Hypertension in Pregnancy

Chapter 26

Hypertension in Pregnancy Rosemary Townsend*,† and Asma Khalil*,† *Department of Fetal Medicine, St George’s University of London, London, United Kingdom, † Molecular & Clinical Sciences Research Institute, St. George’s University of London, London, United Kingdom

Common Clinical Problems l Predicting which women will be affected by hypertension in pregnancy is complicated by the variable phenotypes of disease and differing underlying pathologies. l Most women affected by hypertension in pregnancy are asymptomatic at presentation, so detection must rely on the routine antenatal screening of all women. l Preeclampsia may present with atypical features, and other conditions may present with features typical of preeclampsia. l It is easy to say that the “cure” for hypertensive disorders of pregnancy is delivery; however, it is challenging to determine the optimal balance of the competing interests of mother and infant in planning the timing of delivery. l Women affected by hypertensive disorders of pregnancy are at increased risk of hypertension, diabetes, and cardiovascular and cerebrovascular disease in later life. The postpartum period represents an underutilized opportunity for health education and risk reduction.

26.1 INTRODUCTION 26.1.1

Prevalence and Clinical Significance of Hypertension in Pregnancy

Hypertensive complications of pregnancy are among the top three causes of maternal mortality worldwide, accounting for over 14% of all maternal deaths.1 Over 99% of maternal deaths are avoidable, including many of those attributable to hypertensive disorders of pregnancy (HDPs). Unlike the other two leading causes of maternal death (hemorrhage and sepsis), hospitalization for hypertension in pregnancy is rising.2 Although in the United Kingdom, the risk of a mother dying of hypertensive morbidities in pregnancy is now only 1 in 1 million,3 thanks in large part to increasingly active management of hypertension in pregnancy, HDPs are still associated with significant maternal and perinatal morbidity. In particular, the incidence of iatrogenic preterm delivery continues to rise, and many of these medically indicated deliveries are by cesarean section. HDPs are the indication for between 15% of all premature deliveries and 43% of medically indicated preterm birth,4 making them the cause of significant neonatal and childhood morbidity associated with prematurity and maternal morbidity associated with both hypertension and surgical delivery. HDPs include gestational hypertension (GH), preeclampsia, and preexisting hypertension or white coat hypertension syndrome. Preeclampsia is responsible for the most severe instances of maternal and fetal morbidity, including eclampsia, pulmonary edema, HELLP (hemolysis, elevated liver enzymes and low platelets) syndrome, and renal injury. GH and chronic hypertension are more common than preeclampsia, and although considered milder manifestations of the disease, they are still associated with fetal growth restriction, iatrogenic preterm delivery, maternal cardiovascular and hypertensive morbidity, and maternal and perinatal mortality. Hypertension in pregnancy also has consequences beyond the time of delivery for both mother and offspring. Women who have suffered from hypertension in pregnancy have a 13%–53% risk of recurrence in future pregnancies,5 and also have an increased risk of hypertension and cardiovascular disease in later life. The risk of recurrence and later morbidity is related to the disease severity in the index pregnancy.6–9 Children of mothers with HDP are themselves at increased risk of metabolic syndrome, cardiovascular disease, and preeclampsia in adult life.10

Maternal-Fetal and Neonatal Endocrinology. https://doi.org/10.1016/B978-0-12-814823-5.00026-X Copyright © 2020 Elsevier Inc. All rights reserved.

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Preeclampsia is commonly described as arising from failure of the normal maternal adaptation to pregnancy. There is incomplete trophoblast invasion of the maternal spiral arteries, resulting in placental malperfusion. This leads to the release of circulating factors that cause endothelial injury, leading to the maternal features of the disease.11–13 It has lately been recognized that maternal factors, including prepregnancy cardiovascular function, endothelial health, and impaired lipid and glucose metabolism, play an important role in maldevelopment of the uteroplacental circulation. Moreover, it is very likely that there is more than one pathological pathway that can lead to the syndrome of preeclampsia. Because the pathophysiology of hypertension in pregnancy involves multiple pathways, it is clear that both in screening for and treatment of HDPs, no single intervention is likely to be appropriate for all cases.

26.2

PHYSIOLOGICAL CHANGES IN NORMAL PREGNANCY

Profound hemodynamic and hormonal changes occur in normal pregnancy in order to support the development of the uteroplacental circulation and growth of the fetus. In general, pregnancy is marked by increased endothelial activity and cardiac work. The earliest changes can be observed from the luteal phase of the menstrual cycle, when the corpus luteum starts to generate pregnancy-supporting hormones, including relaxin, progesterone, and estrogen. Relaxin plays a key role in inducing renovascular adaptation to pregnancy, as well as reducing myogenic tone in the uterine vessels in order to support the developing pregnancy.14 It acts to upregulate placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) activity. As the placenta develops, placental hormone production increases, and from 12 weeks onward, this is the principal influence on hemodynamic modulation in pregnancy (Fig. 26.1). Pregnancies conceived using in vitro fertilization techniques in anovulatory women do not benefit from the hormonal output of the corpus luteum, and despite support from exogenous progesterone, they do not demonstrate the systemic fallure of vascular resistance that is typical of normal pregnancy.15 They are also at increased risk of pregnancy complications, including HDP. Estrogen is involved in the increase in uterine blood flow via estrogen receptor (ER)-dependent vasodilation of the uterine arteries in early pregnancy, and it also has systemic effects on stroke volume, heart rate, and systemic vascular resistance.16 Estrogen levels are associated with the expression of endothelial nitric oxide synthase (eNOS), a powerful vasodilator, particularly in uterine vessels, where ER expression is most dense.17 Flow-mediated dilation (FMD), a marker of endothelial function, steadily increases throughout pregnancy until around 32 weeks’ gestation.18 The levels of prostacyclin, another endothelial dependent relaxation factor, are increased in pregnancy and associated with vascular smooth muscle relaxation, angiogenesis, and inhibition of platelet aggregation.19 On its own, progesterone does not increase uterine vasodilation via eNOS activation; however, it may potentiate the effects of estrogen. Progesterone does modulate contractility by increasing alpha-1 adrenergic receptor density in the uterine arterial smooth muscle and sensitizes the uterine vessels to the effect of catecholamines17 (Fig. 26.2).

Utero-placental blood flow

FIG. 26.1 The influence of hormones from the corpus luteum and the placenta on uteroplacental blood flow throughout pregnancy (Adapted from Conrad KP, Baker VL. Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies. Am J Physiol Regul Integr Comp Physiol 2013;304(2):R69–72.)

Placental hormones

Corpus luteal hormones

First trimester

Second and third trimesters

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FIG. 26.2 Mechanisms of vasodilation in normal pregnancy.

Maternal cortisol levels double over the course of pregnancy and contribute to maintaining placental perfusion by affecting both systemic and uterine pathways. Maternal adrenal secretion of cortisol and aldosterone increases systemic plasma volume, and cortisol acts locally on the uterine vascular endothelium and smooth muscle. Although in the nonpregnant state, cortisol is associated with the inhibition of eNOS expression and a vasoconstrictive effect on the vascular smooth muscle, this effect is attenuated in pregnancy and posited to be the result of antiglucocorticoid effects of progesterone, which is elevated in pregnancy.17 Compared with the nonpregnant state, marked changes in cardiac output (CO) and total peripheral resistance can be seen from very early in gestation.20 In normal pregnancy, CO increases rapidly, and there is generalized peripheral vasodilation, resulting in a decrease in total peripheral resistance (TPR).21 Increases in heart rate and stroke volume combine to increase CO from as early as 5 weeks after the last menstrual period, reaching up to 45% above the nonpregnant level by 24 weeks’ gestation. Approximately 70% of the increase in CO occurs by the 16th week of gestation, which is well before the marked increase in uterine blood flow. In multiple pregnancy, there is a further increment in CO of around 15%.22 The increase in CO is linked to an increase in preload, a decrease in afterload, increased compliance of conduit vessels, ventricular remodeling and activation of the renin-angiotensin-aldosterone system. During an uncomplicated pregnancy, a significant reduction of TPR occurs simultaneously with the increase in CO and a decrease in mean arterial pressure (MAP).23,24 This reduced TPR represents an important adaptive response that maintains MAP within the normal range despite the greatly increased CO. This occurs in spite of an upregulation of renin and an increase in circulating angiotensin II in pregnancy.25 This is because pregnancy is typified by a blunting of the pressor response to angiotensin II and other vasopressors26,27 that facilitate this drop in systemic vascular resistance. Clinically, pregnant women present with a drop in blood pressure during the first trimester, reaching a nadir at 20–22 weeks, after which the increasing plasma volume of pregnancy is associated with steadily increasing MAP until delivery. Arterial compliance is increased in pregnancy in concert with the generalized fall in TPR. There is a measurable decrease in arterial stiffness from preconception to midpregnancy, as observed in the pulse wave velocity (PWV) and augmentation index (AIx).18 Uterine blood flow increases 40 times over the course of pregnancy, initially via vasodilation and later via angiogenesis and remodeling of the uterine vasculature. Despite the overall fall in systemic vascular resistance, uterine perfusion pressure (UPP) and placental perfusion are maintained throughout pregnancy by the increase in uterine blood flow. The key vessels limiting uteroplacental flow have been thought to be the maternal spiral arteries, shed every month with the endometrium during menstruation. Recent evidence suggests that the spiral arteries are actually canalized and allow flow to the intervillous space as early as 7 weeks’ gestation, indicating that the key regulators of placental blood flow in the first trimester are actually the proximal radial arteries, which undergo remodeling at a later time than the spiral arteries.28 In normal pregnancy, the balance of angiogenic factors is altered to favor placental angiogenesis and uterine vascular remodeling. The levels of the antiangiogenic soluble fms-like tyrosine kinase 1 (sFlt-1) are reduced, while the angiogenic PlGF and VEGF are increased, promoting angiogenesis and vascular remodeling in the uteroplacental circulatory tree, as well as having vasodilatory effects.19

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Normal pregnancy is also a state of relative insulin resistance and higher-than-normal lipidemia, allowing placental transfer of sufficient nutrition for the developing fetus. This is mediated by human placental lactogen, progesterone, cortisol, and estradiol.29

26.2.1

Altered Pregnancy Physiology in HDP

The physiological changes seen in normal pregnancy are altered or absent in pregnancies affected by HDP, with a number of pathways combining to cause the widespread endothelial dysfunction that typifies preeclampsia (Fig. 26.3). Women affected by HDP demonstrate abnormalities of cardiac function on echocardiography that suggest an inability to meet the massive cardiac and metabolic demands of pregnancy. By term, 40% of pregnancies complicated by preeclampsia demonstrate global diastolic dysfunction compared to 14% of controls.30 The normal inhibition of the pressor response fails in HDP, and preeclamptic women have an increased sensitivity to angiotensin II, particularly in the adrenal cortex and vascular tree.26 Angiotensin II acts via the regulator of G protein-signaling 5 (RGS5), and expression is reduced in women affected by HDP.31 The normal decrease in TPR and MAP does not occur in pregnancies complicated by hypertension, and in those affected by preeclampsia with fetal growth restriction, the rise in CO is significantly less than in normal pregnancies.32 In pregnancies that will ultimately develop HDP, arterial stiffening and impaired endothelial function can be observed from the first trimester. The degree of impairment correlates with disease severity, with the most severe changes observed in early-onset preeclampsia and milder changes in GH.33,34 The angiogenic balance is disturbed in preeclampsia. Levels of sFlt-1, which binds and reduces functional levels of PlGF and VEGF, are increased. Further, sFlt-1 may be released from ischemic placental tissue and also can be induced by platelet-monocyte aggregates.35 The increase in sFlt-1 observed in HDP is preceded by a fall in PlGF and measurable changes in maternal hemodynamic parameters, suggesting that the release of sFlt-1 by hypoxic placental tissue is not the proximate cause of these changes.19 The overall effect is to inhibit eNOS and potentiate vascular sensitivity to vasoconstrictors, thereby leading to hypertension.27 Although hyperinsulinemia and insulin resistance are features of normal pregnancy, they are exaggerated in HDP. This exaggeration may be greater in GH than in preeclampsia,29 but it is associated with significant endothelial dysfunction in both conditions via a number of mechanisms. First, hyperinsulinemia increases sodium reabsorption and thereby sympathetic stimulation, which reduces renal perfusion and impairs endothelial function. Second, increased leptin provides increased oxidized lipids that alter the prostacyclin balance and increase thromboxane levels, further impairing endothelial function. Finally, the lipid balance is altered in preeclampsia, with increased levels of triglycerides and low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio.35 This abnormal lipid profile contributes to inflammation and oxidative stress in HDP. Preeclampsia is associated with hyperandrogenism, and increased testosterone with reduced sex hormone-binding globulin (SHBG); this situation is also found in polycystic ovarian syndrome (PCOS), which is a predictor of later FIG. 26.3 Mechanisms of endothelial dysfunction in preeclamptic pregnancy.

