Preeclampsia Eclampsia

1. Preeclampsia Eclampsia uptodate 2014

2. There are four major hypertensive disorders related to pregnancy • Preeclampsia Eclampsia HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets) HELLP may be an independent disorder. As many as 15 to 20 percent of affected patients do not have concurrent hypertension or proteinuria, leading some experts to believe that HELLP syndrome is a separate disorder from preeclampsia • 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 • Preeclampsia superimposed upon chronic/preexisting hypertension • Gestational hypertension During pregnancy, 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.

3. DEFINITIONS OF PREGNANCY-RELATED HYPERTENSIVE DISORDERS Preeclampsia is a multi-system disorder characterized by the new onset of hypertension and either proteinuriaor end-organ dysfunction in the last half of pregnancy .Although most affected pregnancies deliver at term or near term with good maternal and fetal outcomes, these pregnancies are at increased risk for maternal and/or fetal mortality or serious morbidity

4. Criteria for the diagnosis of preeclampsia

5. The presence of one or more of the following indicates a diagnosis of "preeclampsia with severe features" • In contrast to older criteria, the 2013 criteria do not include proteinuria >5 grams/24 hours and fetal growth restriction as features of severe disease. • Adapted from: Hypertension in pregnancy: Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. Obstet Gynecol 2013; 122:1122. • Graphic 76975 Version 8.0 The presence of one or more of the following indicates a diagnosis of "preeclampsia with severe features"

6. The presence of one or more of the following indicates a diagnosis of "preeclampsia with severe features" • Severe blood pressure elevation: Systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg on two occasions at least four hours apart while the patient is on bedrest (unless the patient is on antihypertensive therapy) • Thrombocytopenia:<100,000 platelets/microL • Renal abnormality: Progressive renal insufficiency (serum creatinine >1.1 mg/dL or doubling of serum creatinine concentration in the absence of other renal disease) • Pulmonary edema

7. In 2013, the American College of Obstetricians and Gynecologists removed proteinuria as an essential criterion for diagnosis of preeclampsia. They also removed massive proteinuria (5 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. • Oliguria wasremoved as a characteristic of severe disease.

8. PREVALENCE — Preeclampsia is estimated to occur in 4.6 percent of pregnancies worldwide. 1.5-fold to 2-fold higher in first pregnancies

9. RISK FACTORS  ●A past history of preeclampsiaincreases the risk of developing preeclampsia in a subsequent pregnancy seven-fold compared to women without this history The severity of preeclampsia strongly impacts this risk. Women with severe features of preeclampsia in the second trimester are at greatest risk of developing preeclampsia in a subsequent pregnancy: rates of 25 to 65 percent have been reported . By comparison, women without severe features of preeclampsia in their first pregnancy develop preeclampsia in 5 to 7 percent of second pregnancies. Women who had a normotensive first delivery develop preeclampsia in less than 1 percent of second pregnancies. ●First pregnancy(nulliparity) .. ●A family history of preeclampsiain a first degree suggesting a heritable mechanism in some cases

10. Preexisting medical conditions: •Pregestational diabete: •Blood pressure ≥130/80 mm Hg. •Antiphospholipid antibodies SYN. •Body mass index ≥26.1 •Chronic kidney disease (CKD) ●Twin pregnancies ●Advanced maternal age • Of note, women who smoke cigarettes have a lower risk of preeclampsia than nonsmokers

11. CLINICAL MANIFESTATIONS Signs and symptoms: ●Severe hypertension (systolic blood pressure ≥160 mm Hg or diastolic ≥110 mm Hg on two occasions at least four hours apart or only once if treated) ●Persistent and/or severe headache ●Visual abnormalities (scotomata, photophobia, blurred vision, or temporary blindness [rare]) ●Upper abdominal or epigastric pain ●Nausea, vomiting ●Dyspnea, retrosternal chest pain ●Altered mental status Laboratory abnormalities: ●Microangiopathic hemolytic anemia (abnormal peripheral smear, elevated bilirubin, or low serum haptoglobin levels U/L) ●Thrombocytopenia (<100,000/microL) ●Elevated serum creatinine concentration (>1.1 mg/dL) ●Elevated liver enzymes (twice the upper limit of normal)

12. Atypical presentation —  ●Onset of signs/symptoms at <20 weeks of gestation ●Hypertension or proteinuria (but not both) with or without characteristic signs and symptoms of severe preeclampsia ●Delayed postpartum onset or exacerbation of disease (>2 days postpartum)

13. Preeclampsia: Pathogenesis • Development abnormalities of the uteroplacental circulation occur long before clinical manifestations of preeclampsia become evident. In preeclampsia, the cytotrophoblast infiltrates the decidual portion of the spiral arteries, but fails to penetrate the myometrial portion. Thus, the large, tortuous vascular channels characteristic of the normal placenta do not develop; instead, the vessels remain narrow, resulting in hypoperfusion. • The focus on immunologic factors as a possible contributor to the placental abnormality is based, in part, upon the observation that prior exposure to paternal/fetal antigens appears to protect against preeclampsia. • Both maternal and paternal contributions to fetal genes may have a role in defective placentationand subsequent preeclampsia. In particular, a genetic locus on chromosome 13 appears to be associated with development of preeclampsia and may be responsible for the production of circulating anti-endothelial factors.

