Anticoagulation During
Pregnancy
Speaker:
Dr. Suneesh.K
Senior Resident, Dept. of Cardiology
24th November 2015
Overview
• Hypercoagulable state of pregnancy
• Review of data and recommendations on anticoagulation
regimens in pregnant patients with PHV*
• DVT** and VTE***
• Other cardiac disorders requiring anticoagulation
• MCQs
*PHV- Prosthetic heart valve
**DVT- Deep vein thrombosis
***VTE - Venous thrombo-embolism
Hypercoagulable state of
pregnancy
Increased
coagulation
factors
Increased
PAI
Decreased
fibrinolysis
Decreased
anticoagulant
factors
Increased
activated
protein c
resistance
1. Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003;16:153–68.
2. Franchini M. Haemostasis and pregnancy. Thromb Haemost 2006;95:401–13.
3. Rosenkranz A, Hiden M, Leschnik B, et al. Calibrated automated thrombin generation in normal pregnancy. Thromb Haemost 2008;99:331–7.
Hypercoagulable state of
pregnancy
• Increased concentration of factors VII, VIII and X
• Increased von Wille-brand factor level
• Decrease in anticoagulant factors, including free and total protein S, as
well as decreased activity during early pregnancy
• Increased activated protein C resistance
• Fibrinolysis is decreased, predominantly because of diminished tPA activity
1. Bremme KA. Haemostatic changes in pregnancy. Best Pract Res Clin Haematol 2003;16:153–68.
2. Franchini M. Haemostasis and pregnancy. Thromb Haemost 2006;95:401–13.
3. Rosenkranz A, Hiden M, Leschnik B, et al. Calibrated automated thrombin generation in normal pregnancy. Thromb Haemost 2008;99:331–7.
Hypercoagulable state of
pregnancy (Contd..)
• PAI-1 and PAI-2 levels are increased
• Placenta produce PAI-2
• Hypercoagulable state of pregnancy last at least 8 weeks after delivery
• Result in a 3-fold to 4-fold increase in arterial thromboembolism*
• 4-fold to 5-fold increase in venous thromboembolism*
• 20-fold increase in both arterial and venous TE in post partum*
*Heit JA, Kobbervig CE, James AH, et al.
Trends in the incidence of venous thromboembolism during pregnancy or postpartum:
a 30-year population based study. Ann Intern Med 2005;143:697–706.
Pregnancy and prosthetic heart valves
Pregnancy and prosthetic heart valves
• Pregnancy presents a unique set of problems for women with PHV
• Increased incidence of thromboembolic events
• Overall incidence of complications in appropriately managed, nonpregnant
patients with PHV is approximately 3 % per year
• Preferred anticoagulant regimen is uncertain
• Bioprosthetic valves typically do not require anticoagulation
Warfarin
• Harmful fetal effects
• FDA Category D for women with PHV and Category X for other pregnant population
• Teratogenic effects appears to be dose related
• 15% to 56% reported risk of miscarriage
• 5% to 30% risk of congenital anomalies and growth retardation
• Placental transfer of warfarin later in pregnancy can result in fetal bleeding or stillbirth
and long-term sequelae
CNS
abnormalities
Pregnancy
loss and fetal
hemorrhage
Warfarin
embryopathy
Warfarin embryopathy
• Chondromalacia punctata with stippled epiphyses
• Nasal and limb hypoplasia
• Optic atrophy
• Microcephaly, mental retardation, spasticity and hypotonia
• Precise risk is unknown, prevalence estimated at 0.6% to 6%
• Different series have reported widely ranging incidences
• Overall estimate of risk is less than 10%
Warfarin embryopathy
Central nervous system abnormalities
• Dorsal midline dysplasia
• Agenesis of the corpus callosum
• Dandy-Walker malformations
• Midline cerebellar atrophy
• Ventral midline dysplasia characterized by optic atrophy;
• Haemorrhage
Central nervous system abnormalities can occur after warfarin
exposure during any trimester
A
B
C
D
Warfarin embryopathy- Evidences in literature
• Reports ranging from none to almost 30%
• Review of 1234 pregnancies calculates a risk of about 6 %*
• This incidence decreased to 3.4% when heparin was used during 1st trimester
• if warfarin was replaced with heparin prior to or at 6th week, no foetal anomalies were seen
• No congenital anomalies were reported in patients exclusively on heparin, throughout the pregnancy
• This review thus upholds the suggestion of previous studies that warfarin embryopathy may be prevented if
oral anticoagulants are discontinued before 6th week and until the 12th week of pregnancy, albeit with an
increased risk of TEC
*Chan WC, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves.
A systematic review of the literature. Arch intern 2000; 160: 191-196.
