Hypertensive disorders in pregnancy

Pre-gestational hypertension, pregnancy induced hypertension and pre-eclampsia

Dr Christos Argyropoulos MD, PhDAssistant Professor

Division of Nephrology

Outline

• Classification of hypertensive disorders of pregnancy

• Physiology and pathophysiology• Blood pressure et al• Specific hypertensive disorders of

pregnancy• Antihypertensive pharmacotherapy

Why care about hypertension (HTN) in pregnancy?

• HTN is common (10% of 1st pregnancies, 8% of all pregnancies)– 18% of maternal mortality in the US

• Development of pre-eclampsia(PE):– Increased maternofetal mortality– Preterm delivery, IUGR/LBW– Increased HTN when these babies become adults

• Pre-existing hypertension:– Increased PE, IUGR/PE, fetal mortality

DEFINITIONS AND CLASSIFICATION

Classification of hypertensive disorders of pregnancy

1. Vesna D. Garovic Hypertension. 2012;59:555-557 2. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000 Jul. 183(1):S1-S22

<20GW with trophoblastic disease

Updated Classification of Hypertensive disorders of pregnancy

1. Preeclampsia (PE)-eclampsia (BP elevation after 20 weeks of gestation with proteinuria or any of the severe features of preeclampsia)

2. Chronic hypertension (CHTN, of any cause that predates pregnancy)

3. Chronic hypertension with superimposed preeclampsia (chronic hypertension in association with preeclampsia)

4. Gestational hypertension (GH: BP elevation >20 weeks of gestation in the absence of proteinuria or any of the severe features of preeclampsia)

Obstetrics & Gynecology, Vol. 122, No. 5, November 2013

The New vs the Old classifications• Pre-eclampsia does not require the presence

of proteinuria for Dx• Pre-eclampsia may be diagnosed if HTN +

– Thrombocytopenia (PLTs<100k)– Liver injury (ALT/AST > x2 UNL)– Renal dysfunction (SCr>1.1 or x2 from baseline*)– Pulmonary edema– New onset cerebral or visual disturbances


*in the absence of other renal disease

CARDIOVASCULAR PHYSIOLOGY, BP TRAJECTORIES AND PATHOPHYSIOLOGY

Hemodynamic changes during pregnancy

Kidney International (1998) 54, 2056–2063

Circ

ulat

ory

Par

amet

ers Renal Hem

odynamics

Renohumoral changes during pregnancy

Hypertension. 2012 Jun;59(6):1241-8.

http://www.ncbi.nlm.nih.gov/pubmed/22526257

Uteroplacental & maternal hemodynamics in hypertensive disorders of pregnancy

Kaplan: Clinical Hypertension, 2010, p414

Trajectories of office blood pressure during pregnancy

Systolic blood pressure Diastolic blood pressure



8wk BP and the ΔSBP/ Δt may identify patients with distinct clinical profiles



8wk BP and the ΔDBP/ Δt may identify patients with distinct clinical profiles


Rate of rise of DBP may be even more discriminating


Pathogenesis of pre-eclampsia: a renal perspective

Kidney International (2005) 67, 2101–2113

Glomerular endotheliosis

Theories about pathogenesis are too numerous to count

• Placentation • Immune theory• Placental debris hypothesis

syncytiotrophoblast (SCT) shedding• Theories are not mutually exclusive and are

likely complimentary (see renal perspective)

Pathogenesis of pre-eclampsia: theories too numerous to count or different converging pathways based on placenta derived biomarkers?

Anne Cathrine Staff et al. Hypertension. 2013;61:932-942

Copyright © American Heart Association, Inc. All rights reserved.

Schematic representation of the proposed initiating events and factors in the pathophysiology of preeclampsia.

Junie P. Warrington et al. Hypertension. 2013;62:666-673

Copyright © American Heart Association, Inc. All rights reserved.

MEASURING BLOOD PRESSURE ET ALThe devil is in the details

How to measure blood pressure• Patient sit quietly with the back supported, the arm bared

(supported at heart level) and an empty bladder• No caffeine or smoking 30 mins prior• Bladder cuff >80% arm circumference and cover 2/3 of the

arm length• Take 2 readings and average; if readings > 5 mmHg keep

taking until 2 are close (and then average)• For diagnosis take 3 sets of measurement over 1 week• Obtain BP in both arms; use the arm with the highest blood

pressure• If arm pressure is elevated r/o coarctation by measuring BP

in one leg

Dipstick − Semi-quantitative, screening only

Affected by urine concentration, highly variable− Detection of urine albumin > 300 mg/day

(1+ approximates albumin excretion of 30 mg/day) Urine protein/creatinine ratio

‒ All proteins, not just albumin (myeloma/CIN) Urine albumin-to-creatinine ratio (UACR)

‒ Quantifies urine albumin− Steps toward standardization currently in progress− Standard for public health, clinical care, and research

24hr collection (or other timed)− gold standard/cumbersome

Use which urine test?