14. Preeclampsia: Pathogenesis • The ischemic placenta appears to elaborate factors into the maternal bloodstream that alter maternal endothelial cell function and lead to the characteristic systemic signs and symptoms of preeclampsia. Many of the clinical features of preeclampsia can be explained as clinical responses to generalized endothelial dysfunction. • Soluble fms–like tyrosine kinase 1 (sFlt-1) is a circulating antagonist to vascular endothelial growth factor (VEGF). It is released by the diseased placenta and is an important mediator of the maternal signs and symptoms of preeclampsia.

15. Prediction of preeclampsia ●Multiple risk factors for development of preeclampsia have been described . However, most of these risk factors are not highly predictive of the disorder, nor are they modifiable. ●No clinically available tests perform well in distinguishing women who will develop preeclampsia from those who will not. Use of these tests has not been proven to improve pregnancy outcome. ●Measurement of angiogenic factors (VEGF, PlGF, sFlt-1, sEng) in blood or urine is the most promising approach for predicting preeclampsia; however, these tests are investigational and are not available for clinical use at present. The ratio of sFlt-1:VEGF (or sFlt-1:PlGF), rather than absolute levels of these factors, appears to be most useful. All pregnant women should be assessed for and educated about the signs and symptoms of the disease. We recommend not using laboratory or imaging tests to screen for preeclampsia

16. Preeclampsia: Prevention • Low-dose aspirinis the only drug for which there is some evidence of benefit in reducing the risk of preeclampsia. • For women at low-risk for development of preeclampsia, we recommend avoiding low-dose aspirin  There is no evidence of benefit. • For women at moderate to high risk of developing preeclampsia, we suggest low-doseaspirin prophylaxis . A modest reduction in the risk of preeclampsia and its sequelae (growth restriction, preterm birth) is possible. There are no validated methods (biomarkers, clinical diagnostic tests, medical history) for identifying women at high risk for preeclampsia. The optimum low dose of aspirin is unclear; we suggest 81 mg per day , beginning at the end of the first trimester. Aspirin is discontinued 5 to 10 days before expected delivery to diminish the risk of bleeding during delivery; however, no adverse maternal or fetal effects related to low-dose aspirin have been proven.

17. Preeclampsia: Prevention • ●We do not recommend routine calcium supplementation above the recommended daily allowance for healthy, nulliparous women to prevent preeclampsia . There may be a benefit for preeclampsia prevention in high-risk populations or in those consuming a low calcium diet. The recommended daily allowance for elemental calcium is 1000 mg per day in pregnant and lactating women 19 to 50 years of age (1300 mg for girls 14 to 18 years old).   • ●We do not recommend vitamin C and E supplementation to prevent preeclampsia • ●We do not recommend fish oil for preventing preeclampsia • ●No drug prevents progression to more severe disease. • ●We suggest not restricting salt intake or activity for primary prevention of preeclampsia or progression of disease . However, reduced physical activity may be useful for improving uterine blood flow in pregnancies with fetal growth restriction, and may be a useful adjunct to antihypertensive therapy in women with high blood pressure.

18. Management and prognosis • The definitive treatment of preeclampsia is delivery:to prevent development of maternal or fetal complications from disease progression. • Timing of delivery is based upon gestational age, the severity of preeclampsia, and maternal and fetal condition • APPROACH BASED ON DISEASE SEVERITY: • Preeclampsia with features of severe disease : is generally regarded as an indication for delivery in the following settings: Before fetal viability At ≤34 weeks of gestation When the maternal or fetal condition is unstable . Cervical ripening agents can be used prior to induction if the cervix is not favorable However, we feel that a prolonged induction and inductions with a low likelihood of success are best avoided. Cesarean delivery is reasonable for women with severe preeclampsia/eclampsia who are under about 32 weeks of gestation and have a low Bishop score, given the high frequency of nonreassuring fetal heart rate tracings and failure of the cervix to dilate in this setting .