Warfarin embryopathy- Evidences in literature
• Vitale et al - Demonstrated a close relationship between warfarin dose and foetal
complications
• A total of 58 pregnancies were observed
• 31 healthy babies (30 full term, 1 premature) and 27 fetal complications
• (22 spontaneous abortions, 2 warfarin embryopathies, 1 stillbirth, 1 ventricular septal defect,
1 growth retardation)
• 2 maternal valve thromboses
*Vitale N, Feo MD, DeSanto LS, et al. Dose-dependent foetal complications of
• No fetal or maternal bleeding was observed
warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol. 1999; 33: 1637-1641
Warfarin embryopathy- Evidences in literature
• Warfarin > 5 mg had 22 fetal complications, whereas dose < or = 5 mg had only 5 fetal
complications (p = 0.0001)
• For an increase of the warfarin dose there was a substantially increased probability of
fetal complications (p < 0.0001; p < 0.7316)
• 88% risk of foetal complications and a 9% incidence of warfarin embryopathy in
women on a warfarin dose exceeding 5 mg/day
• Only 15% of women on warfarin doses of <5 mg/day had foetal complications with no
incidence of embryopathy
*Vitale N, Feo MD, DeSanto LS, et al. Dose-dependent foetal complications of
warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol. 1999; 33: 1637-1641
Foetal Loss
• Spontaneous abortion is the most frequent foetal complication
• Both oral anticoagulants and heparin carry this risk
• Inhibition of the immature liver enzyme system of the foetus
• Bleeding at the utero-placental junction
• Replacing warfarin with heparin during 1st trimester prevents the
occurrence of malformations, but this does not translate into an improved
pregnancy outcome
Foetal Loss
• Foetal loss in women receiving heparin predominantly occurs in 1st trimester
• In women receiving OAC- Similar in the 1st and 2nd trimester and lower in the 3rd
trimester
• Chan et al found- Spontaneous abortions similar in the group using OAC
throughout pregnancy (24.7%) and those switching to heparin in 1st trimester
(23.8%)
• Subgroup where warfarin was discontinued and heparin used at 6 weeks of
gestation, suffered least spontaneous abortions (14.7 %)
*Chan WC, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves.
A systematic review of the literature. Arch intern 2000; 160: 191-196.
Embolic complications- Evidences in literature
• Meschengieser et al in prospective study *
• 92 pregnancies in 59 women were followed between 1986 and 1997
• In 31 pregnancies, OAC discontinued when pregnancy was diagnosed and s/c heparin was started (12500 U every 12 hours)
• In 2nd trimester OAC were resumed but changed to heparin again 15 days before the expected delivery date
• In 61 pregnancies oral anticoagulants were continued during the first trimester
• Embolic complications- highest with s/c heparin (4.92 episodes/100 patient-months) than with OAC (0.33 episodes/100 patientmonths)
Oral anticoagulants seem to be safer for the mother than adjusted S/C heparin.
• Abortion or fetal losses were similar (p = 0. 5717) in women exposed to OAC in 1st trimester (13/61; 25%) compared with those
who receiveddoes
adjustednot
S/C heparin
19%) advantage over OAC in the pregnancy outcome
Heparin
offer(6/31;
a clear
*Meschengieser SS, Fondevila CG, Santarelli MT, Lazzari MA.
Anticoagulation in pregnant women with mechanical heart valve prostheses. Heart 1999; 82: 23-26
Embolic complications- Evidences in literature
• Salazar's study
• 40 patients
• Terminated prematurely on account of two fatal incidences of massive thrombosis of mechanical valve
• Acenocoumarol was substituted with S/C UFH between 6th to 12th weeks
• Both patients with thrombosis had strictly followed aPTT level 55 to 95 sec (Control 30 to 35 sec)
• No thromboembolic events were observed, while the patients were receiving Acenocoumarol
• No signs of coumarin-induced embryopathy were found
• Conclusion- S/C heparin was not effective in preventing thromboembolic phenomena in these patients
*Salazar E, Izaguirre R, Verdejo J, Mutchinick O.Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic
phenomena in pregnant patients with mechanical cardiac valve prosthesis. J Am Coll Cardiol 1996; 27: 1698 -1703.
Embolic complications- Evidences in literature
'HIP-CAT' study (Heparin in Pregnancy-Cardiac Valve Thromboprophylaxis)*
• RCT- designed to compare Enoxaparin with Warfarin and UFH in pregnant women with new-generation PHV
• Enoxaparin (1 mg/kg twice daily) S/C
• Adjusted to maintain a peak (3 hours post-dose) anti-Xa level below 1.2 U/mL
• Study was prematurely discontinued after 2 of the 7 patients who were treated with enoxaparin developed
fatal valve dysfunction
• None of the 4 patients in the heparin/warfarin group died
• A review of anti-Xa levels in all 7 patients treated with enoxaparin in this study demonstrated occasional sub
therapeutic trough values in most of the patients
*Elkayam U, Singh H, Irani A, Akhter MW. Anticoagulation in pregnant women with prosthetic heart valves.
J Cardiovasc Pharmacol Therap 2004; 9: 107-115.
Embolic complications- Evidences in literature
• Literature review by Oran B et al
• Reviewed pregnancies in women with mechanical heart valves treated with LMWH
A very significant increase in thromboembolic events with heparin
• 81 pregnancies in 75 women
•
use
is
evident
from
the
data
available,
and
some
recommend
an
Proportion of valve thrombosis was 8.64%
exclusive
oral
anticoagulant
• Overall
frequency
of TEC
was 12.35%
use throughout the first trimester,
on the
relatively
incidence
of malformations
•banking
51 pregnancies
where
anti Xa levelslower
were monitored,
only one
patient had TEC
reported
• Frequency of live births with LMWH
87.65%literature
inwas
recent
Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in women with prosthetic
mechanical heart valves during pregnancy.Thromb Haemost. 2004; 92: 747-751
Maternal bleeding complications
• Chan and colleagues*
• Systematic review of 28 studies- 976 women with 1234 pregnancies from 1966 to 1997
• Overall rate of major bleeding - 2.5%
• Similar to the risk of bleeding with either heparin therapy (2% in pregnant females with or
without mechanical heart valves and 3.7 in non pregnant females for deep vein thrombosis
prophylaxis) or warfarin therapy (3.1% in non pregnant females with mechanical heart valves)
• Bleeding complications appear to be rare with LMWH
• Out of a total of 31 episodes of bleeding, 25 occurred in patients on heparin
*Chan WC, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves.
A systematic review of the literature. Arch intern 2000; 160: 191-196.
