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Pre-eclampsia

The right clinical information, right where it's needed

Last updated: Aug 24, 2018

Table of ContentsSummary 3

Basics 4

Definition 4

Epidemiology 4

Aetiology 4

Pathophysiology 4

Classification 5

Prevention 7

Primary prevention 7

Screening 7

Secondary prevention 7

Diagnosis 8

Case history 8

Step-by-step diagnostic approach 8

Risk factors 10

History & examination factors 13

Diagnostic tests 14

Differential diagnosis 16

Diagnostic criteria 18

Treatment 21

Step-by-step treatment approach 21

Treatment details overview 23

Treatment options 25

Emerging 30

Follow up 31

Recommendations 31

Complications 31

Prognosis 33

Guidelines 34

Diagnostic guidelines 34

Treatment guidelines 35

Online resources 36

References 37

Images 43

Disclaimer 45

Summary

◊ Hypertensive syndrome that occurs in pregnant women after 20 weeks' gestation, consisting of new-onset, persistent hypertension with either proteinuria or evidence of systemic involvement.

◊ All pregnant women presenting with hypertension and either proteinuria or evidence of systemicinvolvement require close assessment and monitoring for pre-eclampsia and its complications.

◊ Delivery is the definitive treatment; the decision about when and how to deliver should only be madeafter a thorough assessment of the risk and benefits to the mother and baby.

◊ Other mainstays of management include antihypertensive therapy, seizure control, and fluidrestriction.

◊ Maternal mortality is highest after delivery, so vigilance should be maintained in the postpartumperiod.

◊ Can occur in subsequent pregnancies; therefore, women should be counselled about the risk.

Pre-eclampsia BasicsBA

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DefinitionA hypertensive syndrome that occurs in pregnant women after 20 weeks' gestation, consisting of new-onset,persistent hypertension (defined as a BP ≥140 mmHg systolic and/or ≥90 mmHg diastolic, based on atleast 2 measurements taken at least 4 hours apart) with one or more of the following: 1) proteinuria (definedas urinary excretion of ≥0.3 g/24 hours of protein); 2) evidence of systemic involvement, such as renalinsufficiency (elevated creatinine), liver involvement (elevated transaminases and/or right upper quadrantpain), neurological complications, haematological complications; 3) fetal growth restriction.[1] [2]

EpidemiologyWhile the exact incidence is unknown, pre-eclampsia has been reported to occur in about 4% of allpregnancies in the US.[4] When figures include patients who develop pre-eclampsia postpartum, theincidence is between 2% and 8% of all pregnancies worldwide.[5]

The incidence of severe disease and complications varies. Severe disease, which is associated with anincreased risk of morbidity and mortality, has an incidence of only 0.5% in the developed world,[6] but risesto over 1% in low-income countries.[7] Similarly, the incidence of complications such as eclampsia is alsovariable. In developed countries eclampsia is estimated to affect 5 to 7 cases per 10,000.[8] However, in low-income countries the incidence of eclampsia is significantly higher, with estimates in some countries as highas 100 per 10,000.[8]

AetiologyPre-eclampsia is associated with a failure of normal invasion of trophoblast cells leading to maladaptation ofmaternal spiral arterioles, and is associated with hyperplacentation disorders such as diabetes, hydatidiformmole, and multiple pregnancy.[9]

There are numerous risk factors that increase the probability and severity, including primiparity, previousmaternal history or family history, BMI >30, maternal age >35 years, multiple pregnancy, pre-gestationaldiabetes, autoimmune disease, renal disease, chronic hypertension, hypertension at booking, and an intervalof 10 years or more since a previous pregnancy.[10] However, these risk factors do not account for all casesand complications such as eclampsia, HELLP syndrome (a subtype of severe pre-eclampsia characterisedby haemolysis [H], elevated liver enzymes [EL], and low platelets [LP]), and fetal growth restriction are notpresent in all patients.

PathophysiologyPre-eclampsia is associated with a failure of the normal invasion of trophoblast cells leading to maladaptationof maternal spiral arterioles.[9] The maternal arterioles are the source of blood supply to the fetus.Maladaptation of these vessels can interfere with normal villous development leading to placentalinsufficiency and, consequently, fetal growth restriction. The pathophysiology of this insufficient trophoblasticinvasion is likely to be multifactorial, with genetics, immunology, and endothelial dysfunction each playinga role. The extent and specificity with which placental gene expression changes in pre-eclampsia remainsto be fully understood.[11] Raised levels of pro-inflammatory and anti-angiogenic cytokines in the maternalcirculation may contribute to placental vasoconstriction and subsequent hypoxia.[12] [13]

4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Aug 24, 2018.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is

subject to our disclaimer. © BMJ Publishing Group Ltd 2018. All rights reserved.

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Pre-eclampsia Basics

The systemic maternal response results in vasoconstriction and capillary leaking, leading to hypertensionand complications such as:

• cerebral vascular dysregulation and oedema;

• liver vascular dysregulation and oedema; and

• pulmonary oedema.

Although the clinical manifestation does not occur until after 20 weeks’ gestation, the abnormal physiologicalchanges may occur from early in the first trimester.[14] This has been suggested by the presence of variousbiomarkers, such as:

• pregnancy-associated plasma protein A;

• ADAM12 (a disintegrin and metalloproteinase 12);

• placental growth factor;

• soluble endoglin; and

• soluble fms-like tyrosine kinase 1.[12]

ClassificationAmerican College of Obstetricians and Gynecologists:classification of severity[1]Disease severity is based on the blood pressure (BP) measurement and whether there are signs of systemicinvolvement.

• Mild-moderate

• BP is 140 to 159 mmHg systolic and/or 90 to 109 mmHg diastolic.and proteinuria is 300mg/24 hours; or ≥1+ (on 2 random urine samples, collected at least 4 hours apart); orprotein:creatinine ratio is ≥0.3 mg/dL.

• BP is 140 to 159 mmHg systolic and/or 90 to 109 mmHg diastolic and, in the absence ofproteinuria, any of the following is present:

• Thrombocytopenia, platelets count <100,000/uL• Serum creatinine ≥1.1 mg/L or a doubling of the serum creatinine concentration in the

absence of other renal disease• Impaired liver function, elevated blood concentrations of liver transaminases to twice

normal concentration• Pulmonary oedema• Cerebral or visual disturbances.

• Severe

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This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Aug 24, 2018.BMJ Best Practice topics are regularly updated and the most recent versionof the topics can be found on bestpractice.bmj.com . Use of this content is


5


Pre-eclampsia BasicsBA

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• BP is ≥160 mmHg systolic and/or ≥110 mmHg diastolic (on 2 occasions at least 6 hours apart,while the patient is on bed rest) and proteinuria is 300 mg/24 hours; or ≥1+ (on 2 random urinesamples, collected at least 4 hours apart); or the protein:creatinine ratio is ≥0.3 mg/dL.

• BP is ≥160 mmHg systolic and/or ≥110 mmHg diastolic (on 2 occasions at least 6 hoursapart, while the patient is on bed rest) and in the absence of proteinuria, any of the following ispresent:

• Thrombocytopenia, platelets count <100,000/uL• Serum creatinine ≥1.1 mg/L or a doubling of the serum creatinine concentration in the


normal concentration• Pulmonary oedema• Cerebral or visual disturbances.

HELLP syndrome is a subtype of severe pre-eclampsia characterised by haemolysis (H), elevated liverenzymes (EL), and low platelets (LP). The diagnosis and management of HELLP syndrome is not discussedin detail in this topic.

National Institute for Health and Care Excellence (UK):classification of severity[3]Severity of disease is based on BP measurement alone.

• Mild: BP is 140 to 149 mmHg systolic and/or 90 to 99 mmHg diastolic.• Moderate: BP is 150 to 159 mmHg systolic and/or 100 to 109 mmHg diastolic.• Severe: BP is ≥160 mmHg systolic and/or ≥110 mmHg diastolic.




Pre-eclampsia Prevention

Primary preventionStudies have shown low-dose aspirin (75-150 mg/day orally starting at 11-14 weeks' gestation) to bebeneficial at reducing the incidence and severity of pre-eclampsia.[3] [27] [28] The effect appears to beuniform across all risk groups, but results suggest that its use should be targeted at high-risk groups suchas those with hypertension, diabetes, renal disease, autoimmune disease, multiple pregnancy, BMI >30,maternal age >35 years, or interval of 10 years or more since previous pregnancy.[3] [24] [10] Evidencesuggests that it is particularly useful for preventing early onset rather than term disease.[29]

It is important to optimise treatment for hypertension and renal disease prior to pregnancy. Controlled weightloss reduces the incidence of pre-eclampsia.[3] Exercise in pregnancy should also be encouraged in theabsence of complications, such as risk factors for bleeding, premature delivery, and maternal comorbidities.Evidence suggests that a regular supervised exercise programme may reduce the risk of pre-eclampsia,independently of body mass index.[30]

Epidemiological studies have found that low dietary calcium is associated with pre-eclampsia.[31] As such,in populations where dietary calcium intake is low, the World Health Organization recommends that pregnantwomen should receive 1.5 g to 2 g of supplementary calcium in order to reduce pre-eclampsia severity.However, the evidence for widespread adoption of this is limited, so more trials of calcium supplementationfrom early pregnancy and in different populations are required.[32]

Women with hypertension, including those with an isolated elevated diastolic blood pressure at booking,should be followed up in an increased-frequency surveillance programme.

