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  1. 1. Recurrent Miscarriage Guidelines Dr Muhammad El Hennawy Ob/gyn specialist Rass el barr central hospital and dumyat specialised hospital Dumyatt – EGYPT
  2. 2. Definition <ul><li>A recurrent miscarriage is 3 or more consecutive, spontaneous pregnancy losses , under 20 week gestation from the last menstrual period , by the same partner. </li></ul>
  3. 3. <ul><li>Primary recurrent pregnancy loss &quot; refers to couples that have never had a live birth, </li></ul><ul><li>while &quot;secondary RPL&quot; refers to those who have had repetitive losses following a successful pregnancy </li></ul>
  4. 4. <ul><li>a woman who had a miscarriage,instead of getting sympathy and support, is made to feel that it is somehow her fault </li></ul><ul><li>It is all too common to find recurrent miscarriges leading to divorce </li></ul>
  5. 5. Terminology <ul><li>The medical term 'spontaneous abortion' should be replaced with the term 'miscarriage' </li></ul><ul><li>Other names : recurrent pregnancy loss (RPL), </li></ul><ul><li>habitual abortions , </li></ul><ul><li>habitual miscarriages, </li></ul><ul><li>recurrent abortions , </li></ul><ul><li>recurrent miscarriages. </li></ul>
  6. 6. Incidence <ul><li>10–15% of all clinically recognised pregnancies end in a miscarriage </li></ul><ul><li>the theoretical risk of three consecutive pregnancy losses that expected by chance alone is 0.34%. </li></ul><ul><li>This incidence is greater than that expected by chance alone---Recurrent miscarriage affects 1% of all women ---Hence, only a proportion of women presenting with recurrent miscarriage will have a persistent underlying cause for their pregnancy losses </li></ul>
  7. 7. Risk factors <ul><li>Advanced maternal age </li></ul><ul><li>adversely affects ovarian function, giving rise to a decline in the number of good quality oocytes, resulting in chromosomally abnormal conceptions that rarely develop further. </li></ul><ul><li>. previous number of miscarriages </li></ul>
  8. 8. possible causes <ul><li>Recurrent miscarriage is a heterogeneous condition that has many possible causes; more than one contributory factor may underlie the recurrent pregnancy losses. </li></ul><ul><li>each may have had a different cause. </li></ul>
  9. 9. Genetic factors Anatomical factors Endocrine Infective agents Immune factors Inhereted Thrombophilic defect Explained Un-explained Recurent Miscarriage Enviromental factors Body Cervix Paternal karyotyping Cytogenetic Of miscarriage C I Uterine anomalies APS Bacterial Vaginosis
  10. 10. Investigations and treatments Recent information indicates that women should look into RPL testing after two losses when it used to be common to wait until three. This is especially important for women in their 30s and 40s
  11. 11. Diagnosis and investigation <ul><li>EPAUs should use and develop diagnostic and therapeutic algorithms of care. </li></ul><ul><li>In particular, these should include management of 'suspected ectopic pregnancy' (including serum hCG) and the 'indeterminate' ultrasound scan. </li></ul><ul><li>EPAUs should have access to transvaginal ultrasound with staff appropriately trained in its use. </li></ul><ul><li>Non-sensitised rhesus (Rh) negative women should receive anti-D immunoglobulin in the following situations: ectopic pregnancy, all miscarriages over 12 weeks (including threatened), all miscarriages where the uterus is evacuated, and for threatened miscarriages under 12 weeks when bleeding is heavy or associated with pain. </li></ul>
  12. 12. Genetic factors
  13. 13. <ul><li>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. </li></ul><ul><li>3–5% of couples with recurrent miscarriage, one of the partners carries a balanced structural chromosomal anomaly </li></ul><ul><li>5–10% chance of a pregnancy with an unbalanced translocation. </li></ul>
  14. 14. <ul><li>In all couples with a history of recurrent miscarriage cytogenetic analysis of the products of conception should be performed if the next pregnancy fails. </li></ul><ul><li>an abnormal embryo, which is incompatible with life, e.g. chromosomal abnormalities or structural malformations. </li></ul><ul><li>If the karyotype of the miscarried pregnancy is abnormal, there is a better prognosis in the next pregnancy </li></ul><ul><li>Cytogenetic testing is an expensive tool and should be reserved for patients who have undergone treatment in the index pregnancy or have been participants in a research trial </li></ul>
  15. 15. Fetal chromosomal abnormalities <ul><li>This may be due to abnormalities in the egg, sperm or both. The  most common chromosomal defects are </li></ul><ul><li>Trisomy: </li></ul><ul><li>Monosomy:   </li></ul><ul><li>Polyploidy: </li></ul>
