Obstetric and Gynecologic Nephrology: Women’s Health Issues in the Patient With Kidney Disease

The female patient with chronic kidney disease often requires care that differs from the male patient. Particularly in the pregnant patient, a specialized body of knowledge is required to provide optimal care. This book focuses on such issues encountered during pregnancy including physiology and pathophysiology of pregnancy, hypertension, preeclampsia, various electrolyte disorders, nephrolithiasis, pharmacological management in the pregnant patient with kidney disease and during breastfeeding, acute kidney and chronic kidney disease, dialysis of the pregnant patient, lupus nephritis, thrombotic microangiopathy, glomerular disease management, use of renal biopsy during pregnancy, care of the female transplant patient, contraceptive counseling and postpartum care, various endocrine disorders, and bone disease in the female patient with chronic kidney disease.  This book features the latest evidence and clinical approaches for the beginner or for the experienced practitioners who care for pregnant woman or even for those who require expertise in women’s health.

Written by experts in the field, Obstetric and Gynecologic Nephrology: Women’s Health Issues in the Patient with Kidney Disease is a valuable resource for clinicians and practitioners involved in the care and treatment of obstetric and gynecologic patients afflicted with kidney disease. 

• Language: English
• Publisher: Springer
• Release date: Oct 18, 2019
• ISBN: 9783030253240

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© Springer Nature Switzerland AG 2020

M. Sachdeva, I. Miller (eds.)Obstetric and Gynecologic Nephrologyhttps://doi.org/10.1007/978-3-030-25324-0_1

1. Renal Physiology in Pregnancy

Sharon Maynard¹  

(1)

Department of Medicine, Lehigh Valley Health Network, Allentown, PA, USA

Sharon Maynard

Email: [e-mail]

Keywords

Renal physiology in pregnancyPregnancy and renal physiologySystemic hemodynamics during pregnancyUrinary tract in pregnancyGlomerular filtration rate in pregnancyRenal plasma flow in pregnancy

Pregnancy produces changes in the circulatory, renal, and urinary collection systems which support the developing fetus. There is physiologic dilatation of the urinary collecting system. There is systemic vasodilation, leading to decreased systemic vascular resistance, increased cardiac output, activation of the renin-angiotensin-aldosterone system, and plasma volume expansion. Renal blood flow and glomerular filtration rate rise, with a resultant fall in the serum creatinine concentration. Urinary excretion of protein, glucose, and amino acids increases. Electrolyte and acid-base alterations include a chronic respiratory alkalosis and mild hypoosmolarity with hyponatremia. This chapter summarizes the mechanisms and clinical implications of these physiologic changes in pregnancy.

Changes in the Urinary Tract

In pregnancy, there is enlargement of both kidneys by approximately 1–2.0 cm in length and by approximately 30% in volume [1]. Histologically, there is no change in nephron number, but renal vascular and interstitial volume both increase.

In up to 80–90% of pregnant women, there is dilation of the collecting system. The renal pelvises, calyces, and ureters are all involved. Typically the right renal pelvis and ureter are involved more than the left (Fig. 1.1) [2]. This physiologic hydronephrosis and hydroureter is commonly referred to as maternal hydronephrosis of pregnancy. Dilation can occur as early as 6–10 weeks of gestation. These changes may persist for up to 6–12 weeks postpartum [2]. Several hormonal and mechanical factors contribute to this process. Progesterone reduces ureteral tone and peristalsis [3]. In addition, prostaglandin E2 increases during pregnancy which can inhibit ureteral peristalsis and cause ureteral distension [3]. The enlarging uterus displaces, and may compress, the ureters [4]. On the right, ovarian vessels overlie the ureter at the pelvic brim, potentially leading to ureteral compression. Dilatation of the urinary collection system and urinary stasis increase the risk of urinary tract infection which may progress to pyelonephritis in pregnancy [5].

