Hypertensive Disorders in Pregnancy (HDP) lecture (2 ) presented by Dr: Ahmed M. Ali 2018/2019

Preeclampsia (continued)

Preeclampsia BP elevation after 20 weeks of gestation with proteinuria (≥ 300 mg/24 hr) and/or one or more of the severe features of preeclampsia (listed below).

Proteinuria without Hypertension Women who present with proteinuria without hypertension should be monitored for development of preeclampsia or other renal disease, but not treated as preeclamptic. About 51% of women presenting with proteinuria without hypertension will go on to develop preeclampsia later in pregnancy.

Features of Severe Preeclampsia Hypertension: systolic >160 and/or diastolic >110. Thrombocytopenia (platelet count < 100 x 109/L). Impaired liver function (elevated liver transaminases to twice the normal values). Renal insufficiency (serum creatinine > 1.1 mg/dL, or doubling of serum creatinine in the absence of other renal disease).

Features of Severe Preeclampsia (cont.) Pulmonary edema. Cerebral or visual disturbances (new-onset). Epigastric pain unresponsive to medication and not accounted for by alternative diagnoses. Massive proteinuria ( > 5 g/24 hours) and fetal growth restriction (FGR) are NO longer considered as indicators of severe preeclampsia.

The diagnosis of preeclampsia is NO longer dependent only on the presence of proteinuria and/or edema. Do not delay management of preeclampsia in the absence of proteinuria.

Adverse Outcomes of Preeclampsia Preeclampsia is the cause of 9%–26% of global maternal mortality. It is associated with significant proportion of preterm delivery, and maternal and neonatal morbidity. Women who have suffered preeclampsia are at increased risk of CVD throughout life. Children born from pregnancies affected by preeclampsia are more likely to suffer from metabolic syndrome, CVD, and hypertension at earlier ages

Mild preeclampsia BP > 140/90 but < 160/110 with proteinuria in the absence of any of the severe features of preeclampsia.

Current management of preeclampsia Preeclampsia without severe features (i.e. mild): >37 weeks gestation  deliver. < 37 weeks gestation  management until term or maternal/fetal indication for delivery. - Bedrest is no longer “suggested” - Serial maternal assessment (BP, symptoms, labs, weight gain). - Serial fetal assessment (serial US fetal growth, fetal kick count,). - MgSO4 benefit not proven in mild preeclampsia.

Management of preeclampsia (cont.) Preeclampsia with severe features: MgSO4 should be started with the diagnosis of severe preeclampsia. > 34 weeks: deliver 33-34 weeks: Give steroids (for fetal lung maturation) and deliver after 48 hours if maternal/fetal status stable. 22-32 weeks: antihypertensives, steroids, close observation, deliver at 34weeks or earlier in the presence of a maternal and/or fetal indication. < 22 weeks: consider delivery; expectant management is NOT recommended.

Antihypertensive Drugs Commonly Used in the Treatment of Severe Preeclampsia Hydralazine (Apresoline) Initial dose: 5 mg IV or 10 mg IM. When blood pressure is not controlled, repeat initial dose (usually about every 3 hours; maximum, 400 mg/day). Labetalol (Trandate) Initial dose: 20 mg in IV bolus. If blood pressure is not controlled, give 40 mg, 10 minutes after initial dose and then 80 mg every 10 minutes for two additional doses (maximum: 220 mg).

Eclampsia = Preeclampsia + Seizures New-onset seizures (convulsions) in the setting of preeclampsia, not related to other etiologies. Treatment for eclampsia is delivery of the baby! Eclampsia = Preeclampsia + Seizures

Symptoms of eclampsia High blood pressure Nervous system changes (severe headaches, blurred vision, seeing spots) Increased urine production Decreased kidney function Upper abdominal pain

Management of eclampsia Stabilize mother: - Control seizures (MgSO4, lorazepam or diazepam). - Prevent recurrence (MgSO4) - Antihypertensive meds if necessary. Assess fetal status. Delivery is the only DEFINITIVE treatment of eclampsia. - Cesarean delivery is usually performed. - Vaginal delivery is appropriate if would occur in a reasonable time period.

Magnesium Sulphate Goals: - Prevention and control of seizures - HTN control Mechanisms: - Delays neuromuscular transmission Depresses CNS excitability Decreases smooth muscle contractility Magnesium sulphate’s anticonvulsant action may be related to blocking calcium entry into neurons through the N-methyl-D-aspartate (NMDA) receptor-operated calcium channels.

RCT of 685 women with severe preeclampsia MgSO4 : Proven efficacy for seizure prophylaxis RCT of 685 women with severe preeclampsia No MgSO4 (n=340) MgSO4 (n=345) 1 case eclampsia 11 case eclampsia

Magnesium sulphate is used prophylactically against eclampsia in women with preeclampsia with severe features (See above). For preeclamptic women with BP < 160/110 and no maternal symptoms, it is suggested that MgSO4 not to be given commonly to protect against eclampsia.

Magnesium sulphate dosage: 4 g intravenous loading dose (diluted in 20 ml saline) over 20 minutes followed by a constant infusion of 1-2 g/hour. Phenytoin and benzodiazepines can replace MgSO4 for eclampsia prophylaxis or treatment, only when MgSO4 is contraindicated (e.g. in myasthenia gravis) or is ineffective.

