미즈메디병원 최노미 선생님

1. 2013년 6월 04일
강서 미즈메디 최노미
Antihypertensive Medications
during Pregnancy

2. Contents
I. Introduction
II. Management
– Prevention
– Obstetric management
– Antihypertensive medication
III. Postpartum Consideration
IV. Prognosis
V. Summary

3. INTRODUCTION

4. Introduction -1-
Hypertensive Disorders Complicating Pregnancy
• Up to 10% of pregnancies
• 1/3 of all maternal deaths

5. Introduction -2-
Risk factors
• Nulliparity
• Extremes of reproductive
age 15< & >35
• Black race
• Hx of PET in a 1st degree
female relative
• Hx of PET in prior pregnancy
• Chronic HTN
• Chronic renal Disease
• DM
• Autoimmune diseases
• Multiple Pregnancy
→ twins 13 vs 6%
• Hydatidiform mole
• Nonimmune hydrops fetalis
• Obesity → BMI<19.8 ; 4.3%
BMI≥ 35; 13.3%
• Smoking ; ↓ risk of HTN

6. Introduction -3-
• Maternal
– CVA- seizures & stroke
– DIC
• HELLP syndrome
– End-organ failure
– Placental abruption
– Death
• Fetus
– IUGR
– Oligohydramnios
– Prematurity
– Intra-uterine death
Severe Complications

7. Introduction -4-
Definition of HTN
– Elevation of BP ≥140 mmHg systolic &/or
≥90 mmHg diastolic, on two occasions
at least 6 hours apart.

8. Introduction -5-
Variation of BP in pregnancy
Nicolas Szecket, HTN in pregnancy 2004

9. Classification
5 Categories of Hypertensive Disorders
Complicationg pregnancy
• Gestational Hypertension; 6-7% of pregnancies
• Preeclampsia; 5-7%
• Eclampsia; 5-7%
• Superimposed Preeclampsia on Chronic
Hypertension; 20-25% of chronic HTN preg.
• Chronic Hypertension; 1-5%

10. MANAGEMENT

11. Prevention -1-
Diatery Manipulation
• Low-salt diet
• Calcium supplement
• Fish oil supplement
→ Not effective
Cardiovascular drug
• Diuretics
• Antihypertensive drug
→ Not effective

12. Prevention -2-
Low dose aspirin or LMWH with low dose aspirin
 Selective supression of throboxane synthesis by the plt
& sparing endothelial prostacyclin production
 Not effective in preventing preeclampsia
But advise women at high risk of preeclampsia to
take 75mg of aspirin daily from 12wks until the birth
– High Risk; HTN during a previous pregnancy, Chronic renal dz,
Autoimmune dz such SLE or antiphospholipid SD, , Chronic HTN,
Type 1 or type 2 DM heart (2011)
Antioxidants : Vit C & E supplementation
 Significant reduction in preeclampsia (Poston, 2006, Villar, 2007)

13. Management
Goals
• Minimize maternal end-organ damage
• Prevent seizure
• Terminaton of pregnancy with the least possible
trauma to the mother & fetus
Steps of management
• Evaluation of HTN
• Admission vs OPD f/u
• No medication or medication
1. Antihypertensive therapy
2. Anticonvulsant therapy; MgSO4

14. Management
Hospitalization
• Women with new onset BP ≥ 140/90
• Worsening BP
• Development of proteinuria in addition to existing BP
Depends on:
• Severity of HTN in pregnancy
• Duration of gestation
• Condition of the cervix

15. Management
Check up
• Serial U/S for fetal growth. BPP, NST 34wk
• Follow up every 2 wks till 30, then weekly
• Warn the mother about symptoms of superimposed PET
• Investigations ; Renal function test, uric a , calcium ,LFT,
• 24hrs urine for Cr clearance & protein, CBC, U/A, ECG.GTT
• Not allowed to continue past 40wks → consider induction
• Regular diet no salt restriction
• Indication of induction
• For superimposed PET,IUGR, fetal distress, worsening renal
function

16. Management
Indications of Termination of Pregnancy
• Term pregnancy with mild or severe PET
• Severe PET regardless of the gestational age
• Warning signs
 headache , visual disturbance, epigastric pain, oliguria
• Eclampsia
 Pt must be stabilized & delivered immediately
• Preterm with mild PET
 Assess fetal wellbeing by NST, BPP, Doppler

17. Drug Treatment During Pregnancy
• Continuation of prepregnancy antihypertensive Tx
when women become pregnant is debated
Beneficial to mother in the long term, but
theoretically can decrease uteroplacental perfution
• IUGR; from drug or effect from worsening of HTN ?
• Mild to moderate HTN Tx (?)
Antihypertensive Drugs -1-

