia: a population-based cohort study. Am J Obstet Gynecol 2009;201(3) 269.e1–10. [15] Gillon TER, Pels A, von Dadelszen P, MacDonell K, Magee LA. Hypertensive disorders of pregnancy: a systematic review of international practice guidelines. PLoS ONE 2014;9(12):e113715. [16] Algorithm prepared by Drs. Mary Catherine Tolcher, Kyle Traynor and Carl Rose of the Mayo Clinic, Rochester, Minnesota 2016. [17] Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol 1989;161:1200–4. [18] Roberts JM, Redman CW. Preeclampsia: more than pregnancy-induced hypertension. Lancet 1993;341(8858):1447–51. [19] LaMarca B. The role of immune activation in contributing to vascular dysfunction and the pathophysiology of hypertension during preeclampsia. Minerva Ginecol 2010;62:105–20. [20] Palei AC, Spradley FT, Warrington JP, George EM, Granger JP. Pathophysiology of hypertension in preeclampsia: a lesson in integrative physiology. Acta Physiol 2013;208:224–33. [21] Sircar M, Thadhani R, Karumanchi SA. Pathogenesis of preeclampsia. Curr Opin Nephrol Hypertens 2015;24:131–8. [22] Phipps E, Prasanna D, Brima W, Jim B. Preeclampsia: updates in pathogenesis, definitions and guidelines. Clin J Am Soc Nephrol 2016;11:1102–13. [23] Falco ML, Sivanathan J, Laoreti A, Thilaganathan B, Khalil A. Placental histopathology associated with preeclampsia: a systematic review and meta-analysis. Ultrasound Obstet Gynecol 2017;50(3):295–301. [24] Amaral LM, Wallace K, Owens MY, LaMarca B. Pathophysiology and current clinical management of preeclampsia. Curr Hypertens Rep 2017;19:61. [25] Jim B, Karumanchi SA. Preeclampsia: pathogenesis, prevention and long-term complications. Semin Nephrol 2017;37:386–97. [26] von Dadelszen P, Magee LA, Roberts JM. Subclassification of preeclampsia. Hypertens Pregnancy 2003;22:143–8. [27] Staff AC, Benton SJ, von Dadelszen P, et al. Redefining preeclampsia using placenta-derived biomarkers. Hypertension 2013;61(5):932–42. [28] Nelson DB, Ziadie MS, McIntire DD, Rogers BB, Leveno KJ. Placental pathology suggesting that preeclampsia is more than one disease. Am J Obstet Gynecol 2014;210: 66.e1–7. [29] MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol 2001;97:533–8. [30] Mbah AK, Alio AP, Marty PJ, et al. Preeclampsia in the first pregnancy and subsequent risk of stillbirth in black and white gravidas. Eur J Obstet Gynecol Reprod Biol 2010;149:165–9. [31] Mostello D, Kallogjeri D, Tungsiripat R, Leet T. Recurrence of preeclampsia: effects of gestational age at delivery of the first pregnancy, body mass index, paternity, and interval between births. Am J Obstet Gynecol 2008;199: 55.e1–7. [32] Bartsch E, Medcalf KE, Park AL, Ray JG. Clinical risk factors for preeclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies. BMJ 2016;353:i1753. [33] Van Oostwaard ME, Langenveld J, Schuit E, Papatsonis DN, Brown MA, Byaruhanga RN, et al. Recurrence of hypertensive disorders of pregnancy: an individual patient data metaanalysis. Am J Obstet Gynecol 2015;212(5) 624.e1–17. [34] Al-Rubaie Z, Askie LM, Ray JG, Hudson HM, Lord SJ. The performance of risk prediction models for preeclampsia using routinely collected maternal characteristics and comparison with models that include specialized tests and with clinical guideline decision rules: a systematic review. BJOG 2016;123(9):1441–52. [35] Wright D, Syngelaki A, Akolekar R, Poon LC, Nicolaides KH. Competing risks model in screening for preeclampsia by maternal characteristics and medical history. Am J Obstet Gynecol 2015;213: 62.e1–10. [36] North RA, McCowan LME, Dekker GA, Poston L, et al. Clinical risk prediction for preeclampsia in nulliparous women: development of model in international prospective cohort. BMJ 2011;342:d1875. [37] Kenny LC, Black MA, Poston L, Taylor R, et al. Early pregnancy prediction of preeclampsia in nulliparous women, combining clinical risk and biomarkers. Hypertension 2014;64:644–52.