ScreeningAll pregnant women should be seen regularly throughout their pregnancy, and have their blood pressure(BP) measured.[4] If hypertension (defined as BP ≥140 mmHg and/or 90 mmHg) is found, urinalysis ismandatory.[4] If this persists, there should be a step-up in care to an assessment centre or admission toa care facility, depending on findings and symptoms. Uterine artery Doppler may be of limited value inpredicting the onset of disease and is therefore not recommended as a screening tool.[3] [1] [34]

The multifactorial nature of pre-eclampsia has limited the development of first-trimester screeningmethodologies: for example, the complexity of the genetic predisposition to the disease. Biomarker screeningtests reflecting placental development, such as sFlt-1:placental growth factor (PIGF) ratio or PIGF alone, arebecoming commercially available. Studies to determine sensitivity, specificity, and cut-off values will help toestablish the clinical utility of biomarker screening tests,[37] but large prospective trials have not yet beenconducted, and how these tests will alter practice is currently unknown.[38] It is likely that a combination ofbiomarkers will be required.[39] Prediction algorithms utilising a combination of biomarkers and maternalhistory have not yet shown sufficient sensitivity to be recommended for clinical use.[39] [40]

In the UK, at least 50% of the patients who develop pre-eclampsia are picked up by screening throughantenatal care.[24] However, in many parts of the developing world, the presentation is mostly acute, due tolack of screening availability.

Secondary preventionLow-dose aspirin (starting at 12-14 weeks' gestation) is recommended in subsequent pregnancies. Becausethe improvement is the same no matter what the risk, the benefit is dependent on the background risk. If thisis thought to be high (e.g., previous early onset disease, severe disease), the benefits are clear. However,they are less clear in mild to moderate or late disease where the outcome is generally good anyway.[3] [1] [9]

There is some evidence that low molecular weight heparin, with or without aspirin, might reduce the placentalinsufficiency in pre-eclampsia, but long-term safety studies are not available.[65] [66]

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Pre-eclampsia DiagnosisD

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Case historyCase history #1A 25-year-old pregnant woman presents for her routine antenatal visit. She is at 32 weeks' gestation andreports no symptoms. On examination, her BP is 145/95 mmHg and urinalysis reveals proteinuria (2+).She is referred to the antenatal day unit where a quantitative protein measurement of 1.5 g/24 hours isconfirmed. Further laboratory tests reveal elevated liver enzymes; however, platelets and all other testsare normal.

Case history #2A 35-year-old woman presents at 37 weeks' gestation with severe headache and acute abdominal pain.She had a routine antenatal visit 4 days previously with no signs or symptoms reported or observed. Onexamination, her BP is 165/110 mmHg and urinalysis reveals proteinuria (3+). She is admitted to hospitaland is started on labetalol.

Other presentationsPre-eclampsia may also be found on routine examination for lack of fetal movements or generally feelingunwell. The diagnostic criteria for pre-eclampsia also includes fetal growth restriction (FGR), recognisingthe risk of uteroplacental dysfunction for the fetus.[2] As such, women whose babies are affected by FGRshould be investigated accordingly for pre-eclampsia. Uncommon symptoms include breathlessness andvisual disturbances. All women who present with unusual symptoms in pregnancy should be investigatedfor pre-eclampsia.

Step-by-step diagnostic approachA diagnosis of pre-eclampsia should be made when there is persistent, new-onset hypertension usuallywith proteinuria after 20 weeks' gestation.[33] [3] [1] [2] The absence of hypertension excludes thediagnosis, although there are related conditions such as HELLP syndrome that may present with and withouthypertension.[3] The presence of proteinuria is no longer mandatory in the diagnosis of pre-eclampsia;systemic involvement or fetal growth restriction together with hypertension are enough to fulfil the diagnosis,even in the absence of proteinuria.[1] [2] After diagnosis, fetal assessment should be performed with furthermaternal tests to assess systemic involvement.

If there are signs and symptoms of severe pre-eclampsia or complications, immediate treatment is needed.On confirmation of the diagnosis, or if clinical signs are severe, the woman should be admitted to an obstetriccare facility for management.[3] [1]

HistoryPre-eclampsia occurs in women after 20 weeks' gestation.[3] [1] [34] Key risk factors include primiparity,positive family history, pre-eclampsia in a previous pregnancy, BMI >30, maternal age >35 years, multiplepregnancy, gestational hypertension (hypertension developing after 20 weeks' gestation in the absence




Pre-eclampsia Diagnosis

of both proteinuria and systemic symptoms), pre-gestational diabetes, polycystic ovary syndrome,autoimmune disease, renal disease, or chronic hypertension.

The woman may be asymptomatic and diagnosed at a routine clinic visit, or she may present acutely withthe following symptoms.

• Headache: usually frontal; occurs in around 40% of patients with severe disease, and is one thefew symptoms that predict an increased risk of eclampsia.[24]

• Upper abdominal pain: usually right upper quadrant pain; occurs in around 16% of patients withsevere disease, and is a clinical symptom of HELLP syndrome.[24] HELLP syndrome is a subtypeof severe pre-eclampsia characterised by haemolysis (H), elevated liver enzymes (EL), and lowplatelets (LP).

• Visual disturbances: for example, photopsia (perceived flashing lights in the visual fields),scotomata, retinal vasospasm; are relatively rare but predict an increased risk of eclampsia.Cortical blindness should alert a clinician to underlying cerebral oedema.

• Breathlessness: due to pulmonary oedema and may complicate pre-eclampsia. If it occurs afterdelivery, it is one of the main causes of maternal mortality.

• Seizures: mandates admission to intensive care unit, stabilisation, and delivery.• Oliguria.

The presence of these symptoms, in addition to hypertension with or without proteinuria, classifies pre-eclampsia as severe.[1] If fetal movements are reduced, there is a need for immediate fetal ultrasoundassessment.

Physical examinationHypertension (defined as BP ≥140 mmHg systolic and/or ≥90 mmHg diastolic), in a previouslynormotensive woman is diagnostic.[3] [1] [34] At least 2 measurements should be made, at least 4 hoursapart.[1] However, an average of 3 measurements improves accuracy.[3] [1]

Oedema is very common, but is not discriminatory, and so should not be used in diagnosis. Hyper-reflexiaand/or clonus are rare and have little value in the clinical assessment. Fundoscopy is rarely abnormal,but, if it is, underlying chronic hypertension is implied.

If the uterus is small for dates, this implies that the amniotic fluid volume is reduced, which may signifygrowth restriction, and fetal ultrasound assessment is required. Fetal growth restriction is found in around30% of women with pre-eclampsia.[3]

UrinalysisReagent strip testing can be used to screen for proteinuria. A 1+ protein result in association with elevatedblood pressure in the pre-eclampsia range requires referral to a specialist unit or hospital admission. Inthe absence of proteinuria or systemic signs of pre-eclampsia, an alternative diagnosis should be sought.

The standard diagnostic test for urinary protein estimation is a 24-hour urine collection, with a diagnosticlevel considered to be urinary excretion of ≥0.3 g protein/24 hours.[3] [1] The presence of proteinuria≥5 g/24 hours is no longer used as a marker of severity, as the level of proteinuria does not relate tooutcome.[1] However, only 70% of patients complete a 24-hour urine collection successfully.[3]

Alternative tests include reagent strip testing with automated readers, or spot testing using a urineprotein:creatinine ratio, where a result of ≥30 mg/mmol (0.3 mg/dL) is diagnostic.[3] [1] [34]

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Bacause the level of proteinuria does not correlate with outcome, once a diagnosis has been made thereis no benefit in repeating urinalysis.[3]

Fetal assessmentIf fetal movements are reduced or fetal growth restriction is suspected, there is a need for an immediatefetal ultrasound assessment. Other methods of fetal assessment should be done in all patients initiallyusing the following tests:[3] [1] [34]

• Fetal cardiotocography is recommended to assess fetal wellbeing, but is of little prognostic value.It should be performed initially, and then no more than twice weekly, unless there is a cause forconcern such as vaginal bleeding, reduced fetal movements, or increased severity of disease.

• Fetal biometry should be used to diagnose or exclude fetal growth restriction, although growth canonly be fully assessed by scans done 2 weeks apart.

• Umbilical artery Doppler velocimetry is the main assessment tool. Studies show that it reducesperinatal mortality and supports better decision-making, leading to more appropriate deliverydecisions. It should be carried out on admission and, if normal, repeated twice weekly. If abnormal,more intensive monitoring may be required using other means, including Doppler assessment ofother fetal vessels and fetal cardiotocography. Delivery may be necessary within a few days.[Fig-1]

• Amniotic fluid assessment, the single deepest vertical pocket being preferred over the amnioticindex, can easily be combined with umbilical artery Doppler velocimetry.