18. Blood Pressure Classification; JNC-7 Compared with NHBPEP
JNC-7 Blood Pressure Classification
(Nonpregnant), mmHg
NHBPEP Blood Pressure
Classification(Pregnant), mmHg
Normal: SBP≤120, DBP≤80
PreHTN: SBP 120-139 or DBP 80-89
Stage 1 HTN: SBP 140-159 or DBP 90-99
Stage 2 HTN: SBP 160-179 or DBP 100-110
Stage 3 NTN: SBP 180-209 or DBP 110-119
Normal/acceptable in pregnancy:
SBP≤140 and DBP≤90
Mild HTN: SBP 140-150 or DBP 90-109
Severe HTN: SBP≥ 160 or DBP≥110
JNC-7: Ther Seventh Report of the Joint National committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure.
NHBPEP: National High Blood Pressure Education Program Working Group Report on
High Blood Pressure in Pregnancy
Am J Obstet Gynecol. 2000
Antihypertensive Drugs -2-
Grade of HTN BP levels EITHER
systolic OR
diastolic (mmHg)
Treat Levels after Tx
Mild Diastolic: 90-99
Systolic: 140-149
No Not applicable
Moderate Diastolic: 100-109
Systolic: 150-159
Yes <150 systolic
< 100 diastolic
Severe HTN Diastolic: ≥ 110
Systolic: ≥ 160
Yes <150 systolic
< 100 diastolic

19. • Randomized trials of antihypertensive drug therapy in
Pregnancies Complicated by Mild Chronic Hypertension
PIH
Antihypertensive Drugs -3-

20. • Randomized trials of antihypertensive drug therapy in
Pregnancies Complicated by Mild Chronic Hypertension
PIH
Antihypertensive Drugs -4-

21. Mild to moderate chronic or gestational HTN
• Less likely to produce end-organ-disorders
• So, Treatment neither improve neonatal outcomes nor
prevent superimposed preeclampsia
• A Cochrane review of 46 trials
• 4282 patients with modest BP increases
• Showed no benefits of Tx in terms of stillbirth, PTL, or SGA
• Excessive BP lowering in such patients
-> May even prove detrimental to fetal growth via placental
hypoperfusion
Von Dadelszen P, et al. J Obstet Gynaecol Can 2002;24:941–5.
Antihypertensive Drugs -5-

22. Summary of Society Guidelines
regarding BP Tx thresholds & Target

23. Antihypertensive Drugs -6-
• Therapy Recommendation
– By the Working Group on High BP in Pregnancy(2000)
– Indication for empirical therapy
• BP ≥ Systolic 150~160mmHg &/or
≥ Diastolic 100~110mmHg
by NHBPEP & ACOG guidelines 2012
• With target-organ damage
(Left ventricular hypertrophy or renal insufficiency)
Treatment Goal; DBP =90~100mmHg(Grade D)

24. Antihypertensive Drugs -7-
• Severe or Chronic PTN in pregnancy
• Used to control BP until the Pt delivers or in preterm
for 48 hrs to allow time for glucocorticoid
administration for fetal lung maturity then delivery
• Drugs
• Adrenergic-Blocking Agents
• Diuretics
• Vasodilators
• CCB(Calcium channel blockers)
• ACE inhibitors -CIx

25. Antihypertensive Drugs -8-
Drug/Class Doses/
half life
Adverse Events in pregnancy Eviden
ce
Comments
Methyldopa
(FDA-B, L2)
; Adrenergic
Blocking agents,
centrally
500mg~3g
In 2 divided
Peripheral edema, anxiety,
night mares, drowsiness, dry
mouth, hypotension, maternal
hepatitis, but no major fetal
adverse events
Large Large post
marketing
evidence on
safety
1st choice drug in
preg by Cardio
Labetalol
(FDA-C, L2)
; α,B-blocker
200~1,200
mg/d in 2-3
divided
Persistent fetal bradycardia,
hypotension, neonatal
hypoglycemia
Large 1st recom. By
ACOG 2012
Nifedipine
(FDA-C, L2)
; CCB
30mg~120
mg /d of a
slow-
release prep.
Hypotension & inhibition of
particularly if used in
combination with
magnesium sulfate
Small Immediate
release
nifedipine not
recommend
Hydralazine
(FDA C, L2);
Vasodilator
50~300mg/
d in 2~4
divided
Potential ass. With
Hypospadia, neonatal
thrombocytopenia and lupus
Mode
rate
Especially
peripartum IV

26. Antihypertensive Drugs -9-
Drug/Class Doses/
half life
Adverse Events in
pregnancy
Evidence Comments
Atenolol
(FDA-C, L2)
;pure b-
blocker
Depends on
specific
agent
May decrease uteroplacental
blood flow, IUGR when
started 1,2nd trimester,
preterm birth, bradycardia
neonatal hypoglycemia,
Hydrochloro-
thiazide
(FDA- C, L2)
; Diuretics
12.5~25mg/
d
No fetal anomaly, electrolyte
abnormalities, neonatal
hypoglycemia, volume
depletion
Large Not 1st line Tx
during preg,
esp after
20wks
ACE inhibitor
(FDA C/D in
2nd & 3rd ∆,
L2)
Contraindic
ated in
pregnancy
Oligohydramnios, IUGR,
Fetal renal failure, Heart
anomalies, Polydactyly,
Hypospadias, SA, limb,
pulmonary hypoplasia,
craniofacial anomaly
Large

