Preeclampsia 01/01/2020

Approximately 7 to 10% of all pregnancies are complicated by hypertensive disease, 70% of which are pregnancy-associated hypertensive disorders and 30% are due to chronic hypertension. (Sibai, 2010b) In the past, elevated blood pressure of more than 30 mm Hg systolic or more than 15 mm Hg diastolic above the patient’s baseline was used to diagnose preeclampsia, however, this definition has not been shown to be a good prognostic indicator and is no longer recommended. ("Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy," 2000).  Although no longer considered diagnostic of preeclampsia, women demonstrating elevations of this magnitude should be carefully monitored for worsening. In addition, in recognition of the syndromic nature of preeclampsia, the ACOG Task Force on Hypertension in Pregnancy has eliminated the requirement for proteinuria to make the diagnosis. (ACOG, 2013)

The California Maternal Quality Care Collaborative (CMQCC) developed a toolkit entitled “Improving Healthcare Response to Preeclampsia” which can be found at https://www.cmqcc.org/preeclampsia_toolkit . The toolkit includes a compendium of best practice publications; care guidelines in the form of tables, charts, and forms; and a slide set for professional education. This resource is an excellent instrument to assist providers with developing systems of care for women with preeclampsia.

Definitions

High blood pressure in pregnancy can be further classified as below:

1. Chronic hypertension (CHTN)
2. Pregnancy-related hypertensive disorders which include
   • Gestational Hypertension
   • Preeclampsia
   • Eclampsia
   • HELLP Syndrome
3. Preeclampsia superimposed on chronic hypertension

Hypertension is defined as a systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg observed on at least 2 occasions ≥ 4 hours apart, but no more than 7 days apart. CHTN in pregnancy is defined as elevated blood pressure documented either prior to pregnancy or before the 20th week of pregnancy, or continuing more than 12 weeks postpartum. (Sibai, 2010a) Gestational hypertension is defined as onset of high blood pressure after 20 weeks gestation without proteinuria, thrombocytopenia, impaired liver function, the new development of renal insufficiency, pulmonary edema, or new-onset cerebral or visual disturbances

The etiology of preeclampsia is not known.  Preeclampsia appears to be a disease that involves a number of maternal, placental, and fetal factors. These include: placental implantation with abnormal trophoblastic invasion of uterine vessels; abnormal immunological tolerance to placental and fetal tissues; maternal maladaptation to cardiovascular or inflammatory changes of normal pregnancy; and genetic factors.  (Cunningham et al., 2010)
Preeclampsia is defined as a systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg on 2 occasions at least 4 hrs apart after 20 weeks gestation in women with a previously normal blood pressure.  Previously, proteinuria was an additional criterion for PreEclampsia with signified by ≥ 300 mg/24 hrs or a protein/creatinine ratio ≥ 0.3 mg/dL or a dipstick reading of ≥ 1+ (dipstick used only if other quantitative methods not available).   (Table 1)   In the absence of proteinuria, preeclampsia is diagnosed as new-onset hypertension with the new onset of any of the following: thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms. (ACOG, 2013)    Preeclampsia superimposed on chronic hypertension is chronic hypertension in association with preeclampsia. (ACOG, 2013)

Risk factors associated with preeclampsia include: nulliparity, obesity, multiple gestation, family history of preeclampsia or eclampsia, preexisting hypertension or renal disease, previous preeclampsia or eclampsia, diabetes mellitus, nonimmune hydrops, antiphospholipid antibody syndrome, extremes of maternal age, black race, and molar pregnancy.  It is extremely rare for preeclampsia to develop before 20 weeks gestation, but when it does occur it is usually associated with renal disease, molar pregnancy, and more severe manifestations. (Sibai, 2010b) Signs and symptoms of preeclampsia include elevated blood pressure, proteinuria, nondependent edema, visual disturbances, headache, and epigastric pain.  Laboratory abnormalities occur with preeclampsia and are reflective of the end organ injury that can occur in preeclampsia. They include hemoconcentration due to poor volume expansion, elevated serum creatinine and liver enzymes due to vasospasm with decreased organ perfusion, and hemolysis and thrombocytopenia (due to severe vasospasm with endothelial injury and subsequent cell damage/destruction).