134

PART

III Preeclampsia and Long-Term Consequences

[38] Wright D, Gallo DM, Gil Pugliese S, Casanova C, Nicolaides KH. Contingent screening for preterm preeclampsia. Ultrasound Obstet Gynecol 2016;47(5):554–9. [39] Wright D, Dragan I, Syngelaki A, Akolekar R, Nicolaides KH. Proposed clinical management of pregnancies after combined screening for preeclampsia at 30-34 weeks’ gestation. Ultrasound Obstet Gynecol 2017;49(2):194–200. [40] Santillan MK, Santillan DA, Scroggins SM, Min JY, Sandgren JA, Pearson NA, Leslie KK, Zamba GK, Gibson-Corley KN, Grobe JL. Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model. Hypertension 2014;64(4):852–9. [41] Sandgren JA, Scroggins SM, Santillan DA, Devor EJ, Gibson-Corley KN, Pierce GL, Sigmund CD, Santillan MK, Grobe JL. Vasopressin: the missing link for preeclampsia? Am J Phys Regul Integr Comp Phys 2015;309:R1062–4. [42] Yeung EH, Liu A, Mills JL, Zhang C, Mannisto T, Lu Z, Tsai MY, Mendola P. Increased levels of copeptin before clinical diagnosis of preeclampsia. Hypertension 2014;64:1362–7. [43] Karumanchi SA, Granger JP. Preeclampsia and pregnancy-related hypertensive disorders. Hypertension 2016;67(2):238–42. [44] Crandon AJ, Isherwood DM. Effect of aspirin on incidence of preeclampsia. Lancet 1979;1(8130):1356. [45] Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U. S. Preventive Services Task Force. Ann Intern Med 2014;160:695–703. [46] ACOG. Practice advisory on low-dose aspirin and prevention of preeclampsia: updated recommendations, Available from:www.acog.org/AboutACOG/News-Room/Practice-Advisories; 2016. [47] Bergeron TS, Roberge S, Carpentier C, Sibai B, McCaw-Binns A, Bujold E. Prevention of preeclampsia with aspirin in multiple gestations: a systematic review and meta-analysis. Am J Perinatol 2016;33(6):605–10. [48] Abramovici A, Jauk V, Wetta L, Cantu J, Edwards R, Biggio J, Tita A. Lose-dose aspirin, smoking status and the risk of spontaneous preterm birth. Am J Perinatol 2015;32(5):445–50. [49] Pare E, Parry S, McElrath TF, Pucci D, Newton A, Lim K-H. Clinical risk factors for preeclampsia in the 21st century. Obstet Gynecol 2014;124:763–70. [50] National Institute for Health and Care Excellence (NICE). Hypertension in pregnancy: the management of hypertensive disorders during pregnancy, In: NICE CG 107. Manchester: UK National Institute for Health and Clinical Excellence; 2010. [51] Roberge S, Odibo AO, Bujold E. Aspirin for the prevention of preeclampsia and intrauterine growth restriction. Clin Lab Med 2016;36(2):319–29. [52] Roberge S, Nicholaides K, Demers S, Hyett J, Chaillet N, Bujold E. The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis. Am J Obstet Gynecol 2017;216(2). 110–120.e1–6. [53] Moore GS, Allshouse AA, Post AL, Galan HL, Heyborne KD. Early initiation of low-dose aspirin for reduction in preeclampsia risk in high-risk women: a secondary analysis of the MFMU High-Risk Aspirin Study. J Perinatol 2015;35(5):328–31. [54] Meher S, Duley L, Hunter K, Askie L. Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia: an individual participant data meta-analysis. Am J Obstet Gynecol 2017;216(2). 121–128.e1–2. [55] Bujold E, Roberge S, Nicolaides KH. Low dose aspirin for prevention of adverse outcomes related to abnormal placentation. Prenat Diagn 2014;34 (7):642–8. [56] Allshouse AA, Jessel RH, Heyborne KD. The impact of low-dose aspirin on preterm birth: secondary analysis of a randomized controlled trial. J Perinatol 2016;36(6):427–31. [57] Groom KM, McCowan LM, Mackay LK, Lee AC, Said JM, Kane SC, et al. for the Enoxaparin for Prevention of Preeclampsia and Intrauterine Growth Restriction Trial Investigator Group. Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial. Am J Obstet Gynecol 2017;216(3):296.e1–296.e14. [58] Haddad B, Winer N, Chitrit Y, Houfflin-DeBarge V, Chauleur C, Bages K, et al. for the Heparin-Preeclampsia (HEPEPE) Trial Investigators. Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications: a randomized clinical trial. Obstet Gynecol 2016;128(5):1053–63. [59] Mora S, Ames JM, Manson JE. Low-dose aspirin in the primary prevention of cardiovascular disease: shared decision making in clinical practice. JAMA 2016;316(7):709–10. [60] Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L, Torloni MR. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2014;6:CD001059. [61] Tang R, Tang IC, Henry A, Welsh A. Limited evidence for calcium supplementation in preeclampsia prevention: a meta-analysis and systematic review. Hypertens Pregnancy 2015;34(2):181–203. [62] Meertens LJE, Scheepers HCJ, Willemse JPMM, Spaanderman MEA, Smits LJM. Should women be advised to use calcium supplements during pregnancy? A decision analysis. Matern Child Nutr 2018;14(1) https://doi.org/10.1111/mcn.12479. [63] Romero R, Erez O, Huttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, Pacora P, Yoon BH, Grossman LI. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol 2017;217(3):282–302. [64] Costantine MM, Cleary K. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 2013;121(2 Part 1):349–53. [65] Brownfoot FC, Tong S, Hannan NJ, Binder NK, Walker SP, Cannon P, Hastie R, Onda K, Kaitu’u-Lino TJ. Effects of pravastatin on human placenta, endothelium and women with severe preeclampsia. Hypertension 2015;66(3):687–97. [66] Costantine MM, Cleary K, Hebert MF, Ahmed MS, Brown LM, Ren Z, et al. for NICHD Obstetric-Fetal Pharmacology Research Units Network. Safety and pharmacokinetics of pravastatin used for the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled trial. Am J Obstet Gynecol 2016;214(6). 720.e1–17.

