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PREECLAMPSIAAND

HELLP-SYNDROME

D R . KO B R A S H O J A E I

DEFINITIONS OF PREGNANCY-RELATED HYPERTENSIVE DISORDERS• Preeclampsia – Preeclampsia refers to the new onset of hypertension and

either proteinuria or end-organ dysfunction or both after 20 weeks of gestation in a previously normotensive woman .

• Severe hypertension and signs/symptoms of end-organ injury are considered the severe spectrum of the disease .

• In 2013, the American College of Obstetricians and Gynecologists removed proteinuria as an essential criterion for diagnosis of preeclampsia with severe features.

• They also removed massive proteinuria (5 grams/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 .

• Chronic/preexisting hypertension – Chronic/preexisting hypertension is defined as systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg that antedates pregnancy or is present before the 20th week of pregnancy (on at least two occasions) 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

• Preeclampsia superimposed upon chronic/preexisting hypertension – Superimposed preeclampsia is defined by the new onset of either proteinuria or end-organ dysfunction after 20 weeks of gestation in a woman with chronic/preexisting hypertension. For women with chronic/preexisting 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 spectrum of the disease.

• Gestational hypertension – Gestational hypertension refers to hypertension without proteinuria or other signs/symptoms of preeclampsia that develops after 20 weeks of gestation.

• It should resolve by 12 weeks postpartum. If hypertension persists beyond 12 weeks postpartum, the diagnosis is revised to chronic/preexisting hypertension that was masked by the physiologic decrease in blood pressure that occurs in early pregnancy. If hypertension resolves postpartum, the diagnosis is revised to transient hypertension of pregnancy.

DIAGNOSIS

• International guidelines generally agree that the diagnosis of preeclampsia should be made in a previously normotensive woman with new onset of hypertension and either proteinuria or end-organ dysfunction after 20 weeks of gestation.

CRITERIA FOR DIAGNOSIS ARE :• Systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg,

and • Proteinuria ≥0.3 grams in a 24-hour urine specimen or protein:creatinine

ratio ≥0.3, or • Signs of end-organ dysfunction (platelet count <100000 mliter. Serum

ceratinin> 1.1 mg/dL or doubling of the serum creatinine, elevated serum transaminases to twice normal concentration).

• Severe hypertension and signs/symptoms of end-organ injury are considered the severe spectrum of the disease

• Severe Preeclampsia is generally classified as having severe features if any of the following are present in a woman with :

• Severe hypertension (systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg)

• Signs/symptoms of end-organ injury (thrombocytopenia, impaired liver function, progressive renal insufficiency, pulmonary edema, new onset cerebral or visual disturbances)

• Therefore, the history and physical examination should evaluate the patient for:

• ● Persistent and/or severe headache • ● Visual abnormalities (scotomata, photophobia, blurred vision, or

temporary blindness) • ● Upper abdominal or epigastric pain • ● Nausea, vomiting • ● Dyspnea • ● Altered mental status

• The minimum post-diagnostic laboratory/imaging evaluation should include:

• ● Platelet count • ● Serum creatinine • ● Serum aspartate aminotransferase (AST) or alanine aminotransferase

(ALT) • ● Obstetrical ultrasound (fetal weight, amniotic fluid volume) • ● Fetal assessment (biophysical profile or nonstress test)

• Additional tests that can be informative include blood smear and serum lactate dehydrogenase (LDH) and bilirubin concentrations. Microangiopathic hemolysis is suggested by elevated LDH and indirect bilirubin levels and red cell fragmentation (schistocytes or helmet cells) on peripheral blood smear (picture 2A-B).

• Hemoconcentration occurs in preeclampsia , but hemolysis, if present, can decrease the hematocrit to normal or anemic levels.

• Coagulation function tests (eg, prothrombin time, activated partial thromboplastin time, fibrinogen concentration) are usually normal in patients without thrombocytopenia or liver dysfunction; therefore, they are not checked routinely.