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development of preeclampsia. Androgens stimulate the pressor response by increasing angiotensin II receptor sensitivity36 and further reduce prostacyclin synthesis; therefore, they can be implicated in the vicious cycle of endothelial dysfunction that occurs in preeclampsia.

26.3 SCREENING FOR AND PREVENTION OF PREECLAMPSIA The finding that early treatment with low-dose aspirin from the first trimester reduces the risk of preeclampsia37,38 made accurate first-trimester screening tests for preeclampsia a clinical priority. Other plausible potential preventative interventions, including folic acid and vitamin D, have not proved effective in clinical trials.39,40 Calcium has been shown to reduce the risk of preeclampsia, but primarily in women with low calcium intake, and it is recommended in low-resource settings from 20 weeks of pregnancy.41 Further study of other agents is warranted; for example, statins have a proven role in the prevention of cardiovascular disease in the nonpregnant population and could potentially affect preeclampsia by modulating inflammation, increasing eNOS activity, inhibiting platelet aggregation, and reducing the LDL/HDL ratio. Pravastatin, the statin least likely to cross the placenta, has been shown to be safe in pregnancy and effective in reducing cholesterol,42 but further studies are required to establish its efficacy in preventing preeclampsia. Metformin could have a protective effect by improving endothelial function, reducing insulin resistance and sFlt-1 activity,43 but further research is needed. Peroxisome proliferator-activated receptors (PPARs) regulate RGS5 expression, and in mouse models, the use of PPAR-g agonists have been shown to abolish GH, but clinical trials are still needed.31 Because the benefit of aspirin is greatest when initiated prior to 16 weeks’ gestation, the optimal screening test would predict preeclampsia with high sensitivity using data available before then. Because targeted antenatal monitoring could optimize the detection and management of preeclampsia and maximize efficiency in the use of health-care resources, screening models applicable in the second trimester are also of interest to researchers, particularly given that models developed later in pregnancy generally have better predictive performance. Currently, clinical assessment of the risk of preeclampsia is based mainly on maternal history44 with limited predictive accuracy.45–47 Unfortunately, the positive predictive value of this model is low and would lead to nearly half of all women being screen positive.46 Numerous studies have evaluated the accuracy of various tests, including clinical characteristics, biomarkers, and ultrasound markers, individually or in combination, for predicting early-, late-, and any-onset preeclampsia in the first, second, and third trimesters.48 No single test investigated has both sensitivity and specificity above 90%, which would seem to be necessary to make any screening test more cost-effective than a ‘treat-all’ policy in clinical practice. Body mass index (BMI) > 34 kg/m2 had a specificity of 93% but a sensitivity of only 18%. Alpha feto protein (AFP) and bilateral uterine artery Doppler (UAD) notching are reported to have a specificity of >90%, but with low sensitivities of 9% and 48%, respectively.49 Individual markers shown to correlate most strongly with the risk of preeclampsia are UAD indexes and angiogenic biomarkers.50–52 A stepwise (sequential) approach, whereby women are identified as high risk in the first trimester and then reevaluated at the time of the midtrimester anomaly scan is promising in terms of picking up most cases of early-onset preeclampsia.53 The ASPRE trial evaluated the use of a screening model incorporating maternal factors, MAP, uterine artery pulsatility index, pregnancy-associated plasma protein A (PAPP-A), and PlGF applied before 14 weeks of gestaton, then randomized screen-positive women to treatment with 150 mg of aspirin or placebo. There was a significant reduction in preterm (<37 weeks) preeclampsia, but not in term preeclampsia or other secondary maternal and fetal outcomes.37 The model has not yet been externally validated, and additional factors may be necessary to predict the more common condition of term preeclampsia. Nevertheless, this approach of stepwise screening is likely to form the basis of screening for and prevention of preeclampsia in the future.

26.4 ASSESSMENT OF THE HYPERTENSIVE PREGNANT WOMAN 26.4.1 Diagnostic Criteria for Hypertension in Pregnancy and Considerations Specific to the Measurement of Blood Pressure in Pregnancy While hypertension is the common feature of all HDPs, criteria for measuring and defining hypertension can vary. Hypertension in pregnancy is generally agreed to be a blood pressure >140 mm Hg (systolic) or 90 mm Hg (diastolic), measured at least twice and separated by a period of rest.44 Blood pressure should be measured with the woman at rest and with her arm held at the level of the heart with a device validated for use in pregnancy.54 The measurement of diastolic blood pressure is taken at the fifth Korotkoff (K5) sound because it is more reproducible and better reflects intraarterial pressure.55 Historically, some preferred to use the fifth Korotkoff sound, on the basis that using the fifth might miss some episodes of

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hypertension and thereby worsen pregnancy outcomes, but a randomized controlled trial (RCT) published in 1998 demonstrated equivalent outcomes,56 and the use of K5 is recommended by the National Institute for Health and Care Excellence (NICE).44 Manual devices have the advantages of having a low cost and requiring the operator to palpate the pulse herself or himself. Mercury sphygmomanometers have been the gold standard for measurement, but they are being phased out of clinical use because of concerns about the safety of mercury. Aneroid devices are popular, cheap, and portable but easily become inaccurate and require regular calibration. Up to one-third of devices in regular use are inadequately calibrated.57 Automated devices using oscillometric technology are commonly used in most clinical areas and address systematic errors associated with auscultatory measurements, but most have not been validated for use in pregnancy, and many are also insufficiently calibrated. In preeclampsia in particular, the increased arterial stiffness and marked extravascular edema can compromise the measurement of the intraarterial waveform, leading to the underestimation of blood pressure and the possibility of missed diagnosis.55 Devices for use in pregnancy, therefore, must be specifically validated in a cohort including patients affected by preeclampsia. Severe hypertension is defined as a systolic blood pressure of between 160 and 170 mm Hg; the precise cutoff varies among existing guidelines. It is important to understand that because of the increased vascular compliance of pregnancy, neurological complications of hypertension, including cerebral edema and hemorrhage, may be observed at lower levels of hypertension than in the nonpregnant population.58 Systolic hypertension of >180 mm Hg in a pregnant patient is a medical emergency that requires safe and rapid control.

26.4.2

Diagnostic Criteria for Proteinuria in Pregnancy

Although proteinuria is not necessary to make a diagnosis of preeclampsia, it is a key feature that can be used to discriminate preeclampsia from other forms of pregnancy hypertension. While the basement membrane remains relatively intact in preeclampsia, significant proteinuria usually occurs in conjunction with glomerular endotheliosis. Milder endotheliosis is observed in GH.59 Multiple tests for proteinuria are available, but none are ideal. The most accurate is a 24-h urine collection and quantification of protein excretion, but this is cumbersome, time consuming, and susceptible to user error.60 Simultaneous measurement of creatinine excretion can act as quality control and assist in the interpretation of results, but in practical terms, the delay between suspecting the diagnosis of preeclampsia and obtaining the laboratory results necessarily limits its utility in point-of-care clinical management decisions. It is still the best practice to obtain a 24-h specimen, but other tests may be more appropriate for determining immediate clinical management. A cutoff of 300 mg/day (the 95th percentile for normal women) is accepted as representing significant proteinuria where 24-h urine collection is used and there is no preexisting renal pathology or intercurrent urinary tract infection. Available tests with a more rapid turnaround time include the urinary dipstick assessment and a spot protein-creatinine ratio (PCR). A dipstick reading >2 + is likely to represent significant proteinuria, but it should always be followed with an additional test, and clinicians must be aware that the negative predictive value of a normal dipstick test is only 0.6, meaning that relying on dipstick testing alone would lead to significant underdiagnosis of preeclampsia.60 A spot PCR can provide a result within 1 h, and although it is less accurate for quantification of proteinuria than a 24-h collection, it does perform significantly better than dipstick testing to rule out proteinuria.61 The degree of proteinuria was once incorporated into the classification of severity of preeclampsia, but it is clear that once proteinuria has been established, the degree does not correlate with pregnancy outcomes.62 When extreme proteinuria in the severe nephrotic range is detected, consideration should be given to the possibility of an alternative or coexisting diagnosis, because preeclampsia is not typically associated with such extreme proteinuria. For this reason, there is little benefit in the more accurate quantification of the 24-h urine collection when the PCR is significantly abnormal, and it is not normally useful to perform serial measurements of proteinuria once it has clearly been established. The degree of proteinuria should not be considered when making the decision to deliver or start antihypertensive therapy or magnesium sulfate. Hypertension is necessary for a diagnosis of preeclampsia, but a small number of women will initially present with proteinuria without hypertension. These cases should be fully investigated for alternative causes of proteinuria and followed up closely with blood pressure monitoring because up to 51% of these women may go on to develop hypertension and preeclampsia later in pregnancy.63

26.4.3

Fetal Assessment

Fetal growth restriction often coexists in hypertensive women and is now considered a diagnostic criterion for preeclampsia.64 All women presenting with hypertension in pregnancy after 20 weeks should have ultrasound assessment

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of fetal growth, liquor volume, and umbilical and middle cerebral-artery Dopplers. So long as pregnancy continues, scans should be repeated at fortnightly intervals.5 Women known to have preexisting hypertension are at increased risk of fetal growth restriction and should routinely be offered serial growth scans throughout pregnancy. Mothers should be informed of the importance of self-monitoring of fetal movement and where to present if there are subjectively reduced fetal movements. There is no specific evidence related to kick charts or equivalent monitoring tools in preeclampsia, and as these women are high risk for placental insufficiency, it would be reasonable to perform ultrasound assessment at the first presentation with subjectively reduced fetal movement. Where fetal growth restriction has been identified, computerized cardiotocographic (CTG) monitoring and serial assessment of the fetal ductus venosus (DV) Doppler can be used to assess the fetal condition.65

26.4.4

Differential Diagnosis of Preeclampsia

Preeclampsia will always be the most common cause of hypertension and organ dysfunction in pregnancy, but many microangiopathic disorders can present with similar features. Failure to consider a broad differential diagnosis can lead to unnecessary iatrogenic preterm delivery or missed opportunities to treat deteriorating conditions. Delivery at 28 weeks while in a condition not caused by pregnancy will inevitably risk serious morbidity to the offspring and may well be associated with worsening of the maternal condition by the additional insult of a surgical delivery and the hormonal, fluid, and coagulation shifts that occur at the time of delivery. Table 26.1 describes some of the conditions that may present with some of the typical features of preeclampsia in pregnancy. For some specific conditions, additional laboratory testing can help to clarify the diagnosis. For example, acute fatty liver of pregnancy (AFLP) is commonly associated with hypoglycemia, hyperammonemia, and jaundice; systemic lupus erythematosus (SLE) will feature antidouble-stranded DNA or antinuclear antibodies.66 Serum complement levels can indicate the degree of disease activity in SLE and assist in discriminating between a flare of SLE and new preeclampsia. Hemolysis and anemia are common in thrombocytopenic thrombotic purpura (TTP) and hemolytic uremic syndrome (HUS), but von Willebrand factor (vWf) multimers are more commonly elevated than in either AFLP or HELLP. The underlying pathology of TTP relates to a reduced activity of von Willebrand cleaving protease (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also called ADAMTS13, which is detectable via testing; however, this test may not be available in standard hospital laboratories.