Preeclampsia-Spectrum Hypertensive Disorders of Pregnancy Chapter

8

135

[67] Katsi V, Georgountzos G, Kallistratos MS, Zerdes I, Makris T, Manolis AJ, Nihoyannopoulos P, Tousoulis D. The role of statins in prevention of preeclampsia: a promise for the future? Front Pharmacol 2017;8. [68] Brantsaeter AL, Myhre R, Haugen M, Myking S, Sengpiel V, Magnus P, Jacobsson B, Meltzer HM. Intake of probiotic food and risk of preeclampsia in primiparous women: the Norwegian Mother and Child Cohort Study. Am J Epidemiol 2011;174(7):807–15. [69] Mol BW, Roberts CT, Thangaratinam S, Magee LA, de Groot CJ, Hofmeyr GJ. Preeclampsia. Lancet 2016;387(10022):999–1011. [70] National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 1990;163(5 Part 1):1691–712. [71] Papanna R, Mann LK, Kouides RW, Glantz JC. Protein/creatinine ratio in preeclampsia: a systematic review. Obstet Gynecol 2008;112 (1):135–44. [72] Sanchez-Ramos L, Gillen G, Zamora J, Stenyakina A, Kaunitz AM. The protein-to-creatinine ratio for the prediction of significant proteinuria in patients at risk for preeclampsia: a meta-analysis. Ann Clin Lab Sci 2013;43(2):211–20. [73] Cade TJ, Gilbert SA, Polyakov A, Hotchin A. The accuracy of spot urinary protein-to-creatinine ratio in confirming proteinuria in preeclampsia. Aust N Z J Obstet Gynaecol 2012;52:179–82. [74] Garcia-Tizon LS, Tayyar A, Poon LC, Wright D, Nicolaides KH. Competing risks model in screening for preeclampsia by biophysical and biochemical markers at 30-33 weeks’ gestation. Fetal Diagn Ther 2014;36:9–17. [75] Hirashima C, Ohkuchi A, Takahashi K, Suzuki H, Matsubara S, Suzuki M. A novel three-step approach for predicting imminent onset of preeclampsia within 4 weeks after blood sampling at 19-31 weeks’ gestation. Hypertens Res 2014;37:519–25. [76] Lai J, Garcia-Tizon LS, Peeva G, Poon LC, Wright D, Nicolaides KH. Competing risks model in screening for preeclampsia by serum placental growth factor and soluble fms-like tyrosine kinase-1 at 30-33 weeks’ gestation. Fetal Diagn Ther 2014;35:240–8. [77] Rana S, Karumanchi SA, Lindheimer MD. Angiogenic factors in diagnosis, management and research in preeclampsia. Hypertension 2014;63:198–202. [78] Stepan H, Herraiz I, Schlembach D, Verlohren S, Brennecke S, Chantraine F, et al. Implementation of the sFlt-1/PlGF ratio for prediction and diagnosis of preeclampsia in singleton pregnancy: implications for clinical practice. Ultrasound Obstet Gynecol 2015;45:241–6. [79] Van Helden J, Weiskirchen R. Analytic evaluation of the novel soluble fms-like tyrosine kinase 1 and placental growth factor assays for the diagnosis of preeclampsia. Clin Biochem 2015;48(16–17):1113–9. [80] Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstrom M, et al. The sFlt-1/PlGF ratio in women with suspected preeclampsia. N Engl J Med 2016;374:1785–6. [81] Verlohren S, Perschel FH, Thilaganathan B, Droge LA, Henrich W, Busjahn A, Khalil A. Angiogenic markers and cardiovascular