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Fig. 1.1

Physiologic hydronephrosis of pregnancy. Sagittal sonogram showing moderate hydronephrosis in the right kidney in the third trimester of pregnancy. (From Glanc and Maxwell [47], with permission)

In certain circumstances, physiologic hydronephrosis may need to be distinguished from obstructive uropathy. In cases of true urinary retention or obstruction, flank pain is usually present. However, flank pain may rarely be seen in the setting of physiologic hydronephrosis. Obstructive uropathy may result from mechanical compression of the ureters or from nephrolithiasis. Therapeutic approaches may include ureteral stent placement or percutaneous nephrostomy tube placement [6]. In early pregnancy, urinary retention rarely can be caused by incarceration or impaction of the gravid uterus in the pelvis [7]. Such cases can be managed by bladder catheterization and bimanual manipulation of the uterus into an anteverted position [8].

Urinary frequency and nocturia affect 80–95% of women at some point during pregnancy [9, 10]. Several physiologic changes contribute to these symptoms. Compression of the bladder by the enlarging uterus reduces maximum bladder capacity [11]. Detrusor instability has been noted in up to 20% of normal pregnancies [11]. Nocturnal excretion of sodium and water are increased, primarily from mobilization of dependent edema, leading to nocturia [12].

Stress incontinence is also common in pregnancy [11, 13, 14]. As with urinary frequency, this symptom may be attributable to compression of the bladder by the uterus, leading to increased bladder pressure [15]. Increased levator ani hiatal area may also contribute to incontinence [13, 16].

In the early postpartum period, there can be transient urinary retention. Risk factors include nulliparity, long labor, instrumental delivery, long duration of bladder catheterization, and extensive vaginal and perineal laceration [17]. Local, regional, or general anesthesia can also impair voiding as can analgesics. These can cause detrusor atony and decreased sensitivity to intravesicular pressure. Symptoms are typically mild and transient and tend to self-resolve. In cases of severe urinary retention, straight catheterization of the bladder may be indicated to initiate voiding.

Systemic Hemodynamics, Glomerular Filtration Rate, and Renal Plasma Flow

Physiologic changes in systemic hemodynamics during pregnancy are profound (Table 1.1). Beginning in the first trimester, there is increased arterial compliance and vasodilation, leading to decreased systemic vascular resistance, a slight decline in blood pressure, and increased cardiac output [18]. These changes are evident by 6 weeks gestation, prior to the establishment of the fetal-placental circulation (Fig. 1.2) [19]. Renal plasma flow(RPF) rises early in pregnancy, peaks by mid-gestation, falls during the third trimester toward normal, and then falls below normal postpartum for variable number of weeks, even up to 25 weeks postpartum. Glomerular filtration rate (GFR) increases in parallel with RPF, reaching 40–60% above baseline levels by the early second trimester [20]. The GFR remains high through most of the third trimester before declining toward term [21], returning to prepregnancy baseline level by 2 weeks postpartum [22]. As a result of the changes in GFR and hyperfiltration, the serum creatinine concentration falls by an average of 0.4 mg/dL during pregnancy. Thus normal creatinine levels range around 0.4 mg/dL to approximately 0.8 mg/dL during pregnancy. The plasma creatinine level should usually not be greater than 0.8 mg/dL during pregnancy, and a normal creatinine level in a pregnant woman may sometimes indicate underlying renal dysfunction. Blood urea nitrogen (BUN) levels decrease during pregnancy as well to levels of approximately 8–10 mg/dL.

Table 1.1

Summary of the physiologic changes during pregnancy

Created by Mala Sachdeva

../images/393995_1_En_1_Chapter/393995_1_En_1_Fig2_HTML.png

Fig. 1.2

Hemodynamic changes in normal pregnancy. Ten women were studied in the mid-follicular phase of the menstrual cycle and weeks 6, 8, 10, 12, 24, and 36 gestation. Mean arterial pressure (MAP) decreased and cardiac output (CO) increased significantly by week 6 gestation in association with a decrease in systemic vascular resistance (SVR). ∗P < 0.05, ∗∗P < 0.001. (Adapted from Chapman et al. [19]. Kidney International 1998 PMID: 9853271, with permission)

