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Lâm sàng và chẩn đoán tiền sản giật
Preeclampsia: Clinical features and diagnosis
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/contributorsPhyllis August, MD, MPH
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/contributorsBaha M Sibai, MD
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/contributorsCharles J Lockwood, MD, MHCM
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/contributorsVanessa A Barss, MD, FACOG
All topics are updated as new evidence becomes available and our
https://www.uptodate.com/home/editorial-policypeer review process is complete.
Literature review current through: Jun 2017. | This topic last updated: May 12, 2017.
INTRODUCTION — Preeclampsia is a multi-system progressive disorder characterized by the new onset of hypertension and proteinuria, or hypertension and end-organ dysfunction with or without proteinuria, in the last half of pregnancy or postpartum (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F79977&topicKey=OBGYN%2F6814&source=see_linktable 1). The disorder is caused by placental and maternal vascular dysfunction and always resolves after delivery. Although most affected pregnancies deliver at term or near term with good maternal and fetal outcomes, these pregnancies are at increased risk for maternal and/orfetal mortality or serious morbidity. In addition, women with preeclampsia are at increased risk for future cardiovascular disease.
This topic will discuss the clinical features, diagnosis, and differential diagnosis of preeclampsia. Other important issues related to this disease are reviewed separately.
https://www.uptodate.com/contents/preeclampsia-management-and-prognosis?source=see_link"Preeclampsia: Management and prognosis".)
https://www.uptodate.com/contents/early-pregnancy-prediction-of-preeclampsia?source=see_link"Early pregnancy prediction of preeclampsia".)
DEFINITIONS OF PREGNANCY-RELATED HYPERTENSIVE DISORDERS — There are four major hypertensive disorders related to pregnancy [
●Preeclampsia – Preeclampsia refers to the new onset of hypertension and proteinuria or hypertension and end-organ dysfunction with or without proteinuria after 20 weeks of gestation in a previously normotensive woman (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F79977&topicKey=OBGYN%2F6814&source=see_linktable 1). It may also develop postpartum. Severe hypertension or signs/symptoms of end-organ injury represent the severe end of the disease spectrum (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F76975&topicKey=OBGYN%2F6814&source=see_linktable 2) [
In 2013, the American College of Obstetricians and Gynecologists removed proteinuria as an essential criterion for diagnosis of preeclampsia. They also removed massive proteinuria (5 g/24 hours) and fetal growth restriction as possible features of severe disease because massive proteinuria has a poor correlation with outcome and fetal growth restriction is managed similarly whether or not preeclampsia is diagnosed [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/22]. Oliguria was also removed as a characteristic of severe disease.
Eclampsia refers to the development of grand mal seizures in a woman with preeclampsia, in the absence of other neurologic conditions that could account for the seizure. (See
HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) probably represents a severe form of preeclampsia, but this relationship remains controversial; HELLP may be an independent disorder. As many as 15 to 20 percent of affected patients do not have concurrent hypertension or proteinuria, leading some authorities to opine that HELLP syndrome is a separate disorder from preeclampsia. (See
●Chronic/pre-existing hypertension – Chronic/pre-existing hypertension is defined as systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg that antedates pregnancy or is present on at least two occasions before the 20th week of gestation or persists longer than 12 weeks postpartum. It can be primary (primary hypertension, formerly called "essential hypertension") or secondary to a variety of medical disorders. (See
https://www.uptodate.com/contents/overview-of-hypertension-in-adults?source=see_link"Overview of hypertension in adults".)
●Preeclampsia superimposed upon chronic/pre-existing hypertension – Superimposed preeclampsia is defined by the new onset of proteinuria, end-organ dysfunction, or both after 20 weeks of gestation in a woman with chronic/pre-existinghypertension. For women with chronic/pre-existing hypertension who have proteinuria prior to or in early pregnancy, superimposed preeclampsia is defined by worsening or resistant hypertension (especially acutely) in the last half of pregnancy or development of signs/symptoms of the severe end of the disease spectrum (
●Gestational hypertension – Gestational hypertension refers to hypertension without proteinuria or other signs/symptoms of preeclampsia that develops after 20 weeks of gestation (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F56709&topicKey=OBGYN%2F6814&source=see_linktable 3). Some women (10 to 25 percent) with gestational hypertension may ultimately develop signs and symptoms of preeclampsia. It should resolve by 12 weeks postpartum. If hypertension persists beyond 12 weeks postpartum, the diagnosis is "revised" to chronic/pre-existing hypertension that was masked by the physiologic decrease in blood pressure that occurs in early pregnancy. If hypertension resolves postpartum, and if signs and symptoms of preeclampsia have not developed, the diagnosis can be "revised" to transient hypertension of pregnancy. (See
PREVALENCE — In a systematic review, 4.6 percent (95% CI 2.7-8.2) of pregnancies worldwide were complicated by preeclampsia [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/33]. Variations in prevalence reflect, at least in part, differences in the maternal age distribution and proportion of nulliparous pregnant women among populations [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/44]. The prevalence of preeclampsia in the United States is approximately 3.4 percent, but 1.5-fold to 2-fold higher in first pregnancies [
Prevalence also varies by gestational age. Preeclampsia is less prevalent before 34 weeks of gestation. In one population-based study, the prevalence before and after 34 weeks was 0.3 and 2.7 percent, respectively [
BURDEN OF DISEASE — Women with preeclampsia are at an increased risk for life-threatening obstetric or medical complications. Worldwide, 10 to 15 percent of direct maternal deaths (ie, resulting from obstetric complications of pregnancy) are associated with preeclampsia/eclampsia [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/77]. In the United States, preeclampsia/eclampsia is one of the four leading causes of maternal death, along with hemorrhage, cardiovascular conditions, and thromboembolism [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/8-108-10]. There is approximately one maternal death due to preeclampsia-eclampsia per 100,000 live births, with a case-fatality rate of 6.4 deaths per 10,000 cases [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/11,1211,12]. For the fetus, preeclampsia can lead to intrauterine growth restriction and oligohydramnios, as well as medically or obstetrically indicated preterm birth. As a result, perinatal morbidity and mortality are increased.
RISK FACTORS — Risk factors for preeclampsia are listed in the table (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F61266&topicKey=OBGYN%2F6814&source=see_linktable 4). The magnitude of risk depends upon the specific factor and is described below for selected risk factors evaluated in systematic reviews [
●A past history of preeclampsia increases the risk of developing preeclampsia in a subsequent pregnancy sevenfold compared with women without this history (relative risk [RR] 7.19, 95% CI 5.85-8.83) [
The severity of preeclampsia strongly impacts this risk. Women with severe features of preeclampsia in the second trimester are at greatest risk of developing preeclampsia in a subsequent pregnancy: Rates of 25 to 65 percent have been reported [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/15-1815-18]. By comparison, women without severe features of preeclampsia in their first pregnancy develop preeclampsia in 5 to 7 percent of second pregnancies [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/19,2019,20]. Women who had a normotensive first pregnancy develop preeclampsia in less than 1 percent of second pregnancies.
