Pregnancy and puerperium are well established risk factors for venous thromboembolism
Risk factors of VTE OR History of VTE 16–35 Trauma13 Surgery 6–22 Pregnancy 10 Cancer 6 Travel 2–4 Obesity 2–4 Thrombophilias 2–50
VTE is rare in young adults Insidence : 0.76 – 1.72 / 1000 pregnancies Heit JA,et al. Ann Intern Med 2005;143:697
Maternal mortality PE was the most common couse of pregnancy-releated death 1.1 – 1.5 / 100.000 deliveries 1/3 of all maternal deaths • Delayed diagnosis , • Delayed or inadequate treatment, • Inadequated thromboprophylaxis CEMACH 2007
Pregnancy Pregnancy is an acquired thrombophilia
Risk factors for VTE in pregrancy • Procoagulants increase • Factor VII, Factor VIII, Factor X and Fibrinogen • Anticoagulants decrease • - Increase in resistance to activated protein C , • - Decreased Protein S • Activity of the fibrinolytic inhibitors (PAI-1, PAI-2) • increased.
Risk factors for VTE in pregnancy • Venous stasis increases in pregnancy • - Inferior vena cava obstructed from uterus • - Reduction in venous flow velocity ~ 50% in the • legs • ( 25-29. weeks - 6 weeks after delivery ) • Vascular damage related to vaginal and cesarean • delivery
Additional risk factors in pregnancy • Age > 35 years • Obesity • Ceserean delivery( Emergency ! ) • Severe ovarian hyperstimulation • Heart disease, diabetes , Lupus, Smoking • Multipl delivery
Antenatal risk factors OR CI 95% Age > 35 1.5 1.1–2.2 Multiple pregnancies 2.7 1.6–4.5 Gestational diabetes 4.1 2.0–8.9 Assisted reproduction* 4.4 2.6–7.5 *Severe ovarian hyperstimulation syndrome (OHSS) Jacobsen AF, et al. Am J Obstet Gynecol. 2008;198:233.e1-e7.
Thrombophilia and pregnancy( 79 studies ) MTHFR = methylenetetrahydrofolate reductase. Robertson L, et al. Br J Haematol. 2006;132:171-96.
Deep vein thrombosis • 2/3 of cases of DVT occured in the antepartum • period,were distributed relatively equally among all • three trimestersRay JG,et al.Obstet Gynecol Surv 1999;54:265 • Risk of DVT twice as high after ceserean delivery • than vaginal birth Stein PD,et al.Am J Med 2004;117 • DVT is more common in the left leg( left iliac compression ) • Ginsberg JS,et al Thromb Haemost 1992;67:519 • Pelvic DVT is more likely in pregnancy( Diagnosis more difficult ! ) • James AH, et al. Am J Obstet Gynecol 2006;194:1311
Venous thromboembolism in pregnancy • 43-60 % of episodes of PE occure in the puerperium ! James AH, et al. Am J Obstet Gynecol 2006;194:1311 James AH, Tapson VF,Goldhaber SZ. Am J Obstet Gynecol2005;193:216
Postpartum period • VTE was 5 times more likely • PE was 15 times more likely • Postnatal risk factors : • - Ceserean section • - Premature delivery • - History of cardiac disease Heit JA,et al. Ann Intern Med 2005;143:697
Diagnostic problems During pregnancy may be complicated by : • Physiologic changes associated with pregnancy • Reluctance of parents and clinicians to expose the • fetus to even small amounts of ionising radiations
Clinical diagnosis • Leg swelling and discomfort • Tachycardia • Tachypnea • Dispnea …. are common during pregnancy andare usually nonthrombotic in origin !
Clinical diagnosis…. PaO2 • PaO2 is normal during pregnancy • Arterial blood should be drawn in the upright position • - May be lower in the supine position during the • third trimester Ang CK, Tan TH, Walters WA, Wood C. Postural influence on maternal capillary oxygen and carbon dioxide tension. Br Med J 1969;4:201–203.
Clinical prediction rules Well’s …. Have not been validated in pregnancy
D-dimer • Elevations in D-dimer are found in uncomplicated • pregnancy, • Increasing with gestational age , • Peaking at the time of delivery and in the early postpartum • period JA Kline et al. Clin Chem 2005;51:825
D-dimer n= 149 , simpliRED TrimesterNegative D-dimer % I 100 II 76 III 49 Chan WS, et al.Ann Intern Med 2007;147:165
D-dimer A normal D-dimer value has the same Exclusion value for PE in pregnant women As in other patients with suspected PE
DVT…..Compression ultrasonography • Noninvasive , readily available, inexpensive • Less sensitive for calf vein and pelvic thrombosis
DVT…..Magnetic resonance imaging (MRI) • It can detect both thighandpelvic DVT • Sensitivity :~ 100 % in the nonpregnant population • - No comparison studies… in pregnancy ! • - Its safety remains unproven !
