management of preeclampsia -...

Management of Hypertensive Management of Hypertensive Disorders of Pregnancy: Disorders of Pregnancy:

What Is The Evidence, Really?What Is The Evidence, Really?

NaoNao Nakatsuka PGY3Nakatsuka PGY3January 4, 2010January 4, 2010Perinatal RoundsPerinatal Rounds

IntroductionIntroduction

Prevalence of hypertensive disorders of Prevalence of hypertensive disorders of pregnancy (HDP) in pregnant Canadian women:pregnancy (HDP) in pregnant Canadian women:–– 1% 1% -- preexisting HTNpreexisting HTN–– 5 5 -- 6% 6% -- GHTNGHTN–– 1 1 -- 2% 2% -- preeclampsia (2preeclampsia (2--7% in 7% in primipsprimips))–– 0.10.1--0.2% 0.2% -- HELLPHELLP

Preexisting HTN Preexisting HTN ↑↑s risk of preeclampsia by 10s risk of preeclampsia by 10--20%20%

Duley et al. BMJ 2006;332:463-468.Sibai et al. Lancet 2005;365:785–799.

IntroductionIntroduction

Maternal and perinatal outcomes depend on: Maternal and perinatal outcomes depend on: –– GA at disease onsetGA at disease onset–– Severity of diseaseSeverity of disease–– Presence of prePresence of pre--existing medical disorders existing medical disorders –– Quality of managementQuality of management

75% of cases are mild with onset near term or 75% of cases are mild with onset near term or intrapartumintrapartum outcome goodoutcome good

Sibai et al. Lancet 2005;365:785–799.Duley et al. BMJ 2006;332:463-468.

PathophysiologyPathophysiology

Irminger-Finger. Int J Biochem & Cell Biol 2008:40;1979–1983.

(high resistance)

PROCESSINFLAMMATORY

Risk Factors for HDPRisk Factors for HDPCoupleCouple--related:related:

Limited sperm exposureLimited sperm exposurePrimipaternityPrimipaternityMale partner who has Male partner who has fathered fathered preeclampticpreeclampticpregnancypregnancy

Maternal or pregnancyMaternal or pregnancy--related:related:Previous preeclampsiaPrevious preeclampsiaMultifetalMultifetal gestationgestationAntiphospholipidAntiphospholipid AbsAbsPreexisting medical Preexisting medical condition(scondition(s))–– HTNHTN–– Renal Renal dzdz / proteinuria/ proteinuria–– DMDM

Extremes of maternal ageExtremes of maternal ageObesity / excessive wt gain in pregnancyObesity / excessive wt gain in pregnancyInterpregnancyInterpregnancy interval interval ≥≥ 10 yrs10 yrsInfections in pregnancyInfections in pregnancyThrombophiliaThrombophiliaFamily Family hxhx of preeclampsiaof preeclampsiaRace (Black, South Asian, Pacific Island, Race (Black, South Asian, Pacific Island, Nordic)Nordic)NONNON--smoking!smoking!

Sibai et al. Lancet 2005;365:785–799.Magee et al. SOGC Guidelines No. 206 March 2008.

Complications of HDPComplications of HDPMaternal:Maternal:

Placental abruptionPlacental abruptionHELLP / DICHELLP / DICPulmonary edemaPulmonary edemaAcute renal failureAcute renal failureEclampsia Eclampsia Liver failure or Liver failure or hemorrhagehemorrhageStroke (rare)Stroke (rare)Death (rare)Death (rare)LongLong--term cardiovascular term cardiovascular morbiditymorbidity

Fetal/Neonatal:Fetal/Neonatal:Preterm delivery and associated Preterm delivery and associated complicationscomplicationsIUGRIUGRHypoxiaHypoxia--induced neurologic induced neurologic injuryinjuryPerinatal death Perinatal death LongLong--term cardiovascular term cardiovascular morbidity associated with low morbidity associated with low birth wt (fetal origin of adult birth wt (fetal origin of adult dzdzhypothesis)hypothesis)

Sibai et al. Lancet 2005; 365: 785–99.

Diagnosis and Diagnosis and Classification of HDPClassification of HDP

DxDx of GHTN: of GHTN: SOGC Guidelines (Mar 2008)SOGC Guidelines (Mar 2008)

dBPdBP ≥≥ 90 mmHg 90 mmHg –– Average of at least 2 measurements with same arm Average of at least 2 measurements with same arm –– 70% 70%

normalizenormalize–– > 90 mmHg > 90 mmHg perinatal morbidity perinatal morbidity ↑↑–– dBPdBP better predictor of adverse pregnancy outcomes than better predictor of adverse pregnancy outcomes than sBPsBP

sBPsBP ≥≥ 140 mmHg 140 mmHg follow closely for follow closely for ↑↑ dBPdBP–– Higher fluctuation Higher fluctuation not used for not used for DxDx

Isolated office (white coat) HTN = office DBP Isolated office (white coat) HTN = office DBP ≥≥ 90 mmHg but home 90 mmHg but home BP < 135/85 mmHgBP < 135/85 mmHg

Note: Onset of GHTN < 34 wks Note: Onset of GHTN < 34 wks 35% develop preeclampsia35% develop preeclampsia

Magee et al. SOGC Guidelines No. 206 March 2008.