Therapeutic serum MgSO4 level: 4-8 mg/dl. Side effects of MgSO4: hot flushing sensation, respiratory depression, loss of deep tendon reflexes and cardiac arrest. The antidote for magnesium sulfate overdose is 10 ml of 10% calcium chloride or calcium gluconate given intravenously. The corrective effect occurs within seconds.

Biomarkers of Preeclampsia Elevated urinary albumin/creatinine ratio (UACR). Elevated spot urinary protein/creatinine ratio (UPCR). Pregnancy-associated plasma protein A (PAPP-A) (↑). Placental protein 13 (PP-13) (↑). Homocysteine (↑). Asymmetric dimethylarginine (ADMA) (↑). Uric acid (↑). Leptin (↑).

Decreased placental growth factor (PLGF) levels: a proangiogenic factor that from as early as 11–13 weeks of gestation. Low levels are associated with the later development of preeclampsia. Elevated soluble vascular endothelial growth factor receptor-1(sVEGFR-1): an antiangiogenic and levels are elevated as much as 5 weeks prior to the clinical onset of disease. ↑sVEGFR-1/PLGF ratio (highly specific for early PE). These biomarkers are valuable when associated with maternal history and/or ultrasound markers to identify women at risk of preeclampsia

Antenatal corticosteroids They are given when the fetus is expected to be delivered within 24 to 48 hours. They are used to help the lungs of a premature fetus to develop before delivery. Treatment consists of 2 doses of 12 mg of betamethasone given IM 24 hours apart or 4 doses of 6 mg of dexamethasone given IM 12 hours apart. Optimal benefit begins 24 hours after initiation of therapy and lasts 7 days. Betamethasone is preferred over dexamethasone due to its higher efficacy, safety, lower cost and thought to have better prophylaxis of brain softening of premature fetus.

Postpartum hypertension and/or preeclampsia Generally, gestational HTN and preeclampsia are cured by delivery. In some cases, disease process can worsen 24-48 hours postpartum and can confer a higher risk of: - Pulmonary edema - Renal failure - HELLP syndrome - Postpartum eclampsia - Stroke

Management of postpartum hypertension and/or preeclampsia For women with persistent postpartum HTN ≥ 150/100, on at least two measurements that are at least 4-6 hours apart, antihypertensive therapy is recommended. Women with persistent postpartum HTN ≥ 160/110 should be treated within 1 hour.

For women who present with postpartum preeclampsia with severe HTN, parenteral MgSO4 is recommended. For women who present with postpartum new-onset HTN associated with headache or blurred vision, parenteral MgSO4 is recommended.

Prevention of Preeclampsia An evidence-based analysis revealed that LOW-DOSE ASPIRIN (60-81 mg/d) beginning in the late first trimester (after week 12) may reduce the incidence of preeclampsia and adverse perinatal outcomes (perinatal mortality, preterm labor, SGA infants) in women at high-risk for preeclampsia (e.g., history of preeclampsia, chronic hypertension, diabetes, or CKD). Low-dose aspirin reduces the risk of preeclampsia recurrence from 35% to 5-10%.

Low-dose aspirin reduces vascular sensitivity to vasopressor agents. No evidence exists for aspirin benefit for women at low risk for preeclampsia. Calcium: An evidence-based review suggests that calcium may be beneficial in women at high risk of preeclampsia and in those who have low dietary calcium intake. Antioxidants: vitamins C and E are not effective. Bed rest or salt restriction: no evidence of benefit.

ACOG recommends to use low-dose aspirin (81 mg/day), initiated between 12 and 28 weeks of gestation, for the prevention of preeclampsia, especially for women at high-risk. July 11, 2016

Women at High-risk for preeclampsia Women are considered to be at high-risk for preeclampsia if one or more of the following risk factors are present: History of preeclampsia Multifetal gestation Chronic hypertension Diabetes (Type 1 or Type 2) Renal disease Autoimmune disease (such as SLE, antiphospholipid syndrome)

Role of Pharmacist and Patient Education in HDP

If the pregnant woman is considered to be at high risk for HDP, the pharmacist can recommend: More frequent antenatal office visits after 20 weeks of pregnancy. Regular measurement and recording of blood pressure. Regular urinalysis for protein. Self-monitoring of blood pressure at home. Use of one baby aspirin tablet starting from late 1st trimester. A balanced diet (See daily food guide during pregnancy).

Daily Food Guide during Pregnancy Choices (Serving equivalents) Servings Food Group • 1 oz. Lean beef, lamb, veal, chicken, fish or cheese • 1 egg 6 Protein Foods 8 oz. Low fat milk or yogurt 4 Milk Products • ½ cup cereal • ½ cup cooked rice or pasta • 1 slice bread • 6 crackers Breads & Cereals • ½ cup (4 oz.) fresh fruit or juice. • ¼ cup dried fruits such as raisins or prunes • 1 whole small apple, pear or orange 5 Fruits • ½ cup cooked vegetables such as broccoli and carrots • 1 cup raw vegetables Vegetables