Unfractioned heparin
• Does not cross placenta
• FDA category C
• Does not anticoagulate fetus
• Bleeding at the uteroplacental junction is possible
• HIT and osteopenia
• Increased heparin requirement during pregnancy
• Incidence of HIT is low in pregnancy, but the risk is unknown
Low-Molecular-Weight Heparin
• Does not cross placenta
• FDA category B
• Shorter half-life
• Lower peak plasma concentration during pregnancy
• Lower risk of bleeding complications, spontaneous abortion, and
osteoporosis
• Requires higher doses and sometimes more frequent administration
Low-Molecular-Weight Heparin
• Risk of thrombocytopenia and osteoporosis
• Too low target anti-Xa levels or poor compliance contribute to valve thrombosis
pregnancy
• In 2002, FDA mandated a warning in the package insert of enoxaparin, which
stated that the product is not recommended for anti-thrombotic prophylaxis in
patients with PHV; that cases of PHVT, maternal and foetal deaths are reported
with the use of this drug; and that in pregnant women who received this drug,
both teratogenic and non-teratogenic effects have been reported
Low-Molecular-Weight Heparin
• Review of 624 pregnancies in which LMWH was used- no foetal / neonatal adverse effects*
• In 2002, a cardiology consensus statement concluded - role of enoxaparin in pregnant women
with mechanical valves should be more appropriately considered unproven and imperfectly
studied alternative among a trio of suboptimal and potentially unfavourable options
• In view of these reports, the labelling has been rephrased in 2004, suggesting that its use for
thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been
adequately studied
*Lepercq J, Conard J, Borel-Derlon A, et al. Venous thromboembolism during pregnancy:
a retrospective study of enoxaparin safety in 624 pregnancies. Br J Obstet Gynaecol 2001; 108:
Low-Molecular-Weight Heparin
• No LMWH is officially approved (labelled) for pregnant women with PHV
• Superiority of either UFH or LMWH in the first trimester is unproven, though recent
review suggests higher efficacy of LMWH*
• *Retrospective study of 12 pregnancies with MHV, 6 in aortic, 4 in mitral, and 2 in
both positions. Treated with therapeutic doses of S/C LMWH twice daily throughout
pregnancy. Doses were adjusted using anti-Xa monitoring
* Abildgaard U, Sandset PM, Hammerstrom J, Gjestvang FT, Tveit A.
Management of pregnant women with mechanical heart valve prosthesis:
Thromboprophylaxis with low molecular weight heparin. Thromb Res 2009;124:262–267
Low-Molecular-Weight Heparin
• Treatment with adjusted therapeutic doses of LMWH was successful in 10 of 12
pregnancies
• Not associated with fetal complications
• Thromboembolism occurred in 2 pregnancies, possibly attributed to subtherapeutic
doses of LMWH during the initial 3 weeks
• Compared to UFH, therapeutic doses of LMWH appears to be more efficacious
Abildgaard U, Sandset PM, Hammerstrom J, Gjestvang FT, Tveit A.
Management of pregnant women with mechanical heart valve prosthesis:
Thromboprophylaxis with low molecular weight heparin. Thromb Res 2009;124:262–267
LMWH for the prophylaxis of thromboembolism
in women with prosthetic mechanical heart valves
during pregnancy- A meta analysis
• 81 pregnancies in 75 women
• Proportion of valve thrombosis was 8.64% (7/81; 95% CI, 2.52%-14.76%)
• Frequency of overall thromboembolic complication (TEC) was 12.35% (10/81)
• 9 of 10 patients with TEC received a fixed dose of LMWH
• 2 of these received a fixed low dose of LMWH
Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in
women with prosthetic mechanical heart valves during pregnancy.
Thromb Haemost 2004;92:747–51.
LMWH for the prophylaxis of thromboembolism
in women with prosthetic mechanical heart valves
during pregnancy- A meta analysis
• Among 51 pregnancies whose anti-factor Xa levels were monitored, only one patient was
reported to have a thromboembolic complication
• Frequency of live births with LMWH was 87.65% (95%CI, 80.49%-94.81%)
• Use of LMWH warrants monitoring and appropriate dose adjustments to maintain a 4-6
hr post-injection anti-factor Xa level at a minimum of 1.0 U/ml to decrease incidence of
TEC
Oran B, Lee-Parritz A, Ansell J. Low molecular weight heparin for the prophylaxis of thromboembolism in
women with prosthetic mechanical heart valves during pregnancy.
Thromb Haemost 2004;92:747–51.
Anticoagulation of Pregnant Women With
Mechanical Heart Valves- A Systematic Review
Thromboembolic event
• Warfarin alone 3.9%
• Heparin in the first trimester followed by warfarin 9.2%
• Heparin throughout pregnancy 25%
Maternal death
• Warfarin alone 1%
• Heparin in the first trimester 4.2%
• Heparin throughout pregnancy 6.7%
Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves:
a systematic review of the literature. Arch Intern Med. 2000;160:191–196.
Study on risk of warfarin during pregnancy
with mechanical valve prostheses
• Between 1987 and 2000
• 52 patients with MPHV who had 71 pregnancies- warfarin for the entire duration of pregnancy
• Pregnancy loss occurred in 23 of 71 of pregnancies
• Stillbirth in 5 of 71
• Embryopathy in four of 71 (two aborted fetuses and two full-term infants)
Incidence of embryopathy was low (2.6%) when the warfarin dose was less than 5
• No maternal deaths or thromboembolic or hemorrhagic complications
mg and 8% when the warfarin dose was more than 5 mg daily
• Warfarin daily dosage over 5 mg per day was a significant predictor of poor pregnancy outcome (P
<.001)
The dose dependency was confirmed in a recent series
Cotrufo M, De Feo M, De Santo LS, Romano G, Della Corte A, Renzulli A, Gallo C.
Risk of warfarin during pregnancy with mechanical valve prostheses. Obstet Gynecol. 2002;99:35–40.
