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Obstetric Medicine (MDP) WorkshopCSIM Annual Meeting, October 1, 2014

Hypertension, Cardiac Disease, Approach to Abnormal Liver Enzymes, VTE

Dr. Paul Gibson (Calgary) – GIM & OB Internal Medicine

Dr. Jonathan Windram (Edmonton) – Cardiology

Dr. Rshmi Khurana (Edmonton) - GIM & OB Internal Medicine

Dr. David Sam (Calgary) - GIM & OB Internal Medicine

Audience Interaction

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Hypertension in Pregnancy

Paul S. Gibson, MD, FRCPCAssociate Professor of Medicine

and Obstetrics & GynecologyUniversity of Calgary

Recent Sources of Information

SOGC, 2014ACOG, 2013

What We Will Cover1. Why hypertensive disorders in pregnancy (HDPs)

matter

2. Preconception evaluationi. Risk factors for preeclampsia

ii. Choice of medications

3. In-pregnancy evaluationi. Classification of HDPs

ii. Pharmacologic treatment and BP targets

4. Postpartum evaluationi. Recognition and treatment of ‘postpartum

preeclampsia’

ii. Implications of HDPs on women’s future health

Why do hypertensive disorders in pregnancy (HDPs) matter ?

Hypertensive disorders of pregnancy are a leading cause of maternal and fetal morbidity and mortality

They are common (~10%):~ 1% of pregnancies are complicated by pre-existing

hypertension5-6% of pregnancies result in gestational hypertension

without proteinuria 2-4% of pregnancies result in pre-eclampsia

* It can be expected that these numbers will increase given the trend towards an older and more obese obstetric population

Maternal Mortality in Canada:Diagnoses associated with maternal deaths in Canada (excluding Quebec), 2002/03-2009/10.

Canadian Institute for Health Information.Public Health Agency of Canada, 2011.http://www.phac-aspc.gc.ca

Maternal Mortality due to HTN - USA

Causes of Maternal Mortality in the UK: 2006-8

Centre for Maternal and Child Enquiries (CMACE). Saving Mothers’ Lives. BJOG 2011;118(Suppl. 1):1–203.

Saving Mothers’ Lives (2011)

“It is disappointing that in this triennium … the single most serious failing in the clinical care provided for mothers with pre-eclampsia was the inadequate treatment of their systolic hypertension

In several cases, this resulted in fatal intracranial haemorrhage

Systolic hypertension was also a key factor in most of the deaths from aortic dissection”

Case #1

23 y.o. woman, G0P0

Referred to her local General Internist for review re: HTN & proteinuria

PMH:Uncontrolled HTN at age 13Proteinuria – Bx = TBMDOngoing anti-HTN meds sinceHome BP = 115-130 / 72-80 on lisinopril 10 mg/dSerum Cr = 105Urine PCR = 40 mg/mmol, 24h urine = 500 mg/d

Case #1 - continued

Announces that she had just stopped her OCP, hoping to achieve pregnancy ASAP!

Preconception Issues?

Medication changes?

Risks in pregnancy?

Preeclampsia prevention?

ACE-inhibitors in pregnancy

Use in the 2nd & 3rd trimesters long known to cause fetal renal toxicity, leading to: oligohydramnios, IUGR, hypocalvaria, renal dysplasia, anuria, renal failure, and IUFD

N Engl J Med 2006;354:2443-51

Infants exposed to ACE inhibitors in the first trimester were at increased risk for malformations of the:• cardiovascular system (risk ratio,

3.72)• central nervous system (risk ratio,

4.39) Concern that these finding were due to higher prevalence of undiagnosed DMII, rather than true medication effect

What is this woman’s risk of developing preeclampsia?

1. 2%

2. 5%

3. 10%

4. 25%

5. 50%

Other risks of cHTN include IUGR, placental abruption, preterm delivery & prematurity

Most of the morbidity and mortality are from preeclampsia

What is this woman’s risk of developing preeclampsia?

What would you suggest to reduce her risk of preeclampsia?

