1. EARLY PREGNANCY COMPLICATIONS Rukset Attar, MD, PhD Obstetrics and Gynecology Department

2. Nausea, Vomiting & Hyperemesis Gravidarum 70% to 85% of pregnant women often occurs in association with high levels of human chorionic gonadotropin (hCG), such as with multiple pregnancies, trophoblastic disease Conditions that Predispose to Excessive Nausea and Vomiting Viral gastroenteritis Gestational trophoblastic disease Hepatitis Urinary tract infection Multifetal gestation Gallbladder disease Migraine

3. Nausea, Vomiting & Hyperemesis Gravidarum Treatment Dietary modifications and vitamin B6 therapy Phenothiazines (promethazine (Phenergan) often is tried first) potential for dystonic effects. Metoclopramide (Reglan) is the antiemetic drug of choice in pregnancy in several European countries Ondansetron (Zofran) has been compared with promethazine (Phenergan), and the two drugs are equally effective

4. Nausea, Vomiting & Hyperemesis Gravidarum Hyperemesis gravidarum 0.5% to 1% of patients Abnormal electrolytes, dehydration with high urine- specific gravity, ketosis and acetonuria, and untreated have weight loss >5% of body weight. Intravenous hydration is the first line of therapy for patients with severe nausea and vomiting

5. Spontaneous Abortion Spontaneous abortion is the most common complication of pregnancy Spontaneous abortion is the most common complication of pregnancy is defined as the passing of a pregnancy prior to completion of the 20th gestational week or delivery of all or any part of the products of conception, with or without a fetus weighing less than 500 g is defined as the passing of a pregnancy prior to completion of the 20th gestational week or delivery of all or any part of the products of conception, with or without a fetus weighing less than 500 g Threatened abortion is bleeding of intrauterine origin occurring before the 20th completed week, with or without uterine contractions, without dilatation of the cervix, and without expulsion of the products of conception. Threatened abortion is bleeding of intrauterine origin occurring before the 20th completed week, with or without uterine contractions, without dilatation of the cervix, and without expulsion of the products of conception.

6. Spontaneous Abortion Complete abortion is the expulsion of all of the products of conception before the 20th completed week of gestation Complete abortion is the expulsion of all of the products of conception before the 20th completed week of gestation Blighted ovum or anembryonic pregnancy represents a failed development of the embryo so that only a gestational sac, with or without a yolk sac, is present. An alternative hypothesis proposes that the fetal pole has been resorbed prior to ultrasound diagnosis. Blighted ovum or anembryonic pregnancy represents a failed development of the embryo so that only a gestational sac, with or without a yolk sac, is present. An alternative hypothesis proposes that the fetal pole has been resorbed prior to ultrasound diagnosis.

7. Spontaneous Abortion incomplete abortion is the expulsion of some, but not all, of the products of conception Inevitable abortion refers to bleeding of intrauterine origin before the 20th completed week, with dilatation of the cervix without expulsion of the products of conception septic abortion, infection of the uterus and sometimes surrounding structures occur.

8. Spontaneous Abortion approximately 15% of clinically evident pregnancies and 60% of chemically evident pregnancies end in spontaneous abortion. approximately 15% of clinically evident pregnancies and 60% of chemically evident pregnancies end in spontaneous abortion. Eighty percent of spontaneous abortions occur prior to 12 weeks' gestation. Eighty percent of spontaneous abortions occur prior to 12 weeks' gestation. An abnormal karyotype is present in approximately 50% of spontaneous abortions occurring during the first trimester. An abnormal karyotype is present in approximately 50% of spontaneous abortions occurring during the first trimester. The incidence decreases to 20–30% in second-trimester losses and to 5–10% in third-trimester losses The incidence decreases to 20–30% in second-trimester losses and to 5–10% in third-trimester losses

9. Spontaneous Abortion Etiology the first-trimester losses are typically autosomal trisomies or monosomy X, whereas later losses reflect chromosomal abnormalities seen in neonates the first-trimester losses are typically autosomal trisomies or monosomy X, whereas later losses reflect chromosomal abnormalities seen in neonates infection, infection, anatomic defects, anatomic defects, endocrine factors, endocrine factors, immunologic factors, immunologic factors, maternal systemic diseases, maternal systemic diseases, unknown unknown