●First pregnancy (nulliparity) (RR 2.91, 95% CI 1.28-6.61) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/1313]. It is unclear why the nulliparous state is consistently found to be a significant predisposing factor for preeclampsia. One theory is that the immune system of nulliparous women has had limited exposure to paternal antigens, and this lack of desensitization may play a role in the pathogenesis of the disease. Epidemiologic data support this theory: Protection from preeclampsia in subsequent pregnancies is either reduced or eliminated if there is a change in paternity, women using barrier methods of contraception are at increased risk, and risk is reduced with increased duration of sexual activity before pregnancy [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/2121]. However, the notion that the risk of preeclampsia is increased in a second pregnancy with a new partner has been challenged by data suggesting that a longer interval between pregnancies may be the reason for the increased risk with a new partner [
●A family history of preeclampsia in a first-degree relative (RR 2.90, 95% CI 1.70-4.93) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/1313], suggesting a heritable mechanism in some cases [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/23,2423,24]. The occurrence and severity of the disease appears to be influenced primarily by maternal factors, but the paternal contribution to fetal genes may have a role in defective placentation and subsequent preeclampsia. (See
https://www.uptodate.com/contents/preeclampsia-pathogenesis?source=see_link§ionName=GENETIC+FACTORS&anchor=H8"Preeclampsia: Pathogenesis", section on 'Genetic factors'.)
●Pre-existing medical conditions:
•Pregestational diabetes (RR 3.56, 95% CI 2.54-4.99) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/1313]. This increase has been related to a variety of factors, such as underlying renal or vascular disease, high plasma insulin levels/insulin resistance, and abnormal lipid metabolism [
•Blood pressure ≥130/80 mmHg at the first prenatal visit (RR 1.38 to 2.37) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/1313]. The risk of superimposed preeclampsia is highest in women with diastolic blood pressure ≥110 mmHg (RR 5.2) and ≥100 mmHg (RR 3.2) before 20 weeks of gestation.
•Antiphospholipid antibodies (RR 9.72, 95% CI 4.34-21.75) [
•Body mass index ≥26.1 (RR 2.47, 95% CI 1.66-3.67) [
•Chronic kidney disease (CKD) (relative risk varies depending on the degree of reduction of glomerular filtration rate and the presence or absence of hypertension). In one study, the combination of treated hypertension and proteinuria in early pregnancy appeared to increase the risk for superimposed preeclampsia above that for hypertension alone [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/2626]. In other studies, as many as 40 to 60 percent of women with advanced CKD (stages 3, 4, 5) were diagnosed with preeclampsia in the latter half of pregnancy [
●Twin pregnancy (RR 2.93, 95% 2.04-4.21) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/1313]. Preeclampsia is even more frequent with multi-order gestations (triplets, quadruplets) [
●Advanced maternal age (maternal age ≥40: RR 1.96, 95% CI 1.34-2.87 for multiparas and RR 1.68, 95% CI 1.23-2.29 for primiparas) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/1313]. Older women tend to have additional risk factors, such as diabetes mellitus and chronic hypertension, that predispose them to developing preeclampsia.
Whether adolescents are at higher risk of preeclampsia is more controversial [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/3030]; the systematic review did not find an association [
https://www.uptodate.com/contents/effects-of-advanced-maternal-age-on-pregnancy?source=see_link"Effects of advanced maternal age on pregnancy".)
Of note, women who smoke cigarettes have a lower risk of preeclampsia than nonsmokers. (See
https://www.uptodate.com/contents/cigarette-smoking-impact-on-pregnancy-and-the-neonate?source=see_link§ionName=Preeclampsia&anchor=H18"Cigarette smoking: Impact on pregnancy and the neonate", section on 'Preeclampsia'.)
OVERVIEW OF PATHOPHYSIOLOGY — The pathophysiology of preeclampsia likely involves both maternal and fetal/placental factors. Abnormal trophoblast invasion of the spiral arteries of the decidua and myometrium early in pregnancy, weeks to months before development of clinical manifestations of the disease, has been well documented [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/31,3231,32]. Failure to establish an adequate uteroplacental blood flow can result in relatively hypoxic trophoblast tissue, which may promote an exaggerated state of oxidative stress in the placenta [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/3333]. This may further attenuate trophoblast invasion and appears to alter placental villous angiogenesis, leading to poor development of the fetoplacental vasculature and abnormal vascular reactivity. Placental secretion of angiogenic factors (soluble flt1 and endoglin) that bind vascular endothelial growth factor and placental growth factor in the maternal circulation appears to result in widespread maternal vascular dysfunction, leading to hypertension, proteinuria, and the other clinical manifestations of preeclampsia [
Some authorities have characterized preeclampsia as early-onset (<34 weeks of gestation) and late-onset (≥34 weeks of gestation). The clinical features overlap, but the spectrum of disease and outcomes differ: Early-onset disease has been associated with more severe placental and maternal/fetal clinical findings and, in turn, poorer maternal/fetal outcomes [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/36,3736,37]. For this reason, it has been hypothesized that the two phenotypes have different origins and pathophysiologies [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/36,38,3936,38,39]. However, these differences can also be explained by biological variation in the disease process.
SCREENING — Screening for traditional risk factors for preeclampsia is of value at the first prenatal visit to identify women at high risk of developing the disease, as these women are offered low-dose
https://www.uptodate.com/contents/aspirin-drug-information?source=see_linkaspirin therapy to reduce their risk of developing the disease. (See
https://www.uptodate.com/contents/early-pregnancy-prediction-of-preeclampsia?source=see_link§ionName=Universal+screening&anchor=H4108061536"Early pregnancy prediction of preeclampsia", section on 'Universal screening' and
https://www.uptodate.com/contents/preeclampsia-prevention?source=see_link§ionName=Our+approach+to+low-dose+aspirin+therapy&anchor=H65619565"Preeclampsia: Prevention", section on 'Our approach to low-dose aspirin therapy'.)
All pregnant women are at risk for preeclampsia, and evidence supports routinely screening for the disorder by measuring blood pressure at all provider visits throughout pregnancy [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/2,40,412,40,41]. The value of any laboratory or imaging test for screening has not been established (see
https://www.uptodate.com/contents/early-pregnancy-prediction-of-preeclampsia?source=see_link"Early pregnancy prediction of preeclampsia").
It is customary to test for proteinuria at each prenatal visit; however, this practice has not been rigorously evaluated and proven to improve outcomes [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4141]. We suggest performing a urinalysis to test for proteinuria at the first prenatal visit to establish a baseline and, given the possibility for false-positives and false-negatives, repeating the test in asymptomatic normotensive patients on at least one subsequent prenatal visit. In contrast, testing for proteinuria should be performed in women with hypertension as proteinuria changes the diagnosis to preeclampsia. Once a diagnosis of preeclampsia is established, testing for proteinuria is no longer diagnostically or prognostically useful. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Proteinuria' below and
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Definitions of pregnancy-related hypertensive disorders' above.)