27. Antihypertensive Drugs -10-
ACEI(Angiotnesin-Converting Enzyme Inhibitors)
or angiotnesin receptor blockers ; Captopril, Lisinopril
• Contraindicated during all trimesters of pregnancy
Magee LA, et al. BJOG. 2007;114(6):770. e13–20.
ACOG. Obstet Gynecol 2001;98(1):177–85.
• Complication
• Severely underdeveloped calvarial bone, renal agenesis
Pulmonary hypoplasia, IUGR, fetal death, neonatal renal
failure, oilgohydramnios, anuria & neonatal death,
multiple cardiovascular malformations
Others to avoid during pregnancy –FDA D category
– Losartan, Valsartan, Aliskiren(direct renin inhibitor)

28. Antihypertensive Drugs -11-
Summary of Antihypertensive Therapy Selection
• No evidence of major adverse fetal or maternal events.
• Methyldopa
• 1st Choice of Tx by NHBPEP working group
• No fetal anomaly in the first trimester
• Vascular stiffness improved Khalil & colleagues (2009)
• Labetalol
• May ass with fetal growth restriction
• No advantages over Methyldopa Sibai & colleagues (1990)
• Nifedipine
• Experiences and newer safety concerns are not sufficient to
permit recommendations

29. Antihypertensive Drugs -12-
Drugs for urgent control of severe acute HTN in pregnancy
Drug(FDA risk) Dosage Maternal adverse effects
Hydralazine (C) 5mg IV or IM, then 5-10mg
every 20-40min; or
constant infusion of 0.5-
10mg/hr
Long experience of safety &
efficacy . Risk of delayed
maternal hypotension, fetal
bradycardia
Labetalol (C) 20mg IV, then 20-80mg
every 5-15min, up to a
mazimum of 300mg; or
constant infusion of 1-2mg
/min
Probably less risk of tachycardia
& arrhythmia than with other
vasodilators; increasingly
perferred as 1st-line agents
Nifedipine (C) 10-30mg PO, repeat in
45min if needed
Possible interference with labor
Diazoxide (C) 30-50mg IV every 5-15 min Use is waning; may arrest labor;
cause hyperglycemia

30. Fluid Therapy
Hyperosmotic agents not recommended because
Intravascular influx of fluid
Subsequent escape of fluid to vital organs
Pulmonary edema & cerebral edema
LR 60-120 ml/hr Excessive fluid administration
Pulmonary edema & cerebral edema

31. Postpartum Considerations
• Similar with severe chronic HTN & severe preeclampsia-
eclampsia
• Development of cerebral or pulmonary edema,
heart failure, renal dysfunction or cerebral hemorrhage
– Especially high within the 1st 48hrs after delivery
Cunningham, 2005
– Following delivery, as maternal pph resistance ↑,
left ventricular workload ↑
–> further aggrevated by appreciable amounts of
interstitial fluid that are mobilized for extcretion as
endothelial damage is repair
So Promptly HTN control with diuretic therapy
for resolving pulmonary edema

32. Prognosis
Maternal death; rare
– Due to cerebral Hg, aspiration pneumonia, hypoxic
encephalopathy, thromboembolism, hepatic rupture,
renal failure, ansthesia
Recurrence
– Gestational HTN in a future pregnancy; 13~ 53%
– Pre-eclampsia in a future preg; 16%
– Severe preeclampsia, HELLP syndrome or eclampsia
or birth before 34wks -> Preeclampsia in a future; 25%
– Birth before 28wks -> 55% heart, 2011

33. Summary
Level A
– ACE inhibitors & angiotensin receptor blockers
; Contraindicated in all trimesters of pregnancy
Level B
• Woman with severe HTN
-> require antihypertensive medication for acute ↑BP
• Methyldopa & Labetalol ; a good option for 1st line tx of chronic HTN
in pregnancy -> Based on the overall low rate of adverse effects &
good efficacy
• Atenolol ; not currently recommended d/t IUGR
• Thiazide used in women before pregnancy
• No need to be discontinued during pregnancy. ACOG,2012

34. Reference
1. Clinical Obstetrics and Gynecology
vol 48(2) June 2005, pp441~459
2. NICE Guidelines on hypertension in Pregnancy
SpR Training Day,21/01/2011
3. District I ACOG Medical Student Education Module 2011
– Pregnancy induced hypertension
4. Hypertension in Pregnancy.
Amanda R. Vest, et al. Calrdiol Clin 30 (2012 407~423)
5. Chronic Hypertension in Pregnancy
Practice bulletin, Vol 119, No 2, part 1, Feb 2012. ACOG

35. 경청해주셔서
감사합니다.