Hormonal Mediators: Relaxin

Vasodilation in pregnancy reflects reduced vascular responsiveness to vasopressors, including angiotensin II, norepinephrine, and vasopressin [23]. Relaxin is a vasodilatory hormone secreted by the placenta and decidua in response to human chorionic gonadotropin (hCG) [24]. In the kidney, relaxin increases endothelin and nitric oxide production, leading to renal vasodilation, decreased glomerular afferent and efferent arteriolar resistance, increased renal blood flow, and increased GFR. Chronic administration of relaxin to rats reproduces these renal hemodynamic changes of pregnancy. These changes are attenuated by inhibition of nitric oxide synthesis [25]. In pregnant rats, GFR and renal plasma flow fall with administration of antirelaxin antibodies or with removal of the ovaries [26].

Changes in the angiotensin II (AngII) pathway also contribute to vasodilation in pregnancy. Pregnant animals have increased vascular expression of the angiotensin type 2 receptors (AT2R), which leads to vasodilation rather than vasoconstriction in response to angiotensin II [27]. Increased levels of the vasodilatory angiotensin (1–7) in human pregnancy have been described as well [28].

Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system is activated in normal pregnancy [29]. Estrogen directly stimulates angiotensinogen production. In addition, renal renin production is increased likely due to progesterone. High levels of angiotensin II and aldosterone lead to renal sodium retention, plasma volume expansion, and edema formation. As a result, total body volume increases 6–8 liters by late pregnancy. Plasma volume increases by approximately 50%, and the remaining fluid is distributed among the fetus, amniotic, intracellular, and interstitial spaces [30]. High levels of angiotensin II do not produce hypertension because of the diminished vasoconstrictor response to angiotensin II, as previously discussed.

Estimating Glomerular Filtration Rate in Pregnancy

Creatinine is a relatively insensitive marker of decreased GFR. In pregnancy, a serum creatinine within the normal range may represent a significant reduction in GFR. For example, in one study, women with preeclampsia had a 40% reduction in GFR as compared with control pregnant women (89 vs. 149 ml/min/1.73 m² BSA), despite normal serum creatinine levels (0.89 mg/dl vs. 0.60 mg/dl in control pregnancies) [31]. Hence, careful attention to small changes in serum creatinine is required to detect renal injury in pregnancy.

Assessment of glomerular filtration rate during pregnancy is challenging. The 24-hour urine collection for creatinine clearance remains the gold standard; however it can be cumbersome, and both overcollection and undercollection are common, limiting accuracy [32]. Urinary stasis from dilatation of the lower urinary tract in pregnancy may contribute to the inaccuracy of 24-hour urine collections in pregnancy. Creatinine-based estimating equations, such as the Modification of Diet in Renal Disease (MDRD) equation and the CKD-EPI equation, have not been validated in pregnancy. Studies suggest that these equations significantly underestimate GFR, particularly in women with normal or near-normal renal function [33–35]. Despite these limitations, an increase in the serum creatinine, as compared to baseline, remains a useful clinical sign of decreased glomerular filtration rate.

Osmoregulation

The plasma osmolality falls in pregnancy , to a new set point of about 270 mosmol/kg, and plasma sodium concentration falls by approximately 4–5 meq/L [36]. Thirst and antidiuretic hormone release from the posterior pituitary affect water intake and excretion to maintain plasma osmolality at this new set point. Serum osmolality returns to baseline as early as the first day after delivery. The plasma sodium concentration spontaneously returns to prepregnancy levels by 8 weeks postpartum [36, 37].

Hyponatremia in pregnancy is mediated primarily by hormonal factors, particularly antidiuretic hormone (ADH) and human chorionic gonadotropin (hCG) [37, 38]. hCG administered to nonpregnant women during the luteal phase of the menstrual cycle induces hyponatremia [38, 39]. hCG appears to produce these changes via the release of relaxin [25]. Hyponatremia in pregnant rats can be reversed by administration of antirelaxin antibodies [26].