Urinary ACR is NOT perfect

eGFR is not the measured GFR.

The formula to estimate GFR was derived from a population-based study.

eGFR is based on serum creatinine levels.

Previous methods to estimate kidney function also are based on serum creatinine.

Creatinine assays are now standardized.

− Isotope Dilution Mass Spectrometry (IDMS)

Evaluation of renal function: eGFR

Normal: ≥ 60 mL/min/1.73 m2

Kidney disease: 15–59 mL/min/1.73 m2

Kidney failure: < 15 mL/min/1.73 m2

How to explain eGFR results to non-pregnant patients

Stable eGFR levels may mean non-progressive

disease or current therapy is working.

A rapid decline in eGFR may indicate rapid

progression of kidney disease.

A decline within the “>60” range may not

always be benign (even if the eGFR is

technically “normal”) – use CKDEpi formula

Monitor the eGFR trends: non-pregnant

eGFR is not accurate in pregnancy

BJOG: An International Journal of Obstetrics & GynaecologyVolume 115, Issue 1, pages 109-112, 26 OCT 2007 DOI: 10.1111/j.1471-0528.2007.01529.xhttp://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2007.01529.x/full#f1

MDRD substantially underestimates glomerular filtration rate during pregnancy and cannot be recommended for use in clinical practice.

Normal Pregnancy Non-pregnant women

Pre-eclampsia Pregnancy in CKD

http://onlinelibrary.wiley.com/doi/10.1111/bjo.2008.115.issue-1/issuetoc

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-0528.2007.01529.x/full#f1

More name and shame about renal function estimates in human pregnancy

Reprod Sci. 2011 May;18(5):456-62



Table 2. Adjusted coefficients with standard errors (SE) from multiple linear regression analysis of the association between infant birth weight and maternal glomerular filtration rate (GFR) in second-trimester

estimated by Cockroft-Gault (CG), modification of diet in renal disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas, based on data from 470 women with preeclampsia, 483 women

without preeclampsia and the total cohort of 953 pregnant women from the Norwegian Mother and Child Cohort, Norway 2003–2007.

Morken NH, Travlos GS, Wilson RE, Eggesbø M, Longnecker MP (2014) Maternal Glomerular Filtration Rate in Pregnancy and Fetal Size. PLoS ONE 9(7): e101897. doi:10.1371/journal.pone.0101897http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0101897

eGFR and fetal outcomes: it is in the eyes of the formula beholder

http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0101897

Estimating renal function in pregnancy

• Disregard static measures of renal function that are reported by the lab (MDRD eGFR)

• Even creatinine clearance is problematic• Changes in eGFR may be interpretable: they

amplify changes in serum creatinine and thus alert (rather than prove the existence of) changes in renal function

• More important to consider changes within the same patient in creatinine (or eGFR)

Resident research project

Definition of AlbuminuriaMethod Normal Micro-

albuminuriaOvert/Macro-albuminuria

24 hour excretion <30 mg/day 30-300 mg/day >300 mg/day

Timed urine specimen <20 g/min 20-200 g/min >200 g/min

Spot-urine albumin specific dipstick

(screening)<3 mg/dl >3 mg/dl N/A

Spot urine albumin/ creatinine ratio (ADA) < 30 mg/g 30-300 mg/g >300 mg/g

Spot urine albumin/ creatinine ratio (gender

specific) (K/DOQI)

<17 mg/g (men)<25 mg/g (women)

17-250 (men)25-355 (women)

>250 (men)>355 (women)

K/DOQI and ADA

Explaining urine albumin

PRE-ECLAMPSIA/ECLAMPSIA

SPECIFIC HYPERTENSIVE DISORDERS OF PREGNANCY

Diagnostic criteria for pre-eclampsia


ProteinuriaClinical Sample Cutoff

24 hour collection > 300mgTimed collection Extrapolated* > 300mg

Spot Protein/Creatinine > 0.3 (both in mg/dl)

Spot Dipstick > 1+Not recommended unless

other approaches not available

*24/duration of collection in hrs x protein


Massive proteinuria (>5g) and fetal growth restriction were eliminated from the diagnostic criteria of severe pre-eclampsia