Other maternal investigationsFull blood count, serum creatinine, and liver function tests (LFTs) are all useful indicators of diseaseprogression, and are therefore recommended in all patients after initial urinalysis and fetal assessment.Elevated serum creatinine implies underlying renal disease. Although elevated serum uric acid isassociated with severe pre-eclampsia, it does not offer diagnostic value. Decreased platelet andincreased transaminase levels are partly diagnostic for HELLP syndrome. The platelet count is themain criterion used in classifying severity of HELLP syndrome. If the platelet count is <100x10⁹/L, a fullcoagulation screen and LFTs should be carried out. If the platelet count is ≥100x10⁹/L, further coagulationtests are not typically recommended.

The UK National Institute for Health and Care Excellence advocates the use of placental growth factor(PIGF) testing to exclude a diagnosis of pre-eclampsia (within 14 days of testing) in women presentingbetween 20 weeks and 34 weeks plus 6 days of gestation.[35] The Triage PIGF test and the Elecsysimmunoassay sFlt-1/PlGF ratio are recommended as alternatives, although the need for traditional historytaking and examination remains paramount. Equally, it remains unclear whether these investigations arepredictive of placental dysfunction, and therefore fetal wellbeing assessments are required, as describedabove.

Uterine artery Doppler may be of limited value in predicting the onset of disease.[3] [1]

[VIDEO: Venepuncture and phlebotomy animated demonstration ]

Risk factors



http://bestpractice.bmj.com/procedural-videos/en-gb/8f1f38fb-3b8f-4c50-bf01-16760d711738



Strongprimiparity• Pre-eclampsia is strongly associated with primiparity. The incidence is twice as high in these patients

compared with multiparous women. This is thought to be due the development of tolerance to specificimmunological factors after the first pregnancy, thereby reducing risk in subsequent pregnancies.These immunological factors are most likely to be associated with placental adaptations, where theinteraction between maternal and paternal immunological factors is most active. However, someexperts believe that pre-eclampsia is driven by systemic circulation of placental debris, which againallows paternal factors to affect the systemic response.[3] [9] [10] [15] [16]

pre-eclampsia in previous pregnancy• The risk of recurrence is around 10% to 50%, although it is thought to be higher in those with previous

early onset (i.e., <30 weeks) or severe disease, and lower for those with mild-moderate or late-onsetdisease. Because the risk of recurrence is reduced with a change of partner, the increased risk inthese patients is likely to be due to a failure of tolerance to the specific immunological factor.[3] [9] [10]

family history of pre-eclampsia• If a mother had pre-eclampsia, the daughter has a 25% chance of developing the condition. Similarly,

if a sister had pre-eclampsia, there is a 1 in 3 chance of developing it. These findings suggest agenetic component to the condition. Although some studies have suggested associations with variousgenetic markers, larger studies are still required.[3] [10] [17] [18]

BMI >30• Associated with an increased risk of pre-eclampsia. The risk increases as the BMI increases,

becoming more significant when the BMI is >35.[3] [10] [19]• The reasons for this are multifactorial, but may include overdiagnosis due to difficulties in measuring

BP, and the fact that adipose tissue is a potent supplier of inflammatory mediators, thereby makingobese women more likely to mount an exaggerated inflammatory response.[20] [3] [10]

maternal age >35 years• Extremes of age have been associated with pre-eclampsia; however, women >35 years of age, and

certainly those ≥40 years of age, have a greater risk of morbidity and mortality, with a risk of at least 4times that of women <25 years. This is probably due to the ageing process making disease adaptationmore difficult, and an increase in comorbidities.[3] [10]

multiple (twin) pregnancy• The association between pre-eclampsia and a multiple pregnancy is well documented. The data

are most supportive in twin pregnancies. Morbidity and mortality associated with pre-eclampsia areincreased in patients with a twin pregnancy.[3] [10] [21]

sub-fertility• Women with sub-fertility are at higher risk of adverse pregnancy outcomes including pre-

eclampsia.[22] This association is independent of maternal age and multiple pregnancy. Inpregnancies where there is a donor embryo, the incidence of pre-eclampsia is significantly higher.[23]

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gestational hypertension• Over 25% of patients with gestational hypertension (hypertension after 20 weeks' gestation in the

absence of both proteinuria and systemic symptoms) go on to develop pre-eclampsia.[1] Thesepatients should therefore be monitored closely.

pre-gestational diabetes• Diabetes is associated with a larger than average placenta and an increase in inflammatory

vascular disease, so there is a potential risk of both the placental trigger and the degree of maternalresponse.[3] [24] [10] [21]

polycystic ovary syndrome (PCOS)• Women with PCOS may be more likely to develop pre-eclampsia due to their increased risk of obesity,

type 2 diabetes, and treatment for sub-fertility.[3] [10] [21] [25]

autoimmune disease• Women with autoimmune disease, especially those with antiphospholipid antibody syndrome, have an

increased risk of pre-eclampsia, although it can be difficult to distinguish the two.[3] [10] [21]• Patients with autoimmune disease may have pre-existing vascular disease worsening the pre-

eclampsia, resulting in a severely ill patient.• An acute postpartum exacerbation can occur, but this is most likely to be due to the underlying

autoimmune disease.

renal disease• Women with renal disease may already have hypertension and proteinuria, thereby making the

diagnosis of pre-eclampsia difficult. However, the incidence of pre-eclampsia in women with renaldisease of any type is thought to be around 25%. The presence of any autoimmune disease canfurther increase the incidence.[3] [10] [21]

chronic hypertension• The incidence of pre-eclampsia in women with chronic hypertension of any type is thought to be

around 25%. The presence of any autoimmune disease can further increase the incidence.[3] [10] [21]

WeakBP ≥80 mmHg diastolic at booking• Associated with the development of pre-eclampsia; however, it is difficult to know whether this is

due to the fact the woman has a hypertensive tendency, or whether this is a risk factor for diseasedevelopment.[3] [10]

interval of 10 years or more since previous pregnancy• Women with a long interval between pregnancies have an increased risk of pre-eclampsia, but it is

difficult to separate out other compounding factors such as age, obesity, and comorbidities.[3] [15] [17]

high-altitude residence• The incidence of pre-eclampsia may be increased at high altitudes.[26]





History & examination factorsKey diagnostic factors>20 weeks' gestation (common)• Occurs in women after 20 weeks' gestation.[3] [1] [34]

BP ≥140 mmHg systolic and/or ≥90 mmHg diastolic and previouslynormotensive (common)• Hypertension (defined as BP ≥140 mmHg systolic and/or ≥90 mmHg diastolic) in a previously

normotensive woman is diagnostic.[3] [1] [34]• At least 2 measurements should be made, at least 4 hours apart.[1] However, an average of 3

measurements improves accuracy.[3] [1]• Considered severe if BP ≥160 mmHg systolic and/or ≥110 mmHg diastolic.[3] [1]• Correct cuff size should be used. Systolic measurement is taken as the first sound heard (K1) and

the diastolic measurement is the disappearance of sounds completely (K5). Where K5 is absent, K4(muffling) should be accepted.

• High systolic BP is associated with stroke and placental abruption.[3]

headache (common)• Usually frontal headache. Occurs in around 40% of patients with severe disease, and is one the few

factors that predict an increased risk of eclampsia.• Presence of this symptom classifies pre-eclampsia as severe.[1]

upper abdominal pain (common)• Usually right upper quadrant pain. Occurs in around 16% of patients of severe disease, and is a

clinical symptom of HELLP syndrome.• Presence of this symptom classifies pre-eclampsia as severe.[1]

Other diagnostic factorsreduced fetal movement (common)• If fetal movements are reduced, there is a need for an immediate fetal ultrasound assessment.

fetal growth restriction (common)• Fetal growth restriction is found in around 30% of patients.[24]• If the uterus is small for dates, this implies that the amniotic fluid volume is reduced, which may signify

fetal growth restriction.• Fetal ultrasound assessment is required.

oedema (common)• Very common, but is not discriminatory and so should not be used in diagnosis.

visual disturbances (uncommon)• A relatively rare but concerning symptom that may predict an increased risk of eclampsia.[24]• Includes photopsia (perceived flashing lights in the visual fields), scotomata, and retinal vasospasm.

Cortical blindness is a rare but critical symptom implying cerebral oedema.

