Management of Hypertensive disorders

in pregnancy- recent advances

Sowmiya.J, July 2018

Overview
1. Hypertension categories-diff bodies
2. Basic principles of management
3. Pharmacological therapy
4. Specific management
5. Role of MgSO4
6. Role of Corticosteroids
7. New modalities-Apheresis/Pravastatin
 ACOG,2019

Definition:
i. HTN: SBP≥140mmHg and/or DBP ≥90mHg , 4hrs apart
ii. SEVERE:SBP ≥160mmHg and/or DBP ≥110mmHg,4hrs apart

Categories:
a. Chronic hypertension
b. Pre-eclampsia-Eclampsia
c. Chr.HTN with superimposed PE
d. Gestational hypertension
 ISSHP,2018

Definition:
i. HTN: SBP≥140mmHg and/or DBP ≥90mHg , confirmed over a few hrs
ii. SEVERE: SBP ≥160mmHg and/or DBP ≥110mmHg, confirmed within
15mins
Categories:
a. Chr.HTN: essential/secondary
b. White coat HTN
c. Masked HTN
d. GHTN
e. Transient GHTN
f. Pre-eclampsia-de novo/superimposed on chr.HTN
 Hypertension Canada,2018

i. HTN: SBP≥140mmHg and/or DBP ≥90mHg

ii. SEVERE: SBP ≥160mmHg and/or DBP ≥110mmHg

Categories:
a. Chr.HTN

b. GHTN

c. Pre-eclampsia(non severe,severe, HELLP syndrome, Eclampsia)

 NICE guidelines,2019
What’s new?
• Initiation of anti-hypertensive- BP-140/90mmHg
• Target BP on treatment- 135/85mmHg
• Categories of HTN- hypertension and severe HTN
• 24hr urine collection no longer recommeneded for
quantification of proteinuria
• Not all women with PE needs hospital admission
 Basic principles of management
• Definitive treatment is delivery
• Lung maturity and satisfactory gestational age
• Cornerstone of management:
i. Controlling BP
ii. Assessing severity
iii. Monitoring maternal/fetal condition
iv. Preventing onset of eclampsia
Baseline investigations:
• Blood grouping/CBC/ RFT/LFT/Urine analysis/S.LDH
• Dipstick screening with automated reagent strip
reading device
• If dipstick screening 1+ or more- do U.PCR or U.ACR
• Urine PCR or urine ACR-equal specificity and sensitivity
• Not to use first morning urine void to quantify
proteinuria
• U.PCR-30mg/mmol-significant proteinuria

• U.PCR≥30mg/mmol with clinical uncertainity retesting

• U.ACR- 8mg/mmol diagnostic threshold

• U.ACR ≥8mg/mmol with clinical uncertainity retesting

 Non pharmacological methods
Lifestyle changes:
• Body weight(pre pregnancy BMI vs gestational weight
gain)
• Diet
i. Mediterranean style diet
ii. Dietary sodium/potassium
• Physical activity
• Cessation of smoking
 Pharmacological therapy
• Initiation of anti-hypertensive therapy recommended
for a BP of 140/90mmHg

• Target BP for those on treatment- 135/85mmHg

(reduced from 150/100 mmHg)

NICE 2019
 Antihypertensives
1. Sympathetic nervous system inhibitors:

• Centrally acting-Methyldopa, Clonidine

• Peripherally acting- Labetalol

2. CCBs- Nifedipine

3.Direct vasodilators- Hydralazine

• All hypertensive drugs- CATEGORY C except
Methyldopa(Cat.B)
First line agents :
• Labetalol
• Methyldopa
• Long acting Nifedipine
Second line agents:
• Clonidine
• Hydralazine
• Thiazide diuretics
 Methyldopa
• Alpha 2 agonist
• Onset 6-8hrs
• Safety: Cat B
• Preferred for non emergent BP control
• Dose: 0.5-3g PO in 2 divided doses
 Methyldopa contd.
• Prevents subsequent progession to severe HTN in
pregnancy
• No adverse effects on uteroplacental or fetal
hemodynamics
• Safety upto 7yrs of age in offspring
Side effects:
• Sedation, impaired sleep patters
• Elevation of liver enzymes-5% (diagnostic confusion)
• Recommended as first line agent for non severe HTN by
ISSHP,SOMANZ, Canadian guidelines
• Cochrane review, 2018- inferior to CCBs and Beta
blockers in regard to prevention of Sev.HTN