PREECLAMPSIA: MANAGEMENT AND PROGNOSIS

GENERAL PRINCIPLES

• A key aspect of routine prenatal care is monitoring pregnancies for signs and symptoms of preeclampsia. If the diagnosis is made, the definitive treatment is delivery to prevent development of maternal or fetal complications from disease progression (see "Preeclampsia: Clinical features and diagnosis", section on 'Burden of disease').

• When to initiate delivery is based upon gestational age, the severity of the disease, and maternal and fetal condition.

• Patients with preeclampsia at ≥37 weeks of gestation are delivered; however, before term, the risks of serious sequelae from disease progression need to be balanced with the risks of preterm birth.

• Evidence of serious maternal end-organ dysfunction or indeterminate tests of fetal well-being may be indications for prompt delivery at any gestational age.

• On the other hand, when mother and fetus are stable and without findings of serious end-organ dysfunction, a conservative approach with close monitoring for evidence of progression to severe features of the disease (table 2) is reasonable in order to achieve further fetal growth and maturity.

• Preeclampsia with features of severe disease (also called severe preeclampsia) is generally regarded as an indication for delivery in the following settings:

• Before fetal viability • At ≥34 0/7ths weeks of gestation • When the maternal or fetal condition is unstable, regardless of gestational

age

• Delivery minimizes the risk of development of serious maternal and fetal complications (eg, cerebral hemorrhage, hepatic rupture, renal failure, pulmonary edema, seizure, bleeding related to thrombocytopenia, fetal growth restriction, abruptio placentae) .

• With the exception of fetal growth restriction, any of these adverse events can occur suddenly in a woman with severe disease.

PREECLAMPSIA WITHOUT FEATURES OF SEVERE DISEASE• Experts consistently recommend delivery of women with preeclampsia at

≥37 weeks of gestation, even in the absence of features of severe disease (previously called “mild preeclampsia”) .

• Cervical ripening agents should be used in women with unfavorable cervices.

EXPECTANT ANTEPARTUM MANAGEMENT OF PREECLAMPSIA WITHOUT FEATURES OF SEVERE DISEASE

• Women with preterm (<37 weeks of gestation ) preeclampsia without features of severe disease are managed expectantly, with close maternal and fetal monitoring and without anti-hypertensive therapy

INPATIENT VERSUS OUTPATIENT CARE• Close maternal monitoring upon diagnosis of preeclampsia is important to

establish disease severity and the rate of progression. Hospitalization is useful for making these assessments and facilitates rapid intervention in the event of rapid progression. After the initial diagnostic evaluation, outpatient care is a cost-effective option for women with stable nonsevere preeclampsia .

• Outpatient care can be provided in the patient’s home or, where available, at an antenatal day care unit

LABORATORY FOLLOW-UP

• The minimum laboratory evaluation should include platelet count, serum creatinine, and liver enzymes. These tests should be repeated at least weekly in women with nonsevere preeclampsia to assess for disease progression, and more often if clinical signs and symptoms suggest worsening disease

• The value of other tests is less clearly defined. A rising hematocrit can be useful to look for hemoconcentration, which suggests contraction of intravascular volume and progression to more severe disease, while a falling hematocrit may be a sign of hemolysis.

LABORATORY FOLLOW-UP

• . An elevated serum indirect bilirubin concentration is a better sign of hemolysis, although an elevated LDH may also be a marker of severe disease or HELLP syndrome. Hemolysis can be confirmed by observation of schistocytes and helmet cells on a blood smear.

• Since several clinical studies have shown that neither the rate of increase nor the amount of proteinuria affects maternal or perinatal outcome in the setting of preeclampsia , repeated 24-hour urinary protein estimations are not useful once the threshold of 300 mg/24 hours or protein/creatinine ratio ≥0.3 mg/dL/mg/dL for the diagnosis of preeclampsia has been exceeded. Serum creatinine alone can be used to monitor renal function .

TREATMENT OF HYPERTENSION • Blood pressure should be assessed at least twice weekly. • The use of antihypertensive drugs to control mild hypertension in the

setting of preeclampsia does not alter the course of the disease or diminish perinatal morbidity or mortality, and should be avoided in most patients.

