Pharmacology of

Cardiovascular Drugs in Pregnancy

Dyah Wulan Anggrahini

Department of Cardiology and Vascular Medicine
Universitas Gadjah Mada/RSUP dr Sardjito

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 Burden of CV Diseases in Pregnancy

• Rheumatic Heart Disease

• Congenital Heart Diseases
• Hypertension
• Congestive heart failure, including pulmonary edema
• Arrhythmias
• Thromboembolism
• Cardiac Ischemia
• Prosthetic Valves

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 Physiological
REVIEWS changes in pregnancy alter
drug pharmacokinetics

Cardiovascular system and blood Liver

Increases in plasma volume, Changes in oxidative
cardiac output, stroke volume, liver enzymes, such as
and heart rate cytochrome P450
Decreases in serum albumin
concentration and ser um colloid
osmotic pressure
Increases in coagulation Lungs
factors and f brinogen Increase in tidal volume
Compression of the inferior and minute ventilation
vena cava by the uterus Stomach
Stomach and intestines
Kidneys Nausea and vomiting
Increases in renal blood Delayed gastric emptying
f ow and glomerular Prolonged small bowel
f ltration rate transit time
Gastrointestinal ref ux

Figure 1 | Physiological changes in pregnancy that alter Nature

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drug pharmacokinetics.
Reviews | Cardiology
 Medication for heart disease during pregnancy

Pharmacokinetics
• Is an increase or decrease in the dose of the drug
expected to be necessary?
• Should the effect of the drug be monitored?

Teratogenicity and fetotoxicity

• What is the cost:benefit ratio for mother and fetus?
• Is discontinuation or replacement with another drug
necessary?

Patient compliance
• Might be reduced during pregnancy when women fear
harming the fetus by using medication

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 Effects of cardiovascular medication
on the fetus

medication positively influences

maternal cardiac performance

Enhanced
uteroplacental
blood flow
negative effect on uteroplacental
blood flow

Direct negative effects on fetal

heart rate and cardiac output

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 Registry On Pregnancy and Cardiac
Disease (ROPAC) – by ESC
1321 pregnant women in 60 hospitals of 28 countries;
424 on pregnancy with medications
Statins 0,50%

ACE-I 0,80%

Diuretics 7%

Antiplatelets 8%

Betablockers 22%

International Journal of Cardiology 177 (2014) 124–128

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 Maternal Outcome in Patients with
Medications
2.7% maternal mortality and 42% hospital admission
Cardiac Outcome (%) Obstetric Outcome (%)

Bleeding 2,8
C-Section 56

Trhromboemboli 0,7
PP bleeding 6,4

Ventricular Arrhythmias 4,3

Preeclampsia 47

AF 3,1
Hypertension 4,5

Heart Failure IUGR 9,2 25

International Journal of Cardiology 177 (2014) 124–128

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 Anti-hypertensive Drugs

contraindicated
ACE-I, ARBs, renin inhibitors
throughout pregnancy

Labetalol, Methyldopa, First line

Metoprolol

Nifedipine and other CCBs Second line

Diuretics Not recommended

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 Outcome of Pregnancy using
Anti-hypertensive Drugs
ROPAC study
Total (1321) B-Blockers Diuretics ACE-I ARBs (7)
(291) (94) (38)
Fetal mortality (%) 2.1 4.3 2.6 0
Fetal abnormality (%) 4.1 2.1 7.9 0
Pregnancy duration (wks) 37 37 38 37.5
Mean Birth Weight (g) 2830 2720 2921 2652
Low BW <2500 g (%) 23 23.4 13.2 42.9
Pregnancy <37 wks %) 23 31 15.8 14.3
APGAR <7 min (%) 13 12.8 15.8 0

International Journal of Cardiology 177 (2014) 124–128

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 ESC Guideline Recommendation for
Hypertensive Crisis

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 Beta-blockers during Pregnancy

Pharmacological Effect Common Indications:

Supress SA node Arrhythmias
Mild vasodilators Hypertension
Decrease HR Aortic Dilatation ( Marfan Syndrome)
Increase diastolic filling Mitral Stenosis
time LVOT Obstruction
Reduce sympathetic tone Heart Failure

Common Agent used :

Labetalol, Metoprolol, Bisoprolol

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 Pregnancy & Fetal Outcome of β-blockers

small for gestational age -

ROPAC and Quebec Registry

small for gestational age, preterm birth,

and perinatal mortality
- Danish Fertility Registry

hypoglycaemia, bradycardia, and

hypotension in the neonate

Clear indication, careful choice of agents  Increase benefit

over the risk for reduction of poor maternal outcome

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 Use of β-blockers in Pregnancy

• Try, when possible, to avoid initiating long-term therapy

during the first trimester.
• Use the lowest dose possible. The use of adjunctive
antihypertensive drugs might help achieve this goal.
• Discontinue, if possible, therapy at least 2–3 days before
delivery to limit the effect of the drug on uterine
contractility and to prevent possible neonatal
complications.

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 • Neonates born to mothers on b-blockers should be
closely observed for 72 to 96 hours after parturition
unless the drug was stopped well before delivery.
• To avoid interference with b2-mediated uterine relaxation
and peripheral vasodilation, blockers with b1 selectivity,
intrinsic sympathetic activity, or a-adrenergic blocking
activity are preferred.
• Mothers should avoid nursing their infants at the time of
expected peak maternal b-blocker plasma
concentrations, usually occurring 3 to 4 hours after a
dose

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 Pulmonary Hypertension

If pregnancy occurs, termination should be

offered ( WHO risk class IV )

Pregnancy continuation should be managed in

centre with all experts, facilities and treatment
options

Maintenance of circulating volume, prevent

systemic hypotension, hypoxia, and acidosis
which may precipitate refractory heart failure.