Risk factors for Pre-eclampsiaClinical factor Risk Ratio

Renal Disease 20:1

Chronic hypertension 10:1

Antiphospholipid syndrome 10:1

Previous pre-eclampsia 7:1

Family history 5:1

Twin gestation 4:1

Nulliparity 3:1

Age >40 3:1

Diabetes 2:1

African American 1.5:1

Management

• Goal: delivery to balance maternal and fetal risks

• Maintain the safety of the mother• Expectant v.s. immediate delivery:

– Disease severity – Fetal maturity – Maternal condition – Fetal condition – Cervical status

Pre-eclampsia without severe features

• >37 weeks gestation: deliver• <37 weeks gestation: expectant management

until term or maternal/fetal indication for delivery– Bedrest no longer “suggested” – Serial maternal assessment (BP, symptoms, labs,

weight gain) – Serial fetal assessment (NST/BPP, fetal kick count,

serial US for AFI and growth)– Oral antihypertensives

Severe Pre-eclampsia

• >34 weeks: deliver • 33-34 weeks: steroids and deliver after 48

hours if maternal/fetal status allows • 22-32 weeks: antihypertensive meds(oral/IV),

steroids, extensive counseling, close surveillance deliver for maternal/fetal indications or 34 weeks gestation

• <22 wk: expectant mgmt not recommended

Start MgSO4 upon diagnosis

Other issues

Prevention of pre-eclampsia• Smoking cessation• Do’s:

– Low dose ASA before 16GW (high risk populations)

– Moderate exercise• Don’t’s:

– Calcium supplement– Anti-oxidants– Low salt diet– Bed rest

Long term sequeale• Mothers have a higher risk:

– Diabetes– Hypertension– Kidney Disease– Obesity– Cardiovascular disease– Future pre-eclampsia

GESTATIONAL (PREGNANCY INDUCED) HYPERTENSION


Gestational hypertension (PIH) is a transient diagnosis

1. Vesna D. Garovic Hypertension. 2012;59:555-557 2. National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000 Jul. 183(1):S1-S22

Common:− 6-17% of nulliparous − 2-4% of multiparous

25% progress to preeclampsia (in 1-5wks) 22% risk of recurrence in subsequent pregnancies Higher risk for CKD, metabolic syndrome, elevated

BP than wome who remained normotensive in pregnancy

Need two abnormal readings at least 4hr apart Severe PIH: SBP/DBP > 160/110 Severe gestational HTN a/w higher maternal

and perinatal mortality than mild preeclampsia (and similar to PE)

Gestational hypertension

Diagnostic evaluation of GH• Goals:

– Distinguish GH from PE– Determine severity– Exclude benign forms of hypertension (white coat

hypertension)• Approach:

– Exclude proteinuria (do not use the dipstick!)– “Pre-eclampsia” labs– Clinical features of severe pre-eclamptic disease– Assess fetal well being

Risk of progression to pre-eclampsiaFeature Sensitivity Specificity

Gestational age at diagnosis <34w

85% 60%

ABPM avg SBP > 135 61% 76%

Abnormal uterine artery Doppler velocimetry

86% 90%

Uric acid > 5.2 mg/dl 88% 93%

Other factors:•Greater blunting of night-time dipping in PE• ↑anti-angiogenic markers (sFLT-1)• ↓ proangiogenic placental growth factor• ↑ total vascular resistance >1340 dyne/sec/cm5

90% sensitivity91% specificityRequires echo

The humble uric acid level appears to offer the best combo of sensitivity, specificity, cost and availability

Management of GHSBP < 160/110

• Managed as outpatients• Twice weekly BP monitoring• Weekly assessments of proteinuria,

PLTs, LFTs• ASA? after 20wk• Activity:

– Individualize decision to put patient at bed rest

– Advise against strength training/isometric exercises

– In the absence of data re: BP response to aerobic exercise, avoid such exercise

• No BP meds unless end organ damage• Delivery: at term

SBP>160/110 (severe)• Treat with antihypertensives

(<160/110 vs <140/90 with end organ damage)

• Deliver ≥ 34 wk• MgSO4 for peripartum

seizure prophylaxis• Offer ASA in subsequent

pregnancies to reduce risk of pre-eclampsia

CHRONIC HYPERTENSION WITH OR W/O SUPERIMPOSED PRE-ECLAMPSIA


CHRONIC HYPERTENSION• Affects ~3% of pregnant women• Adverse Outcomes

– Pre-eclampsia will develop in 13-40%– ↑ C-section (OR 2.7)– ↑ postpartum hemorrhage (OR 2.2)– ↑ gestational diabetes (OR 1.8) ? Common risk factors– Triples the risk of perinatal mortality over general population– Doubles the risk of placental abruption– If baseline proteinuria, increased risk

• Preterm delivery• SGA infants

Diagnostic criteria for Chronic Hypertension

• Hypertension:– Before pregnancy– Before 20 GW– Persisting > 12 wk post-partum

• Severity:– Mild: BP > 140/90– Severe: BP > 160/110

When to suspect secondary causes of hypertension?