ASSESSMENT OF FETAL WELL-BEING• There are no data from randomized trials on which to base

recommendations for the optimal type and frequency of fetal biophysical monitoring.

• We suggest daily fetal movement counts and twice weekly fetal nonstress testing with assessment of amniotic fluid volume, or twice weekly biophysical profiles.

• Testing is repeated immediately if there is an abrupt change in maternal condition.

ASSESSMENT OF FETAL GROWTH• Early fetal growth restriction may be the first manifestation of

preeclampsia and is a sign of severe uteroplacental insufficiency. We suggest performing sonographic estimation of fetal weight to evaluate for growth restriction and oligohydramnios at the time of diagnosis of preeclampsia. If the initial examination is normal, we repeat the ultrasound examination every three weeks

ANTENATAL CORTICOSTEROIDS• Although preeclampsia may accelerate fetal lung maturation, neonatal

respiratory distress remains common in premature neonates of preeclamptic pregnancies .

• Antenatal corticosteroids (betamethasone) to promote fetal lung maturity should be administered to women .

SEIZURE PROPHYLAXIS

• Based upon data from randomized trials, we administer intrapartum and postpartum magnesium sulfate seizure prophylaxis to all women with preeclampsia.

• Although seizure and death are rare outcomes when magnesium sulfate is omitted in women who do not have severe hypertension or preeclampsia symptoms, we feel the benefit of treatment is justifiable given the low cost and toxicity of magnesium sulfate and the relatively low number of patients that need to be treated to prevent one seizure.

• We do not administer seizure prophylaxis to women with only gestational hypertension (pregnancy-related hypertension without proteinuria or end-organ dysfunction), as the seizure risk in the latter group is less than 0.1 percent .

MAGNESIUM REGIMEN AND MONITORING• There is no consensus on the optimal magnesium regimen, when it should

be started and terminated, or route of administration .• The drug is usually initiated at the onset of labor or induction, or prior to a

cesarean delivery .• It is usually not given to stable antepartum patients off the labor unit, but is

sometimes used in women with severe preeclampsia being considered for expectant management.

• Prolonged antepartum therapy (more than five to seven days) in women with preterm labor has been associated with adverse effects on fetal bones.

DOSING

• Although published dosage regimens for magnesium sulfate vary widely (loading dose of 4 to 6 grams intravenously and maintenance dose of 1 to 3 grams per hour), the most common regimen, and the one that we use, is a loading dose of 6 grams intravenously over 15 to 20 minutes followed by 2 grams per hour as a continuous infusion .

• An alternative regimen is 5 grams intramuscularly into each buttock (total of 10 grams) followed by 5 grams intramuscularly every four hours. These regimens generally result in similar magnesium levels; however, intramuscular administration results in more fluctuation and is associated with more side effects, particularly pain at the injection site

• Since magnesium sulfate is excreted by the kidneys, dosing should be adjusted in women with renal insufficiency (defined as a serum creatinine greater than 1.0 mg/dL).

• Such women should receive a standard loading dose (since their volume of distribution is not altered), but a reduced maintenance dose (1 gram per hour or no maintenance dose if the serum creatinine is greater than 2.5 mg/dL) and close monitoring of their serum magnesium level every six hours or by clinical assessment every one to two hours.

DURATION OF THERAPY

• Magnesium sulfate is usually continued for 24 hours postpartum .• Timing of drug discontinuation has been arbitrary; there are no high quality

data to guide therapy. In women who have nonsevere preeclampsia, discontinuation of therapy after 12 hours may be safe .

• In women with severe preeclampsia or eclampsia, seizure prophylaxis is generally continued for 24 to 48 hours postpartum, after which the risk of recurrent seizures is low.

POSTPARTUM MANAGEMENT

• Nonsteroidal antiinflammatory drugs (NSAIDs) for pain control should be avoided in women with poorly controlled hypertension, oliguria, renal insufficiency, or thrombocytopenia. (See "Nonselective NSAIDs: Overview of adverse effects".)