Class I
• All patients with a PHV should undergo a clinical evaluation and baseline TTE
before pregnancy (Level of Evidence: C)
• TTE should be performed in all pregnant patients with a prosthetic valve if not
done before pregnancy
• Repeat TTE should be performed in all pregnant patients with a prosthetic valve
who develop symptoms (Level of Evidence: C)
Class I
• TEE should be performed in all pregnant patients with a mechanical PHV who have
PHV obstruction or experience an embolic event
• Pregnant patients with a mechanical prosthesis should be monitored in a tertiary
care centre with a dedicated Heart Valve Team of cardiologists, surgeons,
anesthesiologists, and obstetricians with expertise in the management of high-risk
cardiac patients (Level of Evidence: C)
Class I
• Therapeutic anticoagulation with frequent monitoring is recommended for all
pregnant patients with a mechanical prosthesis
• Warfarin is recommended in pregnant patients with a mechanical prosthesis to
achieve a therapeutic INR in the 2nd and 3rd trimesters
• Discontinuation of warfarin with initiation of intravenous UFH (aPTT >2 times
control) is recommended before planned vaginal delivery
Class I
• Low-dose aspirin (75 mg to 100 mg) once per day is recommended for pregnant
patients in the 2nd and 3rd trimesters with either a mechanical prosthesis or
bioprosthesis
Class IIa
• Continuation of warfarin during the first trimester is reasonable for pregnant patients
with a mechanical prosthesis if the dose of warfarin to achieve a therapeutic INR is 5
mg/day or less after full discussion with the patient about risks and benefits
• Dose-adjusted LMWH at least 2 times per day (with a target anti-Xa level of 0.8 U/mL to
1.2 U/mL, 4 to 6 hours post dose) during 1st trimester is reasonable for pregnant patients
with a mechanical prosthesis if the dose of warfarin is greater than 5 mg per day to
achieve a therapeutic INR
Class IIa
• Dose-adjusted continuous intravenous UFH (with an aPTT at least 2
times control) during 1st trimester is reasonable for pregnant patients
with a mechanical prosthesis if the dose of warfarin is greater than 5
mg/day to achieve a therapeutic INR
Class IIb
• Dose-adjusted LMWH at least 2 times per day (with a target anti-Xa level of 0.8 U/mL
to 1.2 U/mL, 4 to 6 hours postdose) during 1st trimester may be reasonable for
pregnant patients with a mechanical prosthesis if the dose of warfarin is 5mg/day or
less to achieve a therapeutic INR
• Dose-adjusted continuous infusion of UFH (with aPTT at least 2 times control) during
1st trimester may be reasonable for pregnant patients with a mechanical prosthesis if
the dose of warfarin is 5 mg/day or less to achieve a therapeutic INR
Class III
• LMWH should not be administered to pregnant patients with
mechanical prostheses unless anti-Xa levels are monitored 4 to 6 hr
after administration
• Continuation of OACs throughout pregnancy should be considered when the
warfarin dose is less than 5 mg/d or phenprocoumon less than 3 mg or
acenocoumarol less than 2 mg daily
• OACs throughout pregnancy is the safest regimen and the risk for embryopathy is
less than 3% if warfarin requirement is less than 5 mg daily
• Anti factor Xa level should be measured once weekly if LMWH is used
• Dose should be adjusted according to increasing weight and anti-Xa levels
• In the case of OACs, INR should be determined at weekly intervals
• Task Force does not recommend the addition of acetylsalicylic acid because there
are no data to prove its efficacy and safety in pregnancy
• Use of LMWH in 1st trimester is limited by the scarceness of data
Follow-up
• Effectiveness of the anticoagulation regimen should be monitored
weekly and clinical follow-up including echo should be performed
monthly
Diagnosis and management of
valve thrombosis
• Comparable with management in non-pregnant patients
• This includes optimizing anticoagulation with i.v. heparin and
resumption of oral anticoagulation in non-critically ill patients and
surgery when anticoagulation fails and for critically ill patients with
obstructive thrombosis
Diagnosis and management of
valve thrombosis
• Most fibrinolytic agents do not cross the placenta
• Risk of embolization 10% and subplacental bleeding is a concern
• Because fetal loss is high with surgery, fibrinolysis may be considered
instead of surgery in non-critically ill patients when anticoagulation fails
• Fibrinolysis is the therapy of choice in right-sided prosthetic valve
thrombosis
Thrombolysis During Pregnancy
• 131I-labeled streptokinase or tissue plasminogen activator studies showed
minimal transplacental passage
• There have been reports of successful thrombolysis in pregnancy(most involving
streptokinase)
• But data regarding safety of thrombolysis is limited
• Thrombolytic therapy is best reserved for life-threatening maternal
thromboembolism
Management of valve thrombosis during
pregnancy- Literature review
• In a series of 10 women treated for 12 episodes of valve thrombosis-12 years
• Surgery (4 cases)
• Thrombolysis (7 cases)
• Heparin (1 case)
• In the surgical group- 1 maternal death and 1 additional fetal death
• In the thrombolysis group- 2 maternal deaths, 1 bleeding event requiring surgical
drainage, but no fetal mortality in the surviving women
Sahnoun-Trabelsi I, Jimenez M, Choussat A, Roudaut R. Prosthetic valve thrombosis in pregnancy.
A single-center study of 12 cases; Arch Mal Coeur Vaiss 2004; 97:305
Management of valve thrombosis during
pregnancy- Literature review
• Reports of both cardiac surgery and thrombolysis in pregnant women are less
• Patient numbers are small and no direct comparisons
Surgical mortality is higher than fibrinolysis
• Weiss BM et al*
• Review of published reports of cardiac surgery during pregnancy
• Total of 70 patients -1984 to 1996 (34 years)
• Perioperative maternal mortality 6 %
• Perioperative fetal mortality 30 %
* Weiss BM, von Segesser LK, Alon E, et al. Outcome of cardiovascular surgery and pregnancy:
a systematic review of the period 1984-1996. Am J Obstet Gynecol 1998; 179:1643.