1. Keep BP < 120/80 throughout

2. Fish oil supplements > 1000 mg/d

3. Maternal sodium intake < 2.0 g/d

4. Low-dose aspirin

5. Antioxidant vitamins (Vits C & E)

Preeclampsia Prevention?SOGC Recommends (for women at increased risk):

ASA 75-162 mg/d, taken at bedtime, started before 16 weeks GA and continued until delivery (for women at increased risk)

Calcium supplementation (>= 1 g/d)

Recommended for other established beneficial effects in pregnancy: abstention from alcohol, periconceptual use of a folate-containing multivitamin, and smoking cessation

The following are not recommended: prostaglandin precursors, dietary salt restriction, calorie restriction in overweight women (during pregnancy), antihypertensive therapy specifically to prevent preeclampsia, and vitamins C and E

WE GENERALLY recommend Vitamin D (1000-2000 IU/d)

BP Monitoring Using Automated Devices in Pregnancy & Preeclampsia

Due to altered hemodynamics in pregnancy, it is recommended that automated devices are validated specifically in pregnant women

Further profound changes in hemodynamics can occur in pregnancies complicated by pre-eclampsia

Some investigators have found large discrepancies between oscillometric devices and auscultation by observers, particularly in pre-eclampsia

Devices for home BP monitoring?

A comprehensive list of approved devices for HBPM can be found at:

http://www.dableducational.org

http://www.bhsoc.org/default.stm

http://www.hypertension.ca/devices-endorsed-by-hypertension-canada-dp1.

What about home BP monitoring?

A comprehensive list of approved devices for HBPM can be found at:

http://www.dableducational.org

http://www.bhsoc.org/default.stm

http://http://hypertension.ca/en/hypertension/what-do-i-need-to-know/how-to-measure-my-blood-pressure/918-public/landing/249-devices-endorsed-by-hypertension-canada

Case #1 - continued

Pt is switched to Labetalol 200 mg BID

BP initially 140/90, then drops and remains ~ 130/80

Prenatal care arranged with an OB/GYNPeriodic follow-up with GIM every 6-8 weeks

At 31 weeks GA she is hospitalized with worsening HTN, despite labetalol 400 TIDBPs exceeding 160/105Hb=132, Plt=309, Cr=50, ALT=7, UA=380, LD=238Repeat urine Prot:Cr = 234 mg/mmol (was 40)

Diagnosis of HTN During Pregnancy

HTN in pregnancy is defined as: SBP ≥ 140mmHg or DBP

≥90mmHg

Severe hypertension is defined as: systolic BP of ≥ 160mmHg

or a diastolic BP of ≥ 110mmHg

* based on the average of at least two measurements, taken in the same arm at least 15 minutes apart

What is “abnormal proteinuria” in

pregnancy

All pregnant women should be assessed for proteinuria Urinary dipstick testing may be used for screening for

proteinuria when the suspicion of preeclampsia is low Proteinuria is highly suspect when urinary dipstick

proteinuria is ≥ 1+

Proteinuria is defined as: Protein ≥ 30 mg/mmol urinary creatinine (0.03 g/mmol)

in a spot urine (protein:creatinine) sample or ≥ 0.3g (300mg) in a 24-hour urine collection

Classification of HTN in Pregnancy

SOGC

Preexisting hypertension-With Comorbid Conditions

-With Preeclampsia

Gestational hypertension-With Comorbid Conditions

-With Preeclampsia

Preeclampsia

Other Hypertensive Effects

Classification of HTN in Pregnancy: Co-morbid Conditions

1. Preexisting Hypertension with Co-morbid Conditions

2. Gestational Hypertension with Co-morbid Conditions

Co-morbid conditions:• Conditions such as type I or II diabetes mellitus and

renal or vascular disease• Strong indications for more aggressive antihypertensive

therapy outside of pregnancy warrant special BP treatment thresholds and goals in

pregnancy

Classification of HTN in Pregnancy

1. Preexisting Hypertension with Co-morbid Conditions with Pre-eclampsia

2. Gestational Hypertension with Co-morbid Conditions with Pre-eclampsia

3. Preeclampsia

Pre-eclampsia• Preeclampsia

Gestational HTN PLUS New proteinuria, or One or more ‘adverse conditions’ or ‘severe

complications’

• Gestational Hypertension with Pre-eclampsia New proteinuria, or One or more ‘adverse conditions’ or ‘severe

complications’

Preexisting Hypertension with Pre-eclampsia Resistant hypertension (>2 drugs), or New or worsening proteinuria, or One or more ‘adverse conditions’ or ‘severe

complications’

Severe Preeclampsia (SOGC)

Pre-eclampsia complicated by one or more severe complications

Severe preeclampsia is an indication to move to delivery (regardless of gestational age)

What is your target BP (range) when treating HTN in pregnancy?