indices in the prediction of hypertensive disorders of pregnancy. Hypertension 2017;69(6):1192–7. [82] Droge LA, Holler A, Ehrlich L, Verlohren S, Henrich W, Perschel FH. Diagnosis of preeclampsia and fetal growth restriction with the sFlt-1/PlGF ratio: diagnostic accuracy of the automated immunoassay Kryptor. Pregnancy Hypertens: Int J Women’s Cardiovasc Health 2017;8:31–6. [83] Saccone G, Berghella V. Antenatal corticosteroids for maturity of term or near term fetuses: systematic review and meta-analysis of randomized clinical trials. BMJ 2016;355:i5044. [84] Bernstein PS, Martin Jr. JN, Barton JR, Shields LE, Druzin ML, Scavone BM, Frost J, Morton CH, Ruhl C, Slager J, Tsigaz EZ, Jaffer S, Menard MK. National partnership for maternal safety: consensus bundle on severe hypertension during pregnancy and the postpartum period. Anesth Analg 2017;125(2):540–7. [85] Committee on Obstetric Practice. ACOG Committee Opinion No. 692: Emergent therapy for acute-onset severe hypertension during pregnancy and the postpartum period. Obstet Gynecol 2017;129(4):e90–5. [86] Martin Jr. JN, Owens MY. Eclampsia: pathogenesis, diagnosis and management. In: Romero Arauz JF, Tena-Alwavez G, Jimenez Solis GA, editors. Preeclampsia-hypertensive disorders of pregnancy. Mexico: McGraw Hill; 2013. p. 153–87. [87] Brewer J, Owens MY, Wallace K, Reeves AA, Morris RF, Khan M, Lamarca B, Martin Jr. JN. Posterior reversible encephalopathy syndrome in 46 of 47 patients with eclampsia. Am J Obstet Gynecol 2013;208(6). 468.e1–6. [88] Martin Jr. JN, Thigpen BD, Moore RC, Rose CH, Cushman J, May W. Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 2005;105:146–254. [89] Martin Jr. JN. Severe systolic hypertension and the search for safer motherhood. Semin Perinatol 2016;40(2):119–23. [90] ElFarra J, Bean C, Martin Jr. JN. Management of hypertensive crisis for the obstetrician-gynecologist. Obstet Gynecol Clin N Am 2016;43 (4):623–37. [91] Soma-Pillay P, Suleman FE, Makin JD, Pattinson RC. Cerebral white matter lesions after preeclampsia. Pregnancy Hypertens: Int J Women’s Cardiovasc Health 2017;8:15–20. [92] Tam Tam KB, Keiser SD, Sims S, Brewer J, Owens MY, Martin Jr. JN. Antepartum eclampsia <34 weeks’ case series: advisable to postpone delivery to administer corticosteroids for fetal pulmonary benefit? J Perinatol 2011;31:161–5. [93] Martin Jr. JN. Milestones in the quest for best management of patients with HELLP syndrome (microangiopathic hemolytic anemia, hepatic dysfunction, thrombocytopenia). Int J Gynaecol Obstet 2013;121(3):202–7. [94] Martin Jr. JN, editor. The 2015 compendium for HELLP syndrome: From bench to bedside. New York: Nova Biomedical; 2015, ISBN 978-163483-221-2. [95] Martin Jr JN, Brewer JM, Wallace K, Sunesara I, Canizaro A, Blake PG, Lamarca B, Owens MY. Hellp syndrome and composite major maternal morbidity: importance of Mississippi classification system. J Matern Fetal Neonatal Med 2013;26(12):1201–6.