Management of valve thrombosis during
pregnancy- Literature review
• Turrentine et al
• A review of thrombolysis during pregnancy
• Included 172 patients
• Maternal mortality 1.2%
• Hemorrhagic complications 8%
• Fetal mortality rate 5.8%
Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic
disease during pregnancy. Obstet Gynecol Surv 1995; 50:534. 3.
Change in anticoagulation during delivery
• OAC should be switched to LMWH or UFH, no later than 36 weeks
• Women treated with LMWH should be switched to IV UFH at least 36 hours prior to the induction of labour
or CS , in order to provide tighter control of anticoagulation throughout the peripartum period
• IV UFH should be discontinued four to six hours prior to anticipated delivery, and should be restarted four to
six hours after delivery at a low infusion rate (500 u/h) if there are no bleeding complications
• Depending on the clinical circumstances, the IV UFH dose should be increased back to therapeutic levels
over 24 to 72 hours
• Cessation of low-dose aspirin in the week prior to planned delivery should be considered.
Urgent delivery
• Life-threatening maternal hemorrhage can occur in this setting, but the risk of
hemorrhage must be balanced against risk of valve thrombosis if anticoagulation
is reversed
• Full reversal of anticoagulation is not necessary for either vaginal or CS
• Partial reversal may be indicated (eg, target INR of approximately 2.0),
particularly if the patient is overanticoagulated
• Full reversal is warranted in patients with life-threatening maternal hemorrhage
Urgent delivery in patients on UFH / LMWH
• If time allows, discontinuation of therapy and a delay of four to six
hours is preferred
• Vaginal delivery is preferred unless there are obstetric indications for
cesarean delivery
• If emergent delivery is necessary, protamine should be considered
Urgent delivery in
patients on OAC with an elevated INR
• Fetus is also therapeutically anticoagulated
• CS is preferred to reduce risks of fetal trauma and hemorrhage
• If time allows, delay and/or administration of small doses of vitamin K to a target INR of 2.0 should permit
safe CS
• If emergent delivery is necessary, FFP should be administered prior to CS in sufficient amount to reach a
target INR of 2.0
• Depending upon timing and dose, administration of vitamin K to the mother prior to delivery can also
reverse the effect of OAC’s in the fetus
• If the mother was not fully reversed at the time of delivery, the new-born may be given FFP and vitamin K
Butchart EG, Gohlke-Bärwolf C, Antunes MJ, et al. Recommendations for
the management of patients after heart valve surgery. Eur Heart J 2005; 26:2463.
Postpartum
• In the absence of significant bleeding, anticoagulation should be resumed shortly after delivery
• IV UFH or SQ LMWH should be resumed four to six hours after delivery at a prophylactic dose,
gradually increasing the dose to achieve therapeutic anticoagulation over 24 to 72 hours
• Use of IV UFH post partum may allow more rigorous control of anticoagulation in post CS patient
• After an uncomplicated vaginal delivery, OAC’s can be resumed the same day
• If caesarean section this should be delayed for 24-48 hours (No consensus)
• Heparin can be discontinued once the INR is in the therapeutic range
Contraception
• Patients need guidance about contraception, as unplanned pregnancies are hazardous
• PHV have shorter life expectancy, and this need makes vasectomy unattractive
• Barrier methods can be recommended, but have higher failure rates
• Oral contraceptives increase thromboembolic risk
• Progesterone only pills have low thromboembolic risk
• Oligo-menorrhea is common with progesterone only pills, and this is an added advantage
• Intrauterine devices (IUDs) carry risk of increased bleeding and also of endocarditis
• IUCD are contra-indicated in patients with past history of endocarditis
Rajiv Bajaj,a,v G. Karthikeyan,b,v Nakul Sinha et al
CSI consensus statement on prosthetic valve follow up, Indian Heart J. 2012 Dec; 64(Suppl 2): S3–S11.
Danaparoid Exposure In Utero
• Negligible transport of danaparoid across the placenta
• There is no demonstrable fetal toxicity with maternal danaparoid use
• However, the quality of evidence available to support that claim is low
• Danaparoid was withdrawn from the US market in 2002
Pentasaccharide Exposure In Utero
• No placental passage of Fondaparinux was demonstrated in human cotyledon model
• Anti-Xa activity (at approximately one-tenth the concentration of maternal plasma) was
found in umbilical cord plasma of five newborns of mothers treated with fondaparinux*
• Quality of evidence regarding supporting use of fondaparinux in pregnancy is very low
• Potential deleterious effects on the fetus cannot be excluded
*Dempfle CE. Minor transplacental passage of fondaparinux in vivo. N Engl J Med. 2004; 350: 1914–1915
Pentasaccharide Exposure In Utero
• Case has been reported describing the successful management with
fondaparinux, during 150 days, of a pregnant patient with protein S deficiency
and prior deep vein thrombosis (DVT) who developed heparin and danaparoid
hypersensitivity*
*Mazzolai L, Hohlfeld P, Spertini F, Hayoz D, Schapira M, Duchosal MA.
Fondaparinux is a safe alternative in case of heparin intolerance during pregnancy.
Blood. 2006; 108: 1569–1570.