26.4.5

Novel Diagnostic Tests—PLGF/sFlt-1

New tests are clearly necessary to address the diagnostic uncertainty that can arise when a woman presents with suspected preeclampsia. Markers investigated include PLGF, sFlt-1, podocyturia, PAPP-A, placental protein 13 (PP-13), homocysteine, asymmetric dimethylarginine (ADMA), uric acid, and leptin. Preeclampsia is associated with a disrupted angiogenic balance, and alterations in these circulating factors can be identified several weeks prior to the clinical manifestation of the disease. PlGF is reduced as early as 11–13 weeks’ gestation in women destined to develop preeclampsia,67 while sFlt-1 is elevated up to 5 weeks prior to the onset of clinical signs. PlGF alone and the sFlt-1/PlGF ratio have been evaluated as diagnostic tests and are particularly sensitive for early-onset disease.68 Neither seems adequate as a diagnostic test by itself, but they perform well as tests to rule out preeclampsia, especially in the context of other diseases causing hypertension. Where the test gives a low probability of development of preeclampsia within the next 2–4 weeks antenatal monitoring frequency may safely be reduced, improving the mother’s experience of care and focusing the use of resources on the highest risk group of patients.69,70 Observational studies have shown that the use of PlGF in the management of preeclampsia might be associated with earlier delivery, but also with fewer perinatal deaths.71 RCTs using PlGF to guide clinical management ultimately will determine the clinical utility of these tests, but there is every reason to be optimistic that they will enable more accurate and targeted treatment of preeclampsia in the future.

26.5 CLASSIFICATION OF HYPERTENSIVE DISORDERS OF PREGNANCY The investigation and management of HDP have been hampered by variable and overlapping definitions in clinical use over time and around the world. International experts are moving toward consensus, although important differences remain between international guideline-issuing bodies, including the American College of Obstetricians and Gynecologists (ACOG), the International Society for the Study of Hypertension in Pregnancy (ISSHP), the National Institute for Clinical Excellence (NICE), the World Health Organization (WHO), and the Society of Obstetricians and Gynecologists of Canada (SOGC).44,64,72–74

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TABLE 26.1 Differential diagnosis of preeclampsia by organ system Vascular

Renal

Gastrointestinal

Hematological

Respiratory

Cardiovascular

Neurological

Pheochromocytoma

Lupus nephritis

Acute fatty liver of pregnancy

Gestational thrombocytopenia

Pneumonia

Periaprtum cardiomyopathy

Epilepsy

Hyperaldosteronism

Glomerulonephritis

Obstetric cholestasis

Thrombotic thrombocytopenic purpura

Pulmonary embolus

Myocardial infarction

Brain tumor

Cushing’s disease

Interstitial nephritis

Cholecystitis/ cholangitis

Hemolytic uremic syndrome

Cerebrovascular accident

Thyrotoxicosis

Pyelonephritis

Viral hepatitis

Idiopathic thrombocytopenic purpura

Hypertensive encephalopathy

Aortic coarctation

Renal artery stenosis

Acute pancreatitis

Antiphospholipid syndrome

Gastritis

Folate deficiency Systemic lupus erythematosus (SLE)

After Steegers EAP, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010;376(9741):631–44.

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There are three key hypertensive disorders—essential or chronic hypertension in pregnancy, gestational or pregnancyinduced hypertension, and preeclampsia.72 Some groups further distinguish preeclampsia superimposed on chronic hypertension and white coat hypertension as separate HDPs.64 The key differences between international diagnostic criteria chiefly relate to the discrimination between preeclampsia and GH and the classification of preeclampsia as severe or nonsevere. Although each condition increases the risk of maternal and offspring morbidity and mortality, the greatest risks are associated with a diagnosis of preeclampsia, either de novo or superimposed on chronic hypertension.75,76

26.5.1

Preexisting Hypertension

Young women of reproductive age may have had little cause to have their blood pressure measured prior to pregnancy, and new diagnosis of hypertension at the time of the first antenatal assessment is not uncommon. The timing of the first visit is important in determining the likely etiology of any hypertension identified for the first time in pregnancy. For the purposes of planning antenatal care and performing screening for aneuploidy, most guidelines recommend that the first antenatal assessment takes place prior to 14 weeks’ gestation.77 At this time, the drop in systemic vascular resistance is not usually great enough to mask preexisting hypertension, but when the first visit takes place between 16 and 20 weeks’ gestation, this is a real possibility. If the first blood pressure recorded was in this period and a woman later develops hypertension, it can be unclear whether this represents new-onset or preexisting hypertension. The safest course is to manage the pregnancy as if it were new hypertension and to arrange postnatal follow-up to ensure that the hypertension has resolved. Young women presenting with hypertension not due to pregnancy should be fully investigated for other underlying pathologies before diagnosing essential hypertension. The prevalence of hypertension in women of reproductive age is between 1% and 10%,78 and preexisting hypertension complicates 1%–5% of pregnancies.75 As with all hypertensive patients, the majority are affected by essential hypertension. Key disorders associated with secondary hypertension in women of childbearing age include renovascular stenosis (which is more likely to be secondary to fibromuscular dysplasia than atheromatous disease in this group, and may be present in 5%–10% of hypertensive patients79), other renal diseases, primary hyperaldosteronism, Cushing’s syndrome, thyroid disease, and pheochromocytoma (affecting only 0.002% of all pregnancies).80,81 The management of the endocrinological causes of hypertension in pregnancy are dealt with in detail elsewhere. In addition to renal and endocrinological disorders, white coat hypertension is recognized in pregnant women and is not entirely benign. Around 50% of women affected will develop GH, and 8% will develop preeclampsia.82 Ambulatory blood pressure recording or home blood pressure monitoring programs may be indicated to confirm the diagnosis.

26.5.2

Gestational Hypertension

When hypertension arises de novo in pregnancy, without any features of preeclampsia or other underlying pathology (including primary renal and endocrine disorders), it is classified as GH, also referred to as pregnancy-induced hypertension (PIH). Where hypertension is diagnosed for the first time in pregnancy management is as for GH, but followup is required to ensure that hypertension persisting beyond the puerperium can be investigated to identify any other underlying causes of hypertension. Any woman presenting with new hypertension requires assessment of all the possible features of preeclampsia prior to arriving at a diagnosis of GH, and testing for proteinuria and laboratory assessment of the full blood count, creatinine, and liver function should always be performed. In addition, ultrasound assessment of fetal growth should be considered, particularly in women presenting with severe hypertension before 37 weeks’ gestation. The risk of progression to preeclampsia after GH is around 25%,64 so close monitoring is required throughout pregnancy. GH can be complicated by cerebral hemorrhage, and the absence of proteinuria is not a reason to relax the target blood pressure during antihypertensive treatment.

26.5.3

Preeclampsia

Preeclampsia is classically defined as new-onset hypertension after 20 weeks’ gestation in pregnancy with proteinuria. With ongoing study of preeclampsia and advances in diagnostic testing, it is clear that the syndrome of preeclampsia is diverse and that not all cases easily fit into this definition. Preeclampsia may present for the first time postpartum or with eclamptic seizures,83 may not be associated with proteinuria, and in certain particularly high risk pregnancies (e.g., molar pregnancies), the syndrome may be detected prior to 20 weeks’ gestation. Although all international guidelines require hypertension to make a diagnosis of preeclampsia, the ISSHP recently elected to recognize that preeclampsia may exist in the form of significant hypertension with other evidence of end-organ dysfunction without necessarily presenting with proteinuria.64 Other international bodies are following suit. This means

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that a woman presenting with hypertension and severe fetal growth restriction will be recognized as suffering from preeclampsia and managed accordingly. In a research setting, it might be appropriate to retain proteinuria as a necessary feature for the diagnosis of preeclampsia to maintain homogeneity in the population under study, but in a clinical setting, recognizing the range of presentations of preeclampsia is pragmatic and minimizes the risk of underdiagnosis and treatment. Preeclampsia is most commonly diagnosed when hypertension is detected during a routine antenatal visit, and most women are asymptomatic at presentation. The typical symptoms of preeclampsia overlap with common minor complaints of pregnancy such as nausea and vomiting, headache, peripheral edema, and heartburn. More serious symptoms tend to appear later in the disease. Upon examination, patients may be hyperreflexic, and marked clonus is associated with an increased risk of progression to eclampsia. In cases with hepatic involvement, patients may have tenderness in the right upper quadrant, and careful examination must be made to exclude the rare but deadly complication of liver hematoma or capsular rupture. In the most severe cases, women may present with confusion or altered consciousness.

26.5.4

Preeclampsia Superimposed on Preexisting Hypertension

It is particularly difficult to diagnose preeclampsia in women with preexisting hypertension, proteinuria, or both. Hypertension alone is not sufficient to diagnose preeclampsia, and a rise in blood pressure in the third trimester is anticipated in all pregnancies, including those in women affected by preexisting hypertension. Many renal pathologies, including glomerulonephritis and SLE, may worsen or relapse in pregnancy. Increasing antihypertensive requirement, therefore, is also not diagnostic of the development of new preeclampsia. When increasingly refractory hypertension is combined with newonset proteinuria, fetal growth restriction, or other evidence of new renal or hepatic dysfunction, then the diagnosis of superimposed preeclampsia may be reached. Where hypertension and proteinuria existed prior to pregnancy, no clinical feature can readily discriminate between new-onset preeclampsia and the preexisting disease. This may be problematic because these women are at very high risk of severe preeclampsia, and those who do develop preeclampsia are at risk of long-term deterioration in their renal function, so diagnostic clarity is of key importance. As described earlier, PlGF is lower in preeclampsia than in normal pregnancies, and the level relates to the severity of the disease. Because placental hypoxia would not be a significant feature in women affected by renal or hypertensive disease alone (i.e., not preeclampsia), sFlt-1 levels should not be increased, nor PlGF suppressed. In the research setting, both PlGF and the sFlt-1-PlGF ratio have demonstrated good diagnostic performance even in women with existing hypertension and proteinuria84,85 and offer the possibility of discriminating accurately between those with preexisting disease alone and those with superimposed preeclampsia.