DxDx of Severe GHTN: of Severe GHTN: SOGC Guidelines (Mar 2008)SOGC Guidelines (Mar 2008)

sBPsBP ≥≥ 160 mmHg or 160 mmHg or dBPdBP ≥≥ 110 mmHg110 mmHg

TxTx thought to prevent thought to prevent cerebrovascularcerebrovascular and cardiovascular and cardiovascular complicationscomplicationssBPsBP cutcut--off based on case series by Martin et al:off based on case series by Martin et al:–– 28 pts with severe preeclampsia and eclampsia & strokes28 pts with severe preeclampsia and eclampsia & strokes–– Hemorrhagic stroke in 25 pts, thrombotic in 2 ptsHemorrhagic stroke in 25 pts, thrombotic in 2 pts–– Of 24 pts being treated immediately before stroke:Of 24 pts being treated immediately before stroke:

sBPsBP ≥≥ 160 mmHg in 23 pts and 160 mmHg in 23 pts and ≥≥ 155 mmHg in all155 mmHg in allBut, But, dBPdBP ≥≥ 110 mmHg in only 3 pts 110 mmHg in only 3 pts

–– Maternal mortality 53.6%; only 3 pts escaped permanent Maternal mortality 53.6%; only 3 pts escaped permanent morbiditymorbidity

EclampsiaEclampsia is not necessarily related to severe HTNis not necessarily related to severe HTN–– UK PRECOG study (BMJ) UK PRECOG study (BMJ) -- 34% of 34% of eclampticeclamptic women had max women had max

dBPdBP ≤≤ 100 mmHg100 mmHgMartin et al. Obstetrics & Gynecology 2005;105:246-254.Frias Jr et al. Current Opinion in Obstetrics and Gynecology 2003, 15:489–495.Milne et al. BMJ 2005;330:576-80. Magee et al. SOGC Guidelines No. 206 March 2008.

Proteinuria: Proteinuria: SOGC Guidelines (Mar 2008)SOGC Guidelines (Mar 2008)

Urine dipstick may be used for screening when Urine dipstick may be used for screening when suspicion of preeclampsia lowsuspicion of preeclampsia low–– +1 correlates with ~ 0.3g/24h+1 correlates with ~ 0.3g/24h–– Strongly suspicious if Strongly suspicious if ≥≥ 2+2+

24h urine or spot urine 24h urine or spot urine Pr:CrPr:Cr ratio encouraged ratio encouraged when when ↑↑ suspicion of preeclampsia (suspicion of preeclampsia (↑↑BP, BP, s/ss/s of of preeclampsia)preeclampsia)–– Proteinuria = 0.3g/24h or 30 mg/Proteinuria = 0.3g/24h or 30 mg/mmolmmol

in spotin spot


Urine Dipstick and Spot Urine Urine Dipstick and Spot Urine Pr:CrPr:Crvs. 24 Hour Urinevs. 24 Hour Urine

How good is the dipstick at detecting proteinuria (gold How good is the dipstick at detecting proteinuria (gold std = 0.3g/24h urine)?std = 0.3g/24h urine)?–– Waugh et al: analysis of 6 studies evaluating dipstick urinalysiWaugh et al: analysis of 6 studies evaluating dipstick urinalysis:s:

≥≥ 1 1 pooled + LR = 3.48, pooled pooled + LR = 3.48, pooled –– LR = 0.6 LR = 0.6

How good is the spot urine How good is the spot urine Pr:CrPr:Cr at detecting proteinuria at detecting proteinuria (gold std = 0.3g/24h urine)?(gold std = 0.3g/24h urine)?–– Cut off of 30mg/mmol Cut off of 30mg/mmol senssens 85%, spec 76%85%, spec 76%

Although spot urine is accepted as diagnostic test by Although spot urine is accepted as diagnostic test by some countries, some countries, CdnCdn guideline still recommends 24h guideline still recommends 24h urine as gold stdurine as gold std

Waugh et al. Obstet Gynecol 2004;103:769–77.Magee et al. SOGC Guidelines No. 206 March 2008.

Classification of HDPClassification of HDPPreexisting HTN

(pre-pregnancy or < 20 wks GA)

With preeclampsia (≥ 20wks GA)

With comorbidconditions

•• Resistant HTN (requires 3 meds for Resistant HTN (requires 3 meds for control of BP)control of BP)

•• New or worsening proteinuria New or worsening proteinuria •• Adverse Adverse condition(scondition(s))

•• DM I or IIDM I or II•• Renal diseaseRenal disease•• Any other condition for antihypertensive Any other condition for antihypertensive therapy outside pregnancytherapy outside pregnancy


Classification of HDPClassification of HDP


Gestational HTN(≥ 20 wks GA)

With preeclampsia (≥ 20wks GA)

With comorbidconditions

•• New proteinuria New proteinuria •• Adverse Adverse condition(scondition(s))

•• DM I or IIDM I or II•• Renal diseaseRenal disease•• Any other condition for antihypertensive Any other condition for antihypertensive therapy outside pregnancytherapy outside pregnancy

Severe PreeclampsiaSevere Preeclampsia

Severe preeclampsia:Severe preeclampsia:–– Onset < 34 wks orOnset < 34 wks or–– Heavy proteinuria (> 3g/d) orHeavy proteinuria (> 3g/d) or–– Adverse Adverse condition(scondition(s))

1010––20% with severe preeclampsia develop HELLP20% with severe preeclampsia develop HELLPsyndromesyndrome

Note: Data on correlation between magnitude of Note: Data on correlation between magnitude of proteinuria & maternal/perinatal prognosis not consistent proteinuria & maternal/perinatal prognosis not consistent

heavy heavy proteinuria retained in definition of severe proteinuria retained in definition of severe preeclampsia until new evidence arisespreeclampsia until new evidence arises

Magee et al. SOGC Guidelines No. 206 March 2008.Irminger-Finger. Int J Biochem & Cell Biol 2008:40;1979–1983.

