HYPERTENSIVE DISEASES IN PREGNANCY


I. Definitions & classification per ACOG

  1. HTN = >140/90 or >30/15 change compared with baseline; Diastolic pressures >75 in 2nd TM or >85 in 3rd merits close observation
  2. Chronic HTN (predating 20th week of pregnancy)
  1. More likely to have preeclampsia than those without chronic HTN
  2. At increased risk for adverse neonatal outcomes independent of the development of preeclampsia (e.g. premature delivery, abruptio placentae, low birth weight, and perinatal mortality), particularly if proteinuric early in pregnancy
  3. Risk factors for development of preeclampsia among women with chronic HTN: HTN > 4y, DBP > 100 early in pregnancy, and proteinuria at baseline (NEJM 339:667, 1998--JW)
  4. There is no evidence that aggressive control of chronic HTN in pregnancy reduces risk of preeclampsia or other adverse outcomes and in fact theoretical risk exists of impairing uteroplacental perfusion
  5. Drugs used for chronic HTN in pregnancy (NEJM reccs tx for DBP >100 or less if end-organ damage)
  1. Methyldopa-Safety demonstrated in randomized trials & one 7yr f/u study (pregnancy category B); can cause fatigue and dizziness
  2. Beta-blockers-Pregnancy category C (pindolol is "B")
  1. Atenolol & metoprolol ass'd with IUGR when used 1st or 2nd TM; probably OK in 3rd TM
  2. Makes fetus more vulnerable to hypoxia in animal studies
  1. Labetalol (mixed alpha-/beta-blocker)-Better tolerated than methyldopa but less well-studied; no evidence of IUGR like with beta-blockers; pregnancy category C
  1. Vasodilators
  1. Hydralazine used often as 2nd-line agent; rare reports of neonatal thrombocytopenia
  2. In a meta-analysis of 21 randomized controlled trials of hydralazine (most in comparison with nifedipine or labetolol) in pregnant women with moderate-to-severe hypertension, hydralazine, in copmarison to other antihypertensives, as ass'd with sig. higher risk for maternal hypotension (RR 3.29), cesarian delivery (RR 1.3), abruptio placentae (RR 4.17), nonreassuring fetal heart rate patterns (RR 2.04), or 1-minute Apgar scores of < 7 (RR 2.7) (BMJ 327:955, 2003--JW)
  1. Diuretics-pregnancy category B, though side effects from reduced maternal blood volume may be common
  2. Ca-blockers-Nifedipine is the only one with sig. data but still pregnancy category C; very limited data on first-trimester exposure and overall more limited data than methyldopa or labetalol; Nifedipine is compatible with breastfeeding
  3. ACEIs and ARBs--CONTRAINDICATED (ass'd with fetal death/fetal renal failure)
  1. Other aspects of prenatal management in mothers with chronic hypertension
    1. It is common to perform serial ultrasounds for fetal growth and nonstress tests 1-2x/wk after 32weeks
    2. Consider low-dose aspirin after 12wks (see below) to reduce risk of preeclampsia
  1. Transient HTN of Pregnancy (formerly known as PAH)
    1. Us. develops in 3rd trimester, often near term or postpartum
    2. Us. mild and not associated with poor outcomes
    3. BP us. recovers within a few weeks postpartum
    4. HTN can recur in subsequent pregnancies, & may be more likely to get essential HTN later in life
    5. Manage conservatively; Benedetti checks PIH labs & tends to induce @ 39wks
  1. Preeclampsia = HTN + renal involvement (proteinuria > 300mg/24h or 1+ on dipstick)
    1. If superimposed on chronic HTN, preeclampsia = BP change either 30/15 or 20 change in mean art. pressure plus either proteinuria or edema
    2. Diagnosis is primarily by these criteria, which are imperfect in predicting who will develop severe preeclampsia or eclampsia; as of 2000, no highly accurate diagnostic test is available for preeclampsia
    3. Edema is a common occurrence in preeclampsia but too nonspecific to be included as a diagnostic criterion for preeclampsia
  1. Note--the NIH recommends a different classification scheme (National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy, July 2000), , viz.:
    1. Chronic HTN (BP > 140/90 present before preg. or at < 20wks OR dx'd during preg. and not resolving postpartum)
    2. Preeclampsia (BP > 140/90 + proteinuria > 300mg/24h or 1+ or greater on dipstick at > 20wks; women who have > 30/15 BP increase over baseline are not included though merit close observation)
    3. Gestational hypertension--(BP > 140/90 detected at > 20wks w/o proteinuria)--In retrospect each case should be classified further as:
      1. Transient hypertension if no preeclampsia at time of delivery and BP returns to normal by 12wks postpartum
      2. Chronic hypertension if HTN persists > 12wks postartum
    4. Preeclampsia superimposed upon chronic hypertension--Suspect with new-onset proteinuria > 300mg/24h or sudden increase in proteinuria or HTN or elevation of ALT or AST or thrombocytopenia