Antidiuretic hormone (ADH) is normally released by the posterior pituitary in response to high plasma osmolality, typically manifested as hypernatremia. ADH acts on the kidney to increase water reabsorption, allowing the excretion of concentrated urine. Beginning in the late first trimester of pregnancy, the metabolic clearance of ADH increases four to sixfold because of an increase in placental production of vasopressinase, which degrades ADH [40]. Vasopressinase activity peaks in the third trimester and falls to undetectable levels 2–4 weeks postpartum. In most pregnant women, plasma concentrations of ADH remain in the normal range despite increased clearance via a compensatory increase in ADH production. As a result, most women do not develop true polyuria, although urinary frequency secondary to lower urinary tract changes are common. Rarely, pregnant women develop polyuria, in a disorder called transient diabetes insipidus of pregnancy [37, 41, 42]. In such cases, life-threatening hypernatremia can occur if fluid intake is restricted, as during labor and delivery [43]. Diabetes insipidus of pregnancy should be suspected in the setting of polyuria (>3 liters/day), high-normal plasma sodium, and a low urine osmolality. This can be treated with desmopressin, or ddAVP.

Increase in ADH during pregnancy also occurs due to systemic vasodilation and arterial underfilling and reset osmostat for vasopressin release and from other stimuli such as nausea or pain during pregnancy.

Proteinuria

Urinary protein excretion rises in pregnancy, from the nonpregnant level of <150 mg/day to up to even 300 mg/day. Values above 300 mg per day may indicate preeclampsia, especially if after 20 weeks gestation, de novo kidney disease, or worsening preexisting kidney disease. Urine protein excretion has been noted to be higher in uncomplicated twin pregnancy. In a prospective study of 50 uncomplicated twin pregnancies, 43% had urine protein excretion of >300 mg/day [44]. In a concentrated urine sample, a positive dipstick may result. Thus, although proteinuria can be a sign of preeclampsia or underlying kidney disease, mild degrees of proteinuria may be a normal finding and should be interpreted on a case by case basis. In the absence of hypertension or other signs or symptoms of preeclampsia or placental insufficiency, close monitoring and reassurance are often appropriate in women with low-grade proteinuria (<500 mg/d or urine protein-creatinine ratio <0.5 g/g). Serial monitoring is recommended once proteinuria is found. A 24-hour collection for proteinuria as well as a random urine protein-creatinine ratio can be performed to monitor trends.

Proximal Tubular Function

In pregnancy, there is reduced fractional reabsorption of glucose, uric acid, and amino acids by the proximal tubule, resulting in higher urinary excretion of these molecules. Thus, pregnant patients may exhibit glycosuria and aminoaciduria in the absence of hyperglycemia, diabetes mellitus, or renal disease [45]. Due to increased urinary excretion of uric acid, levels reach a nadir of 2.0–3.0 mg/dL by 22–24 weeks gestation, followed by a gradual rise to normal nonpregnant levels by term [45]. Since uric acid levels are followed for the development of preeclampsia, it is important to keep these physiologic changes in mind.

Acid-Base Balance

Minute ventilation rises in pregnancy, leading to mild respiratory alkalosis, with a fall in the pCO2 by approximately 25%. Thus the pCO2 decreases to approximately 27–32 mmHg from a normal of 40 mmHg. This is mediated by progesterone, which stimulates the central respiratory center [46]. Hyperventilation facilitates a high-normal pO2 despite a 20–33% increase in oxygen consumption in pregnancy. This chronic respiratory alkalosis leads to a renal metabolic response, lowering the serum bicarbonate concentration to 20–22 mEq/L due to a fall in bicarbonate reabsorption.