Adverse Conditions:Adverse Conditions:Maternal ManifestationsMaternal Manifestations

Persistent / new / unusual headachePersistent / new / unusual headacheVisual disturbanceVisual disturbancePersistent abdominal / RUQ painPersistent abdominal / RUQ painSevere N/V Severe N/V Chest pain, dyspneaChest pain, dyspneaJaundice (late sign of DIC)Jaundice (late sign of DIC)Signs of endSigns of end--organ dysfunction: eclampsia, pulmonary edema, organ dysfunction: eclampsia, pulmonary edema, placental abruptionplacental abruptionSevere HTNSevere HTNAbnormal labsAbnormal labs–– ↑↑ CrCr [according to local lab criteria][according to local lab criteria]–– ↑↑ AST, ALT, LDH [according to local lab criteria]AST, ALT, LDH [according to local lab criteria]–– PltPlt < 100x10^9/L< 100x10^9/L–– Albumin < 20g/LAlbumin < 20g/L


Adverse Conditions:Adverse Conditions:Maternal ManifestationsMaternal Manifestations

NOT part of criteria:NOT part of criteria:–– ClonusClonus / / hyperreflexiahyperreflexia, edema / wt gain: non, edema / wt gain: non--specific, specific,

common in pregnancycommon in pregnancy–– OliguriaOliguria: non: non--specific, many causes (including specific, many causes (including ↑↑ ADH ADH

after stress or surgery, after stress or surgery, oxytocinoxytocin))Do NOT fluidDo NOT fluid--overload overload pulmonary edema is #1 cause of pulmonary edema is #1 cause of death with preeclampsiadeath with preeclampsiaOliguriaOliguria (< 15 (< 15 mL/hmL/h) should be tolerated, at least over first ) should be tolerated, at least over first 6h postpartum, in women who do not have 6h postpartum, in women who do not have ↑↑ Cr or preCr or pre--existing renal existing renal dzdz

–– Uric acid:Uric acid:Literature on uric acid as predictor of Literature on uric acid as predictor of maternal/perinatal complication of preeclampsia maternal/perinatal complication of preeclampsia conflictingconflicting

Magee et al. SOGC Guidelines No. 206 March 2008.Koopmans et al. European J Obst & Gyn and Repro Biol 2009:146;8–14.

Adverse Conditions: Adverse Conditions: Fetal ManifestationsFetal Manifestations

OligohydramniosOligohydramniosIUGR (usually asymmetrical, but IUGR (usually asymmetrical, but may be symmetrical if severe may be symmetrical if severe placental disease)placental disease)Abnormal Doppler Abnormal Doppler velocimetryvelocimetry of of umbilical artery umbilical artery –– S/D ratio, resistance index, S/D ratio, resistance index,

pulsatilitypulsatility indexindex–– AEDF, REDFAEDF, REDF↓↓ resistance to flow in fetal MCA resistance to flow in fetal MCA (brain sparing)(brain sparing)Abnormal Abnormal ductusductus venosusvenosuswaveformwaveformStillbirthStillbirth


Case: Mrs. FMCase: Mrs. FM

Mrs. FMMrs. FMID: 33yo G4P1 Filipino female at 28+1 weeks with ID: 33yo G4P1 Filipino female at 28+1 weeks with preexisting HTN (preexisting HTN (dxdx’’eded at 15 weeks) and IGTat 15 weeks) and IGTHPI:HPI:–– Transferred from GNH Nov 26 due to severe HTN and Transferred from GNH Nov 26 due to severe HTN and

preeclampsiapreeclampsiaSept 4 Sept 4 Pr:CrPr:Cr = 11.39, Nov 18 = 11.39, Nov 18 urateurate = 380, Nov 22 = 380, Nov 22 24h 24h protprot <0.2g<0.2gNov 18 U/S: EFW 10Nov 18 U/S: EFW 10--50%ile, normal 50%ile, normal umbumb artery artery (UA) (UA) dopplerdoppler but abnormal uterine artery but abnormal uterine artery dopplerdopplerNov 25 Nov 25 Pr:CrPr:Cr = 41.79, = 41.79, urateurate 465, 24h 465, 24h protprot 0.7g0.7g

–– Occasional HA, no other symptomsOccasional HA, no other symptomsOb Ob hxhx: 2002 : 2002 –– Urgent C/S at 35 weeks for preeclampsia Urgent C/S at 35 weeks for preeclampsia and failed IOL, 4lb9ozand failed IOL, 4lb9ozPMH: healthyPMH: healthyMeds: Methyldopa 500mg Meds: Methyldopa 500mg qidqid, , LabetalolLabetalol 200mg bid200mg bid

Mrs. FMMrs. FMO/E: O/E: –– BP labile (108BP labile (108--168 / 80168 / 80--110)110)–– NST normal except minimal variabilityNST normal except minimal variability–– No No abdoabdo tenderness, reflexes normal, no tenderness, reflexes normal, no clonusclonus

U/S Nov 26:U/S Nov 26:–– BPP 8/8, AFI 12.5, EFW 10BPP 8/8, AFI 12.5, EFW 10--50%ile, UA 50%ile, UA dopplerdoppler

normalnormalInptInpt surveillance:surveillance:–– VS q shiftVS q shift–– NST dailyNST daily–– Labs 3x/weekLabs 3x/week–– BPP 2x/weekBPP 2x/week

Mrs. FMMrs. FMEpisodes of severe HTN:Episodes of severe HTN:–– Acutely treated with Acutely treated with AdalatAdalat PA 10mg PA 10mg BP down to BP down to

108/80 108/80 plan changed to use IV plan changed to use IV labetalollabetalol insteadinstead–– LabetalolLabetalol ↑↑ed to 200mg ed to 200mg tidtid; ; AdalatAdalat XL 20mg bid XL 20mg bid

added added later later ↓↓ed to 20mg dailyed to 20mg dailyNST NST –– min variability but no min variability but no decelsdecelsU/S Nov 28 U/S Nov 28 -- BPP 8/8, UA BPP 8/8, UA dopplerdoppler ↑↑ resistive index (0.8) resistive index (0.8) and S:D ratio (5.0 and S:D ratio (5.0 95%ile for GA), MCA 95%ile for GA), MCA dopplerdoppler brain brain sparingsparingU/S Dec 3 U/S Dec 3 –– BPP reassuring, UA BPP reassuring, UA dopplerdoppler AEDF, MCA AEDF, MCA dopplerdoppler brain sparing, DV normalbrain sparing, DV normal