1. Anything less than 170/110

2. Less than 150/95

3. 130-155/80-105

4. 120-140/80-90

5. Less than 130/80

Pharmacologic Treatment

Treatment of mild to moderate hypertension in pregnancy is controversial

o Until recently, aggressive treatment has not been shown to improve major maternal and neonatal outcomes

o There is concern that treatment of hypertension during pregnancy will impair fetal growth

Pharmacologic Treatment

Control of Hypertension In Pregnancy Study (CHIPS) International, multicentre (94 sites) RCT Women with chronic and gestational HTN Randomized to target diastolic BP of 85 vs. 100 mmHg Evaluating maternal and perinatal outcome Enrolled 1030 women Primary outcome: pregnancy loss or high level neonatal

care for >48 h in the first 28d of life Secondary outcome: one/more serious maternal comps

results not yet published, abstract only

Arch Dis Child Fetal Neonatal Ed. 2014 Jun;99(Suppl 1):A5-A6. doi: 10.1136/archdischild-2014-306576.15.

CHIPS – preliminary results

75% had pre-existing hypertension, 25% gHTN

Women in 'less tight' (n=497) [vs. 'tight' (n = 490)] control had: higher mean dBP by 4.5 mmHg (95% CI 3.6, 5.4) similar rates of the primary (perinatal) outcome [31.4% vs. 30.7%; aOR

1.03] similar rates of secondary (maternal) outcome [3.7% vs. 2.0%; aOR

1.74]. Women receiving 'less tight' control more frequently developed BP

≥160/110mmHg (40.4% vs. 27.5%; aOR 1.78)

'Tight' control is safer for the mother, with no adverse effects for the baby

Investigators: “A target dBP of 85mmHg should be aimed for”

We should await the full published details before changing Rx

Arch Dis Child Fetal Neonatal Ed. 2014 Jun;99(Suppl 1):A5-A6. doi: 10.1136/archdischild-2014-306576.15.

Treatment of non-severe HTN (SOGC)

For women without co-morbid conditions: drug therapy should be used to keep sBP at

130-155mmHg and dBP at 80-105mmHg

For women with co-morbid conditions: goal sBP < 140 mmHg and dBP at < 90 mmHg

Initial therapy can be with one of a variety of antihypertensive agents: Methyldopa Labetalol Calcium channel blockers (nifedipine) Other beta-blockers (acebutolol, metoprolol,

pindolol, and propranolol)

Classification – our patient1. Preexisting Hypertension

with Co-morbid Conditions with Pre-eclampsia

Resistant hypertension, or New or worsening proteinuria, or One or more ‘adverse conditions’ or “severe

complications”

Case # 1- continued

In hospital x 6 days, antenatal steroids given

BP initially controlled to < 160/100 with addition of Nifedipine XL (30mg BID)

Seen Saturday morningBP = variable up to 180/115Chest tightness and SOB onset overnightOrthopneaSats 92% on room air JVP 3-4 cms, HR 130 with gallop, crackles

CXR: ? Early interstitial changesReport: “low lung volumes, patchy opacities in lingula

and LLL, likely related to atelectasis, pneumonia cannot be r/o”

CT: No PE, interstitial/alveolar edema!

Fetus doing OK

BPs up to 180/115 !!!

Case # 1- continued

Treatment of Severe Hypertension (SBP >160 mmHg or DBP ≥110mmHg)

Severe hypertension should always be treated to prevent acute end-organ damage BP should be promptly lowered to < 160

mmHg systolic and < 110 mmHg diastolic Initial therapy should be with:

• Labetalol IV• Hydralazine IV• Nifedipine PO (capsules or PA tablets)

Meds for Acute BP LoweringAgent Dosage

Labetalol Start with 20mg iv; repeat 20-80mg iv q 30min, or 1-2 mg/min, max 300mg (then switch to oral)

Nifedipine 5-10mg capsule to be bitten and swallowed, or just swallowed, every 30min10mg PA tablet every 45min to a maximum of 80 mg/d

Hydralazine Start with 5mg iv; repeat 5-10mg iv every 30min, or 0.5-10mg/hr iv, to a maximum of 20mg/hr iv (or 30mg IM)

BP lowered to < 160/100 with IV labetalol

Pulmonary edema = Severe Complication Decision to move to delivery!