10. THROMBOPHILIA IN PREGNANCY Rukset Attar, MD, PhD Obstetrics and Gynecology Department

11. Hypercoagulability in Pregnancy During pregnancy, there is a marked increase in the procoagulant activity by elevation of fibrinogen, factors II, V, VII, VIII, IX, X, XII and the von Willebrand factor. Fibrinogen levels increase up to two fold. It is unclear why factor XI decreases. The physiological anticoagulant system becomes less efficient because of an increased resistance to activated protein C in the second and third trimester and a reduced protein S activity, due to estrogen induced decreases in total protein S. higher concentrations of plasminogen activator inhibitors (PAI), and an increased tendency to platelet aggregation Overall fibrinolytic activity is impaired during pregnancy

12. Risk factors for thrombotic complications Pregnancy-related risk factors for VTE include increasing maternal age (35 years), Caesarean section (especially emergency sections), thrombophilia, a family or personal history of thrombosis and obesity The puerperium itself is a risk factor (the most probable trigger for that is delivery itself, because vessel trauma can cause thrombosis, and systemic coagulation activation in the mother’s circulation can easily occur. Immobilisation after delivery can substantially add to this risk.

13. Risk factors for thrombotic complications An individual assessment of the thrombotic risk should be undertaken, ideally before or in early pregnancy. There is an increased risk of thrombosis in pregnant patients with thrombophilia depending on the severity of thrombophilia

14. Thrombophilia in Pregnancy Inherited thrombophilias Acquired thrombophilias Non-thrombotic pregnancy complications and thrombophilias

15. Inherited thrombophilias genetic conditions with an increased thrombotic risk depending on additional risk factors frequent causes of inherited thrombophilia are heterozygosity for Factor V Leiden (FVL) and G20210A mutation of the prothrombin gene; rarer are antithrombin, protein C and S deficiency Hyperhomocysteinemia due to genetic defects (homozygosity for a thermolabile mutant of methylenetetrahydrofolate reductase MTHFR) is controversially discussed as a cause of hereditary thrombophilia.

16. Inherited thrombophilias Rare thrombophilic mutations, such as gene polymorphisms of plasminogen activator inhibitor-1, factor XIII or apolipoprotein B do not generally transfer an independent risk for thrombosis

17. Acquired thrombophilias Antiphospholipid antibodies, such as the lupus anticoagulant or anticardiolipin and b-2-glycoprotein I antibodies are directed against glycoproteins in concert with phospholipids and are associated with thromboembolism and/or obstetrical complications. Antiphospholipid antibodies (aPL) are found in about 5% of the reproductive population and antiphospholipid syndrome (APS) in 15–17% of women with recurrent pregnancy loss

18. Non-thrombotic pregnancy complications and thrombophilias Maternal thrombophilias are not associated with pregnancy loss prior to 8–10 weeks of gestation, explained by the embryogenetic development of the vascular system Before 8 weeks of gestation in the embryo there is only yolk sac vasculature, and thereafter a contact between the maternal and fetal circulation develops. Therefore, it seems unlikely, that maternal thrombophilia can impair embryonic development at that earliest gestational stage.

19. Non-thrombotic pregnancy complications and thrombophilias Women with thrombophilia show an increased risk for pregnancy loss at the end of the first and in the second trimester those with FVL or prothrombin gene variant show a higher risk of late pregnancy loss (24 weeks) Recurrent pregnancy loss has been linked to inherited thrombophilia particularly with protein C and S deficiency,FVL and a prothrombin gene variant A significant association with increased risk for placental abruption was only observed with heterozygous FVL and the prothrombin gene variant IUGR Pre-eclampsia

20. Management of thrombotic disorders during pregnancy Risk-assessment for VTE Major known risk factors for VTE in pregnancy and in the postpartum period are C-section, obesity, Prolonged bed rest, immobility, pre-eclampsia, Nephrotic syndrome, current infection and recent surgery previous VTE and thrombophilia. In women at high risk LMWH prophylaxis should be continued for 4–6 weeks postpartum

21. Management of thrombotic disorders during pregnancy Anticoagulan Therapy coumarin-derivates Unfractionated heparin (UFH) low-molecular-weight heparins (LMWH) and aspirin The choice of the anticoagulant depends on the maternal or fetal complications. UFH and LMWH do not cross the placenta and are safe for the fetus. Maternal bleeding complications appear to be uncommon with LMWH.