CLINICAL PRESENTATION — Most patients are nulliparous and present with new-onset hypertension and proteinuria at ≥34 weeks of gestation, sometimes during labor [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/42,4342,43]. Approximately 10 percent of affected women develop these signs and symptoms at <34 weeks of gestation (ie, early-onset preeclampsia) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4242] and rarely as early as 20 to 22 weeks. In approximately 5 percent, the signs and symptoms are first recognized postpartum (ie, postpartum preeclampsia), usually within 48 hours of delivery [
The degree of maternal hypertension and proteinuria, and the presence/absence of other clinical manifestations of the disease (described below) are highly variable [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4747]. Approximately 25 percent of affected women develop one or more of the following nonspecific symptoms, which characterize the severe spectrum of the disease and signify the need for urgent evaluation and possible delivery:
●Persistent and/or severe headache
●Visual abnormalities (scotomata, photophobia, blurred vision, or temporary blindness [rare])
●Upper abdominal or epigastric pain
●Altered mental status
●Dyspnea, retrosternal chest pain
Epigastric pain may be the presenting symptom of preeclampsia; thus, a high index of suspicion is important to make the diagnosis of preeclampsia rather than gastroesophageal reflux, which is common in pregnant women, especially at night.
Atypical presentations are described separately. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Atypical presentations' below.)
SPECTRUM OF DISEASE
Hypertension — All patients with preeclampsia have hypertension (in patients with HELLP, elevations in blood pressure may be minimal or even absent). It is generally the earliest clinical finding of preeclampsia and the most common clinical clue to the presence of the disease. The blood pressure usually rises gradually, reaching the hypertensive range (≥140/90 mmHg) sometime in the third trimester, often after the 37th week of gestation [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4242]. Blood pressures are often around 135/85 mmHg in the one to two weeks before reaching the hypertensive range. However, in some women, hypertension develops rapidly or before 34 weeks of gestation or postpartum.
Epigastric pain — Epigastric pain, when present, is a cardinal symptom of the severe end of the disease spectrum. It is characterized by severe constant pain that often begins at night, usually maximal in the low retrosternum or epigastrium, but may radiate to the right hypochondrium or back [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4848]. Nausea and vomiting sometimes also occur. On examination, the liver may be tender to palpation due to stretching of Glisson's capsule from hepatic swelling or bleeding.
Liver rupture or hemorrhage is rare, but should be suspected when there is sudden onset of right upper quadrant pain associated with a decrease in blood pressure. (See
https://www.uptodate.com/contents/hellp-syndrome?source=see_link§ionName=Management+of+hepatic+complications&anchor=H17"HELLP syndrome", section on 'Management of hepatic complications'.)
Acute pancreatitis is a rare complication of preeclampsia [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4949] and can mimic the epigastric pain of preeclampsia [
Headache — Headache, when present, is a cardinal symptom of the severe end of the disease spectrum. It may be temporal, frontal, occipital, or diffuse [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/51,5251,52]. The pain usually has a throbbing or pounding quality, but may be piercing. Although not pathognomonic, a feature that suggests preeclampsia-related headache rather than another type of headache is that it persists despite administration of over-the-counter analgesics and it may become severe (ie, incapacitating, "the worst headache of my life").
The mechanism for headache, as well as other cerebrovascular symptoms of preeclampsia, is poorly understood. Cerebral edema and ischemic/hemorrhagic changes in the posterior hemispheres observed on computed tomography and magnetic resonance imaging help to explain, but do not fully account for, the clinical findings [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/53,5453,54]. These findings may result from generalized endothelial cell dysfunction, leading to vasospasm of the cerebral vasculature in response to severe hypertension, or they may result from loss of cerebrovascular autoregulation, leading to areas of both vasoconstriction and forced vasodilation. Thus, they could represent a form of posterior reversible leukoencephalopathy syndrome (PRES) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/55-5755-57]. PRES is typically associated with severe hypertension but can occur with rapid increases in blood pressure in patients with endothelial damage [
https://www.uptodate.com/contents/reversible-posterior-leukoencephalopathy-syndrome?source=see_link"Reversible posterior leukoencephalopathy syndrome" and
https://www.uptodate.com/contents/eclampsia?source=see_link§ionName=CLINICAL+PRESENTATION+AND+FINDINGS&anchor=H5"Eclampsia", section on 'Clinical presentation and findings'.)
Visual symptoms — Visual symptoms, when present, are cardinal symptoms of the severe end of the disease spectrum. They are caused, at least in part, by retinal arteriolar spasm [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/5959]. Symptoms include blurred vision, flashing lights or sparks (photopsia), and scotomata (dark areas or gaps in the visual field) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/60-6260-62]. Diplopia or amaurosis fugax (blindness in one eye) may also occur. Visual disturbances in preeclampsia may also be manifestations of PRES [
Cortical blindness is rare and typically transient [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/6363]. Blindness related to retinal pathology, such as retinal artery or vein occlusion, retinal detachment, optic nerve damage, retinal artery spasm, and retinal ischemia, may be permanent [
Generalized hyperreflexia — Hyperreflexia is a common finding. Sustained ankle clonus may be present.
Peripheral edema — Many pregnant women have edema, whether or not they have preeclampsia. However, sudden and rapid weight gain (eg, >5 lb/week [2.3 kg]) and facial edema are more common in women who develop preeclampsia; thus, these findings warrant diagnostic evaluation for the disease. Peripheral edema in preeclampsia may be due to capillary leaking or represent "overfill" edema.
Pulmonary edema — Pulmonary edema is a feature of the severe end of the disease spectrum. The etiology of pulmonary edema in preeclampsia is multifactorial [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/65-6865-68]. Excessive elevation in pulmonary vascular hydrostatic pressure compared with decreased plasma oncotic pressure may produce pulmonary edema in some women, particularly in the postpartum period. However, not all preeclamptic patients with pulmonary edema demonstrate this phenomenon. Other causes of pulmonary edema are capillary leak, left heart failure, and iatrogenic volume overload.
Oliguria — Urine output may decrease to <500 mL/24 hours in women at the severe end of the disease spectrum. (See
https://www.uptodate.com/contents/acute-kidney-injury-acute-renal-failure-in-pregnancy?source=see_link§ionName=Preeclampsia+with+or+without+HELLP&anchor=H3"Acute kidney injury (acute renal failure) in pregnancy", section on 'Preeclampsia with or without HELLP'.)
Rarely, women with preeclamptic hepatic disease have developed polyuria due to transient diabetes insipidus of pregnancy. The mechanism in these cases is decreased degradation of vasopressinase due to hepatic dysfunction. (See
https://www.uptodate.com/contents/renal-and-urinary-tract-physiology-in-normal-pregnancy?source=see_link§ionName=Transient+DI+of+pregnancy&anchor=H23"Renal and urinary tract physiology in normal pregnancy", section on 'Transient DI of pregnancy'.)