• Resistant hypertension (various definitions: 3-4 drugs, at least one diuretic)

• Hypokalemia – Off treatment with diuretics– Suggests a hyper(aldo/renin) state– Renal disease

• Family history of renal dz (genetic s., RAS)• Board exam patient histories: thyroid dz, pheo,

Cushing, aortic coarctation, hypokalemiaObstetrics & Gynecology, Vol. 122, No. 5, November 2013

Risk Factors in Chronic HTN– Maternal age >40 years old– HTN for >15 years– BP > 160/110 mmHg early in gestation– Diabetes– Renal disease– Cardiomyopathy– Connective tissue disease– Presence of lupus anticoagulant– Previous pregnancy with perinatal loss– Secondary causes of HTN (pheo/renovascular)

Preconception counseling

• Risks associated with CHTN• Education about the signs and symptoms of pre-

eclampsia• Meds adjustment:

Stop angiotensin enzyme inhibitors (the “prils”),angotensin receptor blockers (the “sartans”) and mineralocorticoid blockers BEFORE CONCEPTION

Statins (due to conflicting evidence about fetal effects)

Antepartum management• Assess early or before pregnancy

Level of blood pressure & treatment targets

Evaluation for end organ damage: LVH,kidneyRule out secondary causesBaseline labs: creatinine/eGFR,electrolytes, uric acid,

urine proteinEvaluate glucose tolerance

Refer patients with features suggestive of 2o HTN

Monitor BP Q 4 wk(standard OB practice), but consider ↑ frequency during 2nd half of pregnancy

Home BP for women with CHTN and poor BP control

Ambulatory BP for women with suspected white coat hypertension (10-15% of all individuals with office HTN)

A fistful of guideline recommendations: evaluation/management


Lifestyle modifications help lower blood pressure in the general population

References: Chobanian et al. J Am Med Assoc 2003; 289(19):2560–2571; Neter et al. Hypertension 2003; 42(5):878–884; Dietary Guidelines, 2010

Modification Recommendation Lowers Systolic Blood Pressure by (Range)

Weight reduction •Maintain normal body weight•Body mass index (BMI) 18.5–24.9 kg/m2

5–20 mm Hg / 10 kg 4 mm Hg / 5 kg

DASH •Increase potassium (fruits and vegetables) and calcium (dairy)•DASH may be too high in protein, potassium and phosphorus for CKD

8–14 mm Hg

Physical activity •At least 30 minutes most days 4–9 mm Hg

Moderate alcohol consumption

•Women: ≤ 1 drink per day •Men: ≤ 2 drinks per day

2–4 mm Hg

Sodium restriction •2,300 mg per day•1,500 mg per day for hypertension, diabetes, and CKD

2–8 mm Hg

Modification Recommendation Lowers Systolic Blood Pressure by (Range)

Weight reduction •Maintain normal body weight•Body mass index (BMI) 18.5–24.9 kg/m2

5–20 mm Hg / 10 kg 4 mm Hg / 5 kg

DASH •Increase potassium (fruits and vegetables) and calcium (dairy)•DASH may be too high in protein, potassium and phosphorus for CKD

8–14 mm Hg

Physical activity •At least 30 minutes most days 4–9 mm Hg

Moderate alcohol consumption

•Women: ≤ 1 drink per day •Men: ≤ 2 drinks per day

2–4 mm Hg

Sodium restriction •2,300 mg per day•1,500 mg per day for hypertension, diabetes, and CKD

2–8 mm Hg

Have not beenstudied in pregnancy !!