22. Management of thrombotic disorders during pregnancy Prevention of VTE LMWH is the prophylaxis of choice in pregnancies at risk for VTE No laboratory monitoring is required. All women with previous VTE or a thrombophilia should be additionally encouraged to wear elastic compression stockings throughout their pregnancy and for 6–12 weeks after delivery.

23. Management of thrombotic disorders during pregnancy Women with prior VTE These women should have a postpartum prophylaxis for 6 weeks Two options have been proposed: no routine prophylaxis during pregnancy, but clinical surveillance and immediate investigation in cases with clinical suspicion of VTE- due to transient risk factor ACCP Guidelines, Chest 2008 prophylaxis starting during the first trimester (ideally before 10 gestational weeks) in women with an increased risk for VTE (thrombophilia or a history of a severe thrombotic event like PE or extended deep vein thrombosis, VTE during previous pregnancy, or during HRT)- ACCP Guidelines, Chest 2008

24. Management of thrombotic disorders during pregnancy Treatment of VTE Acute DVT or PE during pregnancy should be managed initially as in non-pregnant women UFH or LMWH have to be given until the diagnosis is confirmed. The first line treatment remains intravenous UFH (70 IU/kg as bolus, followed by 350 IU/kg/24 h as continuous infusion) to rapidly achieve an aPTT at 1.5–2.5 times the control value. Therapeutic doses of LMWH may be started once the patient is hemodynamically stable

25. Management of thrombotic disorders during pregnancy Weight-adjusted subcutaneous LMWH is to be preferred and administered once daily at a therapeutic dose (200 IU/kg/d) throughout pregnancy. Twice-daily administration (100 IU/kg q12 h) might be preferable for obese patients to achieve more stable factor Xa-levels in plasma, Therapeutic anticoagulation should be continued throughout pregnancy and for at least 6 month after thrombosis

26. Patients with recurrent trombosis attacks without trombophilia shoud be on life-long anticoagulan therapy Patients with recurrent trombosis attacks without trombophilia shoud be on life-long anticoagulan therapy Pro with UFH/LMWH during pregnancy and + postpartum period is advised for these patients (Grade 1A) Prophylaxis with UFH/LMWH during pregnancy and + postpartum period is advised for these patients (Grade 1A)

27. Management of thrombotic disorders during pregnancy APS Pregnant women with APS and previous thrombosis should receive antepartum and postpartum thromboprophylaxis with LMWH in a therapeutic dose UFH combined with ASS significantly reduced pregnancy loss compared to ASS alone A typical combined treatment regimen includes aspirin (75–85 mg/day), beginning with attempts at conception, and unfractionated heparin (5,000– 10,000 subcutaneous twice daily), beginning at first indication of pregnancy. A typical combined treatment regimen includes aspirin (75–85 mg/day), beginning with attempts at conception, and unfractionated heparin (5,000– 10,000 subcutaneous twice daily), beginning at first indication of pregnancy.

28. Operations not related to malignancies, lasting no longer than 30 minutes don’t require any prophylaxis unless there is another risc factor. Early mobilisation and IPC is advised for them (Grade 1A) Operations not related to malignancies, lasting no longer than 30 minutes don’t require any prophylaxis unless there is another risc factor. Early mobilisation and IPC is advised for them (Grade 1A) No prophylaxis for laparoskopic procedures unless there is another risc factor (Grade 1B) No prophylaxis for laparoskopic procedures unless there is another risc factor (Grade 1B)

29. Routin trombosis prophylaxis must be done in major gynecologic operations (Grade 1A) Routin trombosis prophylaxis must be done in major gynecologic operations (Grade 1A) With no other risc factor and not related to malignancy- DMAH (Grade 1A) or unfractunated heparin (Grade 1A) or IPC (Grade 1B) With no other risc factor and not related to malignancy- DMAH (Grade 1A) or unfractunated heparin (Grade 1A) or IPC (Grade 1B) With another risc factor or operation for malignancy- heparin + IPC (Grade 1C) With another risc factor or operation for malignancy- heparin + IPC (Grade 1C)