136

PART

III Preeclampsia and Long-Term Consequences

[96] Martin Jr JN, Owens MY, Keiser SD, Parrish MR, Tam Tam KB, Brewer JM, Cushman JL, May WL. Standardized Mississippi Protocol treatment of 190 patients with HELLP syndrome: slowing disease progression and preventing new major maternal morbidity. Hypertens Pregnancy 2012;31 (1):79–90. [97] Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, et al. Less-Tight versus tight control of hypertension in pregnancy. N Engl J Med 2015;372(5):407–17. [98] Webster LM, Conti-Ramsden F, Seed PT, Webb AJ, Nelson-Piercy C, Chappell LC. Impact of antihypertensive treatment on maternal and perinatal outcomes in pregnancy complicated by chronic hypertension: a systematic review and meta-analysis. J Am Heart Assoc 2017;6(5). pii: 005526. [99] Tremonti C, Beddoe J, Brown MA. Reliability of home blood pressure monitoring devices in pregnancy. Pregnancy Hypertens: Int J Women’s Cardiovasc Health 2017;8:9–14. [100] Buchbinder A, Sibai BM, Caritis S, Macpherson C, Hauth J, Lindheimer MD, Klebanoff M, et al. for MFM Unit Network. Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol 2002;186(1):66–71. [101] Walters BN, Walters T. Hypertension in the puerperium. Lancet 1987;2(8554):330. [102] Podymow T, August P. Postpartum course of gestational hypertension and preeclampsia. Hypertens Pregnancy 2010;29:294–300. [103] Bramham K, Nelson-Piercy C, Brown MJ, Chappell LC. Postpartum management of hypertension. BMJ 2013;346:f894. [104] Collier C, Druzin ML, Martin Jr. JN. Postpartum management of severe preeclampsia spectrum disorder: pathophysiology guiding practice. (personal communication). [105] Goel A, Maski MR, Bajracharya S, Wenger JB, Zhang D, Salahuddin S, et al. Epidemiology and mechanisms of De Novo and persistent hypertension in the postpartum period. Circulation 2015;132(18):1726–33. [106] Ascarelli MH, Johnson V, McCreary H, Cushman J, May WL, Martin Jr. JN. Postpartum preeclampsia management with furosemide: a randomized clinical trial. Obstet Gynecol 2005;105(1):29–33. [107] Veena P, Perivela L, Raghavan SS. Furosemide in postpartum management of severe preeclampsia: a randomized clinical trial. Hypertens Pregnancy 2017;36(1):84–9. [108] Goodlin RC. Venous reactivity and pregnancy abnormalities. Acta Obstet Gynecol Scand 1986;65(4):345–8. [109] Tamas P, Hantosi E, Farkas B, Ifi Z, Betlehem J, Bodis J. Preliminary study of the effects of furosemide on blood pressure during late-onset preeclampsia in patients with high cardiac output. Int J Gynaecol Obstet 2017;136(1):87–90. [110] Mao M, Chen C. Corticosteroid therapy for management of hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome: a metaanalysis. Med Sci Monit 2015;21:3777–83. [111] Yang L, Ren C, Mao M, Cui S. Prognostic factors of the efficacy of high dose corticosteroid therapy in hemolysis, elevated liver enzymes, and low platelet count syndrome during pregnancy: a meta-analysis. Medicine 