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Cardiovascular Drug

Selection in Pregnancy
Dr Orchid Barua
D-CARD Student

United States of America Food and Drug


administration ( FDA )drugs in pregnancy
categories :
Category A : adequate and well-controlled studies have failed to show
risk to the fetus in pregnancy.
Category B : animal studies have failed to show risk to the fetus but
there are no adequate and well-controlled studies in humans.
Category C : animal studies have shown risk to the fetus, and there are
no adequate and well-controlled studies in humans, but potential benefits
may warrant use of the drug in pregnant women despite potential risks.
Category D : there is evidence of human fetal risk based on data from
research or clinical experience, but potential benefits may warrant use of
the drug in pregnant women despite potential risks.
Category X : studies in animals or humans have shown fetal
abnormalities and/or there is evidence of human fetal risk based on
research or clinical experience, and the risks involved in use of the drug in
pregnant women clearly outweigh potential benefits.

ANTIHYPERTENSIVE AGENTS IN
PREGNANCY
Heterogenous entity: pre-existing hypertension, gestational
hypertension and pre-eclampsia(sometimes classified into mild
and severe)
No benefit of treating mild to moderate
hypertension(<170/110mmHg)- acc to ESC
Severe HTN(>170/110mmHg) is an emergency requiring
hospitalization
Methyldopa Drug of choice followed by Labetalol, CCB is 2 nd line
ACE and ARB are contraindicated

nitrop
russid
e

reser
pine

Angio
tensin
conve
rting
enzy
me
(ACE)
inhibi
tors

Dru
gs
Cont
rain
dica
ted
diltiaz
em

angio
tensin
recep
tor
block
ers
[ARBs
]

verap
amil

Acute Blood Pressure Lowering


for Severe Hypertension
SBP 160 mmHg or DBP 110 mmHg
treatment goal is reduction in MAP by <25 % over
minutes to hours with halfhourly monitoring of BP and
heart rate

Source:Cardiac Drugs in Pregnancy Editors: Karen Sliwa John Anthony

Treatment of Mild Hypertension,


and Maintenance of
Antihypertensive Effect

no certainty on the value of treating


WHO states explicitly in its guideline of Mx of preeclampsia and eclapsia that no recommendation can be
made

Source:Cardiac Drugs in Pregnancy Editors: Karen Sliwa John Anthony

Methyldopa
Supplied: 125, 250, 500 mg tab, IV also available abroad
Dosage: 250 mg twice daily, increasing if needed to max
1.5 g daily
Adverse effects : include orthostatic hypotension,
sedation, dizziness, fatigue, Coombs positivity; depression
occurs in ~22 %.
Caution: Avoid methyldopa after parturition because the
drug may precipitate or worsen depression

Betablocker
most common beta-blockers used during pregnancy are
labetalol, atenolol, and pindolol

advantages over methyldopa


do not usually cause orthostatic hypotension, somnolence, or significant
depression
given once daily

Adverse effects :

fetal or neonatal bradycardia;


premature or prolonged labor;
delayed spontaneous breathing in the newborn, mainly observed with IV use;
rarely neonatal hypoglycemia
IUGR and low infant birth weight (atenolol)

Labetalol (FDA-C)
Blocks Beta+alpha1, so vasodialation
acute short-term management of severe resistant
hypertension just before labor or during delivery
i/v labetolol more effective than IV hydralazine or
methyldopa as BP lowering effect is more predictable,
causes less tachycardia
appears to cause less fetal distress than hydralazine.

Avoid in asthmatics

Adverse effects of labetalol


Chances of orthostatic hypotension
IUGR(incidence 27%)
perioral numbness, tingling, and itching of the scalp, and rarely a lupuslike illness, a lichenoid rash;
a rare association is retroplacental hemorrhage (Lindheimer and Katz
1985 ).
Also, a rare but life-threatening complication is acute hepatic
necrosis (Clarke et al. 1990 ).
These serious side effects are not caused by other betaadrenergic blockers.
Metoprolol(50, 100 mg) FDA-C
Dosage: 50 mg twice daily, max. 200 mg

Hydralazine (FDA-C)
pure arteriolar vasodilator
causes reflex tachycardia and sodium and water retention
very useful when a modest dose is combined with a low
dose BB, i.e. atenolol 50 mg daily, or with methyldopa
chronic use limited by fetal thrombocytopenia(rare),
dizziness, postural hypotension, a lupus syndrome,
palpitations, and edema
Dosage: 25 mg twice daily, increasing to three times daily;
max. 100 mg daily before the addition of a beta- blocking
drug

CCB: Nifedipine(FDA C)
Extensive experience but Lacks Controlled clinical trial in acute
hypertensive emergencies/fulminating preeclampsia/resistant
severe HTN
For acute severe HTN: 5-10mg capsules orally swallowed, repeat if
necessary every 30min with 10mg, to a max 120mg/day
given in late pregnancy + accelerated severe hypertension
resulted in an average fall in blood pressure of 26/20 mmHg
within 20 min of oral dosing
For mild HTN/maintenance of AntiHTN effect: nifedipine slow
release 30-120mg/day as once daily dose
best combined with short-term use of atenolol 2550 mg daily or
pindolol 5 mg daily to prevent peaking of BP during last trimester.