Table 1. Diagnostic Criteria for Preeclampsia (ACOG, 2013)

 

Blood Pressure	≥ 140 mm Hg systolic or ≥ 90 mm Hg diastolic one 2 occasions at least 4 hrs apart after 20 wks GA in women with a previously normal BP Severe Hypertension: ≥ 160 mm Hg systolic or ≥ 110 mm Hg diastolic, confirmed within a short interval (minutes) to facilitate timely antihypertensive therapy
And
Proteinuria	≥ 300mg per 24-hr urine collection (or this amount extrapolated from a timed collection) OR Protein/creatinine ratio ≥ 0.3 mg/dL Dipstick reading of ≥ 1+ (used only if other quantitative methods not available)
Or	In the absence of proteinuria, new-onset hypertension with the new onset of one or more of the following:
Thrombocytopenia	Platelet count < 100,000/µL
Renal insufficiency	Serum creatinine > 1.1 mg/dL or a doubling of the serum creatinine in the absence of other renal disease
Impaired liver function	Elevated blood levels of liver transaminases to twice normal concentrations
Pulmonary edema
Cerebral or visual symptoms

 

PreEclampsia with severe features is defined by the presence of one or more of the following(ACOG, 2013)

• Systolic BP ≥ 160 mm Hg or diastolic ≥ 110 mm Hg on 2 occasions 4 hours or more apart while the patient is on bed rest. Clinically, treatment of severe hypertension may supplant the criteria for 4 hours.
• Thrombocytopenia (platelet count < 100,000/µL).
• Impaired liver function as indicated by abnormally elevated blood levels of liver enzymes (to twice normal compared to reference ranges), severe persistent right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses, or both.
• Progressive renal insufficiency (serum creatinine > 1.1 mg/dL or a doubling of the serum creatinine in the absence of other renal disease.
• New-onset cerebral or visual disturbances attributable to PreEclampsia and not other etiologies.
• Pulmonary edema.

     Eclampsia is defined as the presence of new-onset grand mal seizures in women with preeclampsia, although in up to 20-25% of patients the presenting signs and symptoms may be seizure activity.

HELLP Syndrome
A particularly severe and serious form of preeclampsia is HELLP syndrome characterized by hemolysis, elevated liver enzymes, and low platelets. Prompt recognition is vital to improving outcomes. Due to the different number of assays used to measure liver enzymes, clinicians should be familiar with the upper limit values used in their own laboratory.  Criteria for HELLP syndrome are: LDH > 600 IU/L (more than 2 times the upper limit of normal values) or bilirubin > 1.2 mg/dL, AST > 70 IU/L  (more than 2 times the upper limit of normal values), and platelets < 100,000/µL.(Sibai, 2004) Proteinuria may or may not be present with HELLP syndrome.

Management

Preeclampsia is a clinical diagnosis.  Despite multiple investigations to identify markers diagnostic markers, there is no single test for preeclampsia that has been found to be reliable and cost-effective.   In addition, preeclampsia is a dynamic process that involves multiple organ systems and is progressive at variable rates. As delivery is the only cure, clinicians must weigh maternal and fetal risks when deciding between immediate delivery and expectant management.  PreEclampsia without severe features can be monitored expectantly unless severe features, HELLP syndrome, or eclampsia develop.   Under one circumstance, PreEclampsia with severe features can be managed expectantly.  If severe hypertension can be controlled with oral medications after initial stabilization, continuation of pregnancy after consideration of risks and benefits can be undertaken on an inpatient basis.

Clinical assessment includes frequent evaluation of maternal and fetal conditions, gestational age, presence of labor, severity of the disease process, Bishop Score, and maternal preferences.

Management of preeclampsia without severe features:

Women with gestational hypertension or preeclampsia without severe features at or beyond 37 weeks of gestation:

• Delivery rather than continued observation is suggested. (ACOG, 2013)
• The American College of Obstetricians and Gynecologists reserves MgSO4 seizure prophylaxis for PreEclampsia with severe features, HELLP, and Eclampsia.
• At UAB, we continue to administer MgSO4 for seizure prophylaxis in the setting of PreEclampsia without severe features (Table 2).
• MgSO4 seizure prophylaxis is not indicated in the setting of isolated Gestational Hypertension.

Women with gestational hypertension or preeclampsia without severe features prior to 37 weeks of gestation:

• Although most patients with preeclampsia without severe features are best managed with inpatient hospitalization, some patients with stable disease following a period of inpatient admission, may be candidates for close outpatient follow up. These patients should be highly compliant and seen for follow up evaluation in the office at least twice per week.
• Outpatient monitoring includes: Twice weekly maternal and fetal assessments.
  • Maternal assessment includes: serial assessment of symptoms and fetal movement (daily by woman), serial measurement of BP (twice weekly), weekly proteinuria assessment and labs including CBC with platelet count, AST, ALT, creatinine, bilirubin, and LDH (as indicated).
  • Fetal assessment includes: NST, BPP, and/or AFI

Hospitalization is often recommended for women with new-onset preeclampsia. Monitoring includes:

• Daily assessment for clinical findings such as headache, visual disturbances, epigastric pain, and rapid weight gain.
• Daily maternal weight and intake and output assessment looking for signs of oliguria.
• Frequent blood pressure readings typically every 4-8 hours.
• Baseline labs: AST, CBC with platelet count, and serum creatinine. Serum uric acid does not add sensitivity or specificity for the diagnosis of preeclampsia and therefore should not be routinely ordered.
• 24 hr urine collection for protein. Once an initial 24 hr urine collection demonstrates that there is significant proteinuria (>300 mg), there is little value to repeat 24 hour measurements. Previously, 5g of protein in a 24h urine collection was considered a severe feature.  However, this is no longer considered a severe feature. Therefore, repeat 24 hr collections should not be routinely obtained as the results in isolation would not be an indication for delivery.
• For preeclampsia without severe features, repeat lab tests weekly if stable values without progression; sooner if disease progression is questionable or if more significant disease is suspected.
• At least weekly non stress tests or biophysical profiles; twice weekly tests for suspected fetal growth restriction or oligohydramnios.
• Daily fetal movement assessment.
• Ultrasound for fetal growth every 3 weeks.
• Weekly assessment of amniotic fluid (modified BPP).
• A course of corticosteroids should be given to women <34 weeks and if not previously given, a course of late preterm steroids can be given between 34weeks and 36w6d. .

Management of preeclampsia with severe features:

• Women with severe features of preeclampsia at or beyond 34 weeks gestation, and in those with unstable maternal or fetal conditions irrespective of gestational age, should be delivered as soon as the maternal status is stabilized.  (ACOG, 2013)
• Vaginal delivery should be attempted unless otherwise contraindicated. A diagnosis of preeclampsia is not an indication for cesarean section. Even with an unfavorable cervix, more than 60% of women with severe pre-eclampsia are able to achieve a vaginal delivery even at preterm gestations.
• Women with severe features of preeclampsia less than 34 weeks gestation with stable maternal and fetal conditions should be transferred to a tertiary care facility capable of caring for the infant and consideration should be given to consultation with a Maternal Fetal Medicine (MFM) specialist. (ACOG, 2013)
• Avoid aggressive hydration to prevent pulmonary edema-limit IV fluids to 150cc/hr.
• MgSO4 for seizure prophylaxis (Table 2).
• Antihypertensive treatment should be given for women with a systolic blood pressure > 160 mm Hg with a goal of < 155 mm Hg or diastolic blood pressure of ≥ 110 mm Hg with a goal of < 100-105 mm Hg. (Table 3).
• < 34 weeks: administer a course of betamethasone. Even if steps need to be taken to immediately move to induction of labor due to maternal or fetal status, corticosteroids should be administered because neonatal benefits may begin to accrue as quickly as 12 hours after the initial dose.
• In women with severe hypertension, but in whom maternal and fetal status is otherwise stable, consideration should be given to expectant management until 34 weeks with initiation of antihypertensive medication if deemed appropriate by a Maternal Fetal Medicine specialist.
• If delivery is indicated due to preeclampsia with severe features between 34 and 37w0d and a course of betamethasone has not already been administered in the pregnancy, late preterm steroids should be given, but delivery should not be delayed.

Table 2. MgSO4 Seizure Prophylaxis

Renal Function	MgSO4 dose	Monitoring	Toxicity Rx
Normal, no pulmonary edema (Cr < 1.2)	Loading dose: 6 grams/20 min Continuous infusion: 2 grams/hour Continue 24hrs PP	Magnesium levels not indicated unless signs of toxicity Monitor for evidence of toxicity: deep tendon reflex, lethargy, respirations	Check magnesium level Discontinue infusion If respiratory or EKG changed are noted: administer calcium gluconate (1 ampule=4.64 mEq IV x 1 dose)
Mild renal insufficiency (Cr 1.2-1.5)	Loading dose: 4 grams/20 min Continuous infusion: 1 gram/hour Continue 24 hrs PP	Serial magnesium levels every 6 hours, target range 5-7 Monitor for evidence of toxicity: deep tendon reflex, lethargy, respirations	Check magnesium level Discontinue infusion If respiratory or EKG changed are noted: administer calcium gluconate (1 ampule=4.64 mEq IV x 1 dose)
Significant renal impairment (Cr >1.5)	Loading dose: 4 grams/20 min Continuous infusion: Individualized, may not be needed	Serial magnesium levels every 6 hours, target range 5-7 Monitor for evidence of toxicity: deep tendon reflex, lethargy, respirations	Check magnesium level Discontinue infusion If respiratory or EKG changed are noted: administer calcium gluconate (1 ampule=4.64 mEq IV x 1 dose)