• There are no evidence-based standards for the optimal approach to postpartum monitoring and follow-up. We monitor vital signs every two hours while the patient remains on magnesium sulfate and we repeat laboratory tests until two consecutive sets of data are normal.

• Severe hypertension should be treated; some patients will have to be discharged on antihypertensive medications, which are discontinued when blood pressure returns to normal. (See "Management of hypertension in pregnant and postpartum women", section on 'Postpartum hypertension'.)

• Patients should be followed closely as outpatients. The American College of Obstetricians and Gynecologists suggests monitoring blood pressure in hospital or at home for the first 72 hours postpartum and again 7 to 10 days post-delivery .Some patients will require longer monitoring; continued follow-up is needed until all of the signs and symptoms of preeclampsia have resolved. Alternative diagnoses should be sought in those with persistent abnormal findings after three to six months .

MANAGEMENT OF HYPERTENSION IN PREGNANT AND POSTPARTUM WOMEN

• The decision to treat hypertension during pregnancy should consider the risks and benefits for both mother and fetus. The level of blood pressure is the most important factor: Treatment of severe hypertension (systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg) is always recommended because it is believed to reduce the risk of maternal stroke.

• The decision to use antihypertensive therapy in women with mild (systolic 140 to 150 mmHg, diastolic 90 to 100 mmHg) to moderate (systolic 150 to 159 mmHg, diastolic 100 to 109 mmHg) hypertension and no comorbidities is less clear.

• Until recently, maternal or fetal benefits from treatment of mild to moderate hypertension over the relatively short duration of a full term pregnancy had not been demonstrated and there is some observational evidence that, in some women, aggressive lowering of blood pressure, or even the medications themselves, can inhibit fetal growth and expose the fetus to potentially harmful physiological effects of these drugs.

• We do not prescribe antihypertensive therapy for mild hypertension, which we define as blood pressures consistently less than 150/100 mmHg.

• The benefit of antihypertensive therapy in pregnant women with mild hypertension is a reduction in risk of developing severe hypertension , which may not be sufficient to warrant exposing the fetus to the potential adverse effects from these drugs

• Severe hypertension should be treated to prevent maternal vascular complications (eg, stroke, heart failure).

• There is no consensus as to the optimal blood pressure threshold for initiating therapy. We initiate antihypertensive therapy in adult women at systolic pressures ≥150 mmHg or diastolic blood pressures ≥100 mmHg. We may initiate treatment earlier in women with signs of cardiac decompensation or cerebral symptoms (eg, severe headache, visual disturbances, chest discomfort, shortness of breath, confusion) and in younger women whose baseline blood pressures were low (less than 90/75 mmHg), but we acknowledge that this recommendation is not strongly evidence based.

• There is some evidence that the pathophysiology of the neurologic manifestations of eclampsia is similar to that of the posterior reversible leukoencephalopathy syndrome .

• If this is the case, then women with preeclampsia may be more susceptible to the neurologic features of severe disease at lower blood pressures (eg, ≥150 mmHg systolic).

ACUTE THERAPY

• Labetalol – We recommend intravenous labetalol for first-line therapy because it is effective, has a rapid onset of action, and a good safety profile.

• Begin with 20 mg intravenously over 2 minutes followed at 10-minute intervals by doses of 20 to 80 mg up to a maximum total cumulative dose of 300 mg.

• As an example, give 20 mg, then 40 mg, then 80 mg, then 80 mg, then 80 mg. A constant infusion of 1 to 2 mg/min can be used instead of intermittent therapy. The fall in blood pressure begins within 5 to 10 minutes and lasts from 3 to 6 hours. Continuous cardiac monitoring is not necessary routinely, but should be used in patients with relevant co-morbidities (eg, coronary artery disease).

• Hydralazine – Begin with 5 mg intravenously over 1 to 2 minutes; if the blood pressure goal is not achieved within 20 minutes, give a 5 to 10 mg bolus depending upon the initial response. The maximum bolus dose is 20 mg.