26.5.5

Severe Preeclampsia

The majority of patients affected by preeclampsia experience only mild symptoms and minor sequelae, particularly with early identification and active management. Most international guidelines recognize the need to identify those women who experience the more severe manifestations of the disease, but the diagnostic criteria for severe preeclampsia vary (Table 26.2).

26.5.6

Classification of Severity by Gestation at Onset

There is a growing recognition that the most important marker of severity is gestation of onset. ACOG defines early onset as <35 weeks’ gestation, while SOGC uses <34 weeks, but both sets of criteria require additional features to classify preeclampsia as severe. Pragmatically, early-onset preeclampsia is usually defined as <34 weeks, reflecting the significantly poorer neonatal prognosis at this time. Early-onset disease is associated with a greater risk of preterm delivery, fetal growth restriction, recurrence in future pregnancies, and later cardiovascular disease and death. Maternal mortality is 20 times higher in preeclampsia diagnosed <32 weeks than when developed at term.86

26.5.7

Clinical Features of Severe Preeclampsia

Other features of severe preeclampsia include severe hypertension and the symptoms and development of any of the complications of preeclampsia. Severe hypertension is variously defined as systolic blood pressure > 160 mm Hg74,87 or 170 mm Hg.44 Severe proteinuria is not a marker of severe disease, but proteinuria in the nephrotic range is an additional risk factor for venous thromboembolism (VTE) over and above the risk of VTE associated with preeclampsia itself.

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TABLE 26.2 Classifications of severe preeclampsia NICE (2010) (Any of the below features with hypertension and proteinuria)

ACOG (2013) (Any of the below with known preeclampsia)

American Society of Hypertension (2008)

Symptoms

Headache Visual disturbance Vomiting Epigastric pain

Severe persistent right-upperquadrant or epigastric pain Cerebral or visual disturbance

Headache Visual disturbance Abdominal pain

Signs

Papilledema Clonus Liver tenderness

Pulmonary edema

Oliguria Early-onset disease (<35 weeks) Nonreassuring fetal monitoring

Hypertension

Severe hypertension and proteinuria alone

Systolic BP > 160 mm Hg Diastolic BP > 110 mm Hg (on two occasions >4 h apart while on bed rest)

Diastolic >110 mm Hg

Other maternal disorders

HELLP syndrome Platelets <100
109/L AST or ALT >70

Platelets <100
109/L Liver enzymes > twice normal concentration Progressive renal insufficiency

Elevated creatinine Nephrotic range proteinuria Elevated AST or LDH

BP, blood pressure; AST, aspartate transferase; ALT, alanine transferase; LDH, lactate dehydrogenase; NICE, National Institute for Clinical Excellence; ACOG, American College of Obstetricians and Gynecologists.

TABLE 26.3 Diagnostic criteria of HELLP syndrome Tennessee89

Martin90

UKOSS91

Hemolysis

LDH > 600 U/L

Falling HCT, LDH > 164 U/L or bleeding diathesis

LDH > 600 IU/L or bilirubin >20.5 mmol/L or abnormal peripheral blood smear

Thrombocytopenia

Platelets <100
103/mL

Platelets <100
103/mL

Platelets <100
109/L

Hepatocellular injury

AST > 70 U/L

AST > 48 U/L and ALT >24 U/L

GGT, AST or ALT >70 U/L

LDH, lactate dehydrogenase; AST, aspartame transferase; ALT, alananine transferase; GGT, gamma glutyl transferase; HCT, hematocrit.

Severe disease can develop rapidly in fulminating preeclampsia, and sudden onset of rapidly worsening abdominal pain, nausea and vomiting, or headache should always be taken seriously, particularly in women with a known diagnosis of preeclampsia or GH.

26.6 COMPLICATIONS OF PREECLAMPSIA Preeclampsia is a multisystem disorder characterized by generalized endothelial damage, which can result in widespread end-organ damage. In current clinical practice, close attention to blood pressure control means that most maternal deaths associated with preeclampsia are attributable to neurological or hepatic complications.88

26.6.1

HELLP Syndrome

HELLP syndrome is a serious condition characterized by hemolysis (anemia with blood film appearances of hemolysis), elevated liver enzymes (transaminases greater than twice the upper limit of normal), and low platelets (<150,000/dL). As with preeclampsia, international diagnostic criteria for HELLP syndrome vary (Table 26.3). HELLP syndrome occurs in

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around 5% of cases of preeclampsia87 or 10%–20% of severe preeclampsia and is associated with 1.1% maternal mortality and severe morbidity, including disseminated intravascular coagulopathy, liver hematoma, liver failure, and renal failure.92 The perinatal mortality rate is reported at 6%–17%.93,94 Shedding of placental debris into the maternal circulation is thought to provoke a widespread inflammatory response, with a more severe response seen in HELLP syndrome. PP1 is synthesized by syncytiotrophoblast and is detectable at higher levels in the umbilical cord blood in pregnancies affected by HELLP syndrome than in healthy or preeclamptic pregnant patients. This may correlate with the degree of damage to the syncytiotrophoblast membrane, pointing to that damage as a possible causative factor of HELLP syndrome.95 As in preeclampsia, endothelial injury results in platelet activation and consumption, vasospasm, release of thromboxane A2 and serotonin, and inhibition of prostacyclin release. The overall effect of the endothelial injury response is to shift the prostacyclin/thromboxane ratio in favor of vasoconstriction. In addition, there are a reduction in endothelium-derived relaxing factor and an increase in fibrin deposition in the endothelium.96 In HELLP syndrome, a number of other pathological processes create the typical picture of thrombocytopenia, hemolysis, and acute liver injury. Acute activation of the endothelium increases the proportion of active vWf released. Pregnancies affected by preeclampsia and HELLP syndrome have markedly elevated vWf antigen levels,97 and vWf in the GpIba-binding conformation (active) can interact spontaneously with platelets without binding to exposed collagen; this is associated with consumptive thrombocytopenia and thrombotic microangiopathy.98 Although the overall level of vWf antigen is similar in preeclampsia and HELLP syndrome, the proportion of active vWf and the functionality of vWF are greater in patients with HELLP syndrome than in those with preeclampsia.97 Although high levels of active vWf in TTP are associated with reduced ADAMTS13 activity, in patients with HELLP ADAMTS13 activity is not significantly different from patients with preeclampsia, so it is not a likely cause for the increased vWf activity. It is more plausible that acute endothelial activation leads to release of the large active vWF multimers that then spontaneously interact with platelets, leading to microvascular thrombi and increasing platelet consumption. Thrombocytopenia is often an early finding in HELLP syndrome, before the hemolysis and liver injury have fully developed. Increasing platelet consumption and formation of microvascular thrombi reduce platelet life span. This, together with increasing adherence to exposed collagen, have the effect of reducing the platelet count. Because the cause of the thrombocytopenia is peripheral, bone marrow aspirate normally demonstrates increased numbers of megakaryocytes, and in fact, megakaryocytes may be detected in the peripheral circulation. Erythrocytes are damaged by passage through vessels affected by endothelial injury and microvascular thrombi, and the characteristic picture of microangiopathic hemolytic anemia develops, where burr cells, schistocytes, and polychromasia may be detected on peripheral blood film microscopy, and elevated lactate dehydrogenase (LDH), bilirubin, and reticulocyte counts also may be detected. Fibrin obstruction of the hepatic sinusoids leads to hepatocellular injury. Liver biopsy is nonspecific, but typical features include periportal and focal parenchymal necrosis. Continued swelling of the liver secondary to hepatocellular injury or subcapsular hematoma may lead to the rare but life-threatening complication of rupture of the liver capsule with attendant major hemorrhage; this can occur in 1.8% of HELLP cases. Rupture occurs most frequently in the right lobe and can occur postpartum. This is one of the most serious complications of HELLP syndrome and is associated with an 18%–86% maternal mortality rate and a perinatal mortality rate as high as 80%.99 Pregnancy and preeclampsia are both prothrombotic states, and where HELLP syndrome occurs in conjunction with antiphospholipid syndrome, there is an increased risk of hepatic infarction.100

26.6.2

Renal Dysfunction in Preeclampsia

The kidney is uniquely vulnerable to preeclampsia because of the toxic combination of relative depletion of the intravascular volume and paradoxical renal vasoconstriction mediated by sodium and water retention. In normal pregnancy, the glomerular filtration rate (GFR) is increased and the normal range of creatinine is lower than in the nonpregnant patient, but in preeclampsia, GFR and renal perfusion are reduced.101 Low or subclinical rises in creatinine can be early signs of severe preeclampsia, and a creatinine >90 mmol/L is a marker of severe disease.64 In preeclampsia, the typical pathological findings on renal biopsy are glomerular endotheliosis, and milder changes can be observed in GH.102 The typical glomerular lesion with reduced endothelial fenestration and increased fibrinoid deposits is strongly associated with renal hypofiltration, independent of the renovascular constriction of preeclampsia.103 Podocyte attachment is damaged in preeclampsia, and podocyturia is detectable prior to the onset of proteinuria.104 Renal dysfunction purely secondary to preeclampsia usually resolves after delivery, but it may be worsened in the short term by the practice of fluid restriction in the management of severe preeclampsia. In those who do not recover their renal

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function, ongoing thrombotic microangiopathy affecting the kidney or thrombosis severely enough to cause renal infarction may be responsible.

26.6.3

Pulmonary Edema

Pulmonary edema is an important cause of death in women with preeclampsia, and yet it is often recognized late. Hypoalbuminemia leads to reduced oncotic pressure and significant interstitial fluid accumulation despite the intravascular depletion of preeclampsia.105 Fluid accumulation is often exacerbated by the administration of intravenous fluids during labor, whether prior to the use of epidural analgesia or at the time of surgical delivery.