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• Fundoscopy is rarely abnormal, but, if it is, underlying chronic hypertension is implied.• Presence of this symptom classifies pre-eclampsia as severe.[1]

seizures (uncommon)• Rare but critical symptom that indicates eclampsia and mandates admission to intensive care unit,

stabilisation, and delivery.[1]

breathlessness (uncommon)• Rare presentation associated with pulmonary oedema. If pulmonary oedema occurs after delivery, it is

one of the main causes of maternal mortality.• Presence of this symptom classifies pre-eclampsia as severe.[1]

oliguria (uncommon)• Defined as <500 mL urine/day or <30 mL urine in 2 consecutive hours.• May be associated with increasing oedema. Patient is at most risk postpartum when pulmonary

oedema is more likely.• Presence of this symptom classifies pre-eclampsia as severe.[1]

hyper-reflexia and/or clonus (uncommon)• Has poor positive and negative predictability for eclampsia.[34]

Diagnostic tests1st test to order

Test Resulturinalysis

• Reagent strip testing can be used for screening proteinuria. A 1+protein result in association with elevated BP in the pre-eclampsiarange requires referral to a specialist unit.

• Standard diagnostic test for urinary protein estimation is 24-hoururine collection. A urinary excretion of ≥0.3 g protein in 24 hours isdiagnostic.[3] [1] [2]

• The presence of proteinuria ≥5 g/24 hours is no longer used asa marker of severity, as the level of proteinuria does not relate tooutcome.[1]

• Alternative tests include reagent strip testing with automated readers,or spot testing using a urine protein:creatinine ratio, where a result of≥30 mg/mmol is diagnostic.[3] [34] [2]

• The presence of proteinuria is no longer mandatory in the diagnosisof pre-eclampsia; systemic involvement or fetal growth restrictiontogether with hypertension are enough to fulfil the diagnosis, even inthe absence of proteinuria.[1] [2]

1+ protein; urinaryexcretion of ≥0.3 g proteinin 24 hours; or urineprotein:creatinine ratio≥30 mg/mmol; may benormal

fetal ultrasound• Provides immediate information about fetal wellbeing from size of

baby and amniotic fluid volume. If fetal movements are reduced, thereis a need for immediate fetal ultrasound assessment.

variable depending onseverity





Test Resultfetal cardiotocography

• Assesses immediate fetal wellbeing, but is of little prognostic value.• Should be used to assess fetal wellbeing initially, and then no more

than twice weekly, unless there is a cause for concern such asvaginal bleeding, reduced fetal movements, or increased severity ofdisease.

no abnormalities intracing indicate assuredfetal wellbeing

fetal biometry• Should be used to diagnose or exclude fetal growth restriction.

Growth can only be fully assessed by scans done 2 weeks apart.• Single scan can give an estimation of fetal weight and an assessment

of whether the baby is small for dates, and gives the neonatologistimportant information about the need for immediate delivery.

may reveal fetal growthrestriction

umbilical artery Doppler velocimetry• The main assessment tool; its use reduces perinatal mortality and

supports better decision-making, leading to more appropriate deliverydecisions.[Fig-1]

• Should be carried out on admission and, if normal, repeated twiceweekly.[3] Presence of end diastolic flow is reassuring.

• If abnormal, more intensive monitoring may be required using othermeans, including Doppler assessment of other fetal vessels andfetal cardiotocography. Delivery is likely to be necessary within a fewdays.[3]

• New evidence suggests that placental vascular indices obtained fromthree-dimensional power Doppler may be predictive of pre-eclampsia.However, further larger studies are required to validate its use in thewider population.[36]

absence of end diastolicflow is a sign thatdelivery will probablybe necessary in the nearfuture

amniotic fluid assessment• Appears to be beneficial (rather than full biophysical profiling) with

the single deepest vertical pocket being preferred over the amnioticindex.

• Easily combined with umbilical artery Doppler velocimetry.[3] [1] [34]• Can assess fetal wellbeing and inform about the need to deliver

immediately.

deepest vertical pocket≥2 cm implies normality;<2 cm is associated withincreased fetal morbidityand delivery should beconsidered

FBC• Useful indicator of disease progression and recommended in all

patients.• Decreased platelet count is partly diagnostic for HELLP syndrome.

HELLP syndrome is a subtype of severe pre-eclampsia characterisedby haemolysis (H), elevated liver enzymes (EL), and low platelets(LP).

• If the platelet count is <100x10⁹/L, a full coagulation screen and bloodfilm should be carried out to diagnose/exclude HELLP syndrome.

may reveal low plateletcount

liver function tests• Useful indicator of disease progression and recommended in all

patients.• Increased transaminase levels are partly diagnostic for HELLP

syndrome.

may be elevated

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Test Resultserum creatinine

• Useful indicator of disease progression and recommended in allpatients.

• Elevated serum creatinine implies underlying renal disease.• Renal failure is a rare complication, and when it occurs, it is usually

acute tubular necrosis associated with co-existing sepsis or placentalabruption.

may be elevated

Other tests to consider

Test Resultcoagulation screen

• Usually normal in a woman with pre-eclampsia. May be abnormalwith advanced disease affecting the liver, or in association withabruption.

• Should also be carried out as an assessment of risk for interventionssuch as spinal or epidural analgesia, or surgical intervention whereexcessive bleeding may increase the morbidity or mortality risk.

typically normal

Differential diagnosis

Condition Differentiating signs /symptoms

Differentiating tests

Chronic hypertension • Pre-existing hypertensionprior to pregnancy.

• Retinopathy commonly seenin longstanding disease.

• Urinalysis: absence of new-onset proteinuria.

Gestational hypertension • No differentiating signs orsymptoms.

• Urinalysis: absence ofproteinuria.

Epilepsy • History of epilepsy orseizures before pregnancy.

• BP normal.• Focal neurological deficits or

symptoms.


Antiphospholipidantibody syndrome

• History of repeated earlypregnancy loss.

• History of venousthrombosis, stroke, ortransient ischaemic attack.

• Lupus anticoagulant:positive.

• Anticardiolipin antibodies:medium or high titre.

• Anti-beta-2-glycoprotein I:titre >99th percentile.







Thromboticthrombocytopenicpurpura

• Presentation before 20weeks' gestation.

• Thrombosis, purpura, orspontaneous bleeding.

• Fever.• Neurological signs (e.g.,

seizures) in the absenceof signs of severe pre-eclampsia.

• ADAMTS-13 activityassay and inhibitor titres:decreased activity.

Haemolytic uraemicsyndrome

• Presentation before 20weeks' gestation.

• Microangiopathic haemolyticanaemia in the absenceof signs of severe pre-eclampsia.

• Thrombosis.• Renal failure in the absence

of signs of severe pre-eclampsia.

• Diarrhoea (especially bloodydiarrhoea), nausea, orvomiting.

• Peripheral blood smear:presence of schistocytes.

• FBC: anaemia,thrombocytopenia.

Renal disease • History of renal diseasebefore pregnancy.

• Serum creatinine: elevatedin the absence of signs ofsevere pre-eclampsia.

Liver disease • History of liver diseasebefore pregnancy.

• History of alcohol abuse.• Jaundice.• BP is normal.• Hepatomegaly.


• Serum bilirubin: elevated.• Liver function tests: very high

in cases of viral disease.• Blood glucose: decreased in

cases of acute fatty liver ofpregnancy.

Gallbladder disease • History of biliary pain beforepregnancy.

• Right upper quadrant (RUQ)pain is colicky in nature, andis usually intense, lasting>30 minutes.

• BP is normal.• Distended, tender

gallbladder may be palpable.

• Liver function tests: elevatedalkaline phosphatase,gamma glutamyltranspeptidase, and bilirubin.

• RUQ ultrasound:pericholecystic fluid;distended gallbladder;thickened gallbladder wall;gallstones; positive Murphysign.

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Pancreatic disease • History prior to pregnancy.• History of alcohol abuse.• BP is normal.• Steatorrhoea.• Jaundice.• Nausea and vomiting.

• Abdominal ultrasound:structural/anatomicalchanges including cavities;duct irregularity; contourirregularity of head/body;calcification.

• Abdominal CT scan:pancreatic calcifications;focal or diffuse enlargementof the pancreas; ductaldilation; vascularcomplications.

• Abdominal x-ray: pancreaticcalcifications.

• Serum amylase: elevated.

Diagnostic criteriaAmerican College of Obstetricians and Gynecologists criteria[1]Disease severity is based on the blood pressure (BP) measurement and whether there are signs of systemicinvolvement.

• Mild-moderate

• BP is 140 to 159 mmHg systolic and/or 90 to 109 mmHg diastolic and proteinuria is 300mg/24 hours; or ≥1+ (on 2 random urine samples, collected at least 4 hours apart); orprotein:creatinine ratio is ≥0.3 mg/dL.

• BP is 140 to 159 mmHg systolic and/or 90 to 109 mmHg diastolic and in the absence ofproteinuria, any of the following is present:

• Thrombocytopenia, platelets count <100,000/uL• Serum creatinine >1.1 mg/L or a doubling of the serum creatinine concentration in the


normal concentration.

• Severe

• BP is ≥160 mmHg systolic and/or ≥110 mmHg diastolic (on 2 occasions at least 4 hours apart,while the patient is on bed rest) and proteinuria is 300 mg/24 hours; or ≥1+ (on 2 random urinesamples, collected at least 4 hours apart); or protein:creatinine ratio is ≥0.3 mg/dL.