Stroke — Stroke leading to death or disability is the most serious complication ofpreeclampsia/eclampsia, which is responsible for approximately 36 percent of pregnancy-associated stroke [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/6969]. Most strokes in this setting are hemorrhagic and preceded by severe headache and severe and fluctuating blood pressure levels. Eclamptic seizures occur in some, but not all, cases. Risk factors for hemorrhagic stroke in women with preeclampsia include persistent severe hypertension associated with significant headacheand/or seizures. Lowering blood pressure may reduce the risk; however, criteria for persistent hypertension and timing of initiation of acute antihypertensive therapy (after 15 minutes, 30 minutes, or >60 minutes) are unclear. (See
https://www.uptodate.com/contents/cerebrovascular-disorders-complicating-pregnancy?source=see_link§ionName=Preeclampsia%2C+eclampsia%2C+and+HELLP&anchor=H5"Cerebrovascular disorders complicating pregnancy", section on 'Preeclampsia, eclampsia, and HELLP'.)
Abruptio placentae — Abruption occurs in less than 1 percent of pregnancies with preeclampsia without severe features but 3 percent of those with severe features [
https://www.uptodate.com/contents/placental-abruption-clinical-features-and-diagnosis?source=see_link"Placental abruption: Clinical features and diagnosis" and
https://www.uptodate.com/contents/placental-abruption-management?source=see_link"Placental abruption: Management".)
Seizure — Seizure in a preeclamptic woman upstages the diagnosis to eclampsia. Eclamptic seizures develop in 1 in 400 women with preeclampsia without severe features and 1 in 50 women with preeclampsia with severe features. Histopathologic correlates include brain hemorrhage, petechiae, edema, vasculopathy, ischemic damage, microinfarcts, and fibrinoid necrosis [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/71,7271,72]. Neuroimaging consistent with posterior reversible encephalopathy syndrome may be seen [
Proteinuria — Proteinuria in preeclampsia can be defined as any of the following [
●Persistent protein ≥1+ (30 mg/dL) on a paper test strip dipped into a fresh, clean voided midstream urine specimen. This finding should be confirmed by one of the following quantitative measurements:
•Random protein:creatinine ratio >0.3 mg protein/mg creatinine. Some clinicians opt to confirm this with a 24-hour collection.
•≥0.3 g protein in a 24-hour urine specimen.
Proteinuria generally increases as preeclampsia progresses, but increased urinary protein excretion may be a late finding [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/74,7574,75]. It usually remains <5 g/day, but levels >10 g/daymay be seen. Preeclampsia is the most common cause of severe proteinuria in pregnant women.
Proteinuria is due, in part, to impaired integrity of the glomerular filtration barrier and altered tubular handling of filtered proteins (hypofiltration) leading to increased protein excretion [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/7676]. Both size and charge selectivity of the glomerular barrier are affected [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/7777]. Using special studies, podocyturia (urinary excretion of podocytes) has been observed in patients with preeclampsia [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/78,7978,79]. Urinary shedding of podocytes may indicate podocyte loss from the glomerulus, which may lead to a disruption of the glomerular filtration barrier and consequent proteinuria. Deficient vascular endothelial growth factor signaling appears to account, at least in part, for these findings. (See
https://www.uptodate.com/contents/preeclampsia-pathogenesis?source=see_link§ionName=Pathogenesis+of+systemic+endothelial+dysfunction&anchor=H11"Preeclampsia: Pathogenesis", section on 'Pathogenesis of systemic endothelial dysfunction'.)
The urine protein concentration in a spot sample is measured in mg/dL and is divided by the urine creatinine concentration, also measured in mg/dL. This value can be used to estimate the 24-hour protein excretion (
https://www.uptodate.com/contents/calculator-estimated-24-hour-urine-protein-excretion-in-pregnancy-from-spot-urine-protein-to-creatinine-ratio?source=see_linkcalculator 1) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/80-8880-88]. Measurement of proteinuria is discussed in detail separately. (See
https://www.uptodate.com/contents/proteinuria-in-pregnancy-evaluation-and-management?source=see_link"Proteinuria in pregnancy: Evaluation and management".)
Elevated creatinine — The physiologic increase in glomerular filtration rate (GFR) during a normal pregnancy results in a decrease in serum creatinine concentration, which falls by an average of 0.4 mg/dL (35 micromol/L) to a range of 0.4 to 0.8 mg/dL (35 to 70micromol/L). The serum creatinine concentration in women with preeclampsia generally remains in this range or only slightly elevated. A creatinine level >1.1 mg/dL (97.3micromol/L) concentration indicates the severe end of the disease spectrum. Some guidelines also include doubling of the patient's baseline creatinine in the absence of other renal disease as indicative of the severe end of the disease spectrum [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/22]. Although creatinine levels remain <1.5 mg/dL (133 micromol/L) in most patients, preeclampsia is the most common cause of acute kidney injury in pregnancy. (See
The rise in serum creatinine is due primarily to a fall in GFR; renal plasma flow also decreases, but to a lesser degree. In severe disease, reduced plasma volume due to capillary leaking and due to systemic vasoconstriction lead to sodium retention and renal vasoconstriction.
Decreased platelet count — The platelet count is normal, unless the patient is at the severe end of the disease spectrum, which is characterized by a platelet count less than100,000/microL.
Thrombocytopenia is the most common coagulation abnormality in preeclampsia. Microangiopathic endothelial injury and activation result in formation of platelet and fibrin thrombi in the microvasculature. Accelerated platelet consumption leads to thrombocytopenia; immune mechanisms may also play a role [
Hemolysis — Schistocytes and helmet cells on the peripheral blood smear (
https://www.uptodate.com/contents/image?imageKey=HEME%2F70851%7EHEME%2F50715&topicKey=OBGYN%2F6814&source=see_linkpicture 1A-B) suggest microangiopathic hemolysis, which is a finding at the severe end of the disease spectrum. Elevation in the serum indirect bilirubin level also suggest hemolysis, whereas elevations in lactate dehydrogenase are usually related to liver dysfunction.
Hemoconcentration — Hemoconcentration may result from a reduction of plasma volume due to capillary leaking. Hematocrit typically increases. When both hemolysis and hemoconcentration occur concurrently, the effects on hematocrit may negate each other, resulting in a normal value. (See
https://www.uptodate.com/contents/thrombocytopenia-in-pregnancy?source=see_link"Thrombocytopenia in pregnancy" and
https://www.uptodate.com/contents/preeclampsia-pathogenesis?source=see_link"Preeclampsia: Pathogenesis" and
https://www.uptodate.com/contents/hematologic-changes-in-pregnancy?source=see_link"Hematologic changes in pregnancy".)
