Dr. Mohammed Abdalla Egypt, Domiat general hospital

1. Dr. Mohammed Abdalla Egypt, Domiat general hospital

2. Pregnancy losses can be classified as: 1-Occult(preclinical or chemical) pregnancy loss prior to missed menses.(40% of implantation embryos) 2-Early pregnancy loss before 12 wk.(13%) 3-Late pregnancy loss after 12 wk. (1%)

3. Recurrence suggests a persistent cause ( not just a bad luck ) which must be identified and treated

4. Causes of pregnancy loss

5. Chromosomal abnormalities The genetic diseases are divided into two categories:

6. occurs in 50-60% of eggs retrieved for IVF. in 50% of all early preg. Loss . in 5% of late losses in 0.5% of live births. Chromosomal abnormalities

7. Cytogenetically abnormal embryos are usually aneuploid (Cells that have chromosomes missing Monosomy or extra chromosomes trisomy ) Monosomy refers to a condition in which there is one chromosome is missing e.g (monosomy X Turner syndrome)

8. SO,The standard of care is to offer genetic amniocentesis for all pregnant women older than 35 years.

10.  Robertsonian translocations occur when two chromosomes fuse together, creating one chromosome that contains most of the original two. (45 chromosomes with one variant)

11. Robertsonian Translocation Robertsonian translocations between chromosomes 14 and 21, one of the most common combinations, are of particular clinical relevance. An individual with this translocation could have a child with three copies of chromosome 21, resulting in Down�s syndrome (trisomy 21).

12. Reciprocal vs Robertsonian Reciprocal --------- 2 derivative chromosomes, 46 chromosomes total Robertsonian -------- 1 derivative chromosome 45 = balanced 46 = unbalanced

13. Polyploidy Polyploidy is a condition in which there is more than 2 sets of chromosomes. Triploids (3N), tetraploids (4N), pentaploids (5N) etc. Polyploids have defects in nearly all organs. Most die as embryos or fetuses. Occasionally an infant survives for a few days.

14. Nondisjunction Nondisjunction occurs when chromosomes fail to "disjoin" during meiosis or mitosis.

15. Nondisjunction during Mitosis

16. Deletions Deletions are fragments of chromosomes that are missing. They are usually lethal when homozygous and cause abnormalities when heterozygous. Cri du Chat Syndrome Cri du chat syndrome is due to a deletion of a portion of chromosome 5. Cri du chat individuals are mentally retarded. "Cri du chat" is French for "cry of the cat". The infants cry sounds like a cat.

17. Genetic counseling after a miscarriage  risk for fetal aneuploidy in couples with recurrent miscarriages is 1.6%, similar to the aneuploidy risk in a woman older than 40 years. In a woman with a prior trisomic livebirth, an approximately 1% increased risk exists for subsequent trisomic birth.

18. All couples with a history of recurrent miscarriage should have peripheral blood karyotyping performed. The finding of an abnormal parental karyotype should prompt referral to a clinical geneticist.

19. In all couples with a history of recurrent miscarriage cytogenetic analysis of the products of conception should be performed if the next pregnancy fails. Genetic counseling after a miscarriage 

20. Amniocentesis Amniocentesis is a technique in which a sample of amniotic fluid is removed and cells that it contains are grown on a culture dish for 2 weeks to obtain sufficient numbers of cells to be karyotyped . a number of biochemical tests can be done on the fluid to determine if any problems exist. Amniocentesis cannot be done until the 14th to 16th week of pregnancy. The risk of inducing a spontaneous abortion by this procedure is 0.5 to 1% above the background rate of spontaneous abortion.

21. Chorionic Villi Sampling Chorionic villi sampling is a procedure in which a small amount of the placenta is removed. It is normally done during the 10th to 12th week but it can be done as early as the 5th week of pregnancy. Karyotype analysis can be performed on these cells immediately after sampling. Although Chorionic villi sampling can be performed earlier in the pregnancy than amniocentesis, the risk of inducing a spontaneous abortion is 1 to 2% higher than the background rate.

22. Part II Recurrent pregnancy loss Dr.Mohammed Abdalla

23. Anatomical factors

24. M�llerian anomaly Incompetent cervix Leiomyomas Asherman syndrome ANATOMICAL FACTORS

25. ANATOMICAL FACTORS The reported prevalence of uterine anomalies in recurrent miscarriage populations range between 1.8% and 37.6%. The prevalence of uterine malformations appears to be higher in women with late miscarriages

26. All women with recurrent miscarriage should have a pelvic ultrasound to assess uterine anatomy and morphology. The routine use of hysterosalpingography as a screening test for uterine anomalies in women with recurrent miscarriage is questionable. ANATOMICAL FACTORS

27. The diagnosis of Cervical weakness is usually based on a history of late miscarriage, preceded by spontaneous rupture of membranes or painless cervical dilatation. Transvaginal ultrasound assessment of the cervix during pregnancy may be useful in predicting preterm birth in some cases of suspected cervical weakness. ANATOMICAL FACTORS

28. Women with recurrent pregnancy loss and a uterine septum should undergo hysteroscopic evaluation and resection.

29. Open uterine surgery is associated with postoperative infertility and carries a significant risk of uterine scar rupture during pregnancy. These complications are less likely to occur after hysteroscopic surgery.