• BP is ≥160 mmHg systolic and/or ≥110 mmHg diastolic (on 2 occasions at least 4 hoursapart, while the patient is on bed rest) and in the absence of proteinuria, any of the following ispresent:

• Thrombocytopenia, platelets count <100,000/uL




Pre-eclampsia Diagnosis• Serum creatinine >1.1 mg/L or a doubling of the serum creatinine concentration in the


normal concentration, right upper quadrant or epigastric pain that is unresponsive tomedication and unexplained by an alternative diagnosis

• Pulmonary oedema• New onset cerebral or visual disturbances.

HELLP syndrome is a subtype of severe pre-eclampsia characterised by haemolysis (H), elevated liverenzymes (EL), and low platelets (LP). The diagnosis and management of HELLP syndrome is discussed indetail elsewhere.

National Institute for Health and Care Excellence (UK) criteria[3]Pre-eclampsia is defined as new-onset hypertension (BP ≥140 mmHg systolic and/or ≥90 mmHg diastolic,based on at least 2 measurements taken at least 4 hours apart) occurring in a pregnant woman after 20weeks' gestation, with proteinuria (defined as urinary excretion of ≥0.3 g protein in 24 hours).

Severity classification:

• Mild: BP is 140 to 149 mmHg systolic and/ or 90 to 99 mmHg diastolic• Moderate: BP is 150 to 159 mmHg systolic and/ or 100 to 109 mmHg diastolic• Severe: BP is ≥160 mmHg systolic and/or ≥110 mmHg diastolic.

Comorbidities:

• Eclampsia is a convulsive condition associated with pre-eclampsia• HELLP syndrome (a subtype of severe pre-eclampsia characterised by haemolysis [H], elevated liver

enzymes [EL], and low platelets [LP]).

Timing of onset:

• Early onset: prior to 34 weeks• Mid-onset: after 34 weeks and prior to 37 weeks• Late-onset or term: after 37 weeks• Post delivery.

Society of Obstetric Medicine of Australia and New Zealandcriteria[34]These guidelines try to expand the diagnostic criteria beyond the traditional BP and proteinuria definitionsusing additional accepted pathologies. A diagnosis of pre-eclampsia can be made when hypertension arisesafter 20 weeks' gestation, and is accompanied by one or more of the following.[34]

• Renal involvement:

• Significant proteinuria: dipstick proteinuria subsequently confirmed by a spot urineprotein:creatinine ratio ≥30 mg/mmol

• Serum or plasma creatinine ≥90 micromol/L• Oliguria.

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• Haematological involvement:

• Thrombocytopenia• Haemolysis• Disseminated intravascular coagulation.

• Hepatic involvement:

• Elevated serum transaminases• Severe epigastric or right upper quadrant pain.

• Neurological involvement:

• Convulsions (eclampsia)• Hyper-reflexia with sustained clonus• Severe headache• Persistent visual disturbances (e.g., photopsia, scotomata, cortical blindness, retinal

vasospasm)• Stroke.

• Pulmonary oedema.• Fetal growth restriction.• Placental abruption.




Pre-eclampsia Treatment

Step-by-step treatment approachManagement of pre-eclampsia is based on disease severity and progression. Mainstays of treatment includemonitoring, deciding on a delivery date and method, lowering blood presuure (BP), controlling seizures, andpostpartum fluid management. The main causes of maternal mortality are cerebrovascular accidents andpulmonary oedema; therefore, lowering BP and managing postpartum fluid are the most important aspects oftreatment, regardless of the presence of other complications such as eclampsia or HELLP syndrome.

Management should be in a tertiary-care setting or in consultation with an obstetrician/gynaecologist withexperience in managing high-risk pregnancies.[1] Management differs between countries; however, the basicprinciples of management are the same.

Hospital admissionAll women, regardless of disease severity, should be managed in an inpatient care facility.[1] [3][2] However, in cases of well-controlled mild to moderate disease, outpatient management can beconsidered, although close outpatient monitoring in a day unit or equivalent is required.[1] [3] [34]

On admission, further assessment is required. BP should be monitored regularly for rising levels, needfor intervention, and response to therapy; however, there is little guidance on how often this should beperformed. A good guide is at least 4 times per day on a ward, or continuously in an intensive care unit.[3]

Plan for deliveryThe definitive treatment for pre-eclampsia is delivery; however, this is not always possible immediately. Inaddition, even after delivery, it may take a few days for the condition to resolve completely. The decisionto deliver can only be made after a thorough assessment of the risks and benefits to both the mother andbaby. The main risk to the baby is prematurity, a cause of neonatal morbidity and mortality.[3] Neonatalhealthcare costs also rise significantly with immediate delivery.[41]

If the patient is considered stable (i.e., absence of seizures, controlled hypertension), a conservativeapproach is usually taken, and the decision to deliver is based on the gestational age.[3] [1] [34]

• At <32 weeks' gestation: prolonging the pregnancy is beneficial for the fetus, as long as maternaland fetal assessments are satisfactory. Antihypertensive therapy can be used for 15 days onaverage before the maternal or fetal condition dictates delivery.[3] This approach requires carefulin-hospital maternal and fetal surveillance.[42] Antenatal corticosteroids are recommended before34 weeks' gestation to mature fetal lungs.[3]

• At 32 to 36 weeks' gestation: there is limited evidence to guide management, and decisionsshould therefore be made on a case-by-case basis. One study compared immediate deliveryversus expectant management in women with non-severe pre-eclampsia at 34 to 37 weeks ofgestation.[43] The likelihood of maternal complications was not significantly affected by delay, butearlier delivery was associated with greater respiratory distress syndrome in the infant.[43] Thissuggests that if the clinical picture is stable, the pregnancy may continue under monitoring up to37 weeks. However, when these results were combined with another randomised trial, plannedearlier delivery was associated with a reduction in maternal morbidity and mortality for pregnanciesat more than 34 weeks’ gestation, although the authors acknowledged that the data are limited.[44]If disease severity in the mother increases, then immediate delivery will be required. In orderto reduce respiratory distress syndrome, antenatal corticosteroids are recommended before 34

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weeks' gestation to mature fetal lungs.[3] There is likely to be benefit from the administration ofantenatal corticosteroids at 34 to 36 weeks, but this is unclear, and a decision should be madebased on the specific case.[3]

• At >36 weeks' gestation: delivery is the most sensible approach.

If the patient is considered unstable (i.e., presence of seizures, uncontrolled hypertension), she shouldbe treated with magnesium sulfate and antihypertensive therapy before delivery is considered.[2] Deliveryshould be considered after the patient has been stabilised, as a rushed delivery in an unstable patient canbe dangerous.

The method of delivery depends on the gestational age, and should be tailored based on the individualpatient.[3] [1] [34]

• At <32 weeks' gestation: caesarean is the most likely mode of delivery, as attempted vaginaldelivery may fail, cause significant fetal morbidity, or be unsafe in a severely ill mother.

• At 32 to 36 weeks' gestation: decision should be made on a case-by-case basis.• At >36 weeks' gestation: vaginal delivery should be attempted, unless the maternal condition

precludes this.

If a caesarean is performed, regional anaesthesia is preferred if the woman can tolerate it and there is nocoagulopathy. If a general anaesthetic is used, care should be taken to prevent the hypertensive responseto intubation and extubation, and the risk of laryngeal oedema.[45]

Management of hypertensionAntihypertensive therapy should be started when the BP is ≥160 mmHg systolic and/or ≥110 mmHgdiastolic.[1] Oral monotherapy is effective in most cases, although some women may require combinationtherapy with two different antihypertensive agents, or intravenous therapy, depending on the clinicalcircumstances. If BP is not adequately reduced within 1 hour of starting therapy, a second dose should begiven, a second drug should be added, or an intravenous regimen should be started. There is no need toreduce the BP too quickly or by too much; the aim is to stop the rise and reduce the BP gradually to <150mmHg systolic and <100 mmHg diastolic.

Labetalol is considered the antihypertensive of choice,[3] [1] [46] [2] and is effective as monotherapy in80% of patients.[6] It appears to be safe and effective in pregnant women for the management of pre-eclampsia; however, it should be avoided in Afro-Caribbean women due to a poor response to beta-blockers, and in women with asthma or any other contraindication to its use.[1]

If severe hypertension does not respond to oral labetalol, oral nifedipine may be as effective asintravenous labetalol.[47] Nifedipine may also be used safely in combination with either labetalol ormethyldopa if required. In extreme circumstances, labetalol, nifedipine, and methyldopa may be usedtogether.

