Transcript Anticoagulation in pregnancy - 1st Qatar Conference on Safe

Anticoagulation in
pregnancy
MAHMOUD MOHAMED
B.PHARM. RPH. MSC (MOLECULAR BIOLOGY)
“A grand adventure is about to begin”
Winnie the Pooh
Case vignette 1
 41
year old lady, G3P1 known case of
prosthetic mitral valve on warfarin 8 mg
and expressed a desire to become
pregnant.
Case vignette 2
 36
years old female, recently diagnosed
with DVT (1/12) on Warfarin 6 mg, came to
ER with 5 weeks amenorrhea. A urine
pregnancy test was positive at home and
ß-hCG was 1500 IU/ml. What is next?
Case concerns

Warfarin versus UFH/LMWH (safety and efficacy)

Management during labor and delivery

Breast feeding
Presentation Objectives

Disease epidemiology

Physiological changes during pregnancy

Virchow’s triad during pregnancy

Pharmacokinetic changes during pregnancy

Safety and efficacy of antithrombotic

Cases management
Background
Background
annual mortality
rate per 100,000 (2010)

The

Italy 3.9

UK 8.2

UAE 8.6

Qatar 14.3

USA 16.7
Hogan MC Foreman KJ Naghavi M Ahn SY Wang M Makela SM Lopez AD Lozano R Murray CJ
Lancet.
Background

VTE accounts for 10 – 13% of maternal
deaths

VTE considered the third leading cause for
maternal death

VTE Risk increases during pregnancy

5 folds during antepartum

20 folds during the peurperium period
Marshall AL
Postgrad Med.
Saucedo M Deneux-Tharaux C Bouvier-Colle MH French National Experts Committee on Maternal Mortality
Obstet Gynecol.
Background
Cases between 2010 - 2014
Total
Pregnancy complicated by deep vein thrombosis
42
Pregnancy complicated by pulmonary embolism
Pregnancy complicated by presence of prosthetic heart
valve
10
Pregnancy complicated by valvular heart disease
175
12
Risk factors
Risk factors
Physiological
changes
Hypercoagulability
Drug
pharmacokinetic
Risk factors
Pharmacokinetic during pregnancy

Absorption

Decrease gastric emptying and intestine motility this leads to increase Tmax and reduce Cmax

Increase gastric pH due to decreased H excretion this would reduce weak acids

SC absorption is enhanced due to enhanced tissue perfusion.

Distribution

Increase intravascular and extravascular volumes which lead to increased volume of distribution

Decrease albumin concentration and heamodilution leads to decrease albumin bound drugs medication

Competetive binding to protein by Estrogen and progesterone leads to increase free drugs concentration

Metabolism

CYP 450 enzymes are induced by Estrogen and progestron while others are competitively inhibited

Elimination

Increase renal flow and hence GFR rise by 50% and almost 80% later in pregnancy which leads to enhanced drug
elimination,

Feto-placenta unit

Both placenta and fetal liver metabolize drugs
Pharmacokinetic in pregnancy

The net result of physiological changes in pregnancy lead to
unpredictable drug therapeutic level.

A signififcant dose alteration through out pregnancy was found,
therefore frequent monitoring and dose changes is expected
(Nancy L. Shapiro 2011).

Heparin found to have lower peak plasma concentration
compared to non-pregnant subjects, while time to peak plasma
concentration is shorter in pregnant women. While aPTT is less in
pregnanct ladies
(Brancazio LR 1995).
Treatment during pregnancy
Antithrombotic
Direct factor Xa
inhibitors
Direct thrombin
inhibitors
Maternal/fetal risk
DURING PREGNANCY
UFH
Maternal risk
• Thrombocytopenia or HIT (2 -3%)
• Vertebral fractures (3 -15%) and osteoporosis (30%)
• Skin reaction due to type 4 hypersensitivity reaction
Fetal risk
• UFH does not cross the placenta
• Safe
LMWH
Maternal risk
• Lower risk of bleeding compared to UFH (overall 1.98%
including APH, PPH and wound hematoma)
• Lower risk of HIT compared to UFH
• Lower risk of osteoporosis and fractures
• Similar adverse skin reactions
Fetal risk
• LMWH does not cross the placenta
• Safe
Warfarin
Maternal risk
• Pregnancy loss
• Bleeding
Fetal risk
• Embryopathy i.e. Midfacial hypoplasia and stippled epiphyses
(exposure 6 – 12 weeks)
• CNS damage e.g. dorsal midline dysplasia and ventral midline
dysplasia (anytrimester)
• Minor neurodevelopmental problems (2nd – 3rd trimester)
• Fetal haemorrhagic complications, e.g. intracranial haemorrhage
Case management
Case vignette 1

41 year old lady, G3P1 known case of prosthetic mitral valve on
warfarin 8 mg and expressed a desire to become pregnant.

Warfarin versus UFH/LMWH (safety and efficacy)

Labor and delivery

Breast feeding
Case vignette 1

Maternal mortality is high (> 5%), and 24% thromboembolic events,
and valve thrombosis without anticoagulation

Anticoagulants carries a fetus risk of fetal abnormality, increase risk
of miscarriage, hemorrhagic complications e.g. retro-placental
bleeding, leading PTB and fetal death.