30. The routine use of hysterosalpingography as a screening test for uterine anomalies in women with recurrent miscarriage is questionable. It is associated with patient discomfort, carries a risk of pelvic infection and radiation exposure and is no more sensitive than the non-invasive two dimensional pelvic ultrasound assessment of the uterine cavity with (or without) Sonohysterography when performed by skilled and experienced personnel.

31. The diagnosis of cervical incompetence is usually based on history of late miscarriage, preceded by spontaneous rupture of membranes or painless cervical dilatation. Transvaginal ultrasound assessment of the cervix during pregnancy may be useful in predicting preterm birth in some cases of suspected cervical weakness.

33. women with diabetes with high glycosylated A1c levels in the first trimester are at a significantly higher risk of both miscarriage and fetal malformation. Insulin-dependent women with inadequate glucose control have a 2- to 3-fold higher rate of miscarriage compared to the general population of women. Diabetes mellitus 

34. Low progesterone levels Progesterone is the principal factor responsible for the conversion of a proliferative to a secretory endometrium, rendering the endometrium receptive for embryo implantation.

35. Luteal-phase defects  Unfortunately, no reliable method is available to diagnose this disorder basal body temperature records . progesterone concentrations . histologic dating of endometrial biopsy specimens using the patient's subsequent menses as a reference point luteal-phase serum progesterone levels which may be found normal in the women with LPD. (abnormal response of the endometrium to progesterone rather than a subnormal production )

36. The endocrine system and the immune system interact closely during implantation and maintenance of pregnancy. at the level of the decidua . Here, under the influence of sex steroids, there is a dramatic increase of lymphocytes, the uterine natural killer (uNK) cells, in early pregnancy. which under hormonal influence, they are believed to promote placental and trophoblast growth and provide immunomodulation at the maternal-fetal interface. Endocrine modulation of decidual immunity 

37. Endocrine modulation of decidual immunity  Progesterone is essential because large granular lymphocytes (LGLs )are not found in endometrium before menarche, after menopause, or in conditions associated with unopposed estrogen, such as endometrial hyperplasia or carcinoma and In women who have undergone oophorectomy. LGLs appear only after treatment with both estrogen and progesterone. The increase in the number of NK cells at the implantation site in the first trimester suggests their role in pregnancy maintenance. The extravillous trophoblast (which expresses modified forms of 1 HLA) is resistant to lysis by decidual NK

39. Thrombophilia the tendency to thrombosis

41. placental vasculopathy Placental pathologists use the term placental vasculopathy to describe pathological placental changes were found to be associated with some clinical conditions such as preeclampsia, IUGR, placental abruption and some cases of fetal loss and preterm labor .

42. villous infarcts. multiple infarcts. fibrinoid necrosis of decidual vessels. fetal stem vessel thrombosis. placental hypoplasia. spiral artery thrombosis . placental vasculopathy

43. antiphospholipid syndrome

44. In the antiphospholipid antibody syndrome the body recognizes phospholipids (part of a cell's membrane) as foreign and produces antibodies against them. antiphospholipid syndrome

45. APA syndrome is an acquired autoimmune thrombophilia in which vascular thrombosis and/or adverse pregnancy outcomes occur in patients having laboratory evidence for antibodies against phospholipids or phospholipid-binding protein cofactors in their blood. antiphospholipid syndrome

46. Antiphospholipid antibodies are a family of approximately 20 antibodies directed against negatively charged phospholipid binding proteins. only the lupus anticoagulant and anticardiolipin antibodies (IgG and IgM subclass, but not IgA) have been shown to be of clinical significance. antiphospholipid syndrome

48. Sapporo criteria An International Consensus Conference held in Sapporo in 1998 clinical criteria of (APAS ) thrombosis, one or more confirmed episodes of venous, arterial, or small vessels disease . pregnancy criteria :

50. Inherited Thrombophilia

51. three important inherited thrombophilias : mutation in factor V causing Resistance to activated protein C (responsible of 20�30% of venous thromboembolism events.) mutation in prothrombin (guanine 20210 adenine ) mutation in methylenetetrahydrofolate reductase (MTHFR) (cytosine 677 thymine (C677T) ) The mutation is responsible for reduced MTHFR activity and is the most frequent cause of mild hyperhomocysteinemia and can be found in 5�15% of the population. Inherited Thrombophilia

52. factor V Leiden(A506G) mutation present in 3-8% of the general population , (heterozygotes) have a seven fold increased risk for thrombosis compared to the general population whereas homozygotes have an eighty fold increase. It has been linked with an increased risk for venous thromboembolism due to Resistance to activated protein C and is responsible of 20�30% of venous thromboembolism events

53. prothrombin (G20210A) mutation A change of G to A at position 20210 in prothrombin (prothrombin 20210A) elevates baseline prothrombin levels and thrombin formation.

54. MTHFR (C677T) mutation responsible for reduced MTHFR activity results in decreased synthesis of 5-methyltetrahydrofolate, the primary methyl donor in the conversion of homocysteine to methionine and the resulting increase in plasma homocysteine concentrations ( Hyperhomocysteinemia ) is a risk factor for thrombosis Dietary restriction of folate and vitamin B12 remains the most common cause.

55. A homozygous (MTHFR) mutation, present in 1-4% of the general population, is associated with a three fold increased risk for DVT or PE, as well as preeclampsia and placental abruption. MTHFR (C677T) mutation

56. Protein S deficiency Protein S deficiency (PSD), present in up to 2% of the general population. is found in approximately 15% of individuals with a DVT or PE . is found in 6% of women with obstetrical complications including a relatively high risk for stillbirth.

57. Thank you