Hydralazine is widely used to manage severe hypertension in pregnancy; however, it can produce anacute fall in BP and should be used along with plasma expansion. Smaller, more frequent doses may beused; however, labetalol is considered the superior choice of drug.[3] [1]

Management of eclampsiaMagnesium sulfate is the treatment of choice for women with eclampsia.[3] [1] [2] Intramuscular orintravenous administration has shown equal efficacy in trials.[48] Higher doses are recommended in theUS; however, this has not been subjected to randomised trials to prove any additional benefits, although





observational studies support this.[3] While seizures are frightening to observe and experience, mostwomen recover without therapy and most do not convulse again, and no regime will prevent furtherseizures occurring.[Fig-2]

If a low-dose regimen is used, monitoring serum magnesium levels is only required if the patient hasrenal impairment.[3] If a high-dose regimen is used, serum magnesium levels should be checked 6 hoursafter administration, and then as needed. Therapeutic levels are 4 to 7 mEq/L (4.8 to 8.4 mg/dL).[1]Respiratory depression may occur and patellar reflexes may disappear once the level reaches 10 mEq/L;however, calcium gluconate may be used to reverse these effects.

Although magnesium sulfate shows benefit in established seizures, its role in the prevention of seizuresis uncertain.[48] In the US, it is recommended for all women with severe pre-eclampsia.[1] In othercountries, including the UK, a more targeted approach is recommended, allowing the physician toexercise individual judgment based on the patient's specific risk factors (e.g., presence of uncontrolledhypertension, proteinuria of ≥5 g/24 hours, or deteriorating maternal condition).[3]

Postpartum managementControl of hypertension and seizures needs to be continued after delivery until recovery is apparent.During this period, the main risk to the mother is fluid overload. Although invasive haemodynamicmonitoring is recommended in the US,[1] in the UK, guidelines are based on a fluid-restriction regimenof 80 mL/hour.[3] There has been no death from pulmonary oedema with the use of this regimen, andthere has been a reduction in admissions to intensive care units.[6] [21] Women should be on a fluidinput/output chart. Intravenous fluids should be restricted to 80 mL/hour until the patient is drinkingfreely, as long as urine output is normal. There is no need to treat low urine output, and fluid challengesshould not be given except after careful consideration and under strict surveillance. As long as there iscardiovascular stability, adequate urine output, and maintenance of oxygen saturation, there is no needfor invasive monitoring.[3]

If fluid overload is suspected due to fluid administration during delivery, especially during caesareansection, judicious use of diuretics is advisable.[3]

[VIDEO: Central venous catheter insertion animated demonstration ]

Treatment details overviewConsult your local pharmaceutical database for comprehensive drug information including contraindications,drug interactions, and alternative dosing. ( see Disclaimer )

Acute ( summary )before delivery

1st hospital admission and monitoring

plus decision regarding delivery

adjunct corticosteroid

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Acute ( summary )with BP ≥160 mmHgsystolic and/or ≥110mmHg diastolic

plus antihypertensive therapy

with seizures plus magnesium sulfate

Ongoing ( summary )after delivery

1st close monitoring of fluid balance

adjunct continue antihypertensives andmagnesium sulfate





Treatment options

Acutebefore delivery

1st hospital admission and monitoring

» All women, regardless of disease severity,should be managed in an inpatient carefacility.[3] [1] [2] However, in cases of well-controlled mild to moderate disease, outpatientmanagement can be considered, although closeoutpatient monitoring in a day unit or equivalentis required.[3] [1] [34]

» On admission, further assessment is required.BP should be monitored regularly for risinglevels, need for intervention, and response totherapy; however, there is little guidance on howoften this should be. A good guide is at least 4times per day on a ward, or continuously in anintensive care unit.[3]

plus decision regarding delivery

» If the patient is stable (i.e., absenceof seizures, controlled hypertension), aconservative approach is usually taken, and thedecision to deliver is based on the gestationalage.[3] [1] [34] At <32 weeks' gestation,prolonging the pregnancy is beneficial for thefetus, as long as maternal and fetal assessmentsare satisfactory. At 32 to 36 weeks' gestation,there is little evidence to guide management,and decisions should be made on a case-by-case basis. At >36 weeks' gestation, delivery isthe most sensible approach.

» Method of delivery depends on the gestationalage, and should be tailored based on theindividual patient.[3] [1] [34] At <32 weeks'gestation, a caesarean is the most likely mode ofdelivery as attempted vaginal delivery may fail,cause significant fetal morbidity, or be unsafein a severely ill mother. At 32 to 36 weeks'gestation, the decision should be made on acase-by-case basis. At >36 weeks' gestation,vaginal delivery should be attempted, unless thematernal condition precludes this.

» If a caesarean is performed, regionalanaesthesia is preferred if the woman cantolerate it and there is no coagulopathy. If ageneral anaesthetic is used, care should betaken to prevent the hypertensive response tointubation and extubation, and the problems oflaryngeal oedema.[45]

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Acute» If the patient is considered unstable(i.e., presence of seizures, uncontrolledhypertension), they should be treated withmagnesium sufate and antihypertensive therapybefore delivery is considered.[2] Delivery shouldbe considered after the patient is stabilised, as arushed delivery can be dangerous.

adjunct corticosteroid

Primary options

» betamethasone: 12 mg intramuscularlyevery 24 hours for 2 doses

OR

» dexamethasone: 6 mg intramuscularlyevery 12 hours for 4 doses

» Antenatal corticosteroids are recommendedbefore 34 weeks' gestation to mature fetallungs.[3]

» There is likely to be a benefit from theadministration of corticosteroids at 34 to 36weeks' gestation, but this is unclear, and adecision should be made based on the specificcase.[3]

with BP ≥160 mmHgsystolic and/or ≥110mmHg diastolic

plus antihypertensive therapy

Primary options

» labetalol: acute (intravenous): 20 mgintravenous bolus initially, followed by 40 mgbolus 10 minutes later, then 80 mg bolusevery 10 minutes until desired response,maximum 220 mg total dose; acute (oral):200 mg orally every hour until desiredresponse, maximum 1600 mg/day; chronic:200-400 mg orally three to four times daily,maximum 1600 mg/day

Secondary options

» nifedipine: acute: 10 mg orally (immediate-release) every hour until desired response,maximum 120 mg/day; chronic: 10-60mg orally (sustained-release) twice daily,maximum 160 mg/day

OR

» hydralazine: acute: 5-10 mg intravenouslyevery 15-20 minutes until desired response

OR





Acute» methyldopa: chronic: 250-750 mg orallythree times daily

Tertiary options

» nifedipine: acute: 10 mg orally (immediate-release) every hour until desired response,maximum 120 mg/day; chronic: 10-60mg orally (sustained-release) twice daily,maximum 160 mg/day-and-» labetalol: acute (intravenous): 20 mgintravenous bolus initially, followed by 40 mgbolus 10 minutes later, then 80 mg bolusevery 10 minutes until desired response,maximum 220 mg total dose; acute (oral):200 mg orally every hour until desiredresponse, maximum 1600 mg/day; chronic:200-400 mg orally three to four times daily,maximum 1600 mg/day-and-» methyldopa: chronic: 250-750 mg orallythree times daily

» Antihypertensive therapy should be startedwhen BP is ≥160 mmHg systolic and/or ≥110mmHg diastolic.[1]

» If the BP is not adequately reduced within 1hour of starting therapy, a second dose shouldbe given, a second drug should be added, or anintravenous regimen should be started. There isno need to reduce the BP too quickly or by toomuch; the aim is to stop the rise and reduce theBP gradually to <160 mmHg systolic and <110mmHg diastolic.

» Labetalol is considered the antihypertensiveof choice,[3] [1] [46] [2] and is effective asmonotherapy in 80% of patients;[6] however, itshould be avoided in Afro-Caribbean womendue to a poor response to beta-blockers, and inwomen with asthma or any other contraindicationto its use.

» In severe hypertension not responding to orallabetalol, oral nifedipine may be as effectiveas intravenous labetalol.[47] Nifedipine mayalso be used safely in combination with eitherlabetalol or methyldopa if required. In extremecircumstances, labetalol, nifedipine, andmethyldopa may be used together.

» Hydralazine is widely used to manage severehypertension in pregnancy; however, it canproduce an acute fall in BP and should be usedalong with plasma expansion. Smaller, more

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Acutefrequent doses may be used; however, labetalolis considered the superior choice of drug.[3] [1]

with seizures plus magnesium sulfate

Primary options

» magnesium sulfate: high-dose regimen:4-6 g intravenous loading dose over 15-20minutes, followed by 2 g/hour intravenousinfusion; low-dose intravenous regimen: 4 gintravenous loading dose, followed by 1 g/hour intravenous infusion for 24 hours; low-dose intramuscular regimen: 4 g intravenousloading dose with 10 g intramuscularly,followed by 5 g intramuscularly every 4 hoursfor 24 hours

» Magnesium sulfate is the treatment ofchoice for women with eclampsia.[3] [1] [2]Intramuscular or intravenous administration hasshown equal efficacy in trials.[48] Higher dosesare recommended in the US; however, this hasnot been subjected to randomised trials to proveany additional benefits, although observationalstudies support this.[3]

» Although magnesium sulfate shows benefit inestablished seizures, its role in the preventionof seizures is uncertain.[48] In the US, it isrecommended for all women with severe pre-eclampsia.[1] In other countries, including theUK, a more targeted approach is recommended,allowing the physician to exercise individualjudgment based on the patient's specificrisk factors (e.g., presence of uncontrolledhypertension, proteinuria of ≥5 g/24 hours, ordeteriorating maternal condition).[3]

» Serum magnesium levels may need to bemonitored in selected patients.[3] [1]

Ongoingafter delivery

1st close monitoring of fluid balance

» During the postpartum period, the main risk tothe mother is fluid overload.