Coagulation studies — The prothrombin time, partial thromboplastin time, and fibrinogen concentration are not affected by preeclampsia, unless there are additional complications, such as abruptio placentae, severe bleeding, or severe liver dysfunction [
Liver chemistries — Liver function tests are normal, except at the severe end of the disease spectrum, which is characterized by elevated transaminase levels (twice the upper limit of normal for the local laboratory).
Elevation in the serum indirect bilirubin level suggests hemolysis. (See
Abnormalities in liver chemistries are due to reduced hepatic blood flow, potentially resulting in ischemia and periportal hemorrhage. Periportal and sinusoidal fibrin deposition and microvesicular fat deposition also occur and may affect hepatocyte function [
Hyperuricemia — The association between hyperuricemia and preeclampsia has been known for decades. The cause is most likely related to a reduction in GFR. However, the increase in serum uric acid is often greater than expected for mild reductions in GFR, leading to the hypothesis that decreased tubular secretion or increased reabsorption play a role [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/9393]. Although meta-analyses published in 2006 concluded that uric acid levels are not an accurate predictor of complications associated with preeclampsia [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/94,9594,95], this issue remains controversial. Data from an ongoing international prospective study of women admitted to the hospital with preeclampsia showed that serum uric acid corrected for gestational age is clinically useful in predicting adverse perinatal, but not maternal, outcomes [
●Urine sediment – The urine sediment is typically benign.
●Lipids – Women with preeclampsia appear to have changes in lipid metabolism resulting in higher total cholesterol and triglyceride levels than normotensive pregnant women [
●Neutrophilia – The white blood count may be slightly higher in preeclampsia due to neutrophilia.
●Troponin – Preeclampsia is not associated with elevated troponin levels in the absence of cardiac disease [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/9999]. A small subgroup of women with severe preeclampsia may develop myocardial damage or global diastolic dysfunction [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/100100]. Therefore, troponin I levels should be obtained when clinically indicated, such as when the patient complains of chest pain suggestive of myocardial ischemia or new electrocardiogram changes are observed [
Fetal ultrasound — Preeclampsia that develops clinically before term may be associated with suboptimal fetal growth due to reduced uteroplacental perfusion [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Overview of pathophysiology' above). Fetal growth restriction may be accompanied by oligohydramnios due to redistribution of the fetal circulation away from the kidneys and toward more vital organs, particularly the brain (see
https://www.uptodate.com/contents/oligohydramnios?source=see_link"Oligohydramnios"). In contrast, preeclampsia that develops clinically at term tends to be associated with fetal growth that is appropriate for gestational age and normal amniotic fluid volume. In some cases, the fetus may be large for gestational age [
Fetal anatomy is usually normal. However, in one population-based study, preeclampsia was associated with a small but statistical increase in noncritical heart defects in offspring; women with onset of preeclampsia before 34 weeks also had an increased risk of critical heart defects in offspring [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/110110]. Further study is required to confirm this observation and, if confirmed, to determine the nature of the relationship.
Fetal hydrops of any etiology is an uncommon cause of preeclampsia-like symptoms. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Mirror syndrome' below.)
Uterine and umbilical artery Doppler — Increased impedance to flow in the uterine arteries due to uteroplacental maldevelopment is manifested by elevation of the pulsatility index accompanied by uterine artery notching on uterine artery Doppler velocimetry. However, this finding is neither sensitive nor specific for preeclampsia. (See
https://www.uptodate.com/contents/early-pregnancy-prediction-of-preeclampsia?source=see_link§ionName=Uterine+artery+Doppler+velocimetry&anchor=H7"Early pregnancy prediction of preeclampsia", section on 'Uterine artery Doppler velocimetry'.)
Increased resistance in the placental vasculature is reflected by rising Doppler indices of the umbilical artery. Absent and reversed end diastolic flow are the most severe abnormalities and associated with a poor perinatal outcome. (See
https://www.uptodate.com/contents/doppler-ultrasound-of-the-umbilical-artery-for-fetal-surveillance?source=see_link"Doppler ultrasound of the umbilical artery for fetal surveillance".)
Maternal hemodynamic imaging studies — Preeclampsia can be associated with a highly variable hemodynamic profile, including cardiac failure [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/111-115111-115]. Changes in cardiac function and morphology may be seen on echocardiography at an asymptomatic early stage and progress with increasing disease severity [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/116116]. Preeclampsia does not affect the myocardium directly, but the heart responds to physiological changes induced by the disease. Left ventricular ejection fraction usually remains within normal limits [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/117117], but reductions in longitudinal, circumferential, and radial systolic strain have been observed [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/118118]. The decrement in left ventricular performance has been attributed to a physiologic response to increased afterload [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/111,117,118111,117,118], but other factors may play a role since systolic strain was depressed in preeclamptic patients compared with pregnant women with nonproteinuric hypertension and similar resting blood pressure [
The high afterload in preeclampsia is associated with elevated cardiac filling pressures, reflected by fourfold higher concentrations of natriuretic peptides in women with preeclampsia compared with pregnant women who are normotensive or who have chronic hypertension [
Intravascular volume may be reduced in preeclampsia, especially with severe features [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/119119]. There is no evidence of underfilling of the arterial circulation; rather, the reduced volume appears to be a consequence of vasoconstriction from enhanced responses to vasoactive substances; however, this issue has not been conclusively resolved.
Placenta — Abnormalities in the placenta are believed to be a critical feature of the preeclampsia syndrome. The parenchymal finding most characteristically associated with preeclampsia is acute atherosis (ie, fibrinoid necrosis of the vessel wall with an accumulation of lipid-laden "foamy" macrophages and a mononuclear perivascular infiltrate). Cytotrophoblast invasion of the interstitial uterine compartment is frequently shallow, with incomplete invasion and remodeling of spiral arteries in many places [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/120120]. This maldevelopment of the uteroplacental circulation can result in reduced placental perfusion, leading to placental infarcts, villous hypoplasia, and, in some cases, the clinical sequelae of intrauterine growth restriction.
Placental histology is described in detail separately. (See
https://www.uptodate.com/contents/the-placental-pathology-report?source=see_link§ionName=Histopathology+of+preeclampsia&anchor=H4506086"The placental pathology report", section on 'Histopathology of preeclampsia'.)
Renal histology — The renal histologic changes described in women with preeclampsia who have had kidney biopsies, and in autopsy specimens obtained from women who died of eclampsia, are termed "glomerular endotheliosis." Light and electron microscopy of glomerular endotheliosis show endothelial cell swelling, loss of fenestrations, and occlusion of capillary lumens (
https://www.uptodate.com/contents/image?imageKey=NEPH%2F78879%7ENEPH%2F59970%7ENEPH%2F68634&topicKey=OBGYN%2F6814&source=see_linkpicture 2A-C) [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/121121]. Foot process effacement is not a prominent feature, despite marked proteinuria.