Summary

The kidneys adapt to pregnancy via changes in urinary tract structure and function, systemic and renal hemodynamics, plasma volume, osmolality, and electrolyte composition. Many pregnant women develop hydronephrosis, which is rarely pathological. Urinary frequency, nocturia, and incontinence are common. In early pregnancy, renal plasma flow and GFR increase substantially. Renal hemodynamic changes are mediated primarily by the vasodilatory hormone, relaxin. Plasma volume expansion occurs early in pregnancy, with a concurrent fall in plasma osmolality. Placental elaboration of vasopressinase leads to increased metabolic clearance of antidiuretic hormone, but this rarely results in clinical diabetes insipidus.

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© Springer Nature Switzerland AG 2020

M. Sachdeva, I. Miller (eds.)Obstetric and Gynecologic Nephrologyhttps://doi.org/10.1007/978-3-030-25324-0_2

2. Hypertensive Disorders in Pregnancy

Silvi Shah¹  

(1)

Division of Nephrology, University of Cincinnati, Cincinnati, OH, USA

Silvi Shah

Email: [e-mail]

Keywords

Gestational hypertensionHypertensive disorders in pregnancyPregnancy and hypertensive disordersPreeclampsia in pregnancySuperimposed preeclampsia in chronic hypertension

Hypertension is the most commonly seen medical disorder of pregnancy occurring in up to one in every ten gestations and complicates up to 10% of pregnancies [1, 2]. In the United States, hypertensive disorders are one of the leading causes of pregnancy-related maternal and perinatal morbidity and mortality contributing to 10–15% of maternal deaths [3, 4]. Hypertensive disorders of pregnancy can be subclassified into four groups as outlined in the American Congress of Obstetricians and Gynecologists (ACOG) guidelines: chronic hypertension, preeclampsia, superimposed preeclampsia in the setting of chronic hypertension, and gestational hypertension [1, 2]. The additional category of white coat hypertension has been included in the International Society for the Study of Hypertension in Pregnancy (ISSHP) guidelines [5]. Each hypertensive disorder of pregnancy increases the risk of maternal and neonatal mortality and morbidity; however, preeclampsia is associated with the greatest risks [6, 7]. Timely diagnosis and proper treatment is therefore essential to prevent these complications.

Diagnostic Criteria

Hypertension

Hypertension in pregnancy is defined as a systolic blood pressure of ≥140 mmHg or diastolic blood pressure of ≥90 mmHg and should be confirmed with an additional determination that is at least 20 minutes apart. Blood pressure should ideally be taken in the upper arm using an appropriately sized cuff with the woman at rest and the arm held at the level of the heart. Although mercury sphygmomanometer is the gold standard for measurement, it may not be routinely used in many outpatient settings. When an automated device is used, it should always be validated especially in the pregnant population [2].

Proteinuria

In pregnancy, proteinuria is defined as total protein of ≥300 mg per day in a 24-hour urine collection. Spot urine protein-creatinine ratio (PCR) has a high negative predictive value and can be performed quickly on a single urine sample to facilitate rapid decision-making. A value greater than or equal to 0.30 mg protein/mg creatinine indicates significant proteinuria but should be followed by 24-hour urine collection in equivocal cases. In a meta-analysis involving 974 pregnant women, it was shown that spot PCR ratio cutoffs between 0.19 and 0.25 have a pooled sensitivity of 90% and specificity of 78% as compared with 24 hours urine protein excretion of ≥300 mg/day [8, 9]. Urine dipstick can be used to detect proteinuria if either 24-hour urine collection or a spot PCR is not available. Management of preeclampsia can be started in women with clinical suspicion of preeclampsia and presence of proteinuria on dipstick (≥1+). However, due to the low sensitivity and variability in the qualitative measurements of urine dipstick, use of this method for diagnosis is discouraged [2, 10]. Approximately half of the women presenting with proteinuria without hypertension will develop preeclampsia during the course of pregnancy and should be monitored closely [11]. About 10% of women with other clinical manifestations of preeclampsia have no proteinuria. Therefore, preeclampsia should be suspected in any pregnant woman with hypertension and characteristic signs or symptoms, even if proteinuria is absent [8].