» Although invasive haemodynamic monitoring isrecommended in the US,[1] in the UK, guidelinesare based on a fluid-restriction regimen of 80mL/hour.[3]

» Women should be on a fluid input/output chart.Intravenous fluids should be restricted to 80 mL/





Ongoinghour until the patient is drinking freely, as long asurine output is normal. There is no need to treatlow urine output, and fluid challenges shouldnot be given except after careful considerationand under strict surveillance. As long as there iscardiovascular stability, adequate urine output,and maintenance of oxygen saturation, there isno need for invasive monitoring.[3]

» If fluid overload is suspected due to fluidadministration during delivery, especially duringcaesarean section, judicious use of diuretics,according to local protocols, is advisable.[3]

adjunct continue antihypertensives andmagnesium sulfate

» Control of hypertension and seizures needsto be continued after delivery until recovery isapparent.

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EmergingTargeted therapiesWith the discovery of various substances thought to be involved in the pathophysiology of pre-eclampsia,the possibility of using targeted therapies in the future is becoming a reality. Potential targets includevascular endothelial growth factor (delivered by adenovirus vector), relaxin analogues, sildenafil, and otherinflammatory agents.[58] [59] [60] However, because the exact role of these substances in the diseaseprocess is unknown at this time, these approaches are not without risk, and there are no treatments currentlyavailable.




Pre-eclampsia Follow up

RecommendationsMonitoringAfter initial assessment and stabilisation, monitoring needs to be at intervals dictated by the severity ofthe condition. Blood pressure should be monitored regularly for rising levels, need for intervention, andresponse to therapy; however, there is little guidance on how often this should be. A good guide is atleast 4 times per day on a ward, or continuously in an intensive care unit.[3] Laboratory tests (i.e., fullblood count, liver function tests, renal function) should be monitored at least twice weekly (daily if severitydictates). There is no strong evidence linking the level of proteinuria with adverse outcome; therefore,once a diagnosis has been made, there is no benefit in repeating urinalysis.[3]

Fetal cardiotocography should be done no more than twice weekly, unless there is a cause for concernsuch as vaginal bleeding, reduced fetal movements, or increased severity of disease, in which case itshould be done daily, or continuously if delivery is planned. Umbilical artery Doppler velocimetry and fetalultrasound are recommended twice weekly.

After delivery, continued maternal monitoring is required until the condition has improved. This can bedone as an outpatient if the condition allows. If the condition has not completely improved by 6 weeks, thediagnosis should be reconsidered and a referral to the appropriate specialist for investigation instigated.

Patient instructionsThere is very little the patient can do once the condition has been diagnosed; however, the need forhospitalisation and early delivery should be explained. After delivery, there are various organisations thatthe patient may find useful.

[Preeclampsia Foundation]

[Action on Pre-eclampsia]

Complications

Complications Timeframe Likelihoodintrauterine growth restriction short term high

Fetal growth restriction is found in around 30% of patients.[24] If the uterus is small for dates, this impliesthat the amniotic fluid volume is reduced, which may signify fetal growth restriction.

Fetal ultrasound assessment is required. Fetal biometry should be used to diagnose or exclude fetalgrowth restriction, although growth can only be fully assessed by scans done 2 weeks apart.

eclampsia short term medium

Although some experts see this as the main complication, and treatment is directed towards preventingthis complication, in practice it does not present the main risk to the mother. Not all women developeclampsia.

With the judicious use of magnesium sulfate, the incidence can be reduced, but not prevented.

pulmonary oedema short term medium

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Pre-eclampsia Follow upFO

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Complications Timeframe LikelihoodLargely a postpartum event indicated by breathlessness, but can be diagnosed early with the use of apulse oximeter (O₂ saturation monitor), which is the best measure of fluid overload.

Can be prevented by careful fluid management.[21]

If present prior to delivery, left ventricular function defects should be excluded by echocardiogram.

pregnancy-associated stroke short term low

Over the years, this has been the main cause of maternal death and morbidity, caused by the elevation ofblood pressure (BP).[21] There is also evidence to suggest that the risk of pregnancy-associated stroke isincreased in women with pre-eclampsia and one or more of the following: infections, chronic hypertension,coagulopathies, or underlying prothrombotic conditions.[64] These patients are likely to require closermonitoring.[64]

Prevented by management of BP; untreated systolic hypertension poses the greater risk of stroke.[21]

placental abruption short term low

Although this is a greatly feared complication, as it can bring sudden fetal demise and severecomplications to the mother, its incidence has been falling over the last 30 years.[21]

Appears to be associated with untreated systolic hypertension, so its reduction in incidence may be due toimproved care.

Generally presents as acute abdominal pain, enlarging uterus, vaginal bleeding of varying degree, andcardiovascular changes.

If the baby is alive, it needs to be delivered quickly and the uterus emptied. Delay can lead to fetaldemise. A worsening abruption leads to coagulation defects, haemorrhage, and major problems with fluidmanagement.

If the baby has died in utero, a vaginal delivery can be considered as long as coagulation parameters andbleeding are stable.

An indication for invasive cardiovascular monitoring.

renal failure long term low

Long-term renal failure is extremely rare, and is due to cortical necrosis.

Short-term renal failure (usually acute tubular necrosis) is also rare and is associated with sepsis andabruption; most patients usually recover.

Maternal death in the developed world from renal failure is very rare due to the availability of supportivemeasures such as dialysis.[21] [48]

In the under-resourced world, renal failure as a sole complication is still rare, but is associated with themultiple organ failure that occurs in prolonged untreated disease and can contribute to death.[21] [48]

stillbirth variable low




Pre-eclampsia Follow up

Complications Timeframe LikelihoodFetal morbidity and mortality is largely dependent on the function of the placenta and the gestation ofdelivery.

Placental insufficiency leads to growth restriction, but rarely to fetal death in later gestations. Growthrestriction is more likely to lead to intrauterine death in early gestations due to an attempt to delay deliveryto prolong the pregnancy.

The main cause of morbidity and mortality is iatrogenic premature delivery due to the severity of thedisease.

Prognosis

Pre-eclampsia is a self-limiting condition of pregnancy that usually resolves once the placenta has beendelivered, although it may persist for a few days post delivery. There are few long-term sequelae; however,there are some long-term disease associations.

Disease courseThe course of pre-eclampsia is altered by treatment, and the condition can be controlled easily in mostpatients, usually within a few hours of starting treatment. Once controlled, the length of the disease dependson when delivery is decided. After delivery, the condition normally settles within 2 to 4 days; however, somewomen have hypertensive problems and proteinuria for some weeks after.

RecurrenceThe overall risk of recurrence in subsequent pregnancies ranges from about 10% to 50%, depending on theseverity of pre-eclampsia, the gestation it occurred at, and subsequent interventions in the next pregnancy.[3]Generally, in previous severe or early onset (i.e., <30 weeks) pre-eclampsia, the risk of recurrence is 50%.[3]In mild to moderate or late-onset pre-eclampsia, the risk of recurrence is reduced to around 10%.[3]

Long-term disease associationsWomen with pre-eclampsia have an increased long-term risk of type 2 diabetes, cardiovascular disease,including hypertension and stroke.[61] [62] [63] There are no clear guidelines on the long-term follow-up ofwomen who have had pre-eclampsia. However, an assessment of their risk for cardiovascular disease shouldinclude previous pre-eclampsia alongside body mass index and other lifestyle factors.[3]

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Pre-eclampsia GuidelinesG

UID

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ES

Diagnostic guidelines

Europe

Hypertension in pregnancy: diagnosis and managementPublished by: National Institute for Health and Care Excellence Last published: 2011

International

The classification, diagnosis and management of the hypertensive disordersof pregnancy: a revised statement from the ISSHPPublished by: International Society for the Study of Hypertension inPregnancy

Last published: 2014

North America

First-trimester risk assessment for early-onset preeclampsiaPublished by: American College of Obstetricians and Gynecologists Last published: 2015

(reaffirmed 2017)

Diagnosis, evaluation, and management of the hypertensive disorders ofpregnancyPublished by: Society of Obstetricians and Gynaecologists of Canada Last published: 2014

Hypertension in pregnancyPublished by: American College of Obstetricians and Gynecologists Last published: 2013

Latin America

7th Brazilian guideline of arterial hypertension: chapter 9 - arterialhypertension in pregnancyPublished by: Arquivos Brasileiros de Cardiologia Last published: 2016