26.6.4

Eclampsia

Eclampsia remains the most feared of all complications of preeclampsia, as indicated by the name of the disease. Eclampsia means lightning, and for centuries, relatives and clinicians have been terrified by the sudden appearance of tonic-clonic seizures in young and apparently healthy pregnant women. Despite all the decades of research that have defined and explored the condition that precedes eclamptic seizures—preeclampsia—the ability to predict the onset of eclampsia remains elusive. Although other pathologies can present with new-onset seizures in pregnancy, eclampsia is the most immediately life-threatening, and treatment should always be initiated in tandem with seeking evidence to support or refute the diagnosis, particularly in a patient not previously known to be hypertensive. Seizures can arise in a woman who has shown no or minimal preceding symptoms and signs, or who has had stable, mild disease for several weeks. The most common preceding symptoms are severe headache, visual disturbance, and nausea, which are present in 79% of cases who go on to present with eclampsia. Eclampsia is around 10–30 times more common in developing countries, largely because of differences in the quality of antenatal monitoring that lead to missed opportunities to treat preeclampsia and prevent deterioration.106 Eclampsia is strongly associated with the finding of posterior reversible encephalopathy syndrome (PRES) on neuroimaging, and it is likely that these changes precede (and in fact may be the mechanism of) eclampsia.107 It is not clear how many women with preeclampsia might have PRES because neuroimaging is usually reserved for cases with seizures or other neurological features. The etiology of PRES has not been fully determined, and similar appearances can occur in nonpregnancy-related conditions, including hypertensive encephalopathy, immunosuppressive states, and hepatic failure. It is likely that in preeclampsia, elevated blood pressure that overrides cerebral autoregulation and cerebral hyperperfusion can lead to disruption of the blood-brain barrier and vasogenic edema.58 Pregnancy enhances the development of edema in response to hypertension, and therefore, the consequences of cerebral edema are observed at lower blood pressure levels than in nonobstetric hypertensive encephalopathy.13 Mild cognitive impairment is reported by women who have suffered from eclampsia even without focal neurological injury, and this may represent long-term white matter damage as a result of eclamptic seizures.108

26.7 ANTENATAL CARE OF WOMEN WITH HYPERTENSIVE DISORDERS IN PREGNANCY Once hypertension has been identified, subsequent management is determined by the specific diagnosis and gestation at onset. Preexisting hypertension is likely to deteriorate with prolonged pregnancy, and it carries a substantial risk of progression to preeclampsia or GH. GH and preeclampsia are both cured by delivery of the baby, and the only reason to prolong the pregnancy in these conditions is to maximize fetal maturity while avoiding clinical deterioration in the mother.

26.7.1

Periconceptual Care

The antenatal management of women with chronic hypertension should ideally begin preconception. With rising mean maternal age, weight, and medical complexity, it has become increasingly common to meet women with an established diagnosis of essential hypertension in early pregnancy. Ideally, all women with a diagnosis of essential hypertension or previous GH or preeclampsia who are considering pregnancy should be referred to an obstetric medicine service prior to conception. There, they can receive periconceptual advice and then targeted antenatal care and monitoring throughout the pregnancy. Women with essential hypertension planning a pregnancy should be informed that there is a 20%–25% chance of developing preeclampsia during pregnancy, with the attendant fetal and maternal risks, and that this condition can be mitigated to

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some extent by the administration of low-dose aspirin from the first trimester. For women who have previously had GH or preeclampsia, the risk of recurrence is related to the gestation at delivery, but all these women are at increased risk compared to normotensive multiparous women. NICE recommends taking 75 mg aspirin once daily until 36 weeks for women at high risk of preeclampsia, although there is emerging evidence that a dose of 150 mg is better at reducing the risk of preeclampsia.109 Additionally, when a woman decides to conceive, a review of established antihypertensive therapy and blood pressure control should be undertaken to ensure the suitability of her existing medical therapy for pregnancy. Women on an angiotensin-converting-enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) should be converted to alternative therapies prior to conception. Blood pressure control at conception and in the first trimester is associated with the risk of developing preeclampsia, severe hypertension, and fetal growth restriction later in pregnancy,110 and ideally, optimal control should be achieved using antihypertensives suitable for use during pregnancy prior to conception. Optimizing diet and weight prior to pregnancy also may reduce the risk of preeclampsia, along with many other pregnancy and long-term health complications, and folic acid should be taken from preconception until up to 12 weeks’ gestation.

26.7.2

Antenatal Treatment of Chronic and Gestational Hypertension

Antihypertensive therapy aims to reduce the risk of severe hypertension and cerebrovascular accidents, cardiovascular strain, and renal injury. The target blood pressure for women with chronic hypertension may differ in pregnancy compared with prepregnancy. Confidential enquiries into maternal mortality in the United Kingdom and United States have stressed repeatedly that failure to control systolic hypertension adequately has been a feature in a number of maternal deaths from aortic dissection and cerebrovascular hemorrhage.111,112 NICE guidance recommends commencing therapy when blood pressure exceeds 150/100 mm Hg, with the aim of maintaining blood pressure below this level; and the SOGC guidelines are similar.5,74 The ACOG guidelines are more conservative, citing concerns about the potential effects of antihypertensive therapy in pregnancy on the fetus and the relative rarity of complications at blood pressures of 150/100 mm Hg, and would recommend treatment only for blood pressure over 160/110 mm Hg, or 160/105 in chronic hypertension. The Control of Hypertension in Pregnancy Study (CHIPS) RCT demonstrated that tight (i.e., target diastolic BP (DBP) < 85 mm Hg) rather than less tight (target DBP < 100 mm Hg) blood pressure control is associated with a lower probability of severe hypertension and no increase in adverse perinatal outcomes in chronic and GH. Bearing in mind the fact that the systemic effects of hypertension may be potentiated in pregnancy by the systemic inflammatory response and altered endothelial function, it is sensible to adopt a tighter approach to blood pressure control for hypertensive pregnant women than for nonpregnant patients.

26.7.3

Choice of Antihypertensive Agents in Pregnancy

The first-line antihypertensive drug in pregnancy is usually labetalol, a mixed beta- and alpha-blocker.5 Acceptable and commonly used alternatives are methyldopa and nifedipine. There is no good evidence as to the most effective agent, although metaanalysis does suggest that there are differences between drug classes in the effectiveness of preventing severe hypertension.113 Beta-blockers seem to be associated with good efficacy in the treatment of hypertension, but they also have effects on the fetus, including lower birth weight, neonatal hypoglycemia, and increased neonatal respiratory morbidity. Afro-Caribbean patients often demonstrate relative insensitivity to beta blockers secondary to relatively high renin levels114 and many argue that calcium channel blockers are the most appropriate first-line agent in these patients. Rapidrelease oral nifedipine is as effective at achieving blood pressure control in severe hypertension as intravenous labetalol or hydralazine, but labetalol is associated with fewer adverse perinatal events.115 ACE inhibitors, ARBs, and alpha blockers are not appropriate in pregnancy because of the risk of fetal teratogenicity. Polypharmacy might be needed in women with persistent severe hypertension, but as a rule of thumb, the first-line antihypertensive dose should be increased to the maximum before adding a supplementary agent. Table 26.4 outlines commonly used antihypertensive drugs in pregnancy..

26.7.4

Antenatal Monitoring in Gestational and Chronic Hypertension

Because of the ongoing risk of preeclampsia, antenatal care of women with chronic and GH includes regular monitoring for worsening hypertension and new proteinuria. Typically, women are invited to attend the day unit for assessment, with increasing frequency of visits as the estimated due date approaches. Serial ultrasound assessment of fetal growth is recommended.

TABLE 26.4 Commonly used antihypertensives and their application in women of reproductive age Preconception

Pregnancy

Breastfeeding

Side effects

Contraindications

ACE inhibitor

Enalapril Captopril

Change to alternative antihypertensive

No: associated with severe fetal anomaly, fetal nephropathy and intrauterine death

No known evidence of harm (NICE). May be of particular benefit for women needing cardiac/renal protection

Cough

Peripheral vascular disease, hereditary angiedema, aortic stenosis

Alpha- and betablockers

Labetalol

Change to alternative antihypertensive

Yes. Can be given intravenously for rapid control of severe resistant hypertension

Manufacturers recommend avoid. Very small amounts in breast milk. No known evidence of harm (NICE)

Tachycardia

Asthma

Alpha-2 agonists

Clonidine Methyldopa

Methyldopa: can be used in periconceptual period.

Methyldopa: Yes, including first trimester. Longest postmarketing surveillance data. Clonidine: may lower fetal heart rate

No known evidence of harm to infants, but NICE recommends avoiding it because of an association with postpartum depression

Depression Reduced variability on CTG Methyldopa hepatitis

Mental illness Hepatic disease

Angiotensinreceptor blockers

Losartan

Change to alternative antihypertensive

Likely similar risk of teratogenicity as ACE-I. In addition known to cause fetal renal failure and retardation in skull ossification in 2/3rd trimesters

No information available—not recommended.

Dizziness, palpitations, headache, hyperkalemia

Electrolyte imbalance, hepatic or renal impairment

Beta-blockers

Bisprolol Atenolol

Change to alternative antihypertensive.

Avoid in first and second trimesters. Associated with fetal growth restriction and bradycardia, reduces uteroplacental blood flow

No known evidence of harm (NICE). Second line after labetalol

Risk of fetal growth restriction and bradycardia in pregnancy

Asthma

Calcium channel antagonists: Dihydropyridines

Nifedipine Amlodipine

Change to alternative antihypertensive

After 20 weeks. Available in short-acting forms for rapid blood pressure control and long-acting forms for maintenance therapy. May be used simultaneously with magnesium sulfate. May inhibit labor

Manufacturers advise avoiding, no known evidence of harm (NICE). Amounts in breast milk too small to be harmful

Headache

Aortic stenosis, acute angina, recent myocardial infarction

26

Example

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Class of drug

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Continued

Class of drug

Example

Preconception

Pregnancy

Breastfeeding

Side effects

Contraindications

Calcium channel antagonists: phenylalkylamines

Verapamil

Change to alternative antihypertensive.

No known teratogenic effect, may relax uterine muscle, may reduce uterine blood flow. Avoid in first trimester.

Excreted in breast milk in very small amounts, unlikely to be significant.

Bradycardia, flushing, peripheral edema

Acute porphyria, accessory conducting pathways, heart failure

Calcium channel antagonists: benzothiazepines

Diltiazem

Change to alternative antihypertensive

Not recommended in pregnancy

Excreted in breast milk in small amounts—avoid breastfeeding if using

Thrombocytopenia, headache, dizziness, AV block, bradycardia

Acute porphyria, LVF, AV block

Mineralocorticoid receptor agonists

Spironolactone Eplerenone

Change to alternative antihypertensive. Spironolactone associated with reduced fertility in mice

Feminization of male fetus in animal studies.

Active metabolite present in milk— avoid

Hyperkalemia, dizziness, leukopenia, hepatic impairment

Renal failure, hyperkalemia, hypercalcemia

Nitroprusside

Nitroprusside

Change to alternative antihypertensive

Although effective for rapid control of hypertension, can lead to accumulation of cyanide in fetus

Caution advised: thiocyanate metabolite

Abdominal pain, phlebitis, thrombotcytopenia, anxiety, and dizziness

Leber’s optic atrophy, severe B12 deficiency

Thiazide diuretics

Bendroflumethiazide

Change to alternative antihypertensive

Decrease placental perfusion, stimulation of labor, increase in meconium staining. Can cause neonatal thrombocytopenia, bone marrow suppression, jaundice, and electrolyte disturbance

Amount present in breast milk too small to be harmful, but large doses may inhibit lactation

Hypokalemia, other metabolic and electrolyte disturbance, postural hypotension, gout

Addison’s disease, hypokalemia, hypercalcemia, hyponatremia

Vasodilators

Hydralazine

Change to alternative antihypertensive

Avoid before third trimester. May be a risk of neonatal thrombocytopenia

Present in milk, not known to be harmful

Rashes, hepatic dysfunction, anxiety, hemolytic anemia, SLE-like syndrome with longterm therapy

Acute porphyria, cor pulmonale, SLE, severe tachycardia

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TABLE 26.4 Commonly used antihypertensives and their application in women of reproductive age—cont’d

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Although this approach maximizes the early detection of preeclampsia in this high-risk group, women still may develop severe hypertension or new proteinuria between visits. Moreover, the frequency of hospital visits and monitoring unnecessarily add to the anxiety and practical challenges of pregnancy for the majority of the affected women who ultimately will not go on to develop preeclampsia. This is particularly the case for women with chronic hypertension, who will require monitoring throughout pregnancy, compared to women with GH, who may need additional monitoring for only a few weeks in the interval between diagnosis and delivery. In carefully selected women, self-monitoring of blood pressure using approved validated and calibrated devices at home may be an effective way to maintain close monitoring, while reducing the impact of frequent visits on the women and their families. Home monitoring using a clear protocol with triggering of hospital assessment when appropriate can reduce the number of antenatal visits, with no adverse effect on maternal and offspring outcomes.116 Although several studies have investigated home monitoring of blood pressure, the problem of testing for proteinuria remains. In fact, most pregnant women have experience with administering home urine tests in the form of beta-human chorionic gonadotropin (bHCG) testing to confirm pregnancy in the first trimester, and it is likely that home testing for proteinuria could further reduce the need for hospital visits. Home testing for proteinuria has been shown to be feasible, accurate, and acceptable to women.117 Using home monitoring of blood pressure and proteinuria with appropriate triage protocols can help to individualise antenatal monitoring for women with chronic and gestational hypertension. Incorporating new technologies (including smart phone apps) can facilitate communication of clinical data with the hospital care team and makes home based care, already popular with women, economically viable and more widely accessible.