Glomerular endotheliosis shares histologic features with non-preeclamptic thrombotic microangiopathies [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/121121], except thrombi are rare in preeclampsia (although fibrin deposition may be observed by immunofluorescence microscopy). Rarely, it may be present without proteinuria and in nonpregnant women [
NATURAL HISTORY/COURSE OF DISEASE — Preeclampsia can be a progressive disease. Although most women develop signs of the disease in late pregnancy with gradual worsening until delivery, in approximately 25 percent of women, especially those with early-onset preeclampsia, hypertension becomes severe and/or signs and symptoms of end-organ damage become apparent over a period of days to weeks [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/124124]. It is important to note that severe sequelae can occur in women without severe hypertension but who have clinical evidence of significant end-organ dysfunction. Chest pain, dyspnea, and low platelet count appear to be particularly predictive of fatal or life-threatening complications [
Delivery of the placenta always results in complete resolution of the maternal signs and symptoms of the disease, with some symptoms disappearing in a matter of hours (eg, headache), while others may take weeks or months (eg, proteinuria). Typically, mobilization of third-space fluid and diuresis begin within 48 hours of delivery. Hypertension may worsen during the first, and occasionally the second, postpartum week, but normalizes in most women within four weeks postpartum [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/126126]. Rarely, hypertension persists beyond three months. Proteinuria usually begins to improve within a few days; however, in women with several grams of protein excretion, complete resolution may take weeks to months [
Long-term prognosis is reviewed separately. (See
https://www.uptodate.com/contents/preeclampsia-management-and-prognosis?source=see_link§ionName=PROGNOSIS&anchor=H21332929"Preeclampsia: Management and prognosis", section on 'Prognosis'.)
Routine — Pregnant women with suspected preeclampsia due to hypertension and proteinuria or hypertension and signs and symptoms associated with the severe end of the disease spectrum (eg, headache, visual symptoms, epigastric pain, pulmonary edema) should have a complete blood count, creatinine level, liver chemistries, and urinary protein determination (protein:creatinine ratio or 24-hour urine protein).
Fetal status is assessed postdiagnosis, depending on the degree of concern when the mother is evaluated. At a minimum, a nonstress test or biophysical profile is performed. Ultrasound is indicated to evaluate amniotic fluid volume and estimate fetal weight, given the increased risk for oligohydramnios and fetal growth restriction.
Measurement of angiogenic factors — In the future, measurement of urinary or plasma angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF]) may be useful for distinguishing preeclampsia from other hypertensive-proteinuric disorders; this test is commercially available in some countries but still considered investigational and should be limited to patients in research studies [
Multiple studies have demonstrated that angiogenic factors (sFlt-1 and PlGF) are altered in women with clinical features of preeclampsia (see
https://www.uptodate.com/contents/preeclampsia-pathogenesis?source=see_link§ionName=sFlt-1%2C+VEGF%2C+PlGF&anchor=H12"Preeclampsia: Pathogenesis", section on 'sFlt-1, VEGF, PlGF'). It has also been demonstrated that the ratio of sFlt-1/PlGF is particularly sensitive in making a clinical diagnosis. What remains to be determined is whether, and in what circumstances, measurement of angiogenic factors could be clinically useful and improve patient outcomes. One particular scenario that is clinically challenging is determining whether a woman with signs of preeclampsia, such as an increase in blood pressure or a slightly elevated level of urinary protein, requires medical intervention, such as hospitalization or even delivery. A biomarker test that improved our ability to predict patients who require or do not require a higher degree of medical intervention would be helpful.
A prospective, multicenter, international observational study (PROGNOSIS) attempted to derive and validate a serum sFlt-1:PlGF ratio that would predict the absence or presence of preeclampsia in the short-term in women who already had signs suggestive of preeclampsia, such as an increase in blood pressure and/or proteinuria [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/131131]. The study included 500 women with singleton pregnancies at 24 to 366/7ths weeks of gestation with suspected preeclampsia based on one or more of the following: new increase in blood pressure but less than 140/90 mmHg, new proteinuria but less than 2+ dipstick, preeclampsia-related laboratory findings but not meeting criteria for HELLP syndrome, preeclampsia-related symptoms (edema, headache, visual changes, sudden weight gain). Although the authors concluded that an sFlt-1:PlGF ratio cutoff of 38 using a specific automated commercial assay had a negative predictive value (no preeclampsia in the next seven days) of 99.3 percent (95% CI 97.9-99.9), with sensitivity of 80 percent (95% CI 51.9-95.7) and specificity of 78.3 percent (95% CI 74.6-81.7), we question the clinical usefulness of this conclusion since the women enrolled in the study appeared to have a clinical profile of mild disease and the prevalence of preeclampsia was quite low in this group. The positive predictive value for preeclampsia was only 36.7 percent in the next four weeks (95% CI 28.4-45.7). Whether this ratio will be helpful in reducing iatrogenic morbidity due to overdiagnosis in women with suggestive signs of preeclampsia is unclear. Further exploration of this test is warranted, including determining whether the cut-off varies among laboratories and patient populations, the best interval for repeat testing, and how this information affects clinical outcomes and costs. The latter can only be answered with a randomized trial.
Diagnostic criteria — Professional guidelines generally agree that the diagnosis of preeclampsia should be made in a previously normotensive woman with new onset of hypertension and proteinuria after 20 weeks of gestation [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/2,132-1342,132-134]. In the absence of proteinuria, the diagnosis can still be made if new-onset hypertension is accompanied by end-organ dysfunction, as shown in the following table (
Criteria for the severe end of the disease spectrum (called "preeclampsia with severe features," formerly "severe preeclampsia") include the presence of any of the following:
●Severe hypertension: systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg); confirmation within 15 to 30 minutes is sufficient.
●New-onset cerebral or visual disturbance, such as:
•Photopsia, scotomata, cortical blindness, or retinal vasospasm.
•Severe headache (ie, incapacitating, "the worst headache I've ever had") or headache that persists and progresses despite analgesic therapy.
•Altered mental status.
●Severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by an alternative diagnosis, or serum transaminase concentration ≥2 times upper limit of normal for a specific laboratory, or both.
●Progressive renal insufficiency (serum creatinine >1.1 mg/dL [97.3 micromol/L]; some guidelines also include doubling of serum creatinine concentration in the absence of other renal disease [
Differential diagnosis — When evaluating women for possible preeclampsia, it is generally safer to assume that new-onset hypertension in pregnancy is due to preeclampsia, even if all the diagnostic criteria are not fulfilled and the blood pressure is only mildly elevated, since preeclampsia may progress to eclampsia or other severe forms of the disease in a short period of time.
Pre-existing hypertension versus preeclampsia — Because of the reduction in blood pressure that typically occurs early in pregnancy, a woman with pre-existent hypertension may be normotensive when first seen by the obstetrical provider. Later in pregnancy when her blood pressure returns to its prepregnancy baseline, she may appear to be developing preeclampsia if there are no documented prepregnancy blood pressure measurements.