II. Preeclampsia

  1. Risk factors
  1. History of prior preeclampsia or hypertension in pregnancy
  2. Chronic hypertension
  3. Age--very young or old
  4. Nulliparity
  5. Diabetes mellitus
  6. Collagen-vascular diseases
  7. Chronic renovascular or renal parenchymal disease
  8. Multiple gestation
  9. High dietary intake of sugar and/or fat (prospective study of 3,133 women; presented at Soc. for Gyn. Invest., FP News 6/1/00)
  10. Tobacco smoking i sassociated with a reduced risk of hypertensive disorders in pregnancy
  1. Natural history & pathophysiology (much speculation on the latter; little known for sure so I include little detail. Neurokinin B, an inflammatory cytokine, may be involved)
  1. Pathophysiology
    1. Antibodies to Angiotensin-II type I (AT-1) receptors
    2. Increased intracellular calcium concentrations in blood cells have been seen; may be caused by above
    3. Anti-angiogenic proteins may play a role in the pathogenesis of preeclampsia
      1. Soluble fms-like tyrosine kinase 1 (sFlt1) (sequesters placental growth factor which is pro-angiogenic).
      2. Soluble endoglin--Levels increased at time of dx of pre-eclampsia and at several months prior to onset of disease in a case-control study of nulliparous women (NEJM 355:992, 2006--JW)
  2. Timing
    1. Most often occurs in in last trimester, often near term. Rarely before 20wks
    2. Early onset ass'd with underlying chronic HTN, renal disease, hydatidiform mole, & nonimmune fetal hydrops
    3. Usually abates rapidly postpartum (us. asymptomatic within 48h)
    4. However, can have onset postpartum (eclampsia reported to occur as late as 10d pp)
    5. Usually edema occurs first, then HTN, then proteinuria
  3. Hypertension
    1. Due to increased SVR from vasospasm; cardiac output is actually reduced
    2. Rarely get systolic BP >200 without preexisting HTN
  4. Edema
  5. Renal dysfunction
    1. Proteinuria
      1. Spot urine protein/creatinine ratio correlates well with 24h protein excretion, including for moderate proteinuria (<1g/24h); no single "cutoff" for protein/creatinine ratio was both sensitive and specific for sig. proteinuria (>300mg/24h), but ratio < 0.15 effectively ruled out such proteinuria in a series of 66 women hosp'd with suspected preeclampsia (J. Fam. Prac 42:385, 1996-JW)
    2. Renal insufficiency--usually oliguric
    3. Usually responds to supportive care alone
  6. Hemoconcentration
    1. Results from 3rd-spacing of fluids
  7. Mild Thrombocytopenia and qualitative platelet defects can be seen (even in the absence of HELLP)
  8. "HELLP syndrome" (hemolysis, elevated liver enzymes, & low platelets)
    1. A potentially life-threatening condition (maternal mortality 1-4%)
    2. Usually accompanied by preeclampsia; occurs in 4-12% of pts with severe preeclampsia or eclampsia; 15% of pts have normal BP
    3. Onset after delivery in 30% of cases
    4. The hemolysis is identified by signs of microangiopathic changes (e.g. schistocytes) on peripheral blood smear; also high serum bili and LDH; some patients have no hemolysis ("ELLP syndrome")
    5. The hepatic dysfunction is probably due to ischemic necrosis due to fibrin deposition in hepatic sinusoids; typically causes RUQ pain; subcapsular hematomas can also occur which can even lead to hepatic rupture (1% of patients)
    6. The thrombocytopenia is due to consumption (intravascular platelet aggregation)
    7. DIC can occur, though rare
    8. Tx
      1. As below for preeclampsia, including MgSO4 until several days postpartum
      2. Also platelet transfusion PRN for severe thrombocytopenia
      3. For severe postpartum HELLP, dexamethasone 10mg IV Q12h and plasma exchange have been used but no controlled trials as of 1998
  9. Eclamptic seizures--See below
  10. Deaths tend to occur from cerebral edema & herniation, hepatic rupture/necrosis, pulmonary edema, & coagulopathy
  11. Progression can be very rapid--see below for "ominous features" of preeclampsia
  1. Prediction of preeclampsia
    1. In a case-control study of 120 women with preeclampsia and 120 matched normotensive controls (all nullipara), spot urinary concentrations of Placental Growth Factor at 21-32wks were sig. lower in women who subsequently developed preeclampsia (RR 22.5 for pts in the lowest quartile, compared with women in all other quartiles)  (Part of "Calcium for Preeclampsia Prevention Trial" JAMA 293:77, 2005--abst)