Table 3. Antihypertensive Drugs

Drug	Dose	Precautions
Hydralazine	5-10mg IV over 2 min May repeat every 20min	If after 30-40mg have been administered and the BP remains above target range, switch to Labetalol If maternal heart rate >120 bpm, discontinue hydralazine
Labetalol	20mg IV q 10-15min in a dose-escalating fashion: 20mg followed by 40mg, followed by  80mg, unless significant time lapses. Repeat every 10-15min:max total 220mg	IM administration should be avoided with a viable IUP due to an inability to titrate dosing effectively Once an initial response has been achieved (even if 40 or 80 were required) subsequent doses should be no greater than 20mg to avoid hypotension
Nifedipine Use in the setting of limited or no IV access or in patients with contraindication to Labetalol	10 mg orally; if in 20 min the BP threshold is exceeded administer 20 mg orally. May repeat 20 mg orally in 20 min for a total dose of 50 mg.	Use IV hydralazine or labetalol as first line option if possible. May cause neonatal bradycardia. Avoid in women with asthma, heart disease, or congestive heart failure. May cause increase in maternal heart rate and/or overshoot hypotension.

Post partum

In women with gestational hypertension, preeclampsia, or superimposed preeclampsia, BP should be monitored in the hospital for 48-72 hours and again within 1 week of delivery or earlier in women with symptoms. Discharge instructions for all women should include information about signs and symptoms of preeclampsia and the importance of prompt reporting of symptoms.

Delivery of the placenta usually halts the disease progression but it does not reverse all of the associated pathophysiological changes of preeclampsia. Moreover, preeclampsia and eclampsia can develop in the postpartum period with 33% of convulsions occurring within the 24-48 hr postpartum period.  Thus, seizure prevention with magnesium sulfate infusion should continue through the first 24 hrs postpartum. Patients with persistent blood pressure elevations: systolic > 150-155 mm Hg or diastolic > 90-100 mm Hg, should be treated with IV and oral antihypertensives to maintain blood pressure at systolic < 150-155 mm Hg and diastolic < 100 mm Hg.  Conventional oral agents such as Nifedipine  XL 30mg daily or Labetalol 200 mg BID can be initiated.  If oral agents are required to maintain blood pressure at goal, the patient should be stable for 24 hours on the final dose prior to discharge home.  Patients discharged home on oral anti-hypertensive therapy require postpartum follow up within 1 week of discharge.  Women should be counseled on possibility of persistence of hypertension, recurrence of PreEclampsia, and an increased risk of essential hypertension in the future.

Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) should be considered if the patient continues to have signs, symptoms, and worsening lab parameters after delivery with preeclampsia. Treatment of patients with these disorders should be individualized by a multidisciplinary team of MFM, nephrology, hematology, and transfusion physicians at a tertiary care facility

Diagnostic criteria of these disorders may include:

• Fever (more common with TTP)
• Anemia (hemolytic)
• Thrombocytopenia, usually progressive even after delivery
• Renal failure, usually progressive even after delivery.
• Central nervous system symptoms: seizures or severe headache (more common with TTP)

Quality Indicators/Benchmarks

• Antenatal corticosteroids <34 weeks GA
• Delivery at appropriate facility

References

ACOG. (2017) Emergent therapy for acute-onset, severe hypertension during pregnancy and the postpartum period. Committee Opinion #692. The American College of Obstetricians and Gynecologists.

ACOG. (2013). Hypertension in Pregnancy Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy. [Executive Summary]. The American College of Obstetricians and Gynecologists, 122(5), 1122-1131.

Cunningham, F. G., Leveno, K. J., Bloom, S. L., Hauth, J. C., Rouse, D. J., & Spong, C. Y. (2010). Williams Obstetrics (23rd ed.). New York, USA: McGraw-Hill.

Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. (2000). [GuidelinePractice Guideline]. Am J Obstet Gynecol, 183(1), S1-S22.

Sibai, B. M. (2004). Diagnosis, controversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. [High-risk pregnancy series: An expert's view]. American College of Obstetrics and Gynecologisits, 103(5), 981-991.

Sibai, B. M. (2010a). Chronic Hypertension. In J. T. Queenan, J. Hobbins & C. Y. Spong (Eds.), Protocols for High-Risk Pregnancies (5th ed., pp. 264-272). West Sussex, UK: Wiley-Blackwell.

Sibai, B. M. (2010b). Preeclampsia. In J. T. Queenan, J. Hobbins & C. Y. Spong (Eds.), Protocols for High-Risk Pregnancies (5th ed.). West Sussex, UK: Wiley-Blackwell.