Weight loss and low Na (<100 meq/d, ~2.3 gm) should not be used

Observational research/small RCTs suggest that exercise may be helpful in preventing pre-eclampsia

In women with CHTN who are accustomed to exercise and in whom BP is well controlled, moderate exercise may continue throughout the pregnancy

A fistful of guideline recommendations: management


Level of RCT evidence: “Because I say so”

− Very few patients with CHTN in trials/meta-analyses Extrapolations from gestational hypertension, pre-

eclampsia, or the general hypertensive population: Treatment of “mild” hypertension (SBP:140-160 DBP: 90-

110):

− Reduction in the rate of HTN

− No effect on pre-eclampsia

− Meta-regression analyses & registries : increased SGA

Treatment targets in CHTN

Cochrane Database Syst Rev. 2007 Jan 24;(1):CD002252Cochrane Database Syst Rev. 2013 Jul 31;7:CD001449. Obstetrics & Gynecology, Vol. 122, No. 5, November 2013





Treat for SBP>160 and DBP>105 Don’t treat for SBP<160, DBP<105 unless end

organ damage Treatment targets (on meds):

−SBP: 120-160−DBP: 80-105

Treatment targets (end organ/kidney damage):−SBP<140−DBP<90

A fistful of guideline recommendations: treatment


Materno-fetal medicine implications of CHTN

• Use U/S (fundal weight/fetal height) to screen for IUGR (suggestion)

• If IUGR, use umbilical artery Doppler velocimetry (recommendation)

• If med-req CHTN/IUGR/pre-eclampsia antenatal fetal testing (NST-BPP) is suggested

• Delivery is not recommended before 38 0/7 if no additional maternal or fetal complications


Superimposed PE and CHTN

• Suspect superimposed pre-eclampsia when:– Sudden increase in BP, or need to escalate Rx– New onset of proteinuria or worsening of proteinuria– Symptoms of non-proteinuric pre-eclampsia

• Evaluate in a hospital environment to:– Confirm diagnosis, evaluate maternal-fetal status and

monitor for disease progression– Obtain pre-eclampsia/HELLP labs (including uric acid

level)


Management of blood pressure in CHTN with superimposed PE

• Lack of clinical trials• Extrapolation from CHTN/pre-eclampsia literature• Same targets/thresholds as isolated CHTN• Same meds as isolated CHTN• Women at risk for premature delivery: fetal lung maturity• MgSO4 is good for seizure prophylaxis but not a good

anti-hypertensive medication in CHTN+PE• Delivery decisions: GW (>37 v.s. <37, PE manifestations,

lung maturity: 34 GW (severe pre-eclampsia), 37 GW without severe features)


Management of CHTN in the postpartum period

• Blood pressure will gradually decline (first 2 weeks may be higher than > 2wk)

• BP targets: <160/90• AVOID NSAIDS!!!• Considerations for breast feeding:

– Methyldopa is safe (low conc)– Atenolol/metoprolol (high conc)– Propranolol/labetalol (low conc)– Low dose ACEi (low conc)– Calcium channel blockers (generally safe)


PRINCIPLES OF ANTIHYPERTENSIVE PHARMACOTHERAPY IN PREGNANCY

Antihypertensives for urgent (inpatient) blood pressure control

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Inadequate evidence to choose among hydralazine, labetalol or calcium blockers

Theoretical concern for neuromuscular blockade when using MgSO4+nifedipine

Nimodipine or MgSO4: higher incidence of persistent HTN




Antihypertensive regimens for urgent hypertension in pregnancy

Drugs. 2014 Mar;74(3):283-96. doi: 10.1007/s40265-014-0187-7.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558097/figure/F1/

Antihypertensives for outpatient blood pressure control

Cochrane Database Syst Rev. 2013 Jul 31;7:CD001449. Obstetrics & Gynecology, Vol. 122, No. 5, November 2013

For women of reproductive age, ACEi/ARB/DRIs/aldo-antagonists not recommended unless compelling reason: proteinuric renal dz

In CHTN who are at risk for pre-eclampsia, initiation of low dose ASA 60-80 mg, will ↓ risk by ~25%




Diuretics in pregnancy

Practice implications• Concerns that diuretics will

adversely effect IUGR due to reductions in plasma volume

• Plasma volume may be reduced but IUGR risk is theoretical

• Women on diuretics before pregnancy may be continued on them

• May have to adjust the dose to reduce the risk of hypoK

• Particularly useful in women with Na-sensitive HTN

Meta-analysesOutcome OR 95% CI

Pre-eclampsia 0.68 0.45-1.03

Perinatal death 0.72 0.40-1.27

Pre-term death 0.67 0.32-1.41

BW 139 gm -484.20 to 762.40

Nauseavomiting

5.81 1.04-32.46

Discontinuation 1.85 0.81-4.22

C-section 1.00 0.26 – 3.81

Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004451Drugs. 2014 Mar;74(3):283-96. doi: 10.1007/s40265-014-0187-7.

Management Options for CHTN

Drugs. 2014 Mar;74(3):283-96. doi: 10.1007/s40265-014-0187-7.

Hypertensive disorders in pregnancy

Health & Medicine

Transcript of Hypertensive disorders in pregnancy