Caution : Theoretical fears of serious interactions with


magnesium sulphate, have not been realised in practice
Headache,
Best avoided if Tachycardia(do not use if HR120/min) coronary
artery disease or fixed cardiac output valvular disease
may inhibit labor;
manufacturer advises to avoid before week 20; always balance
risk with benefit
use only if other treatment options are not indicated or have
failed.

Other drugs as antihypertensive


Diazoxide:
rarely used, and may cause a rapid
drop in BP.
Sodium nitroprusside
last resort treatment in ICU setting with
intra-arterial BP monitoring.
fetal cyanide poisoning, should ideally
only be used postpartum

Diuretics:
potential harmful effects owing to the
reduction of plasma volume, cardiac
output, and uteroplacental perfusion, so
diuretics are not generally indicated
may cause neonatal thrombocytopenia
(rarely)

ACE Inhibitors

are contraindicated during pregnancy.

May adversely affect fetal and neonatal BP control and renal


function.

may cause skull defects and oligohydramnios

teratogenic in animals

associated with a high incidence of intrauterine death.

Acute renal failure with catastrophic consequences has been noted


in neonates of mothers given ACE inhibitors in the third trimester.

Other drugs
Magnesium
Sulfate
mild and transient
lowering of blood
pressure.
most useful agent
for the prevention
of seizures
associated with
severe
preeclampsia

Aspirin

Patients with CKD, DM, autoimmune disease, or chronic HTN are at high risk of developing
preeclampsia and aspirin is advisable.

Dosage 7581 mg once daily from 12th week until the baby is born.

Patients with more than one moderate risk factor

first pregnancy,
aged 40 years,
pregnancy interval >10 years,
BMI 35 kg/m 2 at first visit,
multiple pregnancy, or
family history of preeclampsia

are at risk for developing preeclampsia and aspirin 7581 mg once daily is advised.

DRUG THERAPY FOR HEART


FAILURE
Spectrum of CVD leading to heart failure or pulmonary
edema in pregnancy:
Mitral stenosis(most common) and rarely other VHD
Systemic hypertension associated with preeclampsia
Pulmonary hypertension
Peripartum cardiomyopathy

Table : Recommendations for the management of cardiomyopathies and heart failure in


pregnancy(ESC Guidelines on the Management of Cardiovascular Disease During
Pregnancy (Regitz-Zagrosek et al. 2011 )

Recommendations

Level of evidence

CLASS I
Anticoagulation is recommended in patients with intracardiac
thrombus detected by imaging or with evidence of systemic
embolism.

Women with HF during pregnancy should be treated according to


current guidelines for non-pregnant patients, respecting
contraindications for some drugs in Pregnancy

Therapeutic anticoagulation with LMWH or vitamin K antagonists


according to
stage of pregnancy is recommended for patients with atrial
fibrillation.

CLASS IIa
Delivery should be performed with -blocker protection in
women with HCM.
-blockers should be considered in all patients with HCM and
more than mild
LVOTO or maximal wall thickness >15 mm to prevent sudden
pulmonary Congestion

C
C

Mitral stenosis in Pregnancy


MS aggravates during pregnancy
complications :pulmonary edema or atrial
tachyarrhythmias/atrial fibrillation/flutter
must decrease their activity and commenced on a beta-blocker
eg. Metoprolol +- furosemide (response to therapy 75%)
If aggressive medical therapy fails: Interventional and surgical
options
Interventional procedures should be delayed until 1214 weeks
(period of organogenesis)
best deferred to between 26 and 30 weeks
the procedure of choice : Percutaneous mitral valvuloplasty

BB
Cornerstone of treatment in
medical Mx of MS in pregnancy
BB prevents Pulmonary edema
in MS with pregnancy
marked clinical improvement
when resting heart rate reduced
from a mean of 8678 beats/min
Titrate BB according to HR and
symptom

Digoxin (FDA

no value in the MX of pulmonary edema caused by pure mitral


stenosis

small role in hypertensive heart failure, DCM or other conditions


associated with poor LV systolic function

No teratogenic or untoward adverse fetal effects

50 % reduction in serum levels in the pregnant, as opposed to the


nonpregnant

Diuretics in HF
Thiazides

short-term thiazide diuretic therapy over a few days is indicated


for symptomatic relief along with oxygen and morphine until MS
can be corrected by PTMB or by surgery
rarely cause fetal or neonatal jaundice or thrombocytopenia, but
their use is justifiable for the treatment of pulmonary edema and
hypertension associated with preeclampsia (always compare risk
with benefits)

Furosemide

contraindicated because causes fetal abnormalities

but can be used for pulmonary edema in the last weeks of


pregnancy and in the puerperium to manage life-threatening
pulmonary edema.