Abalos E, Duley L, Steyn DW, et al. Antihypertensive drug therapy for mild to moderate
hypertension during pregnancy. Cochrane Database Syst Rev 2018; 10: CD002252
 Labetalol
• Combined alpha beta blocker
• Safety: Cat.C
• Oral or IV
• Oral: 100mg to 1200mg/day PO in 2-3 divided doses,
max dose 2400mg/day
• IV: 10-20mg,every 30mins repeat upto 80mg max dose-
300mg/day
Side effects:
• Fatigue and Lethargy
• Exercise intolerance
• Sleep disturbances
• Asthma
Foetal concerns:
• LBW infants
• Neonatal hypoglycemia at high doses
To be avoided in women with
• Pre-existing myocardial disease
• Decompensated cardiac function
• Heart block
• Bradycardia
 Studies on Labetalol

• Prospective observational study

• 75% of women responded to Labetalol as

monotherapy
Stott D, Bolten M, Salman M, et al. A prediction model for the response to oral labetalol for
the treatment of antenatal hypertension. J Hum Hypertens 2017; 31(2): 126–131
• Study comparing ambulatory BP measurements of
women on oral Labetalol vs Nifedipine
• Those on Labetalol spent more time with target
DBP <80mmHg than Nifedipine group  higher
risk of poor uteroplacental perfusion

Shawkat E, Mistry H, Chmiel C, et al. The effect of labetalol and nifedipine MR on

blood pressure in women with chronic hypertension in pregnancy. Pregnancy
Hypertens 2018; 11: 92–98
 Nifedipine
• Long acting
• Calcium channel blocker
• Safety: Cat C
• 30-120mg/day
• Side effects:
i. Tachycardia
ii. Palpitations
iii. Edema
iv. Headaches
v. Facial flushing
• Safer than labetalol in controlling BP to a safely low
diastolic BP 1
• Oral Nife vs Labetalol in Ch.HTN in pregnancy
• Central aortic pressure drop of mean 7.4mmHg in Nifidipine
arm, peripheral BP equal in both arms 2
• Slight increase in NICU and neonatal adverse effects
1. Shawkat E, Mistry H, Chmiel C, et al. The effect of labetalol and nifedipine MR on blood
pressure in women with chronic hypertension in pregnancy. Pregnancy Hypertens 2018; 11:
92–98

2. Webster LM, Myers JE, Nelson-Piercy C, et al. Labetalol versus nifedipine as

antihypertensive treatment for chronic hypertension in pregnancy: a randomized controlled
trial. Hypertension 2017; 70(5): 915–922.
 Nifedipine and MgSO4-interaction
• Both are calcium channel antagonists
• Induce myocardial depression and peripheral
vasodilatation
• Combination results in severe hypotension and
neuromuscular blockade
• Inhibition of progress of labour
• Hypocalcemia
 Nifedipine and MgSO4-interaction
• Concurrent use of nifedipine may unmask hypocalcemia in patients
receiving magnesium sulfate

• MgSO4 –competes with calcium to decrease available calcium for

smooth muscle contractility

• Nifedipine inhibits the influx of calcium ions through the cell membrane
by blocking calcium channels smooth muscle relaxation

Veena P, Raghavan S S. Synergistic effect of nifedipine and magnesium sulfate causing symptomatic
hypocalcemia in a preeclamptic patient. Int J Adv Med Health Res 2016;3:105-6
Initially
GHTN
 Foetal monitoring
• Fetal biometry
• AFI At the first diagnosis of pre-
eclampsia
• Fetal Doppler
• Confirmed PE/FGR+ Serial usg from 24 wks onwards
till birth, twice weekly
• Weekly or more frequently if abn. doppler findings+;
seek expert opinion
 Management principles
Chronic hypertension
• Maintain BP range: 110-140/80-85mmHg
• Anti-hypertensives: Labetalol, methyldopa, nifedipine
1st line drugs)
• Hydralazine-2nd line drug
• Home BP charting-essential adjunct