Poor fetal tolerance of labour inductionC/S performed

Neonatal respiratory distress – in NICU x weeks

Mother and baby doing well in follow-up

Case # 1- continued

• 37 y.o. African-Canadian woman, G2P2 • Uneventful pregnancy, no HTN or GDM, BPs ~ 110/70• Induced vaginal delivery at 41 wks with epidural, sent

home on PP day #2• Progressive headache over 7 days postpartum • Taken to ER

• Initial BP = 155/107• Evaluated by MD, no labs• Given morphine, BP settled to 145/95• Told she had a ‘migraine’ • Sent home with NSAIDs

Case #2

• Returned to ER the next day, worse h/a, c/o visual deficits • Initial BP=170/115, • given morphine & IV labetalol x 3• Labs: ALT 176, LD 398, 24hr U protein 1.62 g/day• Exam revealed L homonymous hemianopsia• CT head – small R occipito-parietal ICH

• Admitted to Stroke service • BP controlled with nifedipine XL 60 OD• Remained on antihypertensives for 9 weeks• Aggressive rehab for vision and balance• At 9 weeks postpartum, mild visual defect remaining

but otherwise normal (proteinuria resolved)

Case #2- continued

Etiology of Postpartum HTN

BMJ 2013;346:f894 doi: 10.1136/bmj.f894

Up to 2/3 of women with postpartum preeclampsia had no HTN during pregnancy

Postpartum Preeclampsia - Symptoms

Symptom PrevalenceHeadache 62-82

Visual Changes 19-31

Shortness of Breath/Chest Pain

13-30

Nausea 12.5-18

Vomiting 11.2-14

Abdominal Pain 7-14

Edema 9-10.5

Neurological Deficits 5.3

Al-Safi et al. Obstet Gynecol 2011;118:1102-7.

Postpartum Preeclampsia - Labs• Hemoconcentration (elevated Hg & Hct)• Mild thrombocytopenia (plt 100-150 109/L)• HELLP: hemolysis, transaminitis, thrombocytopenia• Uric Acid >300 μmol/L• Creatinine >70 μmol/L• AST/ALT elevated• LDH >235 U/L• In & out cath for random urine Protein:Creatinine ratio

(≥30 mg/mmol)

Persistent Hypertension PostpartumSystolic ≥155 mmHg & 1 of

HeadacheVisual changesSOB/CPNausea/VomitingAbdo painEdemaNeuro deficits

Fast track to MD Assessment

• detailed History & Physical• Labs: CBC, lytes, Cr, ALT, urate, LD, random U PCr• ECG, CXR

Treat to sBP <155 mmHg• labetalol iv/PO or nifedipine fast then XL

(Symptoms/HTN within 4 weeks of delivery)

ERProtocol

PP Preeclampsia &:Neurological Deficits

MgSO4 infusionCT/CT-A BrainMRI Brain

Neuro/Stroke/ICUOB/MDP

If eclampsia/on Mag:ICU/OB to admit

If stroke:Neuro to admit

If imaging N, no Mag:MTU to admit

PP Preeclampsia &:Pulm Edema/CP

TroponinsEcho

Cardio/MTUOB/MDP

Cardio/MTUto admit

Avoid fluidsDiuretic trialACE-I

PP Preeclampsia &:HELLP

Full liver panelIncluding AST,Bili, BG q1h,DIC w/u

OB/MTU/MDP

OB/MTU toadmit

OB to decideIf MgSO4*SupportiveCare*

If worsening:-TTP/HUS-SLE-APAS-AFLP

PP Preeclampsia &:Hypertension

w/u for 2nd

Cause HTN

MTU/MDP

MTU to admit(≥24 hrs)

Postpartum Preeclampsia

Be alert to this possible diagnosis, even if BP elevation not very ‘severe’ initially

Most important to recognize and treat HTNGoal < 155/105 acutely, then < 140/90

Admit for observation for 24-48h and anticipate further worsening over first 7 days PP

Avoid exacerbating with IVF and/or NSAIDs

Does her HDP have future health

implications for this woman?