Inotropes and vesopressors:


other interventions should be used initially to manage
hypotension,
e.g. administration of intravenous fluids
placing the patient in the left lateral decubitus position to prevent
compression of the inferior vena cava by the gravid uterus.

If above fails use vasopressor therapy


paucity of clinical studies with no consensus about which is
the best vasopressor
Norepinephrine can be used as the first-line vasoactive agent
who fail to respond to early aggressive volume resuscitation.
dopamine and levosimendan can be used as well

Vasodilators :
ACE inhibitors
contraindicated at all stages of pregnancy.

Hydralazine
may be used in the third trimester of pregnancy if afterload
reduction is deemed necessary for the management of heart
failure
toxicity and teratogenic effects in animal studies, so must be
avoided during the first trimester.

Summery of Medical management of


chronic heart failure in pregnancy
Drug/class

Purpose

Comments

Generally reserved for


treatment of pulmonary
edema
Use of lowest possible dose

Can result in uteroplacental


Hypoperfusion
FDA class C

Digoxin

Not considered first-line


therapy
for heart failure in nonpregnant Patients
No improvement in mortality

Generally considered safe


Useful in treatment of
persistent symptoms,
despite standard therapy
FDA class C

Vasodilators
Hydralazine

Commonly used oral


antihypertensive agent in
pregnancy
Can be substituted for ACE
inhibitor during pregnancy

Demonstrated efficacy in
hypertension
Risk of hypotension
Avoid large or precipitous
decreases in blood pressure
FDA class C

Diuretics
Furosemide

Aldosterone
antagonists
Spironolactone,Epleronon
e

Prolong survival in selected


heart failure patients

Not routinely used in


pregnancy
No data to support safety in
pregnancy
FDA class D

Warfarin

Risk/benefit ratio needs to be


discussed with the patient for
treatment and prophylactic
anticoagulation in severe left
ventricular Dysfunction

First trimester teratogenesis


Dosing is complicated in
pregnancy
FDA class X
(contraindicated)

Fig.
Treatmen
t of heart
failure in
women
with
cardiomy
opathy
accordin
g to
stage of
pregnanc
y
Source:Cardiac
Drugs in
Pregnancy Editors:
Karen Sliwa John
Anthony

Nonpregnan
t
According
to
standard
heart
failure

Early
pregnancy

Late
Pregnancy

Diuretics
Hydralazin
e
Beta

Diuretics
Hydralazin
e
Beta

Post Partum
Diuretics
Aceinhibitor
Beta

Peripartum Cardiomyopathy
addition of bromocriptine to standard heart failure therapy
may be beneficial in patients with acute onset PPCM
(Hilfiker-Kleiner et al.2007 )
A proof-of-concept pilot study of PPCM patients with
severely reduced LVEF, diagnosed within 1 month of
delivery, showed a marked improvement in systolic
function and reduced mortality in patients treated with
bromocriptine 2.5 mg twice daily for 2 weeks, followed by
2.5 mg daily for 4 weeks, compared with patients receiving
standard care with ACE-inhibitors and beta-blockers only
RCT currently underway

Drugs in Coronary Artery Disease and


Arrhythmias:

Glycoprotein IIb/IIIa Receptor Antagonists


very limited experience
Only a few case reports are documented in which
patients received IIb/IIIa receptor antagonists after
coronary stenting for an ACS during pregnancy. In these
cases, no complications or adverse fetal outcomes were
noted (Chow et al.1998 ).
might be considered for use in high-risk clinical
circumstances, but, in general, should be avoided,
especially shortly before delivery.

ANTIARRHYTHMICS IN PREGNANCY

Table
:Drugs for
arrhythmi
as in
pregnancy

Anticoagulation in Pregnancy
Heparin
The most common adverse effects observed include
osteoporosis and thrombocytopenia in the mother, if the
drug is used for longer periods (Regitz-Zagrosek et al.
2011 ).
significantly less frequent in low molecular weight
heparin(LMWH) is used.
FDA B

Warfarin
FDA category D
Newer anticoagulants:
Danaparoid (with a heparin like action) FDA category B
Can be used in Heparin induced thrombocytopenia

Dabigatran, and the Factor Xa-inhibitors Rivaroxaban, Apixaban and


Fondaparinux not recommended in pregnant patient
Recent antiplatelets :
prasugrel, ticagrelor, bivalirudin and glycoprotein IIb/IIIa inhibitors
not recommended during pregnancy because of insufficient safety data