The Hypertensive Disorders of Pregnancy

Chronic Hypertension

Chronic hypertension is defined by systolic blood pressure ≥140 mmHg and/or diastolic blood pressure of ≥90 mmHg present before pregnancy or present on at least two occasions before 20 weeks of gestation [12]. Secondary causes should be ruled out in women diagnosed with chronic hypertension. Chronic hypertension complicates 3–5% of all pregnancies in the United States and has been increasing over time due to an increase in obesity and delay in childbearing age. Importantly, about 25% of women with chronic hypertension will develop preeclampsia during pregnancy [13]. Compared with the general population, women with chronic hypertension have a higher incidence of cesarean sections (41%), preterm deliveries (28%), low birth weights (17%), neonatal unit admissions (21%), and perinatal deaths (4.0%) [6]. Although women with chronic hypertension have a higher risk of developing superimposed preeclampsia, many women experience a physiological lowering of blood pressure during pregnancy and a reduction in the requirement for antihypertensive medications. This nadir in blood pressure in the second trimester which is due to the systemic vasodilation occurring in pregnancy can result in diagnostic uncertainty. Since women with chronic hypertension are at increased risk of preeclampsia in pregnancy, they should be closely monitored.

Gestational Hypertension

Gestational hypertension is defined as a new-onset hypertension (defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg) without proteinuria or other features of preeclampsia that develops after 20 weeks of gestation. Gestational hypertension is the most common cause of hypertension during pregnancy, complicating about 6–17% of all pregnancies in nulliparous women. The highest prevalence occurs in women with a prior history of preeclampsia and multiple gestation or those with higher body mass index. About 10–25% of women with gestational hypertension will progress to preeclampsia [2, 14]. Clinical features shown to predict the increased risk of progression to preeclampsia include gestational age <34 weeks at diagnosis, mean systolic blood pressure >135 mmHg, abnormal uterine artery Doppler velocimetry, and elevated serum uric acid level (>5.2 mg/dL) [15]. The diagnosis is modified to the following: [1] preeclampsia, if proteinuria or new signs of end-organ dysfunction develop; [2] chronic (primary or secondary) hypertension, if blood pressure elevation persists ≥12 weeks postpartum; or [3] transient hypertension of pregnancy, if blood pressure resolves by 12 weeks postpartum. Women with gestational hypertension require close monitoring throughout pregnancy. Reassessment at 12 weeks postpartum is crucial in establishing the final diagnosis [2].

Preeclampsia

Preeclampsia is classically defined by new onset of hypertension BP ≥140/90 mmHg on two occasions 4 hours apart, or ≥160/110 mmHg within a shorter interval after 20 weeks of gestation and proteinuria ≥300 mg/24 hour urine (urine PCR 0.3, dipstick 1+) in a previously normotensive woman. Proteinuria may not be present, and in fact, ACOG revised the diagnostic criteria in 2013 so that proteinuria is no longer a necessary component. In the absence of proteinuria, preeclampsia may be diagnosed with new-onset hypertension and any of the following evidence of end-organ dysfunction [2]:

Elevated serum creatinine >1.1 mg/dl or doubling of serum creatinine in the absence of other renal disease

Thrombocytopenia (platelets <100,000/microliter)

Elevated liver transaminases ≥2 times normal

Pulmonary edema

Cerebral or visual symptoms

Preeclampsia Superimposed upon Chronic Hypertension

Superimposed preeclampsia is diagnosed in woman with a prior history of hypertension who demonstrates worsening of her hypertension and the development of new-onset proteinuria after 20 weeks of gestation. A rise in blood pressure and the need for antihypertensive therapy in the third trimester are not unexpected in women with preexisting essential hypertension; hence hypertension alone is not sufficient to diagnose preeclampsia and only if a woman develops worsening hypertension in combination with proteinuria, new end-organ dysfunction, or uteroplacental dysfunction, then preeclampsia may be confidently diagnosed. The diagnosis of preeclampsia remains most challenging in women with long-standing hypertension and renal impairment. Since about 25% of pregnancies in women with chronic hypertension are complicated by superimposed preeclampsia, close monitoring is recommended [16]. Table 2.1 shows the diagnostic features of different subtypes of hypertensive disorders of pregnancy.

