What is recurrent miscarriage?

2. Pregnancy loss - notion, diagnostics, treatment TO BE OR NOT TO BEPetar Ivanov, MD, PhD, Assoc. Prof., OB/GYNsClinical Institute for Reproductive Medicine, IVF UnitMedical University Pleven, Biochemistry Department

3. Happy pregnant Try again Few week later Pain, bleeding loss Recover What is recurrent miscarriage? • Understanding • Definition • Classification • Pathogenesis • Investigation and Diagnosis • Treatment

4. Terms . . . • Miscarriage ( = Abortion = Pregnancy loss