19. Preeclampsia without features of severe disease • For women with preeclampsia without features of severe disease, we suggest expectant management with delivery at ≥37 weeks of gestation • 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.

20. EXPECTANT ANTEPARTUM MANAGEMENT OF PREECLAMPSIA WITHOUT FEATURES OF SEVERE DISEASE • consists of frequent laboratory monitoring (platelet count, liver and renal function tests), assessment of maternal blood pressure and symptoms, and evaluation of fetal growth and well-being. In most patients, antihypertensive therapy is not indicated for systolic blood pressure <160 mmHg or diastolic blood pressure <110 mmHg • For women with a viable fetus and preeclampsia <34 weeks of gestation, we recommend a course of antenatal glucocorticoids (betamethasone) . • For women with preeclampsia and features of severe disease, we recommend intrapartum and postpartum seizure prophylaxis . The benefit of seizure prophylaxis is less clear in women without severe hypertension or preeclampsia symptoms; however, we also suggest intrapartum and postpartum prophylaxis for these women .  We recommend the use of magnesium sulfate as a first-line agent for seizure prophylaxis in preeclampsia

21. Inpatient versus outpatient care • Restricted activity may be recommended since blood pressure is lower in rested patients; however, there is no evidence that bedrest improves pregnancy outcome or delays progression of disease. • bedrest in the hospital increases the risk of venous thromboembolism . • Rest in the left lateral decubitus position can augment uteroplacental flow, which may benefit some pregnancies. • If signs or symptoms of disease progression are noted, hospitalization for more intensive monitoring and possible delivery is indicated. • Outpatients should be aware of the signs and symptoms of preeclampsia and they should monitor fetal movements daily . • They should be told to call their healthcare provider immediately if they develop severe or persistent headache, visual changes, shortness of breath, or right upper quadrant or epigastric pain.

22. 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 hematocritcan be useful to look for hemoconcentration, which suggests contraction of intravascular volume and progression to more severe disease, while a falling hematocritmay be a sign of hemolysis. 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 • 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.

23. 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. • Sodium restriction below the recommended daily intake and diuretics have no role in routine therapy . • Although intravascular volume is reduced, a randomized trial showed that plasma volume expansion did not improve maternal or fetal outcome

24. Assessment of fetal well-being : • daily fetal movement counts • 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. • Evaluation of umbilical artery Doppler indices is also useful, as the results help in optimal timing of delivery. • The frequency of assessment depends on the findings; weekly assessment is reasonable when Doppler indices are normal.

25. 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. Management of the growth restricted fetus is reviewed separately.

26. 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 <34 weeks of gestation since they are at increased risk of progression to severe disease and preterm delivery

27. INTRAPARTUM MANAGEMENT • Intrapartum monitoring : •  Continuous maternal-fetal monitoring is indicated intrapartum to identify worsening hypertension, deteriorating maternal hepatic, renal, cardiopulmonary, neurological, or hematologic function, as well as abruptio placentae or a nonreassuring fetal heart rate tracing • Fluids — Fluid balance should be monitored closely to avoid excessive administration, since women with severe disease are at risk of pulmonary edema and significant third-spacing. Maintenance fluids of 80 mL/hour are often adequate in the absence of ongoing fluid loss, such as bleeding. Oliguria that does not respond to a modest trial of increased fluids should be tolerated. Diuretics are only indicated for treatment of pulmonary edema. • Management of hypertension — Severe hypertension in labor should be treated with intravenous labetalol or hydralazine or oral nifedipine to prevent stroke.Antihypertensive medications do not prevent eclampsia.

28. Invasive hemodynamic monitoring : •  Although not routinely recommended even in the setting of severe preeclampsia, invasive hemodynamic monitoring can be useful in complicated patients, such as those with severe cardiac disease, severe renal disease, severe oliguria, refractory hypertension, or pulmonary edema. • However, most women can be managed without these tools and should not be exposed to the risks associated with arterial and central venous catheterization.

29. Seizure prophylaxis : • we administer intrapartum and postpartum magnesium sulfate seizure prophylaxis to all women with preeclampsia. • 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

30. Magnesium sulfate versus other anticonvulsants:  Major medical organizations worldwide consistently recommend magnesium sulfate as the drug of choice for the prevention of eclampsia • In meta-analyses of randomized trials in eclamptic women, magnesium sulfate was safer and more effective for prevention of recurrent seizures than phenytoin, diazepam

31. Magnesium regimen and monitoring: • —The drug is usually initiated at the onset of labor or induction, or prior to a cesarean delivery . 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. However, this method is associated with more side effects, particularly pain at the injection site. • There does not appear to be a clear threshold concentration for insuring the prevention of convulsions, although a therapeutic range of 4.8 to 8.4 mg/dL (2.0 to 3.5 mmol/L)

32. 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. • The maintenance phase is given only if a patellar reflex is present (loss of reflexes being the first manifestation of symptomatic hypermagnesemia), respirations exceed 12 per minute, and the urine output exceeds 100 mL per four hours.