26.7.5

Timing of Delivery in Chronic and Gestational Hypertension

Blood pressure will continue to rise throughout the third trimester, and ultimately the best way of preventing further progression of hypertension and removing the risk of developing preeclampsia may be to deliver the baby. This would usually be through induction of labor, although in certain cases (very preterm, placenta previa, previous cesarean sections, fetal malposition), this may be contraindicated, and thus a cesarean section would be planned. The decision to deliver is not as simple as removing the risks of prolonged pregnancy once fetal maturity is achieved. Medically indicated delivery is associated with risks to both mother and baby that need to be weighed against the risks to mother and baby of continuing the pregnancy. Induced labor is associated with increased use of regional analgesia in labor and instrumental delivery; the failure to induce labor and the subsequent need for cesarean section is a possibility, particularly in primigravid women induced remote from term. Although 37 weeks is taken as full term, there is a higher incidence of respiratory morbidity and neonatal unit admission in infants born between 37 and 39 weeks compared to those born between 39 and 41 weeks.118 After 37 weeks, any woman with GH or mild-to-moderate disease should have the timing of delivery discussed with her. The HYPITAT trial demonstrated that induction of labor at this gestation time reduces the risk of adverse maternal events and did not carry additional risk for the neonate. In addition, this strategy did not increase the risk of cesarean section, and the women most likely to benefit were those least favorable for induction.119 This has led many clinicians to recommend the induction of labor from 37 weeks’ gestation for women with HDP. However, clinicians should consider that this trial was conducted in a setting where women are not treated for hypertension <160/100 at term, and may not be directly applicable to the U.K. population, where antihypertensive therapy is offered for lower degrees of hypertension, as one of the primary outcomes was the occurrence of severe hypertension. It also can be reasonable, if the woman wishes, to offer antihypertensive treatment and continue pregnancy under close monitoring, so long as blood pressure is controlled and there are no features of severe disease.5 A large observational study concluded that, in women with otherwise uncomplicated preexisting hypertension, the optimal balance of fetal and maternal benefit is achieved by planning delivery at 38–39 weeks’ gestation.120 These considerations should be clearly explained to the mother prior to 37–39 weeks. If she chooses to continue the pregnancy, she should be offered regular monitoring, and a clear plan should be made for when labor will be induced if it has not occurred spontaneously.

26.8 ANTENATAL MANAGEMENT OF PREECLAMPSIA As in gestational and chronic hypertension, the challenges of management in preeclampsia lie in balancing the maternal and fetal risks of continuing pregnancy (expectant management) against the maternal risks of intervention and the fetal risks of

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preterm delivery (interventionist management). Women with preeclampsia are at greater risk of sudden deterioration and serious complications, and management protocols for preeclampsia take this into account. It is important to recognize that, although most guidelines include specific gestational cutoffs for expectant and interventional management, a continuum of risk exists. While opting to continue the pregnancy, the goals of treatment are to maintain a safe blood pressure and monitor the mother for deteriorating disease and the fetus for signs of placental dysfunction and growth restriction.

26.8.1

Inpatient or Outpatient Management?

Most international bodies recommend hospital admission at the point of diagnosis in order to complete a full maternal and fetal assessment, including monitoring of blood pressure over a 24-h period.64,72,73,121 Many women ultimately will be suitable for home and outpatient management, but blood pressure should be controlled, a full maternal assessment for any complications of preeclampsia completed, and fetal status (as assessed by ultrasound scan of growth and Doppler) determined prior to implementing an outpatient management plan. Comprehensive maternal assessment should include a thorough clinical examination, including abdominal examination, fundoscopy, and assessment of deep tendon reflexes and clonus. Full blood count, coagulation, creatinine, urea, and liver function should be checked to screen for HELLP syndrome and renal dysfunction. Uric acid testing can be useful to confirm a diagnosis of preeclampsia, but it is not predictive of pregnancy outcome, and a normal result does not rule out preeclampsia.122 During admission, blood pressure should be checked at least every 4 h, and a 24-h urine collection for quantification of proteinuria should be performed if not already completed. Antihypertensive therapy should be commenced when the blood pressure consistently exceeds 150/100 mm Hg. While inpatients, women with preeclampsia are at increased risk of VTE and should receive thromboprophylaxis. In most cases, this would be with low-molecular-weight heparin. There is no evidence to support bed rest in preeclampsia, and hospital admission for this purpose is associated with increased risk of infection, VTE, and psychosocial morbidity.123 Women with stable blood pressure on treatment, normal laboratory studies, no need for concern about fetal well-being, and a good understanding of their condition are candidates for outpatient management. Outpatient management should be undertaken in the context of a plan for regular monitoring by experienced clinical staff and patient education upon triggers for urgent presentation to hospital services (e.g., headache, abdominal pain, or vaginal bleeding). Maternal outpatient monitoring should include regular blood pressure measurement in a dedicated day assessment unit, or at home in the context of a clearly structured monitoring protocol. No subsequent quantification of proteinuria is necessary after significant proteinuria has been confirmed. Laboratory tests of biochemical and hematological parameters should be repeated two to three times a week, according to the severity and the progression of the disease.5

26.9 26.9.1

TREATMENT OF SEVERE PREECLAMPSIA Severe Hypertension

Severe hypertension (>160–170/100–110 mm Hg) requires rapid control. The ACOG recommends the initiation of treatment within 1 h72 and, in the absence of symptoms suggestive of impending eclampsia, it is reasonable to start with oral therapy if it is tolerated by the mother. When severe hypertension is detected in a primary-care or community setting, administration of oral antihypertensives while arranging transfer to secondary care can protect the mother against the risks of severe hypertension in the short term. Where the systolic blood pressure is >180 mm Hg or refractory to oral therapy, intravenous antihypertensives (usually labetalol or hydralazine) may be required. Because of concerns about potentially compromising uteroplacental circulation by overcorrection of blood pressure (either too rapid or too extreme a drop) using this route, fetal monitoring during therapy is advised, although there is little evidence to support this practice. Oral, fast-acting nifedipine, intravenous hydralazine and labetalol are equivalent for management of acute severe hypertension in pregnancy.124 Invasive monitoring via an arterial line may be of benefit in refractory severe hypertension and critical-care medicine and neonatology teams should be involved in management and planning of delivery.

26.9.2

Magnesium Sulfate for Women with Severe Preeclampsia

Women who meet the criteria for the diagnosis of severe preeclampsia (Table 26.2) or have significant signs and symptoms of impending eclampsia (i.e., severe headache, clonus, neurological impairment) should be considered for treatment with

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magnesium sulfate for eclampsia prophylaxis. Magnesium sulfate reduces cerebral perfusion pressure and the risk of eclampsia in patients with preeclampsia. It is associated with a 50%–67% reduction in the risk of seizures and a reduction in the risk of maternal death, and it may offer a degree of neuroprotection to the baby, which is of particular importance in preterm deliveries.125 The standard protocol is as described in the Collaborative Eclampsia Trial126: a 4-g loading dose with a maintenance infusion of 1 g/h. Treatment with magnesium sulfate requires at least level 2 care. Monitoring for magnesium toxicity should be continuous, and practitioners should be aware that serum magnesium levels correlate poorly with clinically relevant toxicity. Early signs of magnesium toxicity include respiratory depression and loss of deep tendon reflexes, so respiratory rate and reflexes should be checked at least hourly. Toxicity can occur with therapeutic doses, especially in the context of renal impairment, so urine output also should be monitored closely. Magnesium toxicity is associated with electrocardiogram (ECG) changes and arrhythmias, and where it is suspected or the risk of toxicity is elevated, continuous ECG monitoring may be appropriate.

26.9.3

Plasma Volume Expansion and Fluid Restriction

Because preeclampsia is a state of intravascular depletion despite hypoosmolality and sodium and water retention, fluid management is particularly complex in severe cases. Renal function, if not already compromised, is vulnerable, and there is a significant risk of provoking pulmonary edema. Intensive care and multidisciplinary management incorporating nephrologists, intensivists, and obstetricians is necessary in the complex clinical scenario of coexisting renal injury and pulmonary edema in preeclampsia. Where a woman is known to have an HDP, the practice of preloading prior to the use of regional anesthesia should be curtailed. In the case of severe preeclampsia, fluid restriction to 1.5 mL/kg/h may be appropriate, with close monitoring of renal function and urine output. While there has been considerable interest in the possibility of using plasma volume expansion as an intervention to prolong pregnancy at early gestation without worsening extravascular fluid accumulation, it cannot be recommended for routine use.127 There is evidence that the use of plasma expanders improves measures of maternal and fetal hemodynamics,128,129 but this does not correlate with improvement in perinatal outcomes.130

26.9.4

HELLP Syndrome

In HELLP syndrome, initial minor derangement in transaminases and platelets can deteriorate rapidly, and blood tests should be repeated every 6–12 h if the trend is worsening and the decision has been made to prolong pregnancy to allow administration of corticosteroids for fetal lung maturity. Corticosteroids should not be used to treat HELLP syndrome.131 HELLP will ultimately be cured by delivery, but clinicians should anticipate an initial worsening in laboratory indexes postdelivery, with recovery typically starting within 24–48 h of delivery.96 In severe and refractory HELLP syndrome, therapeutic plasma exchange (TPE) may have the benefit of both removing harmful circulating factors, like ammonia, endotoxins, inflammatory cytokines, vasoactive factors, and antibodies, and of replenishing those coagulation factors and albumin that would normally be produced in the liver.132 TPE is an established treatment for the phenotypically similar condition of TTP, and also has been used successfully in women with severe HELLP syndrome. TPE is not without risk; complications may include sepsis, anaphylaxis, or plasma-transmitted disease. Patients most likely to benefit from TPE are those with an ongoing deterioration in laboratory parameters postpartum. Because most patients do recover without TPE and there are significant risks associated with this treatment, it should be considered only in exceptional circumstances, such as 48–72 h postpartum in the face of significant and deteriorating thrombocytopenia, anemia, and elevated liver enzymes. Although liver rupture is rare, it is a surgical emergency and requires multidisciplinary management. A surgical approach should involve both obstetricians and hepatobiliary surgeons, as urgent cesarean section is likely to be necessary before dealing with the liver rupture. Because liver rupture is associated with major hemorrhage in the setting of existing thrombocytopenia and a high risk of disseminated intravascular coagulation, hematology involvement at an early stage is critical, and significant blood product administration is likely to be required. The principle of management is to secure hemostasis, which initially may be achieved by packing the liver, with a planned return to the operating theater 24–48 h later for removal of packs once coagulation has normalized. Alternative strategies include arterial ligation and radiological selective arterial embolization.133 Resection is likely to provoke massive bleeding. Liver transplantation has been reported as an option of last resort.134 A subcapsular hematoma should be managed conservatively, and the liver should be handled gently at cesarean section in women with known HELLP syndrome to minimize the risk of additional hepatic trauma.