Parenteral Direct Thrombin Inhibitor
Exposure In Utero
• r-Hirudin will cross across placenta
• Fetal toxicity in animal studies
• No published reports on the use of bivalirudin in pregnancy
New Oral Direct Thrombin and
Anti-Xa Inhibitor Exposure In Utero
• Pregnant women were excluded from participating in clinical trials
evaluating these new agents
• No published reports describing the use of new oral direct thrombin
inhibitors (eg, Dabigatran) or anti-Xa inhibitors (Rivaroxaban,
Apixaban) in pregnancy
• Human reproductive risks of these medications are unknown
Aspirin Exposure In Utero
• Aspirin crosses the placenta
• Animal studies showed risk of congenital anomalies when used in 1st trimester
• Small-doses of aspirin are safe during the 2nd and 3rd trimesters
• Aspirin reduces the incidence of systemic embolization or death when added to OAC in the nonpregnant population with mechanical heart valve
• Based on current data, 80-100 mg of aspirin during 2nd and 3rd trimester may be added to
improve antithrombotic effects (ACC/AHA)
• Dipyridamole should not be considered an alternative antiplatelet agent
Venous Thrombo-Embolism
during Pregnancy and Puerperium
VTE and pregnancy
• Pregnancy and puerperium- increased of VTE
• Incidence of 0.05–0.20% of all pregnancies
• VTE- 2nd most common cause of maternal death overall
• Case fatality rate is 3.5%
• VTE risk- highest in the immediate post-partum period
• CS > more risk than normal delivery
• Risk return to normal by 6 weeks post partum
Risk factors for VTE in pregnancy
• 79% of women dying from an antenatal PE have identifiable risk factors
• Most significant risk factors for VTE in pregnancy are history of unprovoked
DVT or VTE and thrombophilias
• Half of the women who develop a thrombotic event during pregnancy have
either a thrombophilic disorder or a previous idiopathic VTE
Risk factors for VTE in pregnancy
Pre-existing
risk factors
Transient
risk factors
Obstetric
risk factors
Management of acute
venous thrombo-embolism
• Clinical symptoms and signs are the same as in the non-pregnant
state
• Subjective clinical assessment of pulmonary embolism is, however,
more difficult
Management of acute
venous thrombo-embolism- Diagnosis
D-Dimer
• D-Dimer levels increase physiologically with each trimester
• Mean preconception D-dimer concentration 0.43 (SD 0.49) mg/L, and rose in the first, second,
and third trimester to 0.58 mg/L (SD 0.36), 0.83 (SD 0.46) mg/L, and 1.16 (SD 0.57) mg/L,
respectively, indicating a 39% relative increase in D-dimer concentration for each trimester
compared with the previous one
• Thus a positive D-dimer test based on the conventional cut-off level is not necessarily indicative of
VTE and new cut-off levels are needed
Management of acute
venous thrombo-embolism- Diagnosis
Compression ultrasound
• D-dimer should be measured in patients with suspected PE, followed by b/l compression USG of LL
veins
• If this is normal in the presence of negative D-dimer levels, PE is unlikely and anticoagulation with
LMWH is not warranted
• If positive D-dimer levels and positive USG, anticoagulation is indicated
• If D-dimer levels are elevated and compression USG is negative in suspected patients, further testing is
required
Management of acute
venous thrombo-embolism- Diagnosis
• MRV has high sensitivity and specificity for the diagnosis of iliac vein
thrombosis
• CTPA for definitive diagnosis of PE, if other modalities fail
• CTPA preferred over V-P scan
Treatment of acute massive
venous thrombo-embolism
Thrombolysis
• Thrombolysis is relatively contraindicated during pregnancy and peripartum
and should only be used in high risk patients with severe hypotension or shock
• Risk of haemorrhage, mostly from the genital tract, is 8%
• Both SK and r-tPA do not cross the placenta in significant amounts
• 6% fetal loss and 6% pre-term delivery were reported
Treatment of acute
venous thrombo-embolism
• LMWH is the DOC for prevention and Rx of VTE, instead of UFH
• Recommended therapeutic dose is calculated on body weight
• Enoxaparin 1 mg/kg twice daily
• Dalteparin 100 IU/kg twice daily
• Aiming for 4–6 h peak anti-Xa values of 0.6–1.2 IU/mL
• UFH if CrCl <30 or acute treatment of massive pulmonary emboli
Treatment of acute
venous thrombo-embolism
Monitoring
• The necessity to monitor anti-Xa values regularly in patients with VTE is still
controversial
• It is reasonable to determine anti-Xa levels also during pregnancy in patients with
VTE
• Dose adjustment with increase in weight gain of pregnancy is recommended
Treatment of acute massive
venous thrombo-embolism
UFH Dosage
• In patients with acute PE with haemodynamic compromise, i/v UFH is
recommended
• Loading dose of 80 U/kg, followed by a continuous i.v infusion of 18 U/kg/h
Treatment of acute massive
venous thrombo-embolism
Monitoring
• aPTT has to be determined 4–6 h after the loading dose, 6 h after any dose change, and
then at least daily when in the therapeutic range
• Therapeutic target aPTT ratio is 1.5-2.5 times average laboratory control value
• Dose is then titrated to achieve a therapeutic aPTT, defined as the aPTT that corresponds
to an anti-Xa level of 0.3–0.7 IU/mL
• When haemodynamics are improved, UFH can be switched to LMWH
Treatment of acute massive
venous thrombo-embolism
• LMWH should be switched to i.v. UFH at least 36 h before induction of labour or CS
• UFH should be discontinued 4–6 h before anticipated delivery, and restarted 6 h
after delivery if there are no bleeding complications
• Neither UFH nor LWMH is found in breast milk in any significant amount
Treatment of acute massive
venous thrombo-embolism
Post-partum management of acute VTE pregnant patient
• Pre-partum heparin treatment should be restarted 6 h after a vaginal birth
and 12 h after a CS with subsequent overlap with VKA for at least 5 days
• Start VKA on 2nd day and continued for at least 3 m or for 6 m
• INR should be 2-3
• Vitamin K antagonists do not enter the breast milk in active forms
•
Treatment of acute massive
venous thrombo-embolism
• Fondaparinux and rivaroxaban are not recommended
• Indications for vena cava filters are the same as in non-pregnant patients, but
procedure risk increases
Acute deep vein thrombosis
• DVT is left sided in 85% of cases
• Isolated iliac vein thrombosis may manifest with isolated pain in the
buttock, groin, flank, or abdomen
A clinical decision rule, considering three variables,
• Left leg presentation
• More than 2 cm calf circumference difference
• First trimester, allowed a NPV of 100% (95% CI 95.8–100%)
Acute deep vein thrombosis
• Compression USG is the diagnostic imaging of choice for suspected DVT in pregnancy