33. Duration of therapy: • Magnesium sulfate is usually continued for 24 hours postpartum • 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. • Diuresis (greater than 4 L/day) is believed to be the most accurate clinical indicator of resolution of preeclampsia/eclampsia.

34. Complications and side effects : • — Rapid infusion of magnesium sulfate causes diaphoresis, flushing, and warmth, probably related to peripheral vasodilation . Nausea, vomiting, headache, muscle weakness, visual disturbances, and palpitations can also occur.Dyspnea or chest pain may be symptoms of pulmonary edema, which is a rare side • Toxicity is related to serum magnesium concentration: • loss of deep tendon reflexes occurs at 9.6 to 12.0 mg/dL • respiratory paralysis at 12.0 to 18.0 mg/dL • cardiac arrest at 24 to 30 mg/dL • Calcium gluconate (1 gram intravenously over 5 to 10 minutes) should be administered only to counteract life-threatening symptoms of magnesium toxicity (such as cardiorespiratory compromise). • Magnesium sulfate is contraindicated in women with myasthenia gravis since it can precipitate a severe myasthenic crisis

35. POSTPARTUM MANAGEMENT : • — Nonsteroidalantiinflammatory drugs (NSAIDs) for pain control should be avoided in women with poorly controlled hypertension, oliguria, renal insufficiency, or thrombocytopenia. • 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. • 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.

36. Postpartum onset of preeclampsia: •  In women who are initially diagnosed with preeclampsia after delivery, magnesium sulfate should be administered to those at increased risk of developing seizures • Women with new onset hypertension and headache or blurred vision, or Women with severe hypertension Antihypertensive therapy should also be initiated. The American College of Obstetricians and Gynecologists suggests treatment of systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg on two occasions four to six hours apart .

37. Indications for antihypertensive therapy: •  — We do not prescribe antihypertensive therapy for mild hypertension, which we define as blood pressures consistently less than 150/100 mmHg. The only benefit that has been demonstrated so far of antihypertensive therapy in pregnant women with mild hypertension is a reduction in risk of developing severe hypertension

38. 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. • Other physicians begin antihypertensive treatment when systolic pressure is ≥160 mmHg or diastolic pressure is ≥105 to 110 mmHg .

39. Choice of drug and dose: •  There are two settings in which antihypertensive therapy is used in preeclampsia: • Acute management of severe hypertension, which may require parenteral therapy • Longer-term blood pressure control during expectant management of severe preeclampsia

40. Acute therapy: • — We suggest labetalol or hydralazine as first-line agents for acute therapy of severe hypertension., but nimodipine, diazoxide, and ketanserin were probably best avoided. • ●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. • ●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.

41. Calcium channel blockers – Sustained release nifedipine (30 mg) and immediate release nicardipine are other options. Nicardipine can be given intravenously. If used, a common dose for nifedipine is 10 mg orally administered at 20-minute intervals until the target blood pressure is achieved. • Nitroglycerin– Nitroglycerin (glyceryltrinitrate) is a good option for treatment of hypertension associated with pulmonary edema

42. Drugs to avoid in pregnancy • ACE inhibitors, ARBs, direct renin inhibitors • Nitroprusside

43. PROGNOSIS: • — Prognostic issues include the risk of recurrent preeclampsia and related complications in subsequent pregnancies and long-term maternal health risks. • Recurrence — The recurrence risk varies with the severity and time of onset of the acute episode . • Women with early onset, severe preeclampsia are at greatest risk of recurrence (as high as 25 to 65 percent) . • The risk is much lower (5 to 7 percent) in women who had nonseverepreeclampsia during the first pregnancy, versus less than 1 percent in women who had a normotensive first pregnancy (does not apply to abortions) .

44. Management — Antihypertensive agents may be required temporarily postpartum if hypertension is severe. • We recommend initiating therapy if blood pressures are persistently greater than 140 mm Hg systolic at the time of discharge from the hospital. Oral medications similar to those used in the nonpregnant population can be prescribed, with modifications if the woman is breastfeeding. • Brief furosemide therapy (20 mg orally once or twice per day for five days) may facilitate return to normotension in women with severe, but not mild, preeclampsia, particularly those with significant edema One guideline suggests avoiding methyldopa postpartum because of the risk of postnatal depression