• If a total dose of 30 mg does not achieve optimal blood pressure control, another agent should be used. The fall in blood pressure begins within 10 to 30 minutes and lasts from 2 to 4 hours.

• Calcium channel blockers – Sustained release nifedipine (30 mg) and immediate release nicardipine are other options.

• If used, a common dose for nifedipine is 10 to 20 mg orally administered at 20-minute intervals until the target blood pressure is achieved. In one trial that included 30 pregnant women with sustained severe hypertension (mean 165/108 mmHg), a median of two doses was required for control of blood pressure.

• Nitroglycerin – Nitroglycerin (glyceryl trinitrate) is a good option for treatment of hypertension associated with pulmonary edema .

• It is given as an intravenous infusion of 5 mcg/min and gradually increased every 3 to 5 minutes to a maximum dose of 100 mcg/min.

LONG-TERM ORAL THERAPY

• Occasionally, preeclamptic women with severe hypertension remote from term are stabilized and not delivered immediately.

• Oral antihypertensive therapy is often indicated for these patients. • Options for oral antihypertensive therapy are the same as for women with

preexisting hypertension.

• Choice of drug Our preference is to start treatment with either methyldopa or labetalol.

• A long-acting calcium channel blocker (eg, nifedipine) can be added as either second- or third-line treatment .

• The American College of Obstetricians and Gynecologists (ACOG) Task Force on Hypertension in Pregnancy recommends treatment of persistent chronic hypertension when systolic pressure is ≥160 mmHg or diastolic pressure is ≥105 mmHg and suggests avoiding antihypertensive therapy in women with blood pressures below this level and no evidence of end-organ damage .

• They suggest labetalol, nifedipine, or methyldopa as first-line therapy. They also suggest avoiding angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin inhibitors, and mineralocorticoid receptor antagonists. The goal of management is maintenance of blood pressures between 120/80 and 160/105 mmHg.

• Severe hypertension in pregnancy should be treated with medications such as methyldopa, labetalol, and nifedipine. Treatment of moderate hypertension should be considered to decrease the risk of developing severe hypertension; the risk of stroke may also be decreased. High blood pressure was defined as mild (diastolic 90 to 99 mmHg or systolic 140 to 149 mmHg), moderate (diastolic 100 to 109 mmHg or systolic 150 to 159 mmHg), or severe (diastolic ≥110 mmHg or systolic ≥160 mmHg).

PREVENTION OF DEVELOPMENT OF PREECLAMPSIA

• Our approach to low-dose aspirin therapy• — Based on the available data, we suggest low-dose aspirin for women at

high risk for• preeclampsia. There is no consensus on the criteria that confer high risk.

The United States Preventive Services• Task Force (USPSTF) risk criteria are reasonable.

• USPSTF criteria for high risk include one or more of the following:• Previous pregnancy with preeclampsia, especially early onset and with an

adverse outcome• ● Multifetal gestation• ● Chronic hypertension• ● Type 1 or 2 diabetes mellitus• ● Renal disease• ● Autoimmune disease (antiphospholipid syndrome, systemic lupus

erythematosus)

• We manage women with multiple moderate risk factors for preeclampsia as high risk, as well.

• USPSTF criteria for moderate risk include:• ● Nulliparity• ● Obesity (body mass index >30 kg/m2)• ● Family history of preeclampsia in mother or sister• ● Age ≥35 years• ● Sociodemographic characteristics (African American, low socioeconomic level)• Personal risk factors (eg, history of low birth weight or small for gestational age,

previous adverse pregnancy outcome, >10 year pregnancy interval)

• If used, we suggest beginning low-dose aspirin at 12 to 14 weeks of gestation , although adverse effects from earlier initiation (eg, preconception) have not been documented. The optimum low dose is unclear; 81mg is readily available. The safety of low-dose aspirin use in the second and third trimesters is well established but questions linger regarding use in the first trimester.