DVT…..Diagnosis • Compression ultrasonography • MRI ( Pelvic ! ) • CT Scanning ? • Venography ??..........Radiation to the fetus < 500mcGy( small ! ) ( with abdominal-pelvic shielding)
PE …Diagnosis Pregnancy with suspected PE Compression ultrasonography : Negative Chest radiography To rule out alternative diagnosis To guide further diagnostic testing V / Q lung scanning CT angiography
Radiation Risks Fetal Malformation Growth Retardation Childhood Cancer
Pelvic radiation damage • 0 to 14 days : Embryonic death • 15 to 50 days :Growth retardation and teratogenic effects CNS effects are the most prominent • 50 to 280 days: Decreased organ sensitivity, persistentgrowth sensitivity • Over 280 days:Similar response as a child Putman CE, Ravin CE, Editors, Textbook of Diagnostic Imaging Volumes 1, 2 and 3 W.B.Saunders, Edinburgh (1988).
Radiation Damage • Putman CE, Ravin CE, Editors, Textbook of Diagnostic Imaging Volumes 1, 2 and 3 • W.B.Saunders, Edinburgh (1988). * Sv : Sievert • There is no increase in fetal malformation or growth retardation: < 50 mSv* • The risk of childhood cancer: 10 mSv and 20 mSv ………..1.5 to 5 • Diagnostic radiation to areas other than the abdomen present little hazard to the fetus.
This dose is 100 to 200 times less than……. for fetal anomalies PE is not diagnosed ……maternal mortality : 15 %
In the first or second trimester: V/Q scintigraphydelivers ahigher fetal dosethan does CT pulmonary angiography. Of the 161 professionals surveyed, 93 (58%) appreciated correctly that V/Q scintigraphy delivers a higher fetal dose than does CT pulmonaryangiography. Institute of Nuclear Medicine, University College London
Fetal dose( mSv ) CT 0.003 – 0.131 V / Q scanning 0.64 – 0,8 Groves AM,et al. Radiology 2006;240:765 Mother( mSv ) CT 2.2 - 6 V / Q scanning 1.4 Winer – Muram HT,et al.Radiology 2002;224:487
To reduce fetal radiation ( V/Q scanning) • The dose of perfusion agent can be reduced • up to ½ • Normal perfusion scan ! ( performed first ) • The patient should be hydrated
ESC Guidelines • Diagnostic yield …… ~75 % • A normal perfusion scintigraphy….. Excellent clinic outcome • Ventilation phase does not appear to add enough information • ( Additional radiation ! ) • CT should be preferred ovep pulmonary angiography • ( Higher X-ray exposure for the fetus….2.2-3.7 mSv ) ESC Guidelines European Heart Journal,2008;29:2276 Chan WS, et al. Arch Intern Med 2002;162:1170–1175. Ginsberg JS, et al. Thromb Haemost 1989;61: 189
Anticoagulant management Warfarin embryopathy : 5 % ( 6 - 12. weeks ) • Critical organogenisis4th to 8th week. • Miscarriage 15-56% • Congenital anomalies 30% • Placental transfer of drug after 8th week • - Fetal intracranial hemorrhage : Second and early third trimester • - Stillbirth , adverse neurologic outcome
Anticoagulant management • IV UFH ( PE ) • SC LMWH ( DVT ,PE ) • Fondaparinux ……..Limited experience( FDA: Category B )
Heparin - LMWH • 2% risk of major maternal bleeding • 2 – 36% risk for loss of bone density • HIT ?% • Drug allergy (dermatologic)
ACCP - LMWHs produce a more predictable anticoagulant response than heparin. The bioavailability of LMWHs is about 90% The elimination half-life of LMWHs, which is 3 to 6 h after subcutaneous injection, is dose independent. Anti-Xa levels peak 3 to 5 h after dosing. Clearance of the anti-Xa effect of LMWH is highly correlated with CrCl.
ACCP In patients treated with LMWH, we recommend against routine coagulation monitoring (Grade 1C). In pregnant women treated with therapeutic doses of LMWH, we recommend monitoring of anti-Xa levels (Grade 1C).
Empiric anticoagulant High clinical suspicion for PE Empiric anticoagulant therapy is indicated prior to diagnostic evaluation ( Case by case basis ! )
Elevated risk of bleeding • Persistent hypotension due to PE or IV UFH is prefered ( Clinical experience ! ) - Short half life - Complet reversal with protamine
Isole calf vein thrombosis • The management is controversial • Most iliofemoral thrombosis originate from calf-vein • thrombosis ! Baglin TP,et al. Br J Haematol 2006;134:590
Vena caval filter • The patients : • In whom anticoagulations is contrindicated • In whom extensive VTE develops within 2 weeks • before deliver
LMWH….. Once daily or divided dose ? • Increased renal excretion • Half life decreases in pregnancy • A twice daily weight – based doses has been recommended Marik PE, et al. N Engl J Med 2008;359: 2025
Anti factor Xa activity • Extremes of body weight • Renal disfunction • Twice daily….. 0.6 - 1.0 IU/ml…. • Once daily….. 1-2 IU/ml…. • Measured 6 hours after third dose • Most adjustments should be 10 to 25 % ↓ Greer IA.J Thromb Thrombolysis 2006;2:57
Anticoagulant therapy during labor and delivery • Onset on labor is not predictable • Vaginal , ceserean delivery…..with blood loss Spontan delivery + undergone full anticoagulation Neuraxial anesthesia should not be used ! ( Risk of spinal Hematom ) ACCP Guidelines (8th Ed) Chest 2008;133:844
Spinal anesthesia • 12 hours after….. the last dose (prophylactic) of LMWH • 24 hours after…... the last dose (therapeutic) of LMWH • IV UFH should be stopped 6 hours before…. • A normal aPTT should be confirmed….