     

  2. Assessment of the hypertensive pregnant woman with laboratory studies (for initial diagnosis and also to assess severity and progression)
Lab test Normal pregnant Preeclampsia Notes
HCT 32-42 >40 Elevation suggests the
hemoconcentration of
preeclampsia; hemolysis,
however, can decrease.
Hb 11.5-12.3 >12.3 See above
Platelets 150-400 <125 Thrombocytopenia
suggests "HELLP"
syndrome
Fibrinogen* 300-600 <300 Decrease suggests
consumptive coagulopathy
Creatinine 0.5-0.7 >1.0 Elevated due to renal dysfunction
BUN 6-8 >8 Elevated due to renal dysfunction
Uric Acid** 2.0-5.5 >4.5 Elevated due to renal dysfunction
SGOT/SGPT 0-40 >40 Elevation suggets hepatic
involvement, i.e. "HELLP"
syndrome
Urine protein/creatinine
ratio
See above See above  

*--Check Fibrinogen & PT/PTT only if thrombocytopenic
**--Uric acid is an early, sensitive indicator of renal insufficiency in preeclampsia

  1. Prevention of Preeclampsia
  1. Low-dose Aspirin (60mg QD)--may have mild benefit
  1. At this dose, inhibits production of thromboxane more than of prostacyclins which may help counteract the vasoconstrictive processes in preeclampsia
  2. 2500 high-risk women at 13-26wks gestation (471 w/pregestational IDDM; 774 w/chronic HTN; 688 with mult. gestation;. 606 w/previous preeclampsia) randomized to 60mg ASA QD vs. placebo from enrollment to delivery in a double-blind, multicenter trial. No sig. diff. in incidence of preeclampsia; no adverse maternal or fetal bleeding events were noted (Caritis et al. NEJM 338:701, 1998--JW)
  3. In a systematic review of 39 randomized trials involving 30,563 women, ASA (usually < 75mg/d) was ass'd with RR of 0.85 for preeclampsia, RR 0.92 for preterm birth, and RR 0.86 for fetal or neonatal death (all sig.) (BMJ 322:329, 2001--JW)
  1. Salt restriction--No evidence to support; may harm
  1. Prophylactic diuretics--No evidence to support
  1. Calcium supplementation--prob. not beneficial

a. Meta-analysis of 14 randomized controlled trials involving 2459 pts found lower risk for preeclampsia with Ca supplementation (OR 0.38) and trend for reduced preterm delivery just short of statistical significance (JAMA 275:1113, 1996-JW)

b. Randomized trial of 4,500 healthy nulliparous women randomized to 2g elemental Ca vs. placebo starting at 13-21 weeks gestation, continuing to term. No diff. in incidence of HTN, proteinuria, or pre-eclampsia (for preeclampsia, 6.9% w/Ca vs. 7.3% w/placebo). No obvious subgroup seemed to benefit from the Ca supplementation (NEJM 337:69, 1997-JWWH)