Mrs. FMMrs. FM

Dec 7 (29 weeks):Dec 7 (29 weeks):–– BP BP –– 171/116 171/116 to CR for cont EFMto CR for cont EFM–– NST NST –– min variability, intermittent small min variability, intermittent small decelsdecels x < 1 x < 1

minmin–– U/S U/S –– BPP 8/8, intermittent REDFBPP 8/8, intermittent REDF–– Labs Labs –– PltPlt 149 (149 (↓↓), ALT 41 (), ALT 41 (↑↑))–– BP treated with BP treated with labetalollabetalol 20mg iv x2 then 40mg iv x 1 20mg iv x2 then 40mg iv x 1

still > 160/110still > 160/110–– After discussion among Ob/After discussion among Ob/GynGyn, perinatal and Ob , perinatal and Ob

Med, decision made for urgent C/S Med, decision made for urgent C/S 980g infant, 980g infant, 66118855, bag/mask , bag/mask resusresus only only

Mrs. FMMrs. FM

Postpartum:Postpartum:–– HTN intermittently severe (Dec 8 HTN intermittently severe (Dec 8 –– Dec 12) Dec 12)

AdalatAdalat PA 10mg PA 10mg prnprnAdalatAdalat XL 30mg bid, XL 30mg bid, LabetalolLabetalol 100mg bid100mg bid

–– PltPlt 104 (Dec 8) 104 (Dec 8) 88 (Dec 10) 88 (Dec 10) 133 (Dec 12)133 (Dec 12)–– HbHb 54 (Dec 8) 54 (Dec 8) CT showed bladder flap and ant CT showed bladder flap and ant

abdominal hematoma abdominal hematoma 3U PRBC 3U PRBC HbHb 111111–– D/D/CC’’eded Dec 14 Dec 14

BP 120 BP 120 –– 140140’’s / 80 s / 80 –– 9090’’ssHbHb 115, 115, PltPlt 167167Rx for Rx for AdalatAdalat XL 30mg bid, XL 30mg bid, LabetalolLabetalol 100mg bid100mg bid

Management of HDPManagement of HDP

BedrestBedrest: : Does It Improve Outcomes?Does It Improve Outcomes?

For preeclampsia For preeclampsia –– 2 2 RCTsRCTs, N=145:, N=145:–– Strict (vs. some) Strict (vs. some) bedrestbedrest NONO improvement in improvement in

maternal/perinatal outcomesmaternal/perinatal outcomesnot recommendednot recommended

For GHTN (no preeclampsia) For GHTN (no preeclampsia) –– 1 RCT, N=218: 1 RCT, N=218: –– InIn--pt management with AAT in ward (vs. outpt management with AAT in ward (vs. out--pt pt

routine activity) routine activity) ↓↓ severe HTN (RR 0.58; 95% CI severe HTN (RR 0.58; 95% CI 0.380.38––0.89) and PTB (RR 0.53; 95% CI 0.290.89) and PTB (RR 0.53; 95% CI 0.29––0.990.99), ), but NO improvement in perinatal outcomesbut NO improvement in perinatal outcomes

No No RCTsRCTs on on bedrestbedrest vsvs AATAAT

Conclusion: No evidence that Conclusion: No evidence that bedrestbedrest improves improves outcomes, and may outcomes, and may ↑↑ VTE risk VTE risk consider allowing consider allowing ambulationambulation

Meher et al. Cochrane Database of Systematic Reviews. 2007. CD003514.

Maternal and Fetal Surveillance Maternal and Fetal Surveillance ––How Often?How Often?

No large prospective studies validating No large prospective studies validating frequency of monitoringfrequency of monitoring

Mild GHTN: outMild GHTN: out--ptpt–– Maternal: Maternal:

SelfSelf--assessment of adverse symptoms dailyassessment of adverse symptoms dailyBP and urine dipstick 2x/wkBP and urine dipstick 2x/wkHbHb, , PltPlt, Cr, ALT/AST weekly, Cr, ALT/AST weekly

–– Note: Note: coagcoag function tests NOT needed if function tests NOT needed if pltplt and liver enzymes and liver enzymes normalnormal

–– Fetal: Fetal: NST, U/S for EFW and AFI NST, U/S for EFW and AFI if normal, no need for repeat if normal, no need for repeat testing unless maternal condition changestesting unless maternal condition changes

Sibai. Obstetrics and gynecology. 2003:102(1):181-192.

Maternal and Fetal SurveillanceMaternal and Fetal Surveillance

Mild preeclampsia: outMild preeclampsia: out--ptpt–– Maternal:Maternal:

SelfSelf--assessment of adverse symptoms dailyassessment of adverse symptoms dailyBP and urine dipstick dailyBP and urine dipstick dailyHbHb, , PltPlt, Cr, ALT/AST, 24h urine protein , Cr, ALT/AST, 24h urine protein weekly

–– Fetal:Fetal:Kick count dailyKick count dailyNST (or BPP) weekly NST (or BPP) weekly 2x/wk if oligo/IUGR2x/wk if oligo/IUGRU/S for growth and AFI q 3 weeksU/S for growth and AFI q 3 weeks

Note: Mild GHTN/preeclampsia may be managed Note: Mild GHTN/preeclampsia may be managed as outas out--pt only if compliant, logistically feasible, pt only if compliant, logistically feasible, and not progressing into severe diseaseand not progressing into severe disease

Sibai. Obstetrics and gynecology. 2003:102(1):181-192.ACOG Practice Bulletin #33 Jan 2002.