In this setting, a variety of factors can be helpful in establishing the likely diagnosis:
●Hypertension occurring before the 20th week is usually due to pre-existing hypertension rather than to preeclampsia.
●Proteinuria is usually present and increases with time in preeclampsia, occasionally reaching the nephrotic range; by comparison, protein excretion is usually absent or less than 1 g/day in hypertensive nephrosclerosis [
https://www.uptodate.com/contents/clinical-features-diagnosis-and-treatment-of-hypertensive-nephrosclerosis?source=see_link"Clinical features, diagnosis, and treatment of hypertensive nephrosclerosis".)
●Preeclampsia is more common in nulliparas than in multiparas.
●Preeclampsia is more common in older (>40 years) nulliparas, although these women are also more likely to have pre-existing hypertension, as are older multiparous women. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Risk factors' above.)
Superimposed preeclampsia — Reproductive age women with primary (essential) hypertension typically have no or mild proteinuria so severe proteinuria suggests development of superimposed preeclampsia. In women with chronic/pre-existinghypertension who have proteinuria prior to or in early pregnancy, superimposed preeclampsia is difficult to diagnose definitively, but should be suspected when there is a significant worsening of hypertension (especially acutely) in the last half of pregnancy or development of signs/symptoms associated with the severe end of the disease spectrum.
Exacerbation of pre-existing renal disease — Superimposed preeclampsia frequently develops in women with pre-existing primary or secondary renal disease [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/135,136135,136]. However, worsening hypertension and proteinuria in a woman with pre-existing renal disease may also represent an exacerbation of the underlying disease or the physiological effects of pregnancy. The ability to accurately distinguish among these possibilities is important, as management and complications are different.
Significant clues to the diagnosis of preeclampsia with severe features are the presence of systemic manifestations of the disorder, such as thrombocytopenia, increased serum levels of aminotransferases, and visual symptoms (
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/137137]. Onset of disease in the first half of pregnancy suggests exacerbation of underlying renal disease rather than preeclampsia.
Laboratory evidence suggestive of exacerbation of renal disease includes the presence of findings specific for disease activity (eg, low complement levels in a patient with systemic lupus erythematosus, urinalysis consistent with a proliferative glomerular disorder [red and white cells and/or cellular casts]). An active urine sediment is not a feature of preeclampsia. (See
https://www.uptodate.com/contents/pregnancy-in-women-with-underlying-renal-disease?source=see_link"Pregnancy in women with underlying renal disease" and
https://www.uptodate.com/contents/pregnancy-in-women-with-diabetic-kidney-disease?source=see_link"Pregnancy in women with diabetic kidney disease".)
Antiphospholipid syndrome — Hypertension, proteinuria, and thrombocytopenia, and other signs of end-organ dysfunction, can be seen in antiphospholipid syndrome. The absence of laboratory evidence of antiphospholipid antibodies excludes this diagnosis. (See
https://www.uptodate.com/contents/clinical-manifestations-of-antiphospholipid-syndrome?source=see_link"Clinical manifestations of antiphospholipid syndrome" and
https://www.uptodate.com/contents/diagnosis-of-antiphospholipid-syndrome?source=see_link"Diagnosis of antiphospholipid syndrome" and
https://www.uptodate.com/contents/pregnancy-in-women-with-antiphospholipid-syndrome?source=see_link"Pregnancy in women with antiphospholipid syndrome".)
AFLP, TTP, HUS, SLE — Although preeclampsia/HELLP is the most common cause of hypertension, thrombocytopenia, liver abnormalities, and renal abnormalities in pregnant women, the following conditions should be considered and excluded, if possible. Laboratory findings in these disorders are compared in the tables (
●Acute fatty liver of pregnancy (AFLP) –Anorexia, nausea, and vomiting are common clinical features of AFLP. Low-grade fever can be present in AFLP, but does not occur in preeclampsia/HELLP. AFLP is associated with more serious liver dysfunction: hypoglycemia, elevations in serum ammonia, and disseminated intravascular coagulation are common features, while unusual in preeclampsia/HELLP. AFLP is also usually associated with more significant renal dysfunction compared withpreeclampsia/HELLP. (See
https://www.uptodate.com/contents/acute-fatty-liver-of-pregnancy?source=see_link"Acute fatty liver of pregnancy".)
●Thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS) – Although neurologic abnormalities and acute renal failure are often seen in TTP and HUS, respectively, distinguishing among related thrombotic microangiopathy syndromes may be challenging. An approach to the patient suspected of having TTP or HUS, including urgent interventions before the diagnosis is established, is presented separately. (See
https://www.uptodate.com/contents/approach-to-the-patient-with-suspected-ttp-hus-or-other-thrombotic-microangiopathy-tma?source=see_link"Approach to the patient with suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)
●Exacerbation of systemic lupus erythematosus (SLE) – Flares of SLE are likely to be associated with hypocomplementemia and increased titers of anti-DNA antibodies; by comparison, complement levels are usually, but not always, normal or increased in preeclampsia. Acute onset, accelerated hypertension is more likely to be due to preeclampsia than a lupus flare. (See
https://www.uptodate.com/contents/pregnancy-in-women-with-systemic-lupus-erythematosus?source=see_link"Pregnancy in women with systemic lupus erythematosus".)
Mirror syndrome — Fetal hydrops from any cause (nonimmune or immune) can result in maternal symptoms identical to those seen in preeclampsia. This disorder is called mirror or Ballantyne syndrome and resolves without delivery if hydrops resolves. (See
https://www.uptodate.com/contents/nonimmune-hydrops-fetalis?source=see_link§ionName=Mirror+syndrome&anchor=H6"Nonimmune hydrops fetalis", section on 'Mirror syndrome'.)
Onset <20 weeks — Preeclampsia prior to 20 weeks of gestation is usually associated with a complete or partial molar pregnancy (see
https://www.uptodate.com/contents/hydatidiform-mole-epidemiology-clinical-features-and-diagnosis?source=see_link"Hydatidiform mole: Epidemiology, clinical features, and diagnosis"). Rarely, characteristic signs and symptoms before 20 weeks have been attributed to preeclampsia with severe features after other disorders with similar findings (eg, lupus nephritis, thrombotic thrombocytopenic purpura, hemolytic-uremic syndrome, antiphospholipid syndrome, acute fatty liver of pregnancy) were excluded. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Differential diagnosis' above.)
Severe features of preeclampsia without hypertension — It is uncommon for women to exhibit the severe features of preeclampsia without hypertension, but this may be observed in 15 percent of patients with HELLP syndrome (which some consider a variant of preeclampsia and others consider a separate disorder) and in some patients with eclampsia (a possible sequelae of preeclampsia). It is possible that in such patients, blood pressure is increased above a lower baseline but does not meet diagnostic criteria for hypertension. (See
https://www.uptodate.com/contents/eclampsia?source=see_link§ionName=CAN+ECLAMPSIA+BE+PREDICTED+AND+PREVENTED%3F&anchor=H25"Eclampsia", section on 'Can eclampsia be predicted and prevented?'and
Isolated hypertension — Women with new onset of hypertension but no other criteria for preeclampsia or an underlying disease associated with hypertension are given the diagnosis of gestational hypertension. These women should be followed closely, since 15 to 25 percent will subsequently develop the full diagnostic criteria for preeclampsia. (See
https://www.uptodate.com/contents/gestational-hypertension?source=see_link§ionName=RISK+OF+PROGRESSION+TO+PREECLAMPSIA&anchor=H14926620"Gestational hypertension", section on 'Risk of progression to preeclampsia'.)