  1. Linoleic acid + Calcium-promising!
  1. 89 primips at 28-32 wks with risk factors for preeclampsia (psychosocial criteria, positive "rollover" test, mean arterial pressure > 84mm Hg) & no previous h/o CV or renal disease randomized to 450mg linoleic acid + 600mg Ca/d vs. placebo. All pts also instructed to rest in left lat. decubitus position for 30min/d and avoid ASA and NSAIDs. Incidence of preeclampsia (defined as BP > 140/90 repeatedly + proteinuria > 300mg/l) was 9.3% in tx group and 37.2 in placebo group (sig.). Incidence of c/s, mean length of gestation, mean birth weight, and incidence of LBW infants lower in tx group (Obs. Gyn. 91:585, 1990--AFP)
  1. Ketanserin--promising!
  1. An antihypertensive that also prevents platelet aggregation via selective Serotonin-2-receptor blockade
  2. 138 pregnant women at < 20wks gestation with DBP consistently > 80mm Hg randomized to Ketanserin vs. placebo; all also received AS. Placebo group had sig. higher risk of pre-eclampsia (19% vs. 3%); earlier delivery (mean 36.2 vs. 37.6 wks); and mean birth weight in babies born at 28-34 wks (2.8 vs. 3.1kg); Nonsig. higher rate of perinatal death in placebo group (Lancet 350:1267, 1997--JW)
  1. Antioxidants
    1. 283 women at high risk for preeclampsia (h/o preeclampsia in previous pregnancy or abnormal uterine-artery doppler) randomized to vit. C 1g/d + vit. E 400IU/d vs. placebo between 16-22wks; vitamin group had sig. less incidence of preeclampsia (8% vs. 17%; sig.) (Lancet 354:788, 1999--JW)
    2. In a study in 1,877 pregnant women randomized to (Vit. C 1g/Vit. E 400IU) QD vs. placebo from 14-22wks until delivery, there was no sig. diff. in incidence of preeclampsia, fetal death, serious fetal outcome, or low birth weight. Women in the active-tx group had sig. HIGHER risk of antenatal hospitalization for hypertension (RR 1.54). ("Australian Collaborative Trial of Supplements" ("ACTS") Trial; NEJM 354:1796, 2006--JW)
    3. In a study in 2,395 women felt to be at increased risk for preeclampsia randomized to (vit. C 1000mg + vit. E 400IU) QD vs. placebo there was no sig. diff. in incidence of preeclam0psia, though risk for low-birth-weight infants was sig. higher in the active-treatment group (28% vs. 24%) (Lancet 367:1145, 2006--JW)
  1. Treatment of Preeclampsia
  1. Bedrest, primarily in left lateral decubitus position
    1. As I understand it supported primarily by nonrandomized studies showing better outcomes with hospitalization vs. no hospitalization for preeclampsia.
    2. See also "Bedrest in Pregnancy"
  1. Monitoring pt/fetal condition
    1. Ultrasound to detect IUGR
    2. Monitor BP, reflexes, urine dip for protein, and "PIH labs" (see above)
    3. Monitor Glasgow Coma Scale b/c subjective observation can miss lethargy
    4. Monitor urine output with Foley catheter (expect at least 30-35ml/h)
  1. Delivery is the definitive treatment
    1. Can usually be achieved vaginally with induction
    2. Give corticosteroids if preterm to enhance fetal lung development
    3. In a study in 756 pts with singleton pregnancies at 36-41wks with gestational hypertension or mild preeclampsia randomized to "expectant monitoring" vs. inducation of labor, incidence of "poor maternal outcomes" (based on a composite score) was sig. lower in induction group (31% vs. 44%) though on subgroup analysis the difference was limited to pts at 38+ wks gestation (though power in those subgroups was small) (Lancet 374:979, 2009-JW)
  1. Magnesium Sulfate IV
  1. Ass'd with sig. reductions in seizure and death in women with preeclampsia (see Lancet 359:1877, 2002)
  2. Click on link above for information on dosing, adverse effects, etc.
  3. Continue until 24h postpartum
  1. Snoring is more common in pts with pre-eclampsia, even after adjusting for counfounding characteristics e.g. weight, and nasal CPAP may help reduce BP and edema (ALA/Am. Thoracic Soc. Conference 5/99 cited in FP News 6/1/99)
  1. Treating HTN in preeclampsia:
  1. ALSO recommends using meds to lower BP if it's > 160/110; target is for DBP 90-100mm Hg
  2. Avoid precipitous reduction in BP which may jeopardize placental perfusion
  3. Hydralazine is "drug of choice"
  1. 5-10mg IV (start with 5) Q20-30min or 1mg/min continuous gtt
  2. Pre-treat with much IVF to avoid hypotn and fetal distress
  3. Can cause tachycardia & HA
  1. Labetolol 20mg IV if Hydralazine ineffective of unavailable
  1. Note--Beta-blockers can cause neonatal depression
  1. Diazoxide also used
    1. 30mg "miniboluses" to avoid precipitous drop in BP
    2. Can cause arrest of labor & neonatal hypoglycemia
     
