Recurrent pregnancy loss


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Recurrent pregnancy loss

  1. 1. Recurrent Pregnancy Loss
  2. 2. Definition• Pregnancy loss is defined as the spontaneous loss of pregnancy before the fetus reaches viability (24 weeks)• Recurrent pregnancy loss, defined as the loss of three or more ( ≥ 3) consecutive pregnancies.• Primary- No previous full term pregnancy• Secondary- At least one successful pregnancy
  3. 3. Incidence– 15-20% of all pregnancies– 11-13 % in first pregnancy– 13-17 % after first abortion– 38 % after two abortions– 55% after three abortions
  4. 4. Suspected etiologies Anatomical factors Genetic factors Infective agents Immune factors Antiphospholipid syndromeInherited thrombophilic defects Endocrine factors Epidemiological factors
  5. 5. Anatomical Factors
  6. 6. Uterine Abnormalities • CONGENITAL (Mullerian Duct abnormalities) • UTERINE NEOPLASMS (Growth) • IATROGENIC (Acquired)
  7. 7. How they affect……. •Smaller Uterine Cavities •Fewer suitable implantation sites •Aberrations of vascularisation •May be accompanied by cervical incompetence Lead to both early & later pregnancy losses
  8. 8. Septate Uterus• Most COMMON anomaly 55%• May be complete/ incomplete/segmental 25% early abortions 6.2% late abortions & Premature labors
  9. 9. Unicornuate Uterus • 20% of anomalies • Agenesis or hypoplasia of one Mullerian duct • May be alone or accompanied by Rudimentary horn With presence / absence of cavity Communicating / Non communicating • Associated Renal anomalies occur in 40% patients Ipsilateral to hypoplastic horn
  10. 10. Unicornuate Uterus• Abortion Rate 51%, Premature labours, malpresentations, IUGR, Uterine rupture & ectopic pregnancies common• Cervical encerclage to improve pregnancy outcome• Rudimentary Horn resected to prevent dysmenorrhoea, haematometra,ectopic pregnancy
  11. 11. Uterus Didelphys• Least common anomaly -5-7%• Failure of lateral fusion of uterus &vagina• Abortion rate 43%,Premature birth rate 38%• Resection of Vaginal septum if there is difficulty in intercourse / vaginal delivery• Strassmann Operation not indicated
  12. 12. Bicornuate Uterus• 10% of anomalies• Incomplete fusion of Uterine horns at level of fundus• Two separate but communicating endometrial cavities• Abortion rate 32% Preterm labour 21%• Strassman Metroplasty / Place IUCD in one horn
  13. 13. Arcuate Uterus• Near complete resorption of u-v septum• Mild concave indentation at fundus• Data conflicting Abortion rates ?45% ?13%• Treatment expectant
  14. 14. T shaped Uterus• Diethylstilbestrol treatment for Premature labour started 1940 Banned 1970• 69% female foetuses suffered Uterine anomaly• T-Shaped uterus, small uterus, constriction rings,• Cervical hypoplasia, cervical incompetence, Anterior Cervical collar, pseudopolyps• 2 fold increase in abortion rates & 9 fold increase in Ectopic pregnancy rates
  16. 16. Uterine Neoplasms• Endometrial Polyps
  18. 18. Leiomyomas (Fibroids) most common…. 20-50% of reproductive women
  19. 19. • Preconception myomectomy to improve reproductive outcome can be considered on an individual basis• It is likely to have a place only in women who have recurrent pregnancy loss, – large submucosal fibroids, and no other identifiable cause for recurrent miscarriage Ouyang DW, Obstet Gynecol Clin North Am. 2006
  20. 20. Iatrogenic…Intrauterine adhesions ,“Asherman’s Syndrome”• Lead to Poor implantation,• Decreased blood supply ,• infectionAbortion rates 40% Preterm labour 23%Management :-Hysteroscopic excision of adhesions
  21. 21. HYSTEROSCOPIC CORRECTION• All of the above have a good pregnancy rate post hysteroscopic correction• Except ashermans syndrome
  22. 22. Incompetent Cervix• Funneling of >25% cervical length and/or <2.5 cms cervical length before 24 weeks of pregnancy• USG follow up weekly in cases of prior 2nd trimester loss• Cervical cerclage reduces the rate of preterm birth Carp et al, 2007• Emergency cerclage: beneficial if no infection or uterine contractions
  23. 23. Genetic Etiology• Chromosomal 3.5%-5% – Fetal chromosomal abnormalities – Parental balanced chromosomal rearrangement• Single gene disorders – Alpha thalassemia major – Thrombophilia – X linked dominant disorders
  24. 24. Risk Factors for genetic abnormalities • Gestational age Higher in early gestation 90% in anembryonic preg/Blighted ova 50% at 8-11wk 30% at 16-19 wk 6-12% >20wk
  25. 25. Risk Factors for genetic abnormalities Advanced maternal age  Affects ovarian function, giving rise to a decline in the number of good quality oocytes, resulting in chromosomally abnormal conceptions that rarely develop further.  RM risk -75% in women >45years Previous number of miscarriages 25
  26. 26. Fetal chromosomal abnormality in only 25- 32% of product of conception. This may be due to abnormalities in the egg, sperm or both. The most common chromosomal defects are Trisomy, Monosomy, Polyploidy Sperm aneuploidy (13,18,21,X,Y ) directly influences the rate of aneuploidy in the conceptus (Carrell et al 2003)
  27. 27. • Parental chromosomal abnormality (Balanced chromosomal rearrangements) –General population 6 in 1000(0.6%) –RM 4.1-11%*3-5% of couples with RM are carriers of balanced chromosomal rearrangements
  28. 28. Parental Chromosomal Abnormalities –Translocation (commonest) (1in 500) • Reciprocal [50%] • Robertsonian [24%] –Mosaicism for a numeric aberration [12%] –Inversion 29
  29. 29. TranslocationTranslocation is exchange of chromosomal segmentsbetween two, non-homologous chromosomes.
  30. 30. TranslocationsTwo major typesReciprocal translocation- two non-homologous chromosomes exchangeinformationRobertsonian translocation -two non-homologous acrocentricchromosomes break at the centromereand the long arms fuse. The shortarms are often lost. Source- Emery’s book of principles of Medical Genetics
  31. 31. • Karyotype of the abortus (POC)( fetal/placental tissue)• Peripheral blood Karyotyping of the parents in all couples with RM 32
  32. 32.  No definite recommendations for routinely obtaining abortus karyotype (ACOG 2001) Karyotype analysis of abortus tissue for couples with a subsequent second or third pregnancy loss (Hogge, et al 2003) If abortus is aneuploid, maternal cause is excluded (ACOG, 2001) If POC karyotype not possible, do parental karyotype
  33. 33. Direct parental karyotype is more cost effective.No need for first abortion.POC abnormal karyotype requires parental karyotype
  34. 34. Single Gene Disorders in RM• Second and 3rd trimester losses• Alpha Thalassemia• Myotonic dystrophy• X linked Dominant disorder – Incontinentia Pigmenti – Chondrodysplasia punctata – Focal dermal hypoplasia of Goltz – Rett Syndrome – Aicardi Syndrome 35
  35. 35. Management?
  36. 36. Role of Infections
  37. 37. Its time to say goodbye to TORCH tests……. Cochrane Review has categorically proven inmultiple meta-analysis that none of the “TORCH” group of infections are responsible for RECURRENT SPONTANEOUS ABORTIONS
  38. 38. So which infections, if any are responsible for RM? Female • Viral infections ? ? – Coxasackie B – Parovo-virus B • Bacterial infections – Bacterial Vaginosis – Tuberculosis – Chlamydia trachomatis Male factors: • Semen infections can cause anueploidy and be the reason of RSA
  39. 39. Bacterial Vaginosis• Commonest cause of vaginitis• Amsels criteria for diagnosis of BV Bacterial – Thin, homogeneous discharge Vaginosis – Release of an amine 50% (putrescine, cadaverine, & trimethylamine) or fishy odor Trichomona Candida on addition of KOH is to s vaginalis albicans vaginal discharge 25% 25% – "Clue cells" (Vaginal epithelial cells coated with coccobacilli) – Vaginal pH > 4.5• Nugent score: Gram Stain of vaginal swab
  40. 40. BV and RPL• BV one of the most frequently founded cause of spontaneous abortions and prematurity birth• Diagnostics is easy and not expensive• High vaginal pH is diagnostic• Treatment is simple using Metronidazole/Clindamycin1. Damianov L, Damianova V. Akush Ginekol (Sofiia). 2004;43 Suppl 2:26-7.2. Mania-Pramanik J, Kerkar SC, et al. J Clin Lab Anal. 2008;22(5):375-9.3. Li TC, Makris M, et al. Hum Reprod Update. 2002 Sep-Oct;8(5):463-81
  41. 41. IMMUNOLOGIC FACTORS Autoimmune Alloimmune (directed to self) (directed to foreign) tissues/cells)-Systemic Lupus Erythmatosus An abnormalmaternal-Antiphospholipid Syndrome immune response to fetal or placental antigen.
  42. 42. Antiphospholipid Antibody Syndrome and Recurrent Pregnancy Loss 45
  43. 43. Incidence• About 1% of women have recurrent pregnancy loss.• Antiphospholipid antibodies are found in about 2% of a Caucasian population. Not studied in a general Asian / Indian population• 5 – 20% of women with recurrent pregnancy loss have antiphospholipid antibodies 46
  44. 44. Statistical Distribution• Prevalence of antiphospholipid antibodies in various categories of women was studiedWomen with 3 or more Women with normal Women who have not early fetal losses pregnancy outcome been pregnant (includes women not desiring pregnancy and infertile women) 16% 7% 3% 47
  45. 45. Pitfalls in diagnosis of APS• Usually an overdiagnosed syndrome• Not meeting clinical and the strict laboratory criteria• Not repeating the laboratory test at 6 weeks• Non standardized ELISA for ACL antibodies• Interlaboratory variations for phospholipid dependent coagulation tests used for screening for lupus anticoagulant 49
  46. 46. False results in APS• Improperly collected and processed samples• Temporal and trimester wise fluctuations• VDRL positive patients who may or may not have syphilis• General infections and inflammations• Coagulopathies and anticoagulant medication users (including aspirin, heparin) 50
  47. 47. ManagementWomen with APS without Women with APS witha history of thrombotic history of thromboticevents events (past or present)(most women with RPL)Prophylactic therapies such Full anticoagulation withas aspirin, heparin in heparin (or warfarin) inpregnancy and 6 to 8 pregnancy and postpartumweeks postpartum 51
  48. 48. Aspirin alone v/s Aspirin + Heparin• Recent meta analysis shows that the combination of Aspirin + Heparin is better than Aspirin alone in achieving live births in women with recurrent pregnancy loss and antiphospholipid antibodies Mak A et al, Rheumatology (Oxford) 2010 52
  49. 49. Is Heparin + Aspirin really better? • The metaanalysis was based on data from five trials involving 334 patients across non uniform care platforms • Overall live birth rates were 74.27 and 55.83% in the combination and aspirin alone groups – RR 1.301; 95% CI 1.040, 1.629 – Number needed to treat is 5.6 • There is no placebo group for comparison • Another metaanalysis showed that LMW heparin + Asprin does not significantly improve birth rates. The benefits is present only with unfractionated heparin Zikas PD et al, Obstet Gynecol 2010 53
  50. 50. Clinical Tips for using Heparin• There is controversy as to whether LMW Heparin is effective in preventing recurrent pregnancy loss• Consider costs, convenience and compliance before initiating therapy• Therapy should be started when fetal cardiac activity is demonstrated and continued throughout pregnancy and postpartum• Heparin in prophylactic doses needs to be stopped for about 24 hours around the time of labor and delivery 54
  51. 51. Clinical Tips for using Heparin• Heparin in prophylactic doses can not be monitored and does not require monitoring by coagulation parameters• Do a platelet count at 3 days, 1 week and bimonthly when the patient is on heparin• Standard doses – Unfractionated heparin – 5000 units sc bd – Enoxaparin – 40 mg subQ daily or in two doses 55
  52. 52. Full Anticoagulation : Practical• Preconception : Warfarin• Switch to Heparin when fetal cardiac activity is demonstrated• Warfarin should be considered in the second trimester• Switch back to Heparin at 34 to 36 weeks• After delivery : Warfarin 56
  53. 53. What not to do for APS• Steroid therapy should be avoided for APS because it significantly increases morbidity (hypertension, diabetes, preterm births) without any demonstrable benefit• Immunoglobulin therapy is experimental and not for clinical use at present 57
  54. 54. Alloimmune mechanismTheory: Normally pregnancy(foreign tissue graft) is tolerated by the maternal immune system through formation of antigen blocking antibodies.Felt that in couples that share similar types of HLA, there is inadequate formation of blocking antibodies in the maternal environment.Therefore the maternal immune system mounts an immune response to the implanting pregnancy and a spontaneous abortion occurs.Multiple recent studies have not confirmed this.
  55. 55. ALLOIMMUNITYDIAGNOSIS• HLA crossmatching Husband’s lymphocytes + wife’s serum TREATMENT• Transfusion of husband’s lymphocytes Pure suspension of husband’s lymphocytes [ 300ml of blood = 10ml of suspension ] Inject 5ml IV, 1 ml subcu and 1ml intradermal
  56. 56. Immunologic Factors -Treatment• Immunostimulating Therapies-Leukocyte Immunization• Immunosuppressive Therapies
  57. 57. Intravenous immunoglobulin• theory – an overzealous immune reactivity to their implanting fetus• Mechanism – decreased autoantibody production and increased autoantibody clearance, T-cell and Fc receptor regulation, complement inactivation, enhanced T-cell suppressor function, decreased T-cell adhesion to the extracellular matrix, and downregulation of Th1 cyokine synthesis• disadvantage – expensive, invasive, and time-consuming, requiring multiple intravenous infusions over the course of pregnancy• side effects – nausea, headache, myalgias, hypotension, anaphylaxis
  58. 58. Progesterone• Mechanism – inhibits Th1 immunity – shift from Th1-to Th2 type responses• This benefit of progesterone could be explained by administered its immmunomodulatory actions in inducing a – intramuscularly pregnancy-protective shift from pro-inflammatory – intravaginally Th-1 •cytokine responses to a more favourable anti- may increase local, intrauterine concentration inflammatory Th-2 cytokine response • averting any adverse systemic side effects
  59. 59. Inherited thrombophilic defects (Hypercoagulable state)Factor V Leiden mutation protein C deficiency Protein S deficiencyAntithrombin III deficiency Hyperhomocysteinaemia Prothrombin gene mutation
  60. 60. THROMBOPHILIA• Thrombosis on maternal side of the placenta  impair placental perfusion – Late fetal loss, IUGR, abruption, or PIH• Relationship with early loss is less clear – large and contradictory literature – May be restricted to specific defects not completely defined, or presence of multiple defects
  61. 61. Inherited Thrombophilias
  62. 62. Antithrombotic Therapy• The combined use of low-dose aspirin (75-80mg/dl) and subcutaneous unfractionated heparin (5000unit twice daily)
  63. 63. ENDOCRINE FACTORS• Mild endocrine diseases are likely not causes for recurrent abortion.1)Thyroid disease – Poorly controlled hypo- or hyper-thyroidism • Infertility & pregnancy loss – ↑ thyroid antibody, even if euthyroid. • No strong evidence
  64. 64. 2)Diabetes mellitus – Poorly controlled (↑Blood glucose & HbA1c levels in 1st trimester  risk for loss. – Miscarriage risk rises with the level of HbA1c – Well-controlled : No ↑ risk.
  65. 65. • 3) Polycystic Ovarian Syndrome• 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(RCOG)• Hyperinsulinemia & ↑ level of Plasminogen Activator Inhibitor activity – implicated as the proximate cause of incidence of loss(30-50%)among PCOS women (Br J Obst Gynecol,1993)• METFORMIN treatment can reduce or eliminate risk of miscarriage in PCOS women (Fertility Sterility,2001;J Clin Endocrino 2002)
  66. 66. 4)Luteal phase defect – Progesterone is essential for implantation and maintenance of pregnancy • A defect in Corpus luteum impaired progesterone production. • However, LPD cannot be diagnosed during pregnancy; a consistently short luteal phase duration is the most reliable diagnostic criterion.
  67. 67. TREATMENT– luteal-phase support with progesterone– There is insufficient evidence to evaluate the effect of progesterone supplementation in pregnancy to prevent a miscarriage (RCOG)– However newer evidences is coming up as large multicentre study PROMISE is currently on the way.
  68. 68. 5)Hyperprolactinemia• There is insufficient evidence to assess the effect of hyperprolactinaemia as a risk factor for recurrent miscarriage. RCOG Green-top Guideline No. 17 April 2011
  69. 69. Epidemiologic factors• Cigarette smoking has been suggested to have an adverse• effect on trophoblastic function and is linked to an increased risk of sporadic pregnancy loss.• Obesity has also been shown to be associated with an increased risk of RM in women who conceive naturally.• Other lifestyle habits such as cocaine use, alcohol consumption, and increased caffeine consumption• (>3 cups of coffee) have been associated with risk of miscarriage.
  70. 70. Unexplained…• No apparent causative factor is identified in 50% to 75% of couples with RM.• It is important to emphasize to patients with unexplained RM that the chance for a future successful pregnancy can exceed 50%–60% depending on maternal age and parity.
  71. 71. Take home message…
  72. 72. Investigations TSH HbA1C Anti thyroid Antibody Anatomy screen APS screen Vaginal swab PCOD screen Cytogenetic examination of abortus Karyotyping Thrombophilias screen
  73. 73. Evidence based Progesterone Weight reduction Aspirin + LMWH Cerclage Clindamycin Thyroxin IVF + PGD
  74. 74. Eminence based Spiramycin Steroids Immunoglobulins hCG
  75. 75. Unexplained RM Repeated scanningReinforcement Reassurance
  76. 76. Unexplained RM