Hypertensive disorders in pregnancy
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Transcript of 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
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
*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.
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
Hypertension. 2012 Jun;59(6):1241-8.
8wk BP and the ΔSBP/ Δt may identify patients with distinct clinical profiles
Hypertension. 2012 Jun;59(6):1241-8.
8wk BP and the ΔDBP/ Δt may identify patients with distinct clinical profiles
Hypertension. 2012 Jun;59(6):1241-8.
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
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
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
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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
SPECIFIC HYPERTENSIVE DISORDERS OF PREGNANCY
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
SPECIFIC HYPERTENSIVE DISORDERS OF PREGNANCY
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
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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)
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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)
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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)
Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
PRINCIPLES OF ANTIHYPERTENSIVE PHARMACOTHERAPY IN PREGNANCY
Antihypertensives for urgent (inpatient) blood pressure control
Cochrane Database Syst Rev. 2013 Jul 31;7:CD001449. Obstetrics & Gynecology, Vol. 122, No. 5, November 2013
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.
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.
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