Evidence is accumulating that women who develop hypertensive disorders of pregnancy are at subsequent increased lifetime risk of vascular complications

Bellamy et al. BMJ 2007;335:974-86.

McDonald et al. AHJ 2008;156:918-30.

Two recent meta-analyses

Preeclampsia and Hypertension:

Bellamy et al. BMJ 2007;335:974-86.

RR = 3.7

Preeclampsia and Ischemic Heart Disease:

McDonald et al. AHJ 2008;156:918-30.

RRs = 2.33

Preeclampsia and Stroke

McDonald et al. AHJ 2008;156:918-30.

RRs ≈ 2.0

It is clear from a review of multiple recent studies that …

Women with a history of preeclampsia have an increased risk for the later development of (RR):

• HTN: 3.7• IHD: 2.3• Stroke: 2.0• PVD: 1.9• DVT: 1.2• CV Death: 2.3• Death: 1.5

Risk of Future CVD is Proportional to Timing/Severity of Preeclampsia

McDonald et al. AHJ 2008;156:918-30.

Chicken vs Egg

Is the preeclampsia a CAUSE OF increased systemic vascular risk,

or

is the preeclampsia a RESULT OF an underlying systemic vasculopathy

(unmeasured ?)

CHAMPS study: Link with Metabolic Syndrome

• CHAMPS identified higher risk of future

CVD in women with a MATERNAL

PLACENTAL SYNDROME who develop

elements of metabolic syndrome

(obesity, HTN, DM, dyslipidemia)

• 1-2 features: AHR = 4.5

• 3-4 features: AHR = 11.7

Ray et al. Lancet 2005;366:1797-803.

History of preeclampsia/MPS adds to CV Risk of traditional CV RiskFactors

CV Risk with MPS and features of Metabolic Syndrome

Some women who experience a HDP also have (or develop) features of the METABOLIC SYNDROME (obesity, hypertension, diabetes, dyslipidemia)

Women with these features are at MUCH HIGHER risk of vascular complications

How does this all tie together?

Microvascular dysfunction, metabolic disturbance, endothelial dysfunction and inflammation

play a role in the pathogenesis of preeclampsia similar to the pathogenesis of atherosclerosis

Preeclampsia and subsequent cardiovascular disease may both be manifestations of the metabolic syndrome

Women who have a predisposition for the metabolic syndrome are more likely to:

• develop preeclampsia during pregnancy• subsequently develop clinically evident hypertension,

obesity, atherosclerosis and type 2 diabetes• eventually develop CV disease

Powe et al. Circulation 2011;123:2856-2869.

Pregnancy is a metabolic stress test

Can preeclampsia cause an increased risk of vascular complications?

MAYBE Shared risk factors, but:• Risk of complications is higher in women following preeclampsia than in women simply sharing the same metabolic risk factors• It appears that changes in vascular endothelial function can “outlive” the preeclamptic event

This is an important point for preconception counseling regarding subsequent pregnancies

Population at Risk

Women who have experienced an (early/severe) preeclamptic pregnancy are an at risk population who may benefit from primary prevention regarding modifiable CV risk factors

Primary Prevention Strategies To Consider Following Preeclampsia

• Weight control/exercise programs• Return to pre-pregnancy weight / BMI<25

• Hypertension screening/monitoring and treatment

• Smoking cessation• Diabetes screening• Lipid monitoring +/-

treatment

Conclusions

Hypertensive disorders of pregnancy are common, and remain an important cause of maternal morbidity and mortality

Limited options for preeclampsia prevention in high-risk women ASA and Calcium (+/- Vit D) in high-risk women

ProteinuriaDipstick = screen (≥ 1+)Diagnosis:

Urine protein: Cr ratio (≥ 30 mg/mmol Cr) 24-hour collection (≥ 0.3 g/24h)

Conclusions

HTN in Pregnancy is SBP >= 140 and/or DBP >= 90 mmHg but treatment target is wide (130-155/80-105) Results from CHIPS may change practice/targets

Preeclampsia may present/worsen within the first week postpartum Recognition and prompt BP lowering is critical

Women with a history of preeclampsia have increased risk for vascular disease and chronic renal disease later in life Opportunity for counseling, screening and possibly

enhanced primary prevention of CVD

THANK YOUfor your time and

attention!

THANK YOUfor your time and

attention!

Questions during the Panel Discussion