  2. Calcium-channel blockers

i. May work well; Mg may make them bottom out pressure

  1. Nitroprusside has been associated with fetal cyanide poisoning in animals
  2. NEJM article says to avoid diuretics unless CHF, but doesn't give reason
  3. See section on Chronic Hypertension above for more on antihypertensive meds in pregnancy
  1. Fluids in labor: run slightly dry, e.g. 100cc/h, to avoid pulmonary edema postpartum; however, some fluid resuscitation is generally necessary to counteract intravascular hypovolemia due to 3rd-spacing of fluids
  1. Treating Eclamptic Seizures
    1. Clinical features
      1. Risk not correlated well with BP
      2. Probably result from cerebral edema
      3. Preceded often by headaches, scotomota, hyperreflexia/clonus
      4. Usually last only 1-2min
      5. WBC can be elevated afterward
      6. Expect fetal bradycardia subsequent to sz for up to several minutes
      7. Note--Focal seizures are not typical for eclamptic seizure; consider possibility of intracranial hemorrhage if they occur or if pt has persistent lateralizing neurologic signs
      8. Be alert to possibilty of Abruptio Placentae as a sequela of eclamptic seizure
      9. Be alert to possibility of Pulmonary Edema which often occurs after eclamptic seizure--If occurs, tx includes loop diuretics, morphine, O2, and often invasive hemodynamic monitoring
    2. Treatment for initial seizure:
      1. Supportive care--attention to airway, give O2, turn pt on side to prevent aspiration
      2. DO NOT give benzos or phenytoin to tx an initial eclamptic seizure
      3. DO give Mg-If not on it, start as per dosing guidelines noted elsewhere (see link); if already on it, can give extra 2g bolus over 10min if showing no signs of Mg toxicity
    3. If continuing to have seizures despite therapeutic Mg levels, DO consider an anticonvusant
      1. Phenytoin 10-15mg/kg IV at max 50mg/min then 100mg Q6-8h or
      2. Amobarbital (Sodium Amytal) 65-500mg IV at max 50mg/min
    4. Consider general anesthesia for intractable sz (for control of respiratory function)
    5. For any eclamptic sz: expedite delivery!
      1. If not in labor, begin induction once clinically stable and Mg is in
      2. Cesarian delivery NOT indicated unless other maternal or fetal indications are present
  1. Treatment of coagulation abnormalities in preeclampsia
    1. Fresh frozen plasma--target INR < 1.5 if c/s is planned
    2. Platelets--Target count > 50k if c/s is planned
  1. Consider delivery regardless of gestational age if any of the following "ominous features" are present (associated with high risk of progression to preeclampsia)
  1. Severe HTN (>160/110), esp. if persists after 24-48h of Mg
  2. Deteriorating renal function
    1. Proteinuria >2g/24h or >100mg/dl
    2. Rising creatinine or Cr >2.0
    3. Oliguria
  3. Severe HELLP Syndrome
  4. Signs of cerebral edema: headaches, scotomota, hyperreflexia
  5. Signs of hepatic involvement: epigastric or RUQ pain; high transaminases
  6. Hemoconcentration
  7. CHF
  8. IUGR

(Sources: NEJM 326:927, 1992, JAMA 280:559, 1998, 2002 Advanced Life Support in Obstetrics course syllabus; American Academy of Family Physicians, and others)