Table 2.1

Classification of hypertensive disorders of pregnancy

Risk Factors for Preeclampsia

Preeclampsia is a pregnancy-specific hypertensive disorder with multisystem involvement characterized by generalized endothelial damage which can result in widespread end-organ damage. Preeclampsia affects 2–8% of all pregnancies worldwide, and the incidence has increased by 25% in the United States during the past two decades [17]. It remains the leading cause of maternal and perinatal mortality and morbidity worldwide. Ten percent of maternal deaths are associated with preeclampsia. Furthermore, preeclampsia accounts for 50,000 infant deaths and increases iatrogenic prematurity by fivefold [18, 19]. Risk of preeclampsia is higher in women with a prior history of preeclampsia, presence of anti- phospholipid antibodies, diabetes mellitus, multiple gestation pregnancy, nulliparity, family history of preeclampsia or cardiovascular disease, chronic hypertension, obesity, advanced maternal age ≥40, renal disease, systemic lupus erythematosus, high altitude, and autoimmune disease [20, 21]. A prior episode of clinically recovered acute kidney injury increases the risk of preeclampsia by 4.7-fold. Living kidney donation in women is associated with a 2.4-fold higher risk of preeclampsia [22, 23].

Clinical Features and Complications

While the clinical presentation is highly variable, risk of adverse outcomes increases significantly when preeclampsia develops early before 34 weeks of gestation. Severe preeclampsia is characterized by severe hypertension (BP > 160/110 mmHg), evidence of end-organ damage, or intrauterine growth restriction. The most common presentation of preeclampsia is hypertension that is routinely detected at an antenatal visit in an asymptomatic woman. Most of the signs and symptoms will be present only in severe disease. The common symptoms in severe preeclampsia include vomiting, visual disturbances, headache, worsening of hand or leg edema, or severe persistent right upper quadrant or epigastric pain. On examination, in addition to higher blood pressures, patients can have papilledema, right upper quadrant tenderness, hyperreflexia with marked clonus, pulmonary edema, and altered mental status [2, 24, 25]. Rapidly progressing signs and symptoms indicates impending severe disease that needs close monitoring. The major adverse outcomes include neurological complications such as seizures (eclampsia) and strokes, HELLP syndrome (defined by hemolysis, elevated liver enzymes, and low platelets), and renal dysfunction (ranging from mild reduction in glomerular filtration rate and minimal proteinuria to reversible or irreversible acute renal failure due to acute tubular necrosis or acute cortical necrosis) [26, 27]. HELLP syndrome occurs in about 10–20% of women with severe preeclampsia and is associated with significant maternal and perinatal morbidity [28]. Preeclampsia is a risk factor for cardiovascular disease, and preeclamptic women have 3.7 times higher risk of developing hypertension, 2.2 times increased risk of coronary heart disease, and 1.8 times higher risk of stroke [29]. Although the absolute risk of end stage renal disease (ESRD) in women with history of preeclampsia is low, preeclampsia is associated with cumulative risk of subsequent ESRD. A study from Norwegian Renal Registry concluded that preeclampsia during the first pregnancy was associated with a 4.7 higher risk of ESRD in women who had been pregnant one or more times. Among women with two or more pregnancies, preeclampsia during the first pregnancy was associated with 3.2 higher risk of ESRD, and preeclampsia during the second pregnancy was associated with 6.7 higher risk of ESRD [30]. Preeclampsia can also be complicated by pulmonary edema, placental abruption, oligohydramnios, cesarean delivery, and preterm delivery. Fetal growth restriction is seen in up to 30% of the pregnancies, and long-term effects in the offspring include a higher risk of hypertension and stroke [14, 31–33]. Since preeclampsia is a disease with a highly diverse phenotypic spectrum, it remains challenging to diagnose it in the setting of preexisting hypertension or renal disease.

Pathophysiology of