• Early therapy (before 16 weeks) is probably important since the pathophysiologic features of preeclampsia develop at this time, weeks before clinical disease is apparent. Aspirin is discontinued 5 to 10 days before expected delivery to diminish the risk of bleeding during delivery.

HELLP SYNDROME

DIAGNOSIS

• Laboratory criteria• We require the presence of all of the following criteria to diagnose HELLP :

• Microangiopathic hemolytic anemia with characteristic schistocytes (also called helmet cells) on blood smear (picture 1). Other signs suggestive of hemolysis include an elevated indirect bilirubin level and a low serum haptoglobin concentration (≤25 mg/dL).

• Platelet count ≤100,000 cells/microL.• Total bilirubin ≥1.2 mg/dL (20.52 micromol/L).• Serum AST >2 times upper limit of normal for local laboratory (usually >70 international units/L).

Some investigators obtain alanine aminotransferase (ALT) levels instead of, or in addition to, AST levels. An advantage of the AST is that it is a single test that reflects both hepatocellular necrosis and red cell hemolysis.

• These thresholds were chosen, in part, to avoid problems related to differences in assays used to measure liver enzymes, which may result in an elevated value in one hospital that is near normal in another. We do not include elevated lactate dehydrogenase (LDH) in the laboratory criteria for HELLP syndrome because it is a nonspecific finding associated with both hemolysis and liver disease. These criteria have been adopted by the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy.

• As discussed above, women who do not meet all of the above laboratory abnormalities are considered to have partial HELLP syndrome. However, these patients may progress to complete expression of HELLP syndrome.

• The most common clinical presentation is abdominal pain and tenderness in the midepigastrium, right upper quadrant, or below the sternum. Many patients also have nausea, vomiting, and malaise, which may be mistaken for a viral illness. Hypertension and proteinuria are present in approximately 85 percent of cases.

• Most cases of HELLP are diagnosed between 28 and 36 weeks of gestation, but symptoms may present up to 7 days postpartum.

• The outcome for mothers with HELLP syndrome is generally good, but serious complications such as abruptio placentae, acute renal failure, subcapsular liver hematoma, pulmonary edema, and retinal detachment may occur. Future pregnancies are at increased risk of HELLP, preeclampsia, and gestational hypertension.

MANAGEMENT RECOMMENDATIONS• After the diagnosis is confirmed, the initial steps in management are to

stabilize the mother, assess the fetal condition, and decide whether prompt delivery is indicated. Severe hypertension is treated with antihypertensive therapy and magnesium sulfate is given to prevent convulsions and for neuroprotection of fetuses/neonates at 24 to 32 weeks of gestation.

• HELLP syndrome complicated by multiorgan dysfunction, disseminated intravascular coagulation (DIC), pulmonary edema, liver hemorrhage or infarction, renal failure, abruptio placenta, nonreassuring fetal status, or fetal death is an indication for prompt delivery regardless of gestational age

• For pregnancies ≥34 weeks of gestation, we recommend delivery rather than expectant management (Grade 1C). In this population, the potential risks of preterm birth are outweighed by the risks associated with HELLP syndrome. We also deliver pregnancies <23 weeks of gestation because expectant management is associated with a high risk of maternal complications without significant improvement in perinatal prognosis .

• For pregnancies >= 23 and <34 weeks of gestation in which maternal and fetal status are reassuring, we suggest delivery after a course of corticosteroids to accelerate fetal pulmonary maturity rather than expectant management or prompt delivery (Grade 2C). Although the laboratory abnormalities of HELLP syndrome will reverse in a subgroup of patients managed expectantly and serious maternal complications are uncommon with careful maternal monitoring, overall perinatal outcome is not improved with expectant management.

• For gestations less than 30 to 32 weeks with an unfavorable cervix, we suggest cesarean delivery to avoid a potentially long induction .

• We recommend not giving dexamethasone for treatment of HELLP syndrome (Grade 1B). Dexamethasone does not accelerate resolution of laboratory abnormalities or reduce the risk of maternal complications.

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