• High sensitivity & specificity for proximal DVT, but less for distal DVT and pelvic vein DVT
• Serial compression USG evaluations at days 0, 3, and 7 in pregnancy gives a high NPV of
99.5% (95% CI 97–99% %)
• All suspected DVT in pregnancy should undergo D-dimer and then compression USG
Acute deep vein thrombosis
• If a proximal DVT is detected, Rx should be continued
• In women with a high pre-test probability, a positive D-dimer and a normal initial
compression USG, MRV may be considered to exclude isolated pelvic DVT
• Women with low pre-test probability and normal D-dimer should undergo serial
compression ultrasonography on day 3 and day 7 without anticoagulation
• When compression USG remains negative, DVT can be excluded
• Rx in acute DVT is therapeutic doses of weight adjusted LMWH twice daily
VTE - Prophylaxis
• Recurrence rate of VTE ranged from 2.4% to 12.2%, if no anticoagulation
• LMWH is the drug of choice for prophylaxis
• No studies available on the optimal prophalatic dose and weight ranges
• High risk patients should receive usual prophylactic dose of 0.5 IU /kg
enoxaparin or 50 IU/kg dalteparin twice daily
VTE following cesarean section
• Puerperium is the time of maximal daily risk of pregnancy-associated
VTE
• Absolute risk estimates ranging from , 1 in 1,000 up to 18 of 1,000
cesarean deliveries
VTE following cesarean section
• For women undergoing CS without additional thrombosis risk factors,
thrombosis prophylaxis is not indicated other than early mobilization
• For women at increased risk of VTE after CS because of the presence of one
major or at least two minor risk factors, pharmacologic thromboprophylaxis or
mechanical prophylaxis (if high bleeding risk) recommended (Grade 2B)
Shannon M . Bates et al; VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis,9th ed
American College of Chest Physicians- Evidence-Based Clinical Practice Guidelines 2012
VTE following cesarean section
• For women undergoing CS who are considered to be at very high risk for VTE
and who have multiple additional risk factors for thromboembolism that
persist in the puerperium, prophylactic LMWH is suggested with elastic
stockings and/or intermittent pneumatic compression (Grade 2C)
• For selected high-risk patients in whom significant risk factors persist following
delivery, extended prophylaxis (up to 6 weeks after delivery) is suggested
Shannon M . Bates et al; VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis,9th ed
American College of Chest Physicians- Evidence-Based Clinical Practice Guidelines 2012
VTE Prophylaxis
• For pregnant women with no prior history of VTE who are known to be homozygous
for factor V Leiden or prothrombin 20210A mutation and have a positive family
history for VTE, antepartum prophylaxis is recommended with prophylactic- or
intermediate-dose LMWH and postpartum prophylaxis for 6 weeks with
prophylactic- or intermediate-dose LMWH or VKA targeted (Grade 2B)
• For all other thrombophilias, with a positive family history for VTE, antepartum
clinical vigilance and postpartum prophylaxis is recommended
Shannon M . Bates et al; VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis,9th ed
American College of Chest Physicians- Evidence-Based Clinical Practice Guidelines 2012
VTE Prophylaxis
• For pregnant women with no prior history of VTE who are known to be
homozygous for factor V Leiden or the prothrombin 20210A mutation and
who do not have a positive family history for VTE, antepartum clinical
vigilance and postpartum prophylaxis for 6 weeks with prophylactic- or
intermediate dose LMWH or vitamin K antagonists targeted at INR 2.0 to 3.0 is
recommended
Shannon M . Bates et al; VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis,9th ed
American College of Chest Physicians- Evidence-Based Clinical Practice Guidelines 2012
VTE Prophylaxis
• For women with recurrent early pregnancy loss (3 or more miscarriages before 10
weeks of gestation), screening for APLAs is recommended (Grade 1B)
• For women who fulfil the lab criteria for APLAs and meet the clinical APLA criteria
based on a history of 3 or more pregnancy losses, antepartum administration of
prophylactic- or intermediate dose UFH or prophylactic LMWH combined with lowdose aspirin, 75 to 100 mg/d, is recommended (Grade 1B)
Shannon M . Bates et al; VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis,9th ed
American College of Chest Physicians- Evidence-Based Clinical Practice Guidelines 2012
Thromboprophylaxis in Women Using Vitamin K
Antagonists and Planning Pregnancy
• Following two options can reduce the risk of warfarin embryopathy:
1. Performance of frequent pregnancy tests and substitution of adjusted-dose
LMWH or UFH for warfarin when pregnancy is achieved
2. Replacement of vitamin K antagonists with LMWH or UFH before conception
is attempted
Shannon M . Bates et al; VTE, Thrombophilia, Antithrombotic Therapy, and Pregnancy
Antithrombotic Therapy and Prevention of Thrombosis,9th ed
American College of Chest Physicians- Evidence-Based Clinical Practice Guidelines 2012
Anticoagulation in Atrial Fibrillation
Anticoagulation in atrial fibrillation
• New onset AF is rare in pregnancy
• AF can be secondary to structural heart disease or lone AF
• AF during pregnancy is well tolerated in most patients without VHD or CHD
• Role of anticoagulation to prevent systemic arterial embolism has not been
systematically studied in pregnant patients with nonvalvular AF
• Anticoagulation therapy is not required in pregnant women with a short lone episode of
AF
Anticoagulation in atrial fibrillation
• Thromboprophylaxis is recommended in high risk nonvalvular AF patients with
pregnancy
• Choice of the anticoagulant is made according to stage of pregnancy
• VKA are recommended from 2nd trimester until 1 month before expected delivery
• LMWH is recommended during 1st trimester and last month of pregnancy
• Dabigatran have shown fetotoxicity with high doses and should not be used in
pregnancy
Anticoagulation in Mitral stenosis
• Mitral stenosis is the most common valvular heart disease in
pregnancy
• Carries a significant risk of thromboembolism
• Therapeutic anticoagulation is recommended in the case of AF, LA
thrombus, or prior embolism (Class I C)
Peripartum cardiomyopathy
• Anticoagulation is recommended if Intracardiac thrombus, evidence
of systemic embolism or AF (Class I)
• LMWH or vitamin K antagonists are recommended according to the
stage of pregnancy to prevent stroke
• When LMWH is used, anti-Xa levels should be monitored
Clinical implications and
remaining unanswered questions..