Maternal and Fetal SurveillanceMaternal and Fetal Surveillance

Severe Preeclampsia: inSevere Preeclampsia: in--pt at tertiary pt at tertiary centrecentre–– Maternal:Maternal:

BP, urine output, symptoms/signs of endBP, urine output, symptoms/signs of end--organ organ dysfndysfnLabs daily or more frequentLabs daily or more frequent

–– Fetal:Fetal:Cont EFM Cont EFM intermittent intermittent NSTsNSTsU/S for BPP, AFI, EFW, DopplerU/S for BPP, AFI, EFW, Doppler

Sibai. Obstetrics and gynecology. 2003:102(1):181-192.

Severe HTN Severe HTN sBP ≥ 160 or dBP ≥ 110

Confirm in 15 min then treatDrugDrug DoseDose

LabetalolLabetalol 20 mg iv 20 mg iv rpt 20rpt 20--80 mg q 30 min or80 mg q 30 min or11--2 mg/min iv 2 mg/min iv Max 300 mg (then switch to Max 300 mg (then switch to popo))

NifedipineNifedipine 55--10 mg capsule bitten/swallowed q 30 min or10 mg capsule bitten/swallowed q 30 min or10 mg PA q 45 min 10 mg PA q 45 min Max 80 mg/dMax 80 mg/d

HydralazineHydralazine 5 mg iv 5 mg iv rpt 5rpt 5--10 mg iv q 30 min or10 mg iv q 30 min or0.50.5--10 mg/h iv10 mg/h ivMax 20 mg Max 20 mg


NonNon--Severe HTNSevere HTNsBPsBP 140140––159 or 159 or dBPdBP 9090––109109

Targets: Targets: –– No No comorbidcomorbid conditions: conditions: 130130––155 / 80155 / 80––105105–– + + comorbidcomorbid conditions: conditions: 130130––139 / 80139 / 80––8989–– Avoid low BP Avoid low BP placental placental hypoperfusionhypoperfusion

Debate over Debate over txtx of nonof non--severe HTNsevere HTN–– Systematic review 2006: 28 Systematic review 2006: 28 RCTsRCTs, N=3200 , N=3200

Use of Use of drug(sdrug(s) halved severe HTN (RR 0.50, 95% CI 0.41) halved severe HTN (RR 0.50, 95% CI 0.41-- 0.61)0.61)No diff in preNo diff in pre--eclampsiaeclampsia, perinatal death, preterm birth, SGA, perinatal death, preterm birth, SGA

–– MetaMeta--analysis 2000: 45 analysis 2000: 45 RCTsRCTs, N=3773, N=3773↓↓ in MAP correlated to SGA and lower birth wt in MAP correlated to SGA and lower birth wt Placental Placental hypoperfusionhypoperfusion??

Magee et al. SOGC Guidelines No. 206 March 2008.Abalos et al. Cochrane Database of Systematic Reviews 2006. CD002252.Von Dadelszen et al. Lancet 2000;355:87-92.

NonNon--Severe HTNSevere HTNsBPsBP 140140––159 or 159 or dBPdBP 9090––109109

DrugDrug DoseDose

LabetalolLabetalol 100100--400mg bid400mg bid--tidtid (max 1200mg/d)(max 1200mg/d)

MethyldopaMethyldopa 250250--500mg bid500mg bid--qidqid (max 2g/d)(max 2g/d)

NifedipineNifedipine PA: 10PA: 10--20mg bid20mg bid--tidtid (max 180mg/d)(max 180mg/d)XL: 20XL: 20--60mg daily (max 120mg/d)60mg daily (max 120mg/d)


Notes on Antihypertensive DrugsNotes on Antihypertensive Drugs

LabetalolLabetalol and methyldopa used most frequently in and methyldopa used most frequently in CanadaCanada–– LabetalolLabetalol may be slightly more efficacious (10 trials, N=539; RR may be slightly more efficacious (10 trials, N=539; RR

0.75, 95% CI 0.580.75, 95% CI 0.58––0.94)0.94)

No evidence of adverse pediatric longNo evidence of adverse pediatric long--term health or term health or neurodevelopmentalneurodevelopmental outcomes outcomes ACEI contraindicated in any trimesterACEI contraindicated in any trimester–– T2/3: linked to IUGR, oligohydramnios, renal dysplasiaT2/3: linked to IUGR, oligohydramnios, renal dysplasia–– T1 (T1 (Cohort study 2006, N=29,507)Cohort study 2006, N=29,507): : linked to malformation of linked to malformation of

CVS (RR 3.72) and CNS (RR 4.39)CVS (RR 3.72) and CNS (RR 4.39)–– If pt was on ACEI/ARB preIf pt was on ACEI/ARB pre--conception for conception for renoprotectionrenoprotection, restart , restart

postpartum (compatible with breastfeeding)postpartum (compatible with breastfeeding)

Magee et al. SOGC Guidelines No. 206 March 2008.Cooper et al. NEJM 2006;354:2443-51.