474 SECTION 1 The Mother

26.9.5

Acute Management of Eclampsia

Eclampsia is an obstetric emergency, and the first priority is to stabilize the mother through the application of a standard resuscitation principles, first securing the airway and then assessing breathing and circulation (ABC). Most eclamptic seizures are self-terminating and short-lived; however, magnesium sulfate should be commenced as soon as possible, if not already in progress, according to the protocol described previously. If magnesium sulfate has already begun, a further bolus may be given, and the maintenance infusion may be increased to 2 g/h.126 Hypertension should be controlled as outlined previously; the intravenous route is preferable, as the mother is likely to be in a state of altered consciousness. Recurrent seizures may warrant intubation and paralysis to maintain oxygenation. Fetal monitoring is not a priority until the mother has been stabilized. Auscultation or CTG will inevitably show fetal bradycardia during and immediately after a seizure, but the primary intervention is controlling seizures and blood pressure, not delivery. As soon as the mother’s condition is judged stable, the baby should be delivered by the most expedient route. In certain selected situations, delivery may be achievable vaginally, but it most commonly will occur by cesarean section.

26.10

TIMING AND MODE OF DELIVERY IN PREECLAMPSIA

There is no role for the outpatient management of severe preeclampsia as previously defined. In severe preeclampsia, the clinical scenario is dynamic, and with every advancing day of gestation, the balance of the risks and benefits attending the decision to deliver or continue the pregnancy is altered. Daily review by experienced clinicians is the minimum necessary to ensure that the management plan reflects the current clinical situation. There are general guidelines about the timing of delivery in severe preeclampsia, but the decision must be individualized in every case to the condition of mother and fetus, as well as the ability of local services to meet both of their medical needs. At any gestation (i.e., even before fetal viability), delivery is indicated for life-threatening maternal disease, which may take the form of severe refractory hypertension, eclampsia, placental abruption, or rapidly deteriorating HELLP syndrome or renal dysfunction. After the age of fetal viability (which may vary depending on the country/setting), delivery also may be indicated for serious fetal compromise with abnormal fetal ductus venosus Doppler or computerized CTG findings. If fetal compromise is the primary indication for delivery at 24–26 weeks, a frank discussion should be held with the parents before proceeding, regarding the poor prognosis for the baby, particularly in the setting of marked intrauterine growth restriction and the potential complications of preterm surgery. Preterm cesarean section is associated with greater maternal blood loss and an increased risk of uterine rupture in subsequent pregnancies, and it may not increase the survival of verygrowth-restricted, extremely premature babies. In all cases, the mother should be stabilized before proceeding to delivery. Performing a Category 1 cesarean section immediately after an eclamptic seizure without full assessment of the condition of mother and baby exposes the mother to severe risks associated with general anesthesia (i.e., failed intubation, severe hypertension, aspiration, or a further cerebral event), bleeding secondary to an undetected coagulopathy, and rushed, potentially complex surgery with a higher risk of intraoperative damage to the bladder and ureters. Once the mother is stable, any blood products ordered, and the appropriate obstetric, anesthetic, and neonatal team assembled, delivery can be accomplished safely if indicated. In general, at gestations below 34 weeks, the presumption is that expectant management will be preferred in the absence of critical illness in the mother or fetus.135 Immediate delivery certainly increases neonatal morbidity and may not benefit the mother. A useful clinical tool would be a prediction model that could identify those women likely to develop complications of preeclampsia within the next 7 days. These women then could be offered corticosteroids for fetal lung maturation, transferred to a center with appropriate neonatal care facilities, and receive magnesium sulfate for seizure prophylaxis. Conversely, women identified as being at low risk of disease progression could avoid unnecessary preterm delivery and the attendant neonatal and maternal morbidity. Several such models have been developed and are undergoing investigation in trial settings to inform recommendations for practice. The fullPIERS model incorporates gestational age, chest pain or dyspnea, SpO2, platelet count, creatinine, and aspartate transaminase, and it predicts adverse maternal outcomes within 48 h and 7 days, with area under the curve (AUC) of 0.88 and > 0.7, respectively.136 This model has undergone external validation137 and seems to perform well as a prediction tool, but it has not yet been tested in a clinical context as a decision-making aid. A similar model, miniPIERS, which incorporates physical findings and symptoms rather than the more specialized laboratory tests included in the fullPIERS model, has been developed for use in low-resource clinical settings. The features included are parity, gestational age, systolic blood pressure, degree of proteinuria, vaginal bleeding with abdominal pain, headache and/or visual changes, and chest pain and/or dyspnea; the AUC for this model is 0.768 [95% confidence interval (CI) 0.735–0.801].138

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The PREP prediction models for the risk of complications in early preeclampsia looked specifically at predicting complications in preeclampsia diagnosed <34 weeks’ gestation. The PREP models included maternal age, gestational age at diagnosis, medical history, systolic blood pressure, urine protein-to-creatinine ratio, platelet count, serum urea concentration, oxygen saturation, baseline treatment with antihypertensive drugs, administration of magnesium sulfate, exaggerated tendon reflexes, and serum alanine aminotransaminase and creatinine concentrations.139 The PREP model has undergone external validation and a trial including the model in the management of patients with early-onset preeclampsia is underway. Both the PIERS and PREP models are available online. Although no model has yet been proven to be of clinical utility in practice, it is noteworthy that the parameters common to all models, in particular respiratory symptoms (dyspnea and chest pain) and signs (oxygen saturation) present in all three models, are frequently overlooked by obstetric teams fixated on the arm, abdomen, and ankles in examining hypertensive pregnant patients. After 34 weeks, the threshold for delivery will fall substantially, and any feature of deterioration may prompt consideration of expediting delivery. The HYPITAT II study compared immediate delivery to expectant management between 34 and 37 weeks’ gestation. It found a small increase in adverse maternal outcomes with expectant management, offset by a significant increase in neonatal morbidity after immediate delivery. There is insufficient evidence to make prescriptive recommendations in this gestational window; at present, the woman and her medical team must weigh the individual circumstances and review the situation on a daily basis. In the future, predictive models such as the PIERS and PREP models may assist in making the decision to end a pregnancy. After 37 weeks, a discussion about timing of delivery should take place, even for women with mild and stable preeclampsia. The ideal time of delivery will usually lie between 37 and 39 weeks’ gestation, depending on the clinical situation. Vaginal delivery is preferable to cesarean section because of the lower risk of maternal morbidity, particularly in hypertensive women, who are more vulnerable to the stress of abdominal delivery. Even at preterm gestations, the cervix should be assessed for the possibility of successful induction of labor with cervical-ripening agents. Although half of all inductions before 35 weeks end in cesarean section, and it would be inappropriate to continue an induction for 2–3 days in the presence of severe disease that warrants delivery, sometimes a vaginal delivery is achievable rapidly and may be preferable to operative delivery, with its inherent additional risks of bleeding, thrombosis, infection, and fluid management challenges.

26.11 26.11.1

INTRAPARTUM CARE OF HYPERTENSIVE WOMEN Normal Intrapartum Hemodynamics and Physiological Changes

The maximum CO in pregnancy occurs during labor and delivery; the expulsion of blood from the uterine vascular bed with each contraction increases circulating volume, and catecholamine release and pain increase heart rate. Preload can be further increased by water retention stimulated by oxytocin release or exogenous administration because oxytocin is an analog of antidiuretic hormone (ADH). CO in labor can increase 40%–60% above the increase already seen in normal pregnancy.140 The process of parturition has been described as an inflammatory process and is characterized by proinflammatory cytokines driving an influx of leukocytes into the myometrium and cervix, contributing to uterine contractions and cervical ripening.141

26.11.2

Intrapartum Maternal and Fetal Monitoring

The physiological changes of labor can increase the risk of new or worsening hypertension and pulmonary edema by increasing CO and vascular permeability. Women without the cardiac capacity to maintain this increase, particularly those with long-standing hypertension, can be at risk of cardiovascular events in the intrapartum period. Relative underperfusion of the uteroplacental circulation during this time can contribute to fetal hypoxia during labor and increase the risk of neonatal hypoxic ischemic encephalopathy (HIE). All women with HDP should be offered continuous fetal monitoring in labor. Clinicians interpreting the CTG should take into account the possibility of fetal deterioration occurring more rapidly than would normally be expected because of possible fetal growth restriction, and act accordingly. Maternal blood pressure should be measured hourly in labor and any antihypertensive medication continued as previously prescribed. Additional antihypertensives are often required. In women with severe preeclampsia, more frequent blood pressure measurement is required, and consideration should be given to invasive monitoring, particularly if intravenous

476 SECTION 1 The Mother

antihypertensive therapy is required. Severe uncontrolled hypertension or neurological symptoms in the second stage of labor may be an indication for assisted vaginal delivery with forceps or vacuum to limit the duration of maternal effort. The use of the forceps is preferable to the use of the ventouse because it is associated with less intracranial bleeding; the ventouse is not appropriate for use at gestations <34 weeks.

26.11.3

Intrapartum Analgesia and Anesthetic Considerations

Early epidural or spinal analgesia reduces the risk of requiring general anesthesia for emergency intervention. It can also assist in blood pressure control by causing vasodilation and removing the noxious stimuli of painful contractions. Pharyngolaryngeal edema in preeclamptic patients increases the chances of failed intubation, and intubation increases the chances of severe hypertension and aspiration. Women with hypertensive disorders should not routinely receive a fluid preload prior to initiating epidural or spinal analgesia.5 Although regional anesthesia is preferred, its use may be limited by HDP-associated thrombocytopenia. Epidural hematoma is a feared complication of neuraxial blockade and has been reported in association with pregnancy thrombocytopenia.142 In the patient with additional risk factors for bleeding such as HELLP syndrome or severe PE, the whole clinical picture should be considered, as regional anesthesia may be contraindicated in the setting of a rapidly falling platelet count and concomitant coagulopathy. Due to a scarcity of cases, definitive guidance on the use of regional anesthesia in pregnancy hypertension-associated thrombocytopenia cannot be determined. Local guidelines recommend a threshold of 75–90
109 g/dL, but ultimately, a clinical risk assessment of the whole clinical picture by an experienced anesthetist is more important than the exact platelet count for determining optimal anesthetic management.143,144 Options might include platelet transfusion prior to the insertion of spinal for cesarean section in the context of worsening thrombocytopenia, planned general anesthesia, or use of alternative analgesia (e.g., remifentanil) during attempted vaginal delivery. Consideration should be given to the potential need for blood products based on the hematological and coagulation parameters as measured at the onset of labor, bearing in mind the increased risk of postpartum hemorrhage in preeclampsia. If the platelet count is <50
109/L, falling rapidly, or there is associated coagulopathy, consideration should be given to ordering platelets and other blood products. Platelet transfusion is required if platelets fall below 20
109/L around delivery, whatever the mechanism. Oxytocin should be used for active management of the third stage of labor to reduce the risk of postpartum hemorrhage. Ergometrine (and therefore Syntometrine) should be avoided for women with known hypertensive disease of any kind, even if blood pressure is normal at the time of delivery. Several maternal deaths have been caused by the hypertension associated with ergometrine use.111 This does not preclude the use of ergometrine in the event of severe postpartum hemorrhage after the use of alternative drugs and at the discretion of senior clinical staff, but an increase in antihypertensive requirement after the immediate crisis is managed should be anticipated.