Isolated proteinuria — Isolated gestational proteinuria may be an early manifestation of preeclampsia [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/138138], although this is not well described and we are unaware of prospective studies describing this finding. In a retrospective study of 95 pregnant women with new-onset isolated proteinuria who were followed to term, 13 developed preeclampsia during pregnancy and 8 developed preeclampsia postpartum [
Onset or exacerbation of symptoms >2 days postpartum — Delayed postpartum preeclampsia can be defined as signs and symptoms of the disease leading to readmission more than two days but less than six weeks after delivery [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4646], although various other definitions have been used. Signs and symptoms can be atypical; for example, the patient may have thunderclap headaches alternating with mild headaches or intermittent hypertension. Other etiologies for the signs and symptoms should be considered, such as cerebral vasoconstriction syndrome or impending stroke [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/140-143140-143]. Risk factors for delayed postpartum preeclampsia appear to be similar to those for preeclampsia during pregnancy [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/46,144,14546,144,145], but some patients have no risk factors.
In a retrospective cohort study including 152 patients with delayed postpartum preeclampsia, 63.2 percent had no antecedent diagnosis of hypertensive disease in the current pregnancy, whereas 18.4 percent had preeclampsia, 9.2 percent had chronic hypertension, 4.6 percent had gestational hypertension, and 4.6 percent had preeclampsia superimposed on chronic hypertension during the peripartum period [
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/4646]. Of these patients, 14.5 percent developed postpartum eclampsia.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See
https://www.uptodate.com/contents/society-guideline-links-hypertensive-disorders-of-pregnancy?source=see_link"Society guideline links: Hypertensive disorders of pregnancy".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see
https://www.uptodate.com/contents/preeclampsia-the-basics?source=see_link"Patient education: Preeclampsia (The Basics)" and
https://www.uptodate.com/contents/high-blood-pressure-and-pregnancy-the-basics?source=see_link"Patient education: High blood pressure and pregnancy (The Basics)" and
https://www.uptodate.com/contents/hellp-syndrome-the-basics?source=see_link"Patient education: HELLP syndrome (The Basics)")
●Beyond the Basics topics (see
https://www.uptodate.com/contents/preeclampsia-beyond-the-basics?source=see_link"Patient education: Preeclampsia (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The four major hypertensive disorders related to pregnancy are preeclampsia, chronic hypertension, preeclampsia superimposed upon chronic hypertension, and gestational hypertension. (See
●Major risk factors for development of preeclampsia include past history of preeclampsia, nulliparity, pregestational diabetes, chronic hypertension, obesity, family history of preeclampsia, and multiple gestation (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F61266&topicKey=OBGYN%2F6814&source=see_linktable 4). (See
●The diagnosis of preeclampsia is based on the new onset of hypertension and proteinuria or end-organ dysfunction with or without proteinuria after 20 weeks of gestation in a previously normotensive woman (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F79977&topicKey=OBGYN%2F6814&source=see_linktable 1). Severe hypertension or signs of end-organ dysfunction characterize the severe end of the disease spectrum (
https://www.uptodate.com/contents/image?imageKey=OBGYN%2F76975&topicKey=OBGYN%2F6814&source=see_linktable 2). (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Diagnostic criteria' above.)
●At the first prenatal visit, we evaluate pregnant women for traditional risk factors for preeclampsia to identify those at high risk for developing the disease. These women are offered low-dose
https://www.uptodate.com/contents/aspirin-drug-information?source=see_linkaspirin therapy in the second and third trimesters to reduce their risk of developing preeclampsia. (See
https://www.uptodate.com/contents/early-pregnancy-prediction-of-preeclampsia?source=see_link§ionName=Universal+screening&anchor=H4108061536"Early pregnancy prediction of preeclampsia", section on 'Universal screening' and
●At all provider visits throughout pregnancy, we recommend routinely measuring blood pressure to screen for preeclampsia (
https://www.uptodate.com/contents/grade/2?title=Grade%201B&topicKey=OBGYN/6814Grade 1B). The value of any laboratory or imaging test as a screening tool, including routine assessment of proteinuria at each visit, has not been established. (See
●The gradual development of hypertension and proteinuria in the last half of pregnancy is usually due to preeclampsia, particularly in a nullipara. These findings typically become apparent after 34 weeks of gestation and progress until delivery, but some women develop symptoms earlier in gestation, intrapartum, or postpartum. Delivery of the placenta always results in complete resolution of the maternal signs and symptoms of the disease. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Clinical presentation' above and
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Natural history/course of disease' above.)
●Pregnant women with suspected preeclampsia should have a complete blood count, creatinine level, liver chemistries, and determination of urinary protein excretion. Fetal status is assessed concurrently or postdiagnosis, depending on the degree of concern when the mother is evaluated. At a minimum, a nonstress test or biophysical profile is performed. Ultrasound is indicated to evaluate amniotic fluid volume and estimate fetal weight, given the increased risk for oligohydramnios and fetal growth restriction. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Diagnostic evaluation' above.)
●Differential diagnosis includes exacerbation of underlying renal disease, acute fatty liver of pregnancy, thrombotic thrombocytopenic purpura or hemolytic uremic syndrome, and exacerbation of systemic lupus erythematosus. (See
●Atypical presentations of preeclampsia include onset before 20 weeks of gestation or after the second postpartum day. Some patients initially present with gestational hypertension or proteinuria alone. Others present with end-organ dysfunction, and minimal or even absent hypertension or proteinuria; these patients are typically classified as HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets). (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Atypical presentations' above.)
●Women with preeclampsia are at increased risk for life-threatening events, including placental abruption, acute kidney injury, cerebral hemorrhage, hepatic failure or rupture, pulmonary edema, stroke, cardiac failure, and progression to eclampsia. The fetus is at increased risk for growth restriction and medically or obstetrically indicated preterm birth. (See
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Spectrum of disease' above and
https://www.uptodate.com/contents/preeclampsia-clinical-features-and-diagnosis?source=related_link'Burden of disease' above.)
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Topic 6814 Version 83.0ptodate.com/contents/preeclampsia-clinical-features-and-diagnosis/abstract/130Ohkuchi A, Hirashima C, Suzuki H, et al. Evaluation of a new and automated electrochemiluminescence immunoassay for plasma sFlt-1 and PlGF levels in women with preeclampsia. Hypertens Res 2010; 33:422.