2016;95(13):e3203. [112] D’Alton ME, Friedman AM, Smiley RM, Montgomery DM, Paidas MJ, D’Oria R, Frost JL, Hameed AB, Karsnitz D, Levy BS, Clark SL. National partnership for maternal safety: consensus bundle on venous thromboembolism. Obstet Gynecol 2016;128(4):688–98. [113] Cantu J, Clifton RG, Roberts JM, Leveno KJ, Myatt L, Reddy UM, et al. Laboratory abnormalities in pregnancy-associated hypertension: frequency and association with pregnancy outcomes. Obstet Gynecol 2014;124(5):933–40. [114] Ferrero DM, Larson J, Jacobsson B, Di Renzo GC, Norman JE, Martin Jr. JN, et al. Cross-country individual participant analysis of 4.1 million singleton births in 5 countries with very high human development index confirms known associations but provides no biologic explanation for 2/3 of all preterm births. PLoS One 2016;11(9):e0162506. [115] Basso O, Rasmussen S, Weinberg CR. Trends in fetal and infant survival following preeclampsia. JAMA 2006;296:1357–62. [116] Xiong X, Demianczuk NN, Buekens P, Saunders LD. Association of preeclampsia with high birth weight for age. Am J Obstet Gynecol 2000;183:148–55. [117] Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of preeclampsia and the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol 2011;25:391–403. [118] Sibai BM. Imitators of severe preeclampsia. Semin Perinatol 2009;33(3):196–205. [119] Morris RF, Martin Jr JN. When HELLP might be something else: the differential diagnosis of HELLP syndrome. In: Martin Jr. JN, editor. The 2015 compendium for HELLP syndrome—from bench to bedside. New York: Nova Biomedical; 2015. p. 173–82 [Chapter 14]. [120] Pourrat O, Coudroy R, Pierre F. Differentiation between severe HELLP syndrome and thrombotic microangiopathy, thrombotic thrombocytopenic purpura and other imitators. Eur J Obstet Gynecol Reprod Biol 2015;189:68–72. [121] Verdonk K, Visser W, Russcher H, Jan Danser AH, Steegers EAP, van den Meiracker AH. Differential diagnosis of preeclampsia: remember the soluble fms-like tyrosine kinase 1/placental growth factor ratio. Hypertension 2012;60:884–90. [122] Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in later life: a systematic review and meta-analysis. BMJ 2007;335:974. [123] Behrens I, Basit S, Lykke JA, Ranthe MF, Wohlfahrt J, Bundgaard H, et al. Association between hypertensive disorders of pregnancy and later risk of cardiomyopathy. JAMA 2016;315:1026–33. [124] Chen CW, Jaffe IZ, Karumanchi SA. Preeclampsia and cardiovascular disease. Cardiovasc Res 2014;101:579–86. [125] Paauw ND, Luijken K, Franx A, Verhaar MC, Lely AT. Long-term renal and cardiovascular risk after preeclampsia: towards screening and prevention. Clin Sci (Lond) 2016;130(4):239–46. [126] Schokker SA, van Oostwaard MF, Melman EM, van Kessel JP, Baharoglu MI, Roos YB, et al. Cerebrovascular, cardiovascular and renal hypertensive disease after hypertensive disorders of pregnancy. Pregnancy Hypertens 2015;5(4):287–93.