Magnesium Sulfate and Magnesium Sulfate and EclampsiaEclampsia

TxTx of of eclampsiaeclampsia: : –– MgSO4 more effectively reduces recurrent seizures than MgSO4 more effectively reduces recurrent seizures than

phenytoinphenytoin (6 trials, N=897) or diazepam (7 trials, N=1441)(6 trials, N=897) or diazepam (7 trials, N=1441)

Prevention of Prevention of eclampsiaeclampsia::–– MAGPIE: Multicentre RCT, N=10,141MAGPIE: Multicentre RCT, N=10,141–– Antepartum or Antepartum or ≤≤ 24h postpartum, BP 24h postpartum, BP ≥≥ 140/90, proteinuria 140/90, proteinuria ≥≥ 1+, 1+,

clinical uncertainty about using MgSO4clinical uncertainty about using MgSO4–– IV: MgSO4 4g over 10IV: MgSO4 4g over 10--15min then 1g/h x 24h15min then 1g/h x 24h–– IM: MgSO4 5g in each buttock then 5g q4h x 24hIM: MgSO4 5g in each buttock then 5g q4h x 24h–– Recurrent Recurrent szsz: 2g iv bolus over 5: 2g iv bolus over 5--10min10min–– MgSO4 reduced risk of eclampsia by 58% (95% CI 0.40MgSO4 reduced risk of eclampsia by 58% (95% CI 0.40––0.71), 0.71),

NNT=91NNT=91

Duley et al. Lancet 2002;359:1877-90.

To Deliver or To Deliver or Not To Deliver?Not To Deliver?

Mode of DeliveryMode of Delivery

Consider IOL first; C/S only for usual obstetrical Consider IOL first; C/S only for usual obstetrical indicationsindicationsIOL with severe preeclampsia takes more time IOL with severe preeclampsia takes more time and less successful than with normal BP and less successful than with normal BP –– Success 60% at > 32 wks, 10% at < 26 wks Success 60% at > 32 wks, 10% at < 26 wks –– IUGR or oligohydramnios not contraindications IUGR or oligohydramnios not contraindications -- may may

consider consider oxytocinoxytocin challenge testchallenge test–– Doppler findings:Doppler findings:

↑↑ resistance to diastolic flow resistance to diastolic flow vaginal delivery rate > 50%vaginal delivery rate > 50%AEDF or REDF AEDF or REDF most babies delivered by most babies delivered by C/SC/S

If thrombocytopenic or DIC, If thrombocytopenic or DIC, ↑↑ risk of PPHrisk of PPH–– Do NOT use Do NOT use ergometrineergometrine! (! (↑↑ risk of stroke)risk of stroke)


Management Management ≥≥ 36 Weeks36 Weeks

SOGC Guidelines: Preeclampsia (severe or nonSOGC Guidelines: Preeclampsia (severe or non--severe) severe) consider deliveryconsider delivery

HAPITAT study HAPITAT study –– multicentre RCT, N=383:multicentre RCT, N=383:–– Population: 36Population: 36--41 weeks, non41 weeks, non--severe GHTN or severe GHTN or

preeclampsia preeclampsia –– IOL IOL vsvs expectantexpectant–– 11°° outcome: composite of poor outcome: composite of poor maternal maternal outcomesoutcomes

Death, eclampsia, HELLP, pulmonary edema, VTE, Death, eclampsia, HELLP, pulmonary edema, VTE, placental abruption, progression to severe HTN or placental abruption, progression to severe HTN or proteinuria, major PPH proteinuria, major PPH

Magee et al. SOGC Guidelines No. 206 March 2008.Koopmans et al. Lancet 2009;374:979-88.

Management Management ≥≥ 36 Weeks36 WeeksHAPITAT studyHAPITAT study–– Results: Results:

Poor maternal outcome in 31% of IOL Poor maternal outcome in 31% of IOL group group vsvs 44% of expectant group (RR 0.71, 44% of expectant group (RR 0.71, 95% CI 0.5995% CI 0.59--0.86, p<0.0001)0.86, p<0.0001)No No eclampsiaeclampsia, maternal/neonatal death , maternal/neonatal death

–– Conclusion: IOL has better maternal outcome Conclusion: IOL has better maternal outcome with nonwith non--severe HDP severe HDP ≥≥ 36 36 weeks weeks recommendedrecommended

Koopmans et al. Lancet 2009;374:979-88.

Management 34 Management 34 -- 35 Weeks35 Weeks

NonNon--severe preeclampsia severe preeclampsia insufficient insufficient evidence to recommend delivery evidence to recommend delivery vsvsexpectantexpectant•• In addition to neonatal concerns, In addition to neonatal concerns, ↑↑ data that data that

late preterm birth is associated with delayed late preterm birth is associated with delayed academic performanceacademic performance

Severe preeclampsia Severe preeclampsia deliverydelivery

Magee et al. SOGC Guidelines No. 206 March 2008.Von Dadelszen et al. Semin Perinatol 2009:33;152-157.


NonNon--severe preeclampsia severe preeclampsia expectantexpectantSevere preeclampsia Severe preeclampsia deliver deliver or expectant?? or expectant??

Cochrane Systematic Review: Cochrane Systematic Review: –– 2 2 RCTsRCTs ((SibaiSibai/Mercer 1994, /Mercer 1994, OdenhaalOdenhaal 1990), N=133 1990), N=133

with severe preeclampsia, GA 28with severe preeclampsia, GA 28--34 weeks34 weeks–– On admission:On admission:

BetamethasoneBetamethasoneMgSO4 x 24 hMgSO4 x 24 hBP BP ≥≥ 160/110 treated160/110 treated

Churchill et al. Cochrane Database of Systematic Reviews 2002 CD003106.