Oceania

Guidelines for the management of hypertensive disorders of pregnancy 2014Published by: Society of Obstetric Medicine of Australia and NewZealand




http://guidance.nice.org.uk/CG107

http://www.isshp.org/guildelines/


https://access.acog.org/eweb/DynamicPage.aspx?WebCode=LoginRequired

http://www.jogc.com/clinical-practice-guidelines



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319470/


http://www.somanz.org/guidelines.asp


Pre-eclampsia Guidelines

Treatment guidelines

Europe

Hypertension in pregnancy: diagnosis and managementPublished by: National Institute for Health and Care Excellence Last published: 2011

International

The classification, diagnosis and management of the hypertensive disordersof pregnancy: a revised statement from the ISSHPPublished by: International Society for the Study of Hypertension inPregnancy


North America

Low-dose aspirin use for the prevention of morbidity and mortality frompreeclampsiaPublished by: US Preventive Services Task Force Last published: 2014

Diagnosis, evaluation, and management of the hypertensive disorders ofpregnancyPublished by: Society of Obstetricians and Gynaecologists of Canada Last published: 2014

Hypertension in pregnancyPublished by: American College of Obstetricians and Gynecologists Last published: 2013

Latin America

7th Brazilian guideline of arterial hypertension: chapter 9 - arterialhypertension in pregnancyPublished by: Arquivos Brasileiros de Cardiologia Last published: 2016

Oceania

Guidelines for the management of hypertensive disorders of pregnancy 2014Published by: Society of Obstetric Medicine of Australia and NewZealand


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http://guidance.nice.org.uk/CG107



http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication

http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/low-dose-aspirin-use-for-the-prevention-of-morbidity-and-mortality-from-preeclampsia-preventive-medication






http://www.somanz.org/guidelines.asp


Pre-eclampsia Online resourcesO

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Online resources

1. Preeclampsia Foundation (external link)

2. Action on Pre-eclampsia (external link)



http://www.preeclampsia.org/

http://action-on-pre-eclampsia.org.uk/


Pre-eclampsia References

Key articles

• National Institute for Health and Care Excellence. Hypertension in pregnancy: diagnosis andmanagement. January 2011 [internet publication]. Full text

• Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol. 2002 Sep;2(9):656-63. [Erratumin: Nat Rev Immunol 2002 Dec;2(12):975.] Abstract

• Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review ofcontrolled studies. BMJ. 2005 Mar 12;330(7491):565. Full text Abstract

• National Institute for Health and Care Excellence. PlGF-based testing to help diagnose suspected pre-eclampsia (Triage PlGF test, Elecsys immunoassay sFlt-1/PlGF ratio, DELFIA Xpress PlGF 1-2-3 test,and BRAHMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio). May 2016 [internet publication]. Full text

• Which anticonvulsant for women with eclampsia? Evidence from the Collaborative Eclampsia Trial.Lancet. 1995 Jun 10;345(8963):1455-63. Abstract

References

1. American College of Obstetricians and Gynecologists; Task Force on Hypertension in Pregnancy.Hypertension in pregnancy: report of the American College of Obstetricians and Gynecologists’ TaskForce on Hypertension in Pregnancy. Obstet Gynecol. 2013 Nov;122(5):1122-31. Full text Abstract

2. Tranquilli AL, Dekker G, Magee L, et al. The classification, diagnosis and management of thehypertensive disorders of pregnancy: a revised statement from the ISSHP. Pregnancy Hypertens. 2014Apr;4(2):97-104. Abstract

3. National Institute for Health and Care Excellence. Hypertension in pregnancy: diagnosis andmanagement. January 2011 [internet publication]. Full text

4. US Preventive Services Task Force; Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screeningfor preeclampsia: US Preventive Services Task Force recommendation statement. JAMA. 2017 Apr25;317(16):1661-7. Full text Abstract

5. Jeyabalan A. Epidemiology of preeclampsia: impact of obesity. Nutr Rev. 2013 Oct;71(suppl1):S18-25. Full text Abstract

6. Tuffnell DJ, Jankowicz D, Lindow SW, et al. Outcomes of severe pre-eclampsia/eclampsia in Yorkshire1999/2003. BJOG. 2005 Jul;112(7):875-80. Full text Abstract

7. Ngwenya S. Severe preeclampsia and eclampsia: incidence, complications, and perinatal outcomes ata low-resource setting, Mpilo Central Hospital, Bulawayo, Zimbabwe. Int J Womens Health. 2017 May17;9:353-7. Full text Abstract

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https://www.nice.org.uk/guidance/dg23



http://www.acog.org/Resources-And-Publications/Task-Force-and-Work-Group-Reports/Hypertension-in-Pregnancy



http://www.nice.org.uk/guidance/cg107

http://jamanetwork.com/journals/jama/fullarticle/2620095




http://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2005.00565.x/full





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10. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review ofcontrolled studies. BMJ. 2005 Mar 12;330(7491):565. Full text Abstract

11. Brew O, Sullivan MH, Woodman A. Comparison of normal and pre-eclamptic placental geneexpression: a systematic review with meta-analysis. PLoS One. 2016 Aug 25;11(8):e0161504. Fulltext Abstract

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26. Palmer SK, Moore LG, Young D, et al. Altered blood pressure course during normal pregnancy andincreased preeclampsia at high altitude (3100 meters) in Colorado. Am J Obstet Gynecol. 1999May;180(5):1161-8. Abstract

27. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for pretermpreeclampsia. N Engl J Med. 2017 Aug 17;377(7):613-22. Full text Abstract

28. Gan J, He H, Qi H. Preventing preeclampsia and its fetal complications with low-dose aspirin in EastAsians and non-East Asians: a systematic review and meta-analysis. Hypertens Pregnancy. 2016Aug;35(3):426-35. Abstract

29. Roberge S, Villa P, Nicolaides K, et al. Early administration of low-dose aspirin for the preventionof preterm and term preeclampsia: a systematic review and meta-analysis. Fetal Diagn Ther.2012;31(3):141-6. Full text Abstract

30. Barakat R, Pelaez M, Cordero Y, et al. Exercise during pregnancy protects against hypertension andmacrosomia: randomized clinical trial. Am J Obstet Gynecol. 2016 May;214(5):649;e1-8. Abstract

31. Villar J, Abdel-Aleem H, Merialdi M, et al; World Health Organization Calcium Supplementationfor the Prevention of Preeclampsia Trial Group. World Health Organization randomized trial ofcalcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol. 2006Mar;194(3):639-49. Full text Abstract

32. Hofmeyr GJ, Manyame S. Calcium supplementation commencing before or early in pregnancy, or foodfortification with calcium, for preventing hypertensive disorders of pregnancy. Cochrane Database SystRev. 2017;(9):CD011192. Full text Abstract

33. Davey DA, MacGillivray I. The classification and definition of the hypertensive disorders of pregnancy.Am J Obstet Gynecol. 1988 Apr;158(4):892-8. Abstract

34. Lowe SA, Bowyer L, Lust K, et al. SOMANZ guidelines for the management of hypertensive disordersof pregnancy 2014. Aust N Z J Obstet Gynaecol. 2015 Oct;55(5):e1-29. Full text Abstract

35. National Institute for Health and Care Excellence. PlGF-based testing to help diagnose suspected pre-eclampsia (Triage PlGF test, Elecsys immunoassay sFlt-1/PlGF ratio, DELFIA Xpress PlGF 1-2-3 test,and BRAHMS sFlt-1 Kryptor/BRAHMS PlGF plus Kryptor PE ratio). May 2016 [internet publication]. Full text

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Pre-eclampsia Images

Images

Figure 1: Umbilical artery Doppler velocimetry: (1) normal pattern; (2) reduced end diastolic flow; (3) absentend diastolic flow; (4) reverse end diastolic flow

From the personal collection of Dr James J. Walker; used with permission

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Pre-eclampsia ImagesIM

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Figure 2: Patient with severe pre-eclampsia in intensive care unit post seizure

From the personal collection of Dr James J. Walker; used with permission




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Contributors:

// Authors:

James J. Walker, MD, FRCPS (Glas), FRCP (Edin), FRCOGProfessorAcademic Department of Obstetrics and Gynaecology, Leeds Teaching Hospitals Trust, Leeds, UKDISCLOSURES: JJW is Medical Director of Action on Pre-eclampsia (unpaid position). JJW lectures onpre-eclampsia at educational meetings (unpaid). He is a member of the International Society for the study ofHypertension in Pregnancy, and contributes towards guideline development in hypertension in pregnancy.

Lara Morley, MBCHB, BscClinical Research FellowLeeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UKDISCLOSURES: LM declares that she has no competing interests.

// Peer Reviewers:

Thomas R. Easterling, MDProfessorDepartment of Obstetrics & Gynecology, University of Washington, Seattle, WADISCLOSURES: TRE declares that he has no competing interests.

Andrew Shennan, MBBS, MD FRCOGProfessor of ObstetricsMaternal and Fetal Research Unit, St Thomas' Hospital, King's College London, London, UKDISCLOSURES: Not disclosed.

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