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 Agents for Pulmonary Hypertension

High dose CCB is recommended for Safe during pregnancy

(Category B)
vasoreactive PH: Amlodipin, nifedipin

Endothelin receptor blockers : Bosentan, Contraindicated

Maxicentan, Ambricentan (Category D)

Phosphodiesterase-5 inhibitors: Safe during pregnancy

Sildenafil, Tadalafil (Category B)

Prostacylin analogue: Epoprostenol iv., Safe during pregnancy

Iloprost, beraprost (Category B)

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 Arrhythmias in Pregnancy
Case #1

History:
Female, 26 y.o. with palpitations
G2P1A0 30 weeks of pregnancy
History of palpitations previously induced by fatigue
History of Verapamil 2x80 mg, stopped during pregnancy
No family history of heart disease

Physical Exams:
BP: 110/70 mmHg HR: 170 bpm RR: 22x/m SpO2: 96%
Heart exams: normal heart size, normal heart sound, no murmurs
detected
Other exams within normal limit

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 Arrhythmias in Pregnancy

ECG : Supraventricular Tachycardia, short RP interval HR 170 bpm

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 Arrhythmias in Pregnancy
Management consideration:

1. Stabil condition  vagal manouver  failed

2. Medications :
3. What kind of agents?
4. AV nodal blocking is necessary  any harm to the fetal heart
rate acutely?
5. Maintenance drugs: Any long term effects to the fetus until
delivery

Iv. Adenosine ( ATP) 10 mg followed by 20 mg fast bolus

Continues with Metoprolol 2x50 mg for maintenance

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 Anti-arrhythmias during Pregnancy

Supraventricular tachycardia

• For acute conversion of paroxysmal supraventricular

tachycardia, intravenous adenosine is the first-line treatment;
intravenous metoprolol or propranolol can also be used
• For long-term management of chronic supraventricular
tachycardia, digoxin, metoprolol, and propranolol are the
first-line drugs; if these medications are not effective, flecainide
or sotalol can be used
• Oral verapamil can be used for rate control of supraventricular
tachycardia if other agents have not been effective
• Procainamide or propafenone can be used if all other agents
prove to be ineffective

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 ESC Guidelines 2011

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 Anti-arrhythmias during Pregnancy

Ventricular tachycardia

•Intravenous procainamide or sotalol are alternative treatments for

sustained monomorphic ventricular tachycardia when the patent is
haemodynamically stable
•β-Blockers or verapamil (first-line agents) or flecainide,
propafenone, or sotalol (second-line agents) can be used in long-
term management
•Amiodarone should be reserved for the treatment of arrhythmias
that are life-threatening and resistant to other therapies
•Electrical cardioversion is the first choice of therapy for sustained
ventricular tachycardia with severe symptoms and drug refractory.

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 ESC Guidelines 2011

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 Heart Failure in Pregnancy
• Hydralazine and nitrates can be used instead of
angiotensin-converting-enzyme inhibitors and
angiotensin-receptor blockers
• Dopamine can be used for positive inotropy
• β-Blockers can be used (as recommended for
nonpregnant women)
• Diuretics can be used for clinical signs of heart
failure
• Spironolactone should be avoided

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 Anticoagulation during Pregnancy
Common indication:

Mitral stenosis with thrombus in LA

Atrial Fibrillation
Prosthetic valves
LV thrombus
DVT/PE (Thromboembolism)

Common agents:
OAC
LMWH
Unfractionated Heparin

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 OAC vs. UFH vs. LMWH
• OACs cross the placenta and their use in the first trimester can
result in embryopathy in 0.6–10% of cases.
• UFH and LMWH do not cross the placenta and embryopathy does
not occur.
• Substitution of OACs with UFH in weeks 6–12 greatly decreases the
risk.
• The incidence of embryopathy was low (2.6%) when the warfarin
dose was <5 mg and 8% when the warfarin dose was >5 mg daily 
dose dependency

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 Prosthetic Valves and other indications
• Low risk of valve thrombosis with OACs throughout pregnancy
(2.4%, 7/287 pregnancies) compared with UFH in the first trimester
(10.3%, 16/156 pregnancies)
• UFH or LMWH throughout pregnancy is not recommended
because of the high risk of valve thrombosis with these regimens
in combination with low fetal risk with OACs in the second and
third trimester
• LMWH requires higher doses in pregnancy and periodic
monitoring of anti-Xa to reduce the risk of valve thrombosis
• OACs throughout pregnancy under strict INR control, is the safest
regimen for the mother and should be considered when the
warfarin dose is <5 mg daily (or phenprocoumon <3 mg or ace-
nocoumarol <2 mg daily)

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 Anti-ischemic drugs during pregnancy

• β-Blockers are the first-line anti-ischaemic drugs

• Calcium-channel blockers and nitrates can also be used
• Statins are associated with a low risk of congenital
malformations and should be avoided if possible
• Low-dose aspirin is the first choice of antiplatelet agent
• Clopidogrel can be considered, but other antiplatelet
agents are not recommended

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 Conclusions

• The number of pregnant women with CVD is increasing,

and one-third of these patients use medication for their
diseases
• Cardiologists who manage women with CVD must have
knowledge of the cardiovascular effects of medication
used for obstetric indications, and be able to advise the
obstetrician on their use in these patients.
• the data on safety and efficacy during pregnancy are
insuffi- cient.

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Locally rooted, globally respected