Therefore, anticoagulation is recommended over no
anticoagulation, and due to physiological changes, monitoring
through out pregnancy is recommended.
Case vignette 1

UFH has the highest risk of thromboembolic events followd by UFH in
the 1st trimester and warfarin after when compared to warfarin
through out pregnancy (33%, 9.2% versus 4%) and massive
thrombosis of prosthetic valves in pregnancy and maternal risk of
osteoporosis and thrombocytopenia

LMWH has lower risk compared to UFH but valve thrombosis are also
reported

Warfarin is recommended in the second and third trimester with little
teratogenic effect.

Aspirin is recommended in the 2nd and 3rd trimester.
Case vignette 1
warfarin dose < 5
mg
1st trimester
IV UFH q12h
warfarin dose > 5
mg, or < 5 mg but
the patient refuses
warfarin
Pregnant with
mechanical valve
2nd & 3rd trimester
Continue warfarin
Warfarin + aspirin
75 mg
aPTT > 2X control
LMWH q12h
anti-Xa 0.8 – 1.2
U/ml (4 – 6 hours),
Case vignette 1
Planned delivery
Switch warfarin to
LMWH or UFH
Switch to UFH 36
hrs prior to delivery
D/C UFH 4-6 hrs
prior to delivery
Switch to UFH 36
hrs prior to delivery
If the patient on
LMWH
Consider
protamine in
emergent delivery
Urgent delivery
Vitamin K to target
INR of 2
If the patient on
Warfarin
FFP in cases of
emergent delivery
D/C UFH 4-6 hrs
prior to delivery
Case vignette 1

Warfarin crosses the placenta and result in fetus and mother
anticoagulation

Higher risk of intracranial hemorrhage of mother is fully
anticoagulated

Therefore planned vaginal delivery with D/C of warfarin and starting
UFH with aPTT > 2 times ULN is recommended, OR,

Planned C/S with short stop of warfarin
Case vignette 1

Resume UFH gradually at rate 500 U/hr and increase to therapeutic
level over 24 – 72 hours

Warfarin can be started:

Same day of uncomplicated vaginal delivery

24 – 48 hours after C section
Case vignette 2

36 years old female, recently diagnosed with DVT (1/12) on Warfarin
6 mg, came to ER with 5 weeks amenorrhea. A urine pregnancy test
was positive at home and BHCG was 1500 IU/ml. What is next?
Acute VTE
ACCP
2012
Adjusted dose LMWH is preferred over UFH and Warfarin
Therapy to be continued for 6 weeks postpartum and minimum of
3 months
Discontinue LMWH 24 hours before induction of labor or LSCS or
starting of neuraxial anesthesia
Switch to IV UFH for patient with high risk of recurrent DVT of PE
and discontinue 4 – 6 hours prior to delivery or epidural insertion
History of VTE
ACCP
2012
Antepartum clinical vigilance for patient with low risk of
recurrent VTE
Antepartum prophylaxis with prophylactic or
intermediate dose LMWH
Postpartum prophylaxis with prophylactic or
intermediate dose of LMWH, OR
Postpartum prophylaxis with Vitamin K antagonist with
targeted INR 2 - 3
Adjusted dose or 75% of therapeutic dose for patient
on long term Vitamin K antagonist.
Case vignette 2
Drug
Route
Dose
Target
Monitoring
Enoxaparin
SubQ
1 mg/Kg q12h
Increased by 10-25%
Anti-Xa
0.6 to 1.0 IU/mL
Starting: 4 hrs after 3rd or 4th dose
Adjustment: 4 hrs after 3rd dose
Maint.: Every 1-3 months
UFH
IV
80 units/kg then, 18
units/kg per hour
aPTT correspond to Starting: every 6 hrs
anti-Xa 0.3 – 0.7 U. Maint.: 1-2 times/day
SubQ
17500 units q12h
Increased by 10-30%
aPTT correspond to Starting: 6 hrs after 2nd dose
anti-Xa 0.3 – 0.7 U. Maint.: 6 hrs after 2nd dose. Then,
3-4 days, then every few weeks
Frequent monitoring is
recommended > 30/52
Case vignette 2
Labor and
delivery
Low risk
High risk
Very high
risk
D/C 24
hours prior
to delivery
Switched to IV UFH,
D/C 4 to 6 hours
prior to delivery
No neuraxial
anaesthesia
Insert an inferior
Vena cava
catheter. OR
proceed with full
anticoagulation
Unexpected
delivery
Preterm
delivery
expected
No neuraxial
anaesthesia
switch to IV
UFH at 36
weeks
Proceed with full
anticoagulation
Case vignette 2 - Post delivery


Restart LMWH, IV UFH, or SC UFH:

12 hours after a cesarean delivery or

6 hours after a vaginal birth
Warfarin therapy

Warfarin and heparin administered for at least five days.

D/C The heparin if INR within therapeutic range (usually 2 to 3) for
two consecutive days
Breastfeeding


Continue use of the following during breastfeeding

UFH

LMWH

Warfarin

Danaparoid and

R-hirudin
Use alternative anticoagulant during breastfeeding for the following:

Fondaparinux

Oral direct thrombin

Oral Factor Xa inhibitors
“
A baby is something you carry inside you for
nine months, in your arms for three years, and
in your heart until the day you die
MARY MASON
Thank you
”