• Limited data regarding anticoagulation during pregnancy and there is no
perfect anticoagulation regimen for the pregnant woman with PHV
• Current guideline recommendations were written in terms of generalisation
for all PHV
• Thrombotic risk of each prosthesis vary at each position
• The socioeconomic aspects of each approach must also be considered
Clinical implications and
remaining unanswered questions..
• The use of warfarin during 2nd or 3rd trimester is not a universally accepted
approach because..
• Methodology for giving and monitoring LMWH— the optimal peak factor Xa level
required for dose adjustment, the appropriate frequency of monitoring and dosing,
and the utility of using trough as well as peak levels of factor Xa are to be addressed
• The additive benefit of measuring other factors that LMWH impacts, such as factor II
levels, has yet to be explored
Clinical implications and
remaining unanswered questions..
• The exact ‘cut-off’ dosage of VKA balancing the risk of maternal thrombosis
versus fetal outcome needs to be further evaluated
• The additive use of low-dose aspirin appears to be helpful but unproven,
recommended by the AHA/ACC guidelines but not the ESC guidelines
• The safest approach to restarting anticoagulation following delivery remains
to be determined
Take home message
• Normal pregnancy is accompanied by changes in hemostasis that produce a hypercoagulable state
• Most clotting factors usually increase in pregnancy, whereas several anticoagulants and fibrinolytic
activity decrease
• The optimal care for a young woman with valvular heart disease requires pre-pregnancy counselling
• The selection of an anticoagulation regimen must be individualised and requires long and detailed
discussions with the patient and partner
• The safety of the mother should be weighed against the desire for an optimal fetal outcome
Take home message
• Women are at an increased risk of both venous and arterial thromboembolism during pregnancy
• Candidates for anticoagulation are women with a current thrombosis, a history of thrombosis,
thrombophilia, and a history of poor pregnancy outcome, or postpartum risk factors for VTE
• For fetal reasons, the preferred agents for anticoagulation for VTE in pregnancy are heparins
• Prophylactic anticoagulation is indicated in patients with MS with AF or a previous history of TE
• Anticoagulation therapy is not required in pregnant women with a short episode of lone AF
• There are no large trials of anticoagulants in pregnancy and recommendations are based on case
series and the opinion of experts
MCQs
1. Maximum risk of VTE is at?
A. 3rd trimester
B. 2nd and 3rd trimester
C. Immediate post partum
D. 1weeks after delivery
2. Which of the following is not a high risk
factor for VTE in pregnancy?
A. Previous recurrent VTEs
B. Pre-eclampsia
C. Previous unprovoked VTE
D. Previous estrogen-related VTE
3. True about Hypercoagulable state
of pregnancy except
A. Increased concentration of factor VIII
B. Protein C level remain unchanged
C. Decreased activated protein C resistance
D. Decreased tPA activity
4. What is the risk of embryopathy if the warfarin is given
in the 1st trimester at a dose more than 5 mg/day, as per
currently available data in literature?
A. 56%
B. 2.6%
C. 8%
D. 25%
5. Which is not a Class I recommendation according to ESC
guidelines regarding management of VTE in pregnancy?
A. High risk patients should receive 6week LMWH prophylaxis postpartum
B. Both D-Dimer and compression USG is recommended in pregnant
patients with suspected VTE
C. For Rx of acute VTE during pregnancy, UFH is recommended in highrisk and LMWH in non-high risk patients
D. In intermediate risk patients with 3 or more risk factors, antenatal
prophylaxis with LMWH should be considered
6. Normal pregnancy is accompanied by increased
concentrations of clotting factors except?
A. Factor VII
B. Factor VIII
C. Factor X
D. Factor II
7. Which of the following is not a CNS teratogenic
effect of warfarin?
A. Limb hypoplasia
B. Optic atrophy
C. Dandy-Walker malformations
D. Sensory neural hearing loss
8. The most important risk factor for VTE in
pregnancy is
A. History of heart disease
B. History of thrombosis
C. Factor V Leiden–homozygosity
D.Factor V Leiden–heterozygosity
9. What is the target anti-Factor Xa level (IU/mL) at 1st
trimester if LMWH is given in PHV patient?
A. 0.8-1.2
B. 1.2-1.8
C. 0.6-0.8
D.0.1-0.15
10. What is this sign called?
Which drug is responsible?
"Viking helmet"
Thank you