Cochrane Systematic Review:Cochrane Systematic Review:–– Intervention group: C/S or IOLIntervention group: C/S or IOL–– Expectant group: Expectant group: bedrestbedrest, maternal and fetal , maternal and fetal

monitoringmonitoringIndications for delivery: Indications for delivery: 1) Reached 34 weeks 1) Reached 34 weeks 2) Maternal deteriorations (2) Maternal deteriorations (oliguriaoliguria, , thrombocytopenia, thrombocytopenia, ↑↑ ALT/ASTALT/AST, imminent , imminent eclampsiaeclampsia, severe HTN resistant to drugs) , severe HTN resistant to drugs) 3) Fetal distress3) Fetal distress



–– Results: Results: Mean prolongation of pregnancy in expectant group = 7Mean prolongation of pregnancy in expectant group = 7--14d14dMaternal: no diff in Maternal: no diff in eclampsiaeclampsia, renal failure, , renal failure, pulmpulm edema, edema, HELLP, C/S, abruptionHELLP, C/S, abruptionFetal/Neonatal: Fetal/Neonatal:

–– No diff in death rateNo diff in death rate–– Expectant group Expectant group -- ↓↓ RDS, NEC, NICU RDS, NEC, NICU admadm; ; ↑↑ SGASGA

–– Conclusion: Expectant management improves Conclusion: Expectant management improves perinatalperinatal outcome outcome without compromising maternal outcome without compromising maternal outcome recommended recommended **As long as close monitoring possible!**As long as close monitoring possible!

–– Caveat: N was not large enough to study rare mat conditions Caveat: N was not large enough to study rare mat conditions ((egeg) NO incidence of ) NO incidence of eclampsiaeclampsia or pulmonary edema)!or pulmonary edema)!



No RCTNo RCT

SibaiSibai, retrospective review, N=84, 24, retrospective review, N=84, 24--27+6 weeks, 27+6 weeks, severe preeclampsia:severe preeclampsia:–– N=30 N=30 immediate delivery 48h after steroidsimmediate delivery 48h after steroids–– N=54 N=54 expectant managementexpectant management

Bed rest, steroids, antihypertensive Bed rest, steroids, antihypertensive txtx for DBP > for DBP > 100, MgSO4 x 24100, MgSO4 x 24--72h, close surveillance72h, close surveillancePregnancy continued until onset of maternal/fetal Pregnancy continued until onset of maternal/fetal complicationscomplications

Sibai et al. Am J Obstet Gynecol. 1990;163(3):733-8.

Management 24 Management 24 -- 28 Weeks28 WeeksRetrospective review:Retrospective review:–– Results of expectant management (Results of expectant management (vsvs delivery):delivery):

Mean prolongation 13.2d (range 2Mean prolongation 13.2d (range 2--26d)26d)Sig. Sig. ↑↑ perinatalperinatal survival (76.4% survival (76.4% vsvs 35%)35%)Sig. Sig. ↑↑ birth wt (880g birth wt (880g vsvs 709g)709g)Sig. Sig. ↓↓ neonatal complicationsneonatal complicationsNo diff in maternal complications No diff in maternal complications

–– Conclusion: Expectant management improves Conclusion: Expectant management improves perinatalperinatal outcome without compromising maternal outcome without compromising maternal outcome outcome recommendedrecommended**As long as close monitoring possible!**As long as close monitoring possible!

Sibai et al. Am J Obstet Gynecol. 1990;163(3):733-8.

Management < 24 Weeks: Management < 24 Weeks: Retrospective Studies on Expectant ManagementRetrospective Studies on Expectant Management

PattinsonPattinson et al et al (1988)(1988)

GauglerGaugler--SendenSendenet al (2006) et al (2006)

BuddenBudden et al et al (2006)(2006)

BombrysBombrys et al et al (2008)(2008)

NN 4545 2626 3131 46 (51 fetuses)46 (51 fetuses)

GA (wks)GA (wks) <24 <24 <24<24 <25<25 <27<27

PregPreg prolongation (days)prolongation (days) 1414 24 [324 [3--46]46] 6 [26 [2--46]46]

Perinatal mortalityPerinatal mortality(Wks = GA (Wks = GA at at admissionadmission))

100%100% 82%82% 23wks 23wks –– 100%100%24wks 24wks –– 38%38%

<23wks <23wks –– 100%100%23 wks 23 wks –– 80%80%24 wks 24 wks –– 29%29%25 wks 25 wks –– 24%24%26 wks 26 wks –– 10%10%

Maternal mortalityMaternal mortality 4% (1 case)4% (1 case) 0%0% 0%0%

Major maternal Major maternal complicationscomplications

Eclampsia Eclampsia –– 19% 19% HELLP HELLP –– 62%62%PulmPulm edema edema ––15%15%

Eclampsia Eclampsia –– 0%0%HELLP HELLP –– 66% 66% Renal Renal insuffinsuff ––26%26%

Eclampsia Eclampsia –– 2%2%HELLP HELLP –– 24%24%Abruption Abruption –– 13%13%PulmPulm edema edema ––4%4%Renal Renal insuffinsuff ––4%4%

Management < 24 WeeksManagement < 24 Weeks

Conclusion: Expectant management <24 Conclusion: Expectant management <24 weeks weeks hhigh perinatal mortality and igh perinatal mortality and maternal morbidity maternal morbidity

Termination of pregnancy should be Termination of pregnancy should be offered after extensive counselingoffered after extensive counseling

Pattinson et al. S Afr Med J 1988;73:516-518.Gaugler-Senden et al. Eur J Obstet Gynecol Reprod Biol 2006;128:216-221.Budden et al. Aust N Z J Obstet Gynaecol 2006;46:407-412.Bombrys et al. Am J Obstet Gynecol 2008;199:e1-e6.

Management of HELLPManagement of HELLP

Haddad et al Haddad et al –– no stat diff in adverse maternal no stat diff in adverse maternal or neonatal outcomes of HELLP or neonatal outcomes of HELLP vsvs severe severe preeclampsia preeclampsia ≤≤ 28 weeks (N=64)28 weeks (N=64)

Delivery concerns:Delivery concerns:–– IOL in IOL in nullipsnullips <30 wks often very prolonged <30 wks often very prolonged may may

consider C/S consider C/S outright as risk of eventually requiring outright as risk of eventually requiring C/S high C/S high

–– IntraIntra-- and and postoppostop oozing common oozing common consider leaving consider leaving sub/sub/suprafascialsuprafascial drains to drains to ↓↓ need for repeat need for repeat laparotomylaparotomy

Haddad et al. Am J Obstet Gynecol 2000:183;1475 –9.Baxter et al. Obst and Gyn Survey 2004:59(12);838-845.