26.12 POSTNATAL CARE AND FOLLOW-UP OF WOMEN AFFECTED BY HYPERTENSION IN PREGNANCY 26.12.1

Immediate Postpartum Management of Women Affected by HDP

Although delivery will ultimately cure pregnancy-related hypertension, resolution is not immediate, and hypertension and the abnormalities of HELLP syndrome typically continue to worsen before ultimate improvement. In normal pregnancy, blood pressure falls immediately after delivery due to the blood loss associated with delivery and removal of the sympathetic stimulation associated with labor. As the uterus contracts, around 500–700 mL of blood are returned from the uterine to the systemic circulation. There is further mobilization of extracellular fluid and subsequent expansion of intravascular volume, and most women experience a peak of blood pressure between the third and sixth days postpartum. In hypertensive women, a similar process will take place, which can lead to the development of severe hypertension a few days after delivery at a time when surveillance may have been relaxed. Other factors that can cause or exacerbate hypertension postpartum are pain, anxiety, the use of certain drugs (e.g., ergometrine), and fluid overload in labor. These factors should be assessed and analgesia and fluid management adjusted as necessary prior to altering antihypertensive management. Women who did not have hypertension during pregnancy may also present with hypertension for the first time during this period, and up to 44% of eclampsia presents postpartum de novo.78 After delivery, antihypertensive therapy should be continued and the same targets for control of hypertension apply as during pregnancy—the aim should be to control the blood pressure at <150/100 mm Hg if on medication. If any new

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features of severe disease develop, mothers should be moved to a higher level of care and consideration given to administering at least 24 h of magnesium sulfate as eclampsia prophylaxis. Any woman with a new-onset severe headache, with or without neurological symptoms, should be assessed to evaluate the possibility of postpartum stroke or venous thrombosis. Women may be suitable for hospital discharge within 1–2 days of delivery if blood pressure is well controlled and no other complications exist, but arrangements should be made for daily blood pressure assessment in the community by home visits, home monitoring, or an appointment in primary care or the obstetric day assessment unit.

26.12.2

Choice of Antihypertensive in the Puerperium and Lactation

Most women who have required antihypertensive therapy during pregnancy will still require treatment for several days or weeks postpartum. A wider range of effective drugs are available for use in lactating women, so the choice of agent should be reviewed at the earliest opportunity after delivery. An alternative agent might have a more convenient dosing schedule or offer renal protection for women with preexisting hypertensive or renal disease. No antihypertensive drugs are licensed for use in breastfeeding, so most recommendations are based on observational studies and expert opinion. In addition to the drugs used in pregnancy, ACE-inhibitors (enalapril and captopril) have been shown to be safe and effective in breastfeeding women (Table 26.4). They are particularly appropriate for women needing renal or cardiac protection because of prepregnancy comorbidities. Methyldopa should be avoided because of its side-effect profile, which includes depression and sedation.5

26.12.3

Complications of Hypertensive Disease in the Puerperium

GH, proteinuria, and any associated hepatic, renal, or hematological abnormalities should return to baseline by 6 weeks postpartum.145 Women with persistent hypertension or proteinuria at this time may have had chronic disease revealed by pregnancy and require further investigation in order to establish a diagnosis. Early-onset preeclampsia is associated with antiphospholipid syndrome, and consideration should be given to screening affected women after the puerperium, particularly if there are other features of the disorder. Peripartum cardiomyopathy is a rare complication of pregnancy that usually presents within the first few months after delivery. Although only a rare cause, preeclampsia is a risk factor, and symptoms of heart failure (including fatigue, dyspnea, and peripheral edema) may not be recognized immediately in the mother recovering from preeclampsia and managing the demands of a new baby.

26.13 26.13.1

LONG-TERM IMPLICATIONS OF HYPERTENSION IN PREGNANCY Future Pregnancies

All women affected by HDP should receive postnatal counseling regarding the management of future pregnancies. For women with GH, the risk of recurrence in the next pregnancy is 16%–47% and the risk of preeclampsia is 2%–7%. For women with preeclampsia, the risk of recurrence is 16% if they delivered at term, 25% if they delivered before 34 weeks, and 55% if they delivered before 28 weeks.78 All women affected by HDP should be considered for administration of low-dose aspirin for preeclampsia prophylaxis in subsequent pregnancies. Most obstetric units will offer more frequent visits or the option of home monitoring for patients at high risk of developing hypertension during pregnancy.

26.13.2

Longer-Term Maternal Health Implications

Hypertension in pregnancy is a risk factor for cardiovascular disease in later life, and postnatal consultation with women affected by preeclampsia represents a pivotal opportunity to inform about and provide advice on risk-reduction strategies. A year after severe preeclampsia, 42% of women still will have hypertension detectable upon clinical assessment, with around half of them having hypertension uncovered only with a period of ambulatory monitoring.146 Around 14% of women who had any HDP in their first pregnancy will go on to develop clinically apparent hypertension within the next 10 years, and the risk of developing hypertension within 20 years of pregnancy is doubled in women affected by HDP compared to women normotensive in pregnancy.147 It is not clear whether the endothelial dysfunction of preeclampsia causes later pathology or whether pregnancy, by increasing the demand on cardiovascular physiology, temporarily unmasks women at risk of dysfunction in later life.

478 SECTION 1 The Mother

Hypertensive disorders of pregnancy also have been associated with cerebrovascular disease, Type 2 diabetes, hypertension, and VTE.147–149 The puerperium represents an underutilized opportunity to encourage women to adopt diet and lifestyle changes that may mitigate the increased risk associated with HDP. Women are motivated to improve their health immediately after pregnancy,78 and clinicians who have been closely involved in detailed counseling and care during pregnancy should not overlook this opportunity to close their therapeutic relationship with the best available advice for their patients’ long-term health and quality of life.

26.14 l

l

l l

l

l l

l

CONCLUSION

Hypertension in pregnancy is common and extensively investigated, but the precise mechanisms of disease remain unclear. Endothelial dysfunction with a background of disrupted maternal hemodynamics, angiogenic balance, lipid and glucose metabolism, and hormonal signaling is typical of hypertension in pregnancy. The risk of HDP can be reduced with administration of low-dose aspirin from the first trimester in high-risk women. Models combining maternal characteristics, uterine artery Dopplers, and biomarkers can screen effectively for women at high risk of severe and early-onset preeclampsia. New technology in validated automated devices for home monitoring of blood pressure, together with digital distance monitoring from the hospital team, can reduce costs and improve women’s experience of antenatal monitoring. The diagnosis of preeclampsia can be clarified by the use of novel tests including PlGF and the sFlt-1/PlGF ratio. Models predicting the development of maternal complications can be used to address the clinical conundrum of timing of delivery in preterm preeclampsia. The postnatal period is a critical time for monitoring and prevention of late complications of preeclampsia, as well as health education directed at reducing the risk of cardiovascular disease associated with a history of hypertension in pregnancy.

Directions for future research and investigation include the following: l

l

l

l

l

Preeclampsia may be the presentation of women with subclinical cardiovascular dysfunction revealed by the stress of pregnancy. Preconception and longitudinal studies of maternal cardiac function could help to clarify this process. Models that predict late-onset preeclampsia or perform well as a screening test to rule it out would lead to major changes in antenatal care schedules. Additional agents for prevention of preeclampsia beyond aspirin require investigation, and the choice of agent for risk reduction may vary with the maternal phenotype at conception. Novel diagnostic tests have been developed for preeclampsia, and trials of management based on these tests now need to be reported to assess clinical effects and cost effectiveness. Additional treatments for preeclampsia, including relaxin, PPAR antagonists, nitric oxide donors, and statins, should be evaluated to add to the interventions available to allow prolongation of pregnancy.

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137. Akkermans J, Payne B, von Dadelszen P, Groen H, de Vries J, Magee LA, et al. Predicting complications in pre-eclampsia: external validation of the fullPIERS model using the PETRA trial dataset. Eur J Obstet Gynecol Reprod Biol 2014;179:58–62. 138. Payne BA, Hutcheon JA, Ansermino JM, Hall DR, Bhutta ZA, Bhutta SZ, et al. A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study. Lawn JE, editor. PLoS Med 2014;11(1):e1001589. 139. Thangaratinam S, Allotey J, Marlin N, Mol BW, Von Dadelszen P, Ganzevoort W, et al. Development and validation of prediction models for risks of complications in early-onset pre-eclampsia (PREP): a prospective cohort study. Health Technol Assess (Rockv) 2017;21(18):1–100. 140. Sanghavi M, Rutherford JD. Cardiovascular physiology of pregnancy. Circulation 2014;130(12):1003–8. 141. Norman JE, Bollapragada S, Yuan M, Nelson SM. Inflammatory pathways in the mechanism of parturition. BMC Pregnancy Childbirth 2007; 7(Suppl 1):S7. 142. Douglas JM. The use of neuraxial anesthesia in parturients with thrombocytopenia: what is an adequate platelet count? Evidence-based obstetric anesthesia. Oxford, UK: Blackwell Publishing Ltd; 2007. p. 165–77. 143. Douglas MJ. The use of neuraxial anesthesia in parturients with thrombocytopenia: what is an adequate platelet count? In: Halpern SH, Douglas MJ, editors. Evidence based obstetric anesthesia. Massachusetts: Blackwell Publishing; 2005. p. 165–177. 144. Obstetric Anaesthetists’ Association. Regional Anaesthesia and Coagulation [Internet]. [cited July 10], Available from:http://www.oaa-anaes.ac.uk/ ui/content/content.aspx?id¼188; 2018. 145. Berks D, Steegers EAP, Molas M, Visser W. Resolution of hypertension and proteinuria after preeclampsia. Obstet Gynecol 2009;114:1307–14. 146. Benschop L, Duvekot JJ, Versmissen J, van Broekhoven V, Steegers EAP, Roeters van Lennep JE. Blood pressure profile 1 year after severe preeclampsia. Hypertension 2018;71(3):491–8. 147. Behrens I, Basit S, Melbye M, Lykke JA, Wohlfahrt J, Bundgaard H, et al. Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study. BMJ 2017;358:j3078. 148. Savitz DA, Danilack VA, Elston B, Lipkind HS. Pregnancy-induced hypertension and diabetes and the risk of cardiovascular disease, stroke, and diabetes hospitalization in the year following delivery. Am J Epidemiol 2014;180(1):41–4. 149. Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ. Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother. Hypertension 2009;53(6):944–51. 150. Steegers EAP, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet 2010;376(9741):631–44.