30. Sectio One risk factor besides pregnancy and sectio - heparin prophylaxis or (IPC, GCS) during hospital stay (Grade 2C) One risk factor besides pregnancy and sectio - heparin prophylaxis or (IPC, GCS) during hospital stay (Grade 2C) multipl risk factors- heparin prophylaxis or (IPC, GCS) (Grade 2C) multipl risk factors- heparin prophylaxis or (IPC, GCS) (Grade 2C) patients with high risk - prophylaxis for 6 weeks patients with high risk - prophylaxis for 6 weeks

31. Routin trombosis prophylaxis should be started before the major gynecologic operations Routin trombosis prophylaxis should be started before the major gynecologic operations Should continue during hospital stay (Grade 1A) Should continue during hospital stay (Grade 1A) İf it was a cancer surgery or if the patient had a VTE before LMWH should be continued for 28 days after discharge from the hospital (Grade 2C) İf it was a cancer surgery or if the patient had a VTE before LMWH should be continued for 28 days after discharge from the hospital (Grade 2C)

32. Acute trombosis in pregnancy UFH heparin (IV bolus, then infusion, aPTT measurement every 4 hours) or LMWH ( twice a day, s.c.) at least for 5 days (Grade 1A) UFH heparin (IV bolus, then infusion, aPTT measurement every 4 hours) or LMWH ( twice a day, s.c.) at least for 5 days (Grade 1A) Then prophylactic dosage Then prophylactic dosage Should continue thoroughout pregnancy (Grade 1B) and 6 weeks postpartum (Grade 2C) Should continue thoroughout pregnancy (Grade 1B) and 6 weeks postpartum (Grade 2C) Should be stopped 24 hours before delivery (Grade 1C) if delivered at therapeutic dosage Should be stopped 24 hours before delivery (Grade 1C) if delivered at therapeutic dosage

34. Unfractunated Heparin 3000- 30.000 Da 3000- 30.000 Da Binds to antitrombin, FIX, FX, FXI ve FXII Binds to antitrombin, FIX, FX, FXI ve FXII Also binds to beta tromboglobulin, PF4, histidin rich protein, vitronektin, platelets, osteoblasts and endothelial cells Also binds to beta tromboglobulin, PF4, histidin rich protein, vitronektin, platelets, osteoblasts and endothelial cells IV IV followed with aPTT measurements x1.5-2.5 followed with aPTT measurements x1.5-2.5 neutralised with Protamin neutralised with Protamin

35. LMWH 2000- 9.000 Da 2000- 9.000 Da Exreacted from UH via chemical and enzimatic procedures Exreacted from UH via chemical and enzimatic procedures İnhibits Fxa İnhibits Fxa Low affinity for endothelial cells, osteoblasts and PLT Low affinity for endothelial cells, osteoblasts and PLT Sc Sc monitorised via antiXa- anti-Xa level should be 0.5-1.2 U/ml monitorised via antiXa- anti-Xa level should be 0.5-1.2 U/ml neutralisation with Protamin is low neutralisation with Protamin is low

36. Whom should receive prohylaxis with heparin during pregnancy? Whom should receive prohylaxis with heparin during pregnancy? Those with valvular dieases or ritm disorders who are already on anticoagulation therapy Those with valvular dieases or ritm disorders who are already on anticoagulation therapy Recurrent VTE attacks- who are already on anticoagulation therapy Recurrent VTE attacks- who are already on anticoagulation therapy Patients with one VTE + trombophilia Patients with one VTE + trombophilia Patients with VTE during previous pregnancy or HRT Patients with VTE during previous pregnancy or HRT

37. Trombosis risks FV Leiden heterozigotx 4-7 FV Leiden homozigotx 80 P-20210 Ax 2-5 Hiperhomosisteinemiax 2-6 OC x 4 FVL+ P-20210 Ax 20 FVL+ hiperhomosisteinemiax 21.6 FVL+ OCx 35 FVL+ smoking x 30

38. FV Leiden mutation FV Leiden mutation Protrombin G20210A Protrombin G20210A Protein C activity Protein C activity Protein S activity Protein S activity AT activity AT activity Fasting homosistein level Fasting homosistein level Lupus anticoagulant Lupus anticoagulant ACA IgG ve IgM ACA IgG ve IgM Anti-B2 GPI IgG ve IgM Anti-B2 GPI IgG ve IgM ANA, anti-DNA ANA, anti-DNA