ACOG,2019
Key risks:
i. Superimposed PE
ii. FGR
iii. Accelerated maternal HTN
Monitor pt for development of PE with
• Urine analysis every week+ clinical assessment+ blood
investigations at 28 and 34 weeks as a minimum
Assess fetal well being with USG from 26wks onwards, 2-4weekly
thereafter
• Deliver at 39wks(ISSHP,2018) / 38-39wks (ACOG2019) weeks if
no compelling maternal/fetal risk factor
 CHIPS trial,2015
• Control of Hypertension in Pregnancy Study
• Compared outcomes of less-tight control (target DBP
100mmHg) and tight control (target DBP<85mmHg)
• 987 women;
i. 75% had pre-existing hypertension
ii. 25% with gestational hypertension
iii. 50% developed Pre-eclampsia
 Results
• Similar primary outcome: pregnancy loss/ high-level neonatal care
• Severe HTN (≥160/110) :
i. 40.6% in the less-tight control group
ii. 27.5% in tight control group (P<0.001)
• “tight” control achieved a lower blood pressure (by 5 mmHg)
• women at high risk of the complications of severe hypertension, seizures, and
intracerebral hemorrhage-benefit in tighter control of blood pressure
Hence the current recommendation of DBP<85mmHg

Magee LA, von Dadelszen P, Rey E, et al.: Less-tight versus tight control of hypertension in pregnancy. N
Engl J Med. 2015; 372(5): 407–17
 White coat HTN
• Regular home BP assessments
• Limited studies
• Withold antihypertensive therapy in this group
• Continuous home BP charting
• Increased surveillance throughout pregnancy
 Gestational HTN (ISSHP,2018)

• Control BP 110-140/85mmHg

• Monitor for development of PE and foetal growth

• Delivery delayed upto 39+6wks,if BP under control,

reassuring fetus, pre eclampsia not developed
 GHTN(ACOG,2019)

Level A recommendation:

GHTN or PE with no severe features:

• Delivery > expectant management at or beyond 37(0-7)

 NO EXPECTANT MANAGEMENT

Maternal factors:
• Uncontrolled severe BP (non • Stroke
responsive to anti-hypertensives) • HELLP syndrome
• Persistent refractory headaches • New/worsening renal dysfunction
• Epigastric pain or right upper • Pulmonary edema
quadrant pain • Eclampsia
• MI • Suspected acute placental
• Visual disturbances, motor abruption or vaginal bleeding in
deficit, altered sensorium the absence of placenta previa
Fetal factors:
• Abnormal fetal testing
• Fetal death
• Fetus without expectation for survival at the time of
maternal diagnosis(lethal anomaly, extreme prematurity)
• Persistent REDF in umbilical artery

Balagon,Siabi et al, counseling, management and outcome in severe PE at

23-8wks, Clin Obstet Gynecol 2017; 60:183-9
 Pre eclampsia
• To assess in hospital when diagnosed first
• If stable, managed on OPD basis

Foetal monitoring :
(biometry/AFI/Doppler): two weekly
Maternal monitoring:
• BP
• Repeated assessments of proteinuria if not already present
• Clinical assessment, including clonus
• Blood tests- twice weekly (Hb, platelts, LFT,creatinine, uric acid)
 Deliver at ≥ 37wks or immediately if any of the foll.present:

• Repeated episodes of severe HTN • Pulmonary edema

despite maintenance treatment • Abn.neurological
features(intractable headache/visual
with three classes of anti-
scotomata/convulsions)
hypertensive agents • Non-reassuring fetal status
• Progressively abn. RFT/LFT • Placental abruption
• Progressive thrombocytopenia • REDF in UA Doppler