Management of HELLPManagement of HELLP

SOGC Guidelines:SOGC Guidelines:–– Consider transfusing Consider transfusing pltsplts when when pltplt < 50x10^9/L, < 50x10^9/L, pltsplts

falling rapidly, and/or falling rapidly, and/or coagulopathycoagulopathy–– Strongly consider transfusing Strongly consider transfusing pltsplts when when pltplt < <

20x10^9/L for C/S and vaginal delivery20x10^9/L for C/S and vaginal delivery–– PltsPlts may contain may contain RBCsRBCs (4U (4U pltsplts can contain up to 2ml can contain up to 2ml

RBCsRBCs) ) give give WinRhoWinRho 300mcg if 300mcg if RhRh --veve–– Consider steroids when Consider steroids when pltplt < 50x10^9/L < 50x10^9/L

Systematic review: Systematic review: –– Improvement in BP, urine output, lab values (Improvement in BP, urine output, lab values (pltsplts and and

liver enzymes), BUT liver enzymes), BUT –– No diff in mat/perinatal outcomesNo diff in mat/perinatal outcomes

Magee et al. SOGC Guidelines No. 206 March 2008.Matchaba et al. Cochrane Database of Systematic Reviews. 2003. CD002076.

Postpartum TreatmentPostpartum Treatment

~50% with HDP have PP HTN~50% with HDP have PP HTNBP often peaks at PP day 3BP often peaks at PP day 3--6 due to fluid shifts6 due to fluid shiftsProteinuria and adverse conditions may worsen for few Proteinuria and adverse conditions may worsen for few days PPdays PPTxTx of PP HTN: of PP HTN: –– ≥≥ 160/110 160/110 –– treat in same manner as with antepartumtreat in same manner as with antepartum–– NonNon--severe with comorbidities: treat (as per severe with comorbidities: treat (as per CdnCdn HTN HTN

guidelines) guidelines) –– NonNon--severe without comorbidities: insufficient datasevere without comorbidities: insufficient data

Consider Consider thromboprophylaxisthromboprophylaxis in women with in women with preeclampsia, esp. post C/S or antenatal preeclampsia, esp. post C/S or antenatal bedrestbedrest > 4 days > 4 days (unproven benefit)(unproven benefit)


Postpartum Resolution of Postpartum Resolution of GHTN and GHTN and ProteinuriaProteinuria –– How Long How Long

Does It Take?Does It Take?Berks et al Berks et al -- prospective cohort study, N=205 with preeclampsiaprospective cohort study, N=205 with preeclampsia–– F/U at 1.5, 3, 6, 12, 18, and 24 mo PPF/U at 1.5, 3, 6, 12, 18, and 24 mo PP–– Results: Results:

HTN: 39% + at 3 mo PP HTN: 39% + at 3 mo PP 18% + at 2 yrs PP18% + at 2 yrs PP–– Resolution time Resolution time ↑↑ with higher max BP and with longer with higher max BP and with longer

dxdx--toto--delivery intervaldelivery intervalProteinuria:14% + at 3 mo PP Proteinuria:14% + at 3 mo PP 2% + at 2 yrs PP2% + at 2 yrs PP

–– Resolution time Resolution time ↑↑ with higher max with higher max proteinuriaproteinuriaGA at onset of preeclampsia not correlated with resolution GA at onset of preeclampsia not correlated with resolution time of HTN and proteinuriatime of HTN and proteinuria

–– Conclusion: Up to 2 yrs for HTN and proteinuria to resolve Conclusion: Up to 2 yrs for HTN and proteinuria to resolve may postpone further invasive workmay postpone further invasive work--up for underlying renal up for underlying renal disease until 2 yrs PPdisease until 2 yrs PP

Berks et al. Obstetrics and gynecology Dec 2009;114(6):1307-14.

TakeTake--Home PointsHome Points

Classification: Classification: Gestational/preexisting HTN Gestational/preexisting HTN ±± Preeclampsia Preeclampsia ±± ComorbidComorbid conditionsconditions

24h urine for proteins still gold standard24h urine for proteins still gold standardNo evidence for No evidence for bedrestbedrestNo No RCTsRCTs on frequency of maternal/fetal on frequency of maternal/fetal surveillancesurveillanceDebate over whether or not to treat nonDebate over whether or not to treat non--severe severe GHTNGHTN


Management:Management:–– ≥≥ 36 weeks: deliver36 weeks: deliver–– 34 34 –– 35 weeks: 35 weeks:

Severe preeclampsia Severe preeclampsia deliverdeliverNonNon--severe preeclampsia severe preeclampsia insufficient datainsufficient data

–– 24 24 -- 34 weeks: expectant34 weeks: expectant–– < 24 weeks: offer termination of pregnancy< 24 weeks: offer termination of pregnancy


Postpartum:Postpartum:–– Treat severe HTN and nonTreat severe HTN and non--severe HTN severe HTN

with comorbiditieswith comorbidities–– Insufficient data on Insufficient data on txtx of nonof non--severe severe

HTN w/o comorbiditiesHTN w/o comorbidities–– GHTN and proteinuria do not resolve in GHTN and proteinuria do not resolve in

many women for prolonged period of many women for prolonged period of timetime

–– FollowFollow--up importantup important

THANK YOU!!THANK YOU!!Special Thanks to Dr. Special Thanks to Dr. VenuVenu JainJain

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