  16. 16. <ul><li>Chromosome Testing on Fetal (Miscarriage) Tissue </li></ul><ul><li>This can only be done right at the time of miscarriage. </li></ul><ul><li>It is an analysis of the genetic makeup of the fetus. </li></ul><ul><li>It can indicate genetic problems that lead to RPL. </li></ul><ul><li>Many miscarriages are caused by chromosomal abnormalities that are unlikely to repeat. To know if the problem is likely to recur, it is necessary to study the genetics of both parents as well. </li></ul><ul><li>Karyotyping of Parents </li></ul><ul><li>each Chromosome analysis of blood of both parents. </li></ul><ul><li>It can show if there is a potential problem with one of the parents that leads to miscarriage, but often has to be done in conjunction with fetal testing to provide answers. </li></ul><ul><li>These tests help rule out the 3% or so of partners that carry a &quot;hidden&quot; chromosomal problem called a balanced translocation. </li></ul>
  17. 17. KARYOTYPING , HOW? <ul><li>It is A display of an individual’s chromosome pairs. </li></ul><ul><li>Process : Sample of cells is taken, usually blood cells. </li></ul><ul><li>Cells are chemically stimulated to undergo mitosis. Mitosis is stopped at metaphase . </li></ul><ul><li>Chromosomes are separated out, </li></ul><ul><li>viewed with a microscope </li></ul><ul><li>and photographed. </li></ul><ul><li>The photograph is then rearranged to show the paired chromosomes. Size , shape and banding pattern are used to pair up the chromosomes . </li></ul>
  18. 19. Anatomical factors One in six to ten women with recurrent miscarriages has a structural defect like uterine septum or adhesions
  19. 20. <ul><li>Hysterosalpingogram (HSG) </li></ul><ul><li>two dimensional pelvic ultrasound with (or without) Sonohysterography </li></ul><ul><li>3D Ultrasound </li></ul><ul><li>Laparoscopy </li></ul><ul><li>Hysteroscopy </li></ul>
  20. 21. <ul><li>The reported prevalence of uterine anomalies in recurrent miscarriage populations range between 1.8% and 37.6%. </li></ul><ul><li>The prevalence of uterine malformations appears to be higher in women with late miscarriages compared with women who suffer early miscarriages but this may be related to the cervical weakness that is frequently associated with uterine malformation. </li></ul><ul><li>untreated uterine anomalies has a term delivery rate of only 50%. </li></ul><ul><li>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 but no randomised trial assessing the benefits of surgical correction of uterine abnormalities on pregnancy outcome has been performed. </li></ul>
  21. 22. Congenital anomalies <ul><li>an abnormal or irregularly shaped uterus. </li></ul><ul><li>Sometimes the uterus has an extra wall down its centre, which makes it look as if it is divided into </li></ul><ul><li>two (bicornuate or septate uterus) </li></ul><ul><li>a septate uterus Where as a partial septum increases the risk to 60%-75%; a total septum carries a risk for loss of up to 90%. </li></ul><ul><li>Today a relatively simple surgical procedure can remove a uterine septum </li></ul><ul><li>or it may have only developed one half (unicornuate uterus) . </li></ul><ul><li>It is not clear if such problems cause recurrent miscarriage, </li></ul>
  22. 23. fibroids <ul><li>If fibroids are detected on the inside of the uterus (termed submucous fibroids) and distort the uterine lining, they are a significant cause of reproductive problems and should be removed. It is less clear whether fibroids in the wall of the uterus cause reproductive problems </li></ul>
  23. 24. scar tissue in the uterus <ul><li>scar tissue in the uterus which may hinder implantation or growth of the fetus. </li></ul>
  24. 25. Hysterosalpingography <ul><li>The routine use of hysterosalpingography as a screening test for uterine anomalies in women with recurrent miscarriage is questionable . </li></ul><ul><li>It is associated with patient discomfort, </li></ul><ul><li>carries a risk of pelvic infection and radiation exposure </li></ul><ul><li>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. </li></ul>
  25. 26. Hysterosonography <ul><li>Hysterosonography provides a sensitive and specific screening tool for evaluating the uterine cavity and it could be an accurate alternative to HSG in screening for uterine abnormalities </li></ul>
  26. 27. Ultrasound <ul><li>It is sometimes possible to see abnormalities inside the uterus at the time of a scan, especially a </li></ul><ul><li>vaginal scan. A scan will also enable the ovaries to be examined at the same time. Occasionally </li></ul><ul><li>polycystic ovaries are diagnosed by ultrasound scan (see above). </li></ul><ul><li>Some units will offer a scan and an examination of the inside of the uterus at the same time - saline </li></ul><ul><li>installation sonography (SIS). A small plastic tube is passed through the cervix and a water-like </li></ul><ul><li>solution injected through it. The scan can determine whether there is any abnormality inside the </li></ul><ul><li>uterus. </li></ul>
  27. 28. All women with recurrent miscarriage should have a pelvic ultrasound to assess uterine anatomy and morphology <ul><li>Two dimensional pelvic ultrasound assessment of the uterine cavity with (or without) Sonohysterography </li></ul>
  28. 29. three-dimensional ultrasound <ul><li>The diagnostic value of three-dimensional ultrasound has been explored and appears promising. </li></ul><ul><li>Since three-dimensional ultrasound offer both diagnosis and classification of uterine malformation its use may obviate the need for diagnostic hysteroscopy and laparoscopy. </li></ul>
  29. 30. Hysteroscopy <ul><li>This investigation, performed under general anaesthetic, examines the inside of the uterus with a thin </li></ul><ul><li>telescope (3-5 mm in diameter) . By inserting this telescope through the cervix and into the uterus, </li></ul><ul><li>the doctor can see the shape of the uterus and examine its lining. </li></ul>
  30. 31. Cervical weakness
  31. 32. <ul><li>Cervical cerclage is associated with potential hazards related to the surgery and the risk of stimulating uterine contractions and hence should only be considered in women who are likely to benefit. </li></ul><ul><li>Cervical weakness is often over-diagnosed as a cause of mid-trimester miscarriage. </li></ul><ul><li>The diagnosis is usually based on a history of late miscarriage, preceded by spontaneous rupture of membranes or painless cervical dilatation. </li></ul><ul><li>Transvaginal ultrasound assessment of the cervix during pregnancy may be useful in predicting preterm birth in some cases of suspected cervical weakness </li></ul><ul><li>Transabdominal cerclage has been advocated as a treatment for second-trimester miscarriage and the prevention of early preterm labour in selected women with previous failed transvaginal cerclage and/or a very short and scarred cervix </li></ul>
  32. 33. Endocrine factors
  33. 34. Routine screening for occult diabetes and thyroid disease with oral glucose tolerance and thyroid function tests in asymptomatic women presenting with recurrent miscarriage is uninformative <ul><li>well-controlled diabetes mellitus is not a risk factor for recurrent miscarriage, nor is treated thyroid dysfunction </li></ul>
  34. 35. There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage <ul><li>hormonal treatments for luteal phase deficiency concluded that the benefits are uncertain the low progesterone levels that have been reported in early pregnancy loss may reflect a pregnancy that has already failed. Exogenous progesterone supplementation should only be used in the context of randomised controlled trials. </li></ul><ul><li>Progesterone doesn't prevent miscarriages. Miscarriages happen for many reasons, </li></ul><ul><li>but lack of progesterone as a cause for miscarriage is not proven. The low progesterone levels found in pregnancies which go on to become miscarriages is a sign that the pregnancy is already failing </li></ul>
  35. 36. There is insufficient evidence to evaluate the effect of human chorionic gonadotrophin (hCG) in pregnancy to prevent miscarriage . <ul><li>early pregnancy hCG supplementation failed to show any benefit in pregnancy outcome </li></ul>
  36. 37. Prepregnancy suppression of high luteinising hormone (LH) concentration among ovulatory women with recurrent miscarriage and polycystic ovaries who hypersecrete LH does not improve the live birth rate <ul><li>the outcome of pregnancy without pituitary suppression is similar to that of patients without raised LH. </li></ul>
  37. 38. Polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously . <ul><li>pelvic ultrasound criteria, is significantly higher among women with recurrent miscarriage (41%) when compared with the general population (22%). </li></ul><ul><li>However, despite this high prevalence, polycystic ovary morphology itself does not predict an increased risk of future pregnancy loss among ovulatory women with a history of recurrent miscarriage who conceive spontaneously. </li></ul>
  38. 39. There is insufficient evidence to assess the effect of hyperprolactinaemia as a risk factor for recurrent miscarriage .
  39. 40. Immune factors One in ten women with recurrent miscarriages show evidence of auto immune factors on investigation As much as 40 percent of unexplained infertility may be the result of immune problems, as are as many as 80 percent of &quot;unexplained&quot; pregnancy losses. Unfortunately for couples with immunological problems, their chances of recurrent loss increase with each successive pregnancy.
  40. 41. Antithyroid antibodies <ul><li>Routine screening for thyroid antibodies in women with recurrent miscarriage is not recommended. </li></ul>
  41. 42. Antiphospholipid syndrome <ul><li>To diagnose APS it is mandatory that the patient should have two positive tests at least six weeks apart for either lupus anticoagulant or anticardiolipin (aCL) antibodies of IgG and/or IgM class present in medium or high titre. </li></ul><ul><li>Adverse pregnancy outcomes include </li></ul><ul><li>(a) three or more consecutive miscarriages before ten weeks of gestation, </li></ul><ul><li>(b) one or more morphologically normal fetal deaths after the tenth week of gestation and </li></ul><ul><li>(c) one or more preterm births before the 34th week of gestation due to severe pre-eclampsia, eclampsia or placental insufficiency. </li></ul>
  42. 43. <ul><li>Currently there is no reliable evidence to show that steroids improve the live birth rate of women with recurrent miscarriage associated with aPL when compared with other treatment modalities; their use may provoke significant maternal and fetal morbidity. </li></ul><ul><li>In women with a history of recurrent miscarriage and aPL, future live birth rate is significantly improved when a combination therapy of aspirin plus heparin is prescribed. </li></ul><ul><li>Pregnancies associated with aPL treated with aspirin and heparin remain at high risk of complications during all three trimesters . </li></ul>
  43. 44. Alloimmune factors <ul><li>Immunotherapy, including paternal cell immunisation, third-party donor leucocytes, trophoblast membranes and intravenous immunoglobulin (IVIG), in women with previous unexplained recurrent miscarriage does not improve the live birth rate </li></ul>
  44. 45. Infective agents
  45. 46. <ul><li>TORCH (toxoplasmosis rubella, cytomegalovirus and herpes simplex virus), other [congenital syphilis and viruses], screening is unhelpful in the investigation of recurrent miscarriage. </li></ul><ul><li>For an infective agent to be implicated in the aetiology of repeated pregnancy loss, it must be capable of persisting in the genital tract and avoiding detection or must cause insufficient symptoms to disturb the women. Toxoplasmosis, rubella, cytomegalovirus, herpes and listeria infections do not fulfil these criteria and routine TORCH screening should be abandone </li></ul>
  46. 47. <ul><li>Screening for and treatment of bacterial vaginosis in early pregnancy among high risk women with a previous history of second-trimester miscarriage or spontaneous preterm labour may reduce the risk of recurrent late loss and preterm birth. </li></ul>
  47. 48. Group B Streptococcus <ul><li>Pre and Post-conceptional, broad-spectrum intravenous antibiotic therapy was used in patients with multiple miscarriages </li></ul><ul><li>Although this is a relatively small series and does not establish a cause and effect relationship between Group B Streptococcus and habitual abortions, the beneficial effects of antibiotic therapy is unquestionable </li></ul>
  48. 49. Inherited thrombophilic defects
  49. 50. <ul><li>Inherited thrombophilic defects, </li></ul><ul><li>including activated protein C resistance (most commonly due to factor V Leiden gene mutation), deficiencies of protein C/S and antithrombin III, hyperhomocysteinaemia and prothrombin gene mutation, </li></ul><ul><li>are established causes of systemic thrombosis </li></ul>
  50. 51. Environmental factors
  51. 52. <ul><li>Exposture to noxious or toxic substances are known to be associated with recurrent miscarriage ( social drugs, cigarretes,alcohol and caffeine ,anaestetic gases,petrolium products ) </li></ul>
  52. 53. Unexplained recurrent miscarriage In about half the women in the research studies, no cause could be found, so no specific treatment could be given . However, this group responded very well to a programme which removed as many stress factors as possible from their lives, resulting in an 80% success rate with the subsequent pregnancy
  53. 54. Women with unexplained recurrent miscarriage have an excellent prognosis for future pregnancy outcome without pharmacological intervention if offered supportive care alone in the setting of a dedicated early pregnancy assessment unit . After all these investigations 50% of recurrent aborters will be found to have no abnormalities and these should be attributed to chromosomal defect in the conceptus.
  54. 55. According to the American College of Obstetricians and Gynecologists <ul><li>cultures for bacteria and viruses </li></ul><ul><li>glucose tolerance testing </li></ul><ul><li>thyroid tests </li></ul><ul><li>antibodies to infectious agents </li></ul><ul><li>antithyroid antibodies </li></ul><ul><li>paternal human leukocyte antigen status, or maternal antiparental antibodies </li></ul><ul><li>are not beneficial and, therefore, </li></ul><ul><li>are not recommended in the evaluation of otherwise normal women with recurrent pregnancy loss . </li></ul>
  55. 56. Things unlikely to cause recurrent miscarriage <ul><li>Retroversion - or backward tilting of the uterus. </li></ul><ul><li>Infection - such as toxoplasmosis, listeria, brucella, chlamydia, herpes simplex and cytomegalovirus. </li></ul><ul><li>Endocrine or metabolic disease - hypothyroidism (underactive thyroid), diabetes mellitus, Crohn's disease, sickle cell or endometriosis. </li></ul><ul><li>Occupational exposures - very little reliable evidence exists for things such as herbicide spraying, electromagnetic fields, chemical inhalation, anaesthetic gases or VDU usage. </li></ul><ul><li>Not resting enough - bedrest doesn't alter whether you miscarry or not. Nor does working when you're pregnant, exercise, making love or flying. </li></ul>
  56. 58. Management <ul><li>Miscarriages, like infertility, is a problem of a couple and they should be seen together. The majority can be reassuared. </li></ul><ul><li>most cases, neither a woman nor her doctor can do anything to prevent a miscarriage </li></ul>
  57. 59. Controversies surrounding treatment for pregnancy loss <ul><li>Evidence-based medicine (EBM) has not succeeded in giving patients and physicians the data they need to choose (or not choose) a therapy in the field of pregnancy loss </li></ul>
  58. 60. If any of the above tests should come back indicating an underlying reason for the problem <ul><li>treatment is direced at the cause </li></ul><ul><li>eg : genetic counselling, </li></ul><ul><li>removal of fibroids, </li></ul><ul><li>cervical stitch </li></ul>
  59. 61. If all of the above have been excluded <ul><li>(as they will do in most cases), the diagnosis is recurrent miscarriage of unknown cause </li></ul><ul><li>the use of empirical treatment in women with unexplained recurrent miscarriage is unnecessary and should be resisted </li></ul><ul><li>for both partners to be as healthy as possible before she conceive (avoid drugs, alcohol, chemicals, etc) and to get any other medical conditions under control. </li></ul><ul><li>The only intervention to have demonstrated benefit is serial ultrasound scans in the early months of pregnancy. </li></ul><ul><li>It is certainly not unreasonable to expect this psychological support to improve outcome given the close interaction between the higher areas of the mind and the delicately balanced hormonal system. </li></ul><ul><li>Education and reassuarance with these good statistical odds </li></ul><ul><li>Education about smoking, alcohol and drug abuse is also important </li></ul>
  60. 62. Psychological support <ul><li>The value of psychological support in improving pregnancy outcome has not been tested in the form of a randomised controlled trial. However, data from several non-randomised studies86–88 have suggested that attendance at a dedicated early pregnancy clinic has a beneficial effect, although the mechanism is unclear </li></ul><ul><li>All professionals should be aware of the psychological sequelae associated with miscarriage and should provide support and follow-up, as well as access to formal counselling when necessary. </li></ul>
  61. 63. Emprical treatment <ul><li>the use of empirical treatment in women with unexplained recurrent miscarriage is unnecessary and should be resisted </li></ul><ul><li>BUT </li></ul><ul><li>Some doctors give treatment like </li></ul><ul><li>Low dose asprin </li></ul><ul><li>Subcutaneous hepaein </li></ul><ul><li>Folic acid </li></ul><ul><li>Progesterone </li></ul><ul><li>Solcoseryl(increase oxygen supply) </li></ul><ul><li>Nitroglycerin (increase implantation by increase uterine blood flow) </li></ul><ul><li>tocolytic </li></ul>
  62. 64. Treatment of miscarriage <ul><li>Surgical uterine evacuation for miscarriage should be performed using suction curettage. </li></ul><ul><li>All at risk women undergoing surgical uterine evacuation for miscarriage should be screened for Chlamydia trachomatis. </li></ul><ul><li>Medical and expectant methods are also effective in the management of confirmed miscarriage. </li></ul><ul><li>Medical and expectant management should be offered only in units where patients have access to 24-hour telephone advice and immediate admission can be arranged. </li></ul><ul><li>Tissue obtained at the time of miscarriage should be examined histologically to confirm pregnancy and to exclude ectopic pregnancy or gestational trophoblastic disease. </li></ul>
  63. 65. Fate <ul><li>A woman who has suffered a single sporadic miscarriage has an 80% chance and a woman with three consecutive miscarriages a 60% chance of her next pregnancy being successful </li></ul>