Neither S.uric acid nor level of proteinuria used as indicator for delivery
 When to deliver?
Depending on gestational age:
• Onset of pre-eclampsia ≥ 37 wks deliver
• Between 34-37 wks: expectant/conservative
management
i. <34 wks- expectant management in a centre with
maternal and fetal medicine expertise
ii. <24wks/at the limits of viability- counsel for
termination
ISSHP,2018
 HYPITAT-II
• Immediate delivery vs expectant management between 34 and 37
weeks’ gestation in non-severe hypertension including, but not
limited to, pre-eclampsia
• Women diagnosed between 34 and 37 weeks of gestation,
immediate delivery might reduce the small risk of adverse
maternal outcomes, but significant increase in risk of neonatal
RDS
Broekhuijsen K, van Baaren GJ, van Pampus MG, et al.: Immediate delivery versus
expectant monitoring for hypertensive disorders of pregnancy between 34 and 37
weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial. Lancet.
2015; 385(9986): 2492–501
 Severe Pre eclampsia
• >34 weeks: deliver
• 33-34 weeks: Steroids and deliver after 48hrs if maternal/fetal
status allows
• 22-32 weeks: Anti-hypertensives (oral/IV), steroids, extensive
counseling, close surveillance; deliver for maternal/fetal
indications or 34 weeks gestation
• <22weeks: Expectant management not recommended
Start MgSO4 upon diagnosis irrespective of gestational age
 HELLP management
• Close monitoring at a tertiary care centre
• Lab tests 12hourly
• AST>2000 IU/L or S.LDH>3000 IU/L- increased
mortality risk
• Platelet count decreases at an avg rate of 40%/day
• Lowest platelet count-23 hrs after delivery
• Peak disease intensity-first 2 days after delivery
ACOG,2019
 Mississippi classification
Class Platelet count LDH(IU/L) AST,ALT
(cells/microL) (IU/L)

1 ≤50,000 >600 ≥70

2 >50,000 <1 L >600 ≥70

3 >1L <1.5L >600 ≥40

 Indications of transfusion
Red cell transfusion:
• Hb < 7g/dL
• Pres.of hematuria
• Abruption
Platelets transfusion:
• <20,000
• If LSCS planned- pre op platelet count: >40,000-50,000
 LSCS in HELLP syndrome

• Midline skin incision preferred

• Increased risk of sub fascial and wound hematoma:
place a subfascial drain
• Leave skin incision open for the first 48 post op hrs/
close with staples
 Role of steroids in HELLP syndrome

• Meta analysis of 11 trials(550 women) comparing placebo

and corticosteroid in HELLP synd.

 no convincing reduction in maternal death/maternal

morbidity/perinatal/infant death

Favoured increase in platelet count

Woudstra DM, Chandra S, Hofmeyr GJ, Downswell T

Cochrane Database Syst.Rev. 2010;
 Eclampsia
• Most eclamptic seizures- self limited
• MgSO4- not to arrest seizure, but to prevent recurrent
convulsions
• During seizure: fetal bradycardia/increase in uterine contractility
• Post seizure: CTG-recurrent decelerations,tachycardia,reduced
variability
• Maternal hemodynamic stabilization delivery
• Maternal resuscitaion normalization of fetal tracing
ACOG,2019
 Management of eclampsia
Basic supportive measures
• Call for help
• Prevention of maternal injury/maternal hypoxia
• Lateral decubitus position/bedrails
• Prevention of aspiration
• Oxygen(8-10L/min)
• Vitals monitoring
• Treating sev.HTN
• Evaluation for prompt delivery
 Eclampsia
• MgSO4 superior to phenytoin/diazepam/lytic
cocktail, a/w less maternal and neonatal
morbidity
Advantages:
• Low cost, ease of administration, lack of sedation

Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for

eclampsia. Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.:
CD000128. (Systematic Review and Meta-Analysis
 Mechanism of action
Acute cerebral ischemia

Excitotoxic amino acids

MgSO4
blocks
NMDA receptors activate calcium channels NMDA

Calcium influx

Cell injury and release of cytotoxic enzymes

 ISSHP,2018
• For IV infusion:
LD: use 4g(8mL) MgSO4 in 100ml NS
• Administer IVI at 300mL/hr via infusion device(20 mins)
MD: remove 20 mL from 100mL NS infusion bag and
discard
• Add 10g MgSO4(4amps=20mL) to the bag
• Infuse at 10mL/hr(1g/hr)
• Maintain infusion for 24hrs postnatally
 IM Magnesium
LD: 4g IV
5g in each buttock
MD: 5g in alternate buttock every 4hrs for 24hrs
Management of toxicity:
Calcium gluconate 10% 10mL in 100mL NS IVI over 10-20
mins
• In extremely agitated pt, IV clonazepam 1mg/10mg
Diazepam/midazolam: for sedation
• Only if absolutely necessary
• When convulsions recur, futher 2-4g MgSO4 IV over 5mins
• If refractory(seizing at 20mins after bolus/ more than 2
recurrences):
i. sodium amobarbital 250mg IV in 3 minutes
ii. Thiopental/phenytoin 1250mg IV at 50mg/minute
• Endotracheal intubation and assisted ventilation, head imaging
ACOG,2019
Observations and care during MgSO4 infusion:
• Cont.CTG (if ≥26wks,perform 30minutely auscultation)
Maternal observations:
• RR and pulse oximetry every 30mins
• BP 30 minutely
• Maternal pulse hourly
• Urine output hourly
• Reflexes at the completion of the LD and then every 2hrs
Study in Latin America: women who received 8g MgSO4

before delivery had no benefit if continued for 24 hrs

postpartum

• Further studies yet to confirm

Ludmir et al on MgSO4 use in postpartum, Am.J.Obstet Gynecol.2018,216 S3-

4)
 Prophylactic MgSO4
• Low resource settings: all women with PE receive
MgSO4 for convulsion prophylaxis
LD: 4g IV or 10g IM
MD: 5g IM every 4h or 1g/hr IV infusion until delivery
and for atleast 24 hr postpartum

• Other centres: MgSO4 if sev HTN(BP≥160/110) and

proteinuria or premonitory signs of eclampsia
 PIPES trial
• Compared the efficacy and safety of low-dose Dhaka
regime vs Loading dose only regime for seizure
prophylaxis in severe preeclampsia
• Incidence of eclampsia:
low-dose Dhaka regime-1.49%
• Loading dose only regime-2.98%
• LD alternative to Low dose Dhaka
Keepanasseril A, Maurya DK, Manikandan K, Suriya J Y, Habeebullah S, Raghavan SS.
Prophylactic magnesium sulphate in prevention of eclampsia in women with severe
preeclampsia: randomised controlled trial (PIPES trial).
J Obstet Gynaecol. 2018 Apr;38(3):305-309. doi: 10.1080/01443615.2017.1351931. Epub
2017 Oct 3.
 MgSO4 for neuroprotection
Mechanisms:
• Stabilizing cerebral circulation(BP/cerebral blood flow)
• Prevention of excitatory injury by stabilizing neuronal
membranes
• Protection against oxidative injury
• Protection against inflammatory injury
RCTs with MgSO4
RCTs subjects
MagNET 1049 women Tocolytic arm Terminated due to deaths
1995-1997 25-33 weeks Neuroprotective
arm
ACTOMgSO4 1062 women Mgso4-4g f/b 1g/hr CP rate similar but motor
1996-2000 <30 weeks for 24hr or birth dysfunction was less

PREMAG 573 women 4g bolus Mgso4 Motor dysfucnction at

1997-2003 <33 weeks 2yr less.

BEAM 2241 women 6g bolus f/b 2g/hr CP/stillbirth-same

1997-2004 <32 weeks for 12 hr Severe CP cases-less

MAGPIE 10,141 women No difference in mortality

1998-2001 PE, <37 weeks and neurological
outcome

MASP (2015) and MAGENTA (2013) – current RCT

Chollat C, Sentilhes L and Marret S (2018) Fetal Neuroprotection by Magnesium Sulfate: From Translational Research to Clinical Application.
Front. Neurol. 9:247. doi: 10.3389/fneur.2018.00247
 Candidates for treatment
• Women at risk of imminent (within 24hrs) preterm
birth
• Recent PROM
• PTL with membranes intact
• Planned medically or obstetrically indicated PTL
• Contra-indications:
• Myasthenia gravis
• Myocardial compromise
• Gestational age: 24-32 wks
• Dose: 4g LD + 1g/hr MD
• If LSCS is scheduled: 6-12hrs of Maintenance therapy
before surgery
• Duration: till baby deliver or max 24hrs if delivery has not
occurred
• No need for retreatment
Choice of tocolytic: Indomethacin
 Intra partum management

• Oral anti-hypertensive at the onset of labour

• Treat HTN urgently with oral Nifedipine or IV labetalol or
Hydralazine, if BP ≥ 160/110 mmHg
• Total fluid intake limited to 60-80ml/h
• Replace insensible loss(30ml/h) and anticipated urinary loss
(0.5-1ml/kg/h)
• No ‘run-dry’
 Severe hypertension
SBP≥ 160 and/or DBP ≥110mmHg
10mg Nifedipine orally

Monitor BP every 15mins/coninuous CTG

If persists after 45 mins: 2nd dose of oral Nifedipine 10mg

Monitor BP every 15mins till stabilizes

After another 45mins(90mins from 1st dose)

Severe HTN persists IV management
 IV management

Labetalol 20mg IV over 2 mins

Repeat BP in 10mins Onset of action
within 5 mins
40mg IV over 2 mins Peaks at 10-
20mins
Repeat BP in 10mins
80mg IV over 2 mins
Repeat BP in 10mins
Max.cumulative dose 300mg
 Corticosterioids for lung maturity

• Between 23+ to 33+6 weeks

• May be given upto 38 wks if planned for elective LSCS

• Multiple steroid course not recommended

Cochrane Database Syst Rev. 2017;3: CD004454. Epub 2017 Mar 21

 Corticosteroids for lung maturity
• Betamethasone: singleton pregnancy at 34+0 to 36+6
wks with foll.caveats:
• Not administered in chorioamnionitis
• Not to repeat if already received
• Monito newborns for hypoglycemia
• Tocolysis not recommended for a woman with PTL to
allow administration of steroids

Obstet Gynecol.2017; 130(2): e102

NICE guidelines(NG 25)
• Steroids b/w 34+ and 35+6 recommended
Meta analysis 2018 compared efficacy of steroids/placebo
between 37+-39+6wks: reduction in
• TTN (2.3% vs 5.4%)
• RDS(2.6% vs 5.4%)
• NICU admission( 2.3% vs 5.1%)
Sotiradis A et al, Cochrane Database Syst Rev. 2018; 8:CD00661. Epub
2018 Aug 3
 H.E.L.P apheresis
• Heparin-mediated extracorporeal LDL-precipitation
• specific removal of sFlt-1 via dextran sulfate cellulose
(DSC)-apheresis was suggested as cure to allow
prolongation of pregnancy in preterm PE
Results:
• safe and prolongs pregnancies in PE

Pregnancy Hypertens.2018 Apr;12:136-143. doi: 10.1016/j.preghy.2018.04.007. Epub

2018 Apr 11
 Pravastatin in Pre eclampsia
Statins currently contra-indicated in pregnancy
• Act by inhibiting HMG CoA reductase enzyme prevents
cardiovascular mortality and morbidity
• One pilot study and several animal studies
• No difference in drug side effects,congenital anomalies, adverse
reactions
• More favourable pregnancy angiogenic profile
Needs to be evaluated through well-designed clinical trials
Costantine MM, Cleary K, Hebert MF, et al. Safety and pharmacokinetics of pravastatin used for
the prevention of preeclampsia in high-risk pregnant women: a pilot randomized controlled
trial. Am J Obstet Gynecol. 2016;214(6):720.e1–720.e17. doi:10.1016/j.ajog.2015.12.038
 Summary
• Initiation of anti-hypertensive- BP-140/90mmHg
• Target BP on treatment- 135/85mmHg
• 24hr urine collection no longer recommeneded for
quantification of proteinuria
• Not all women with PE needs hospital admission
• Women who received 8g MgSO4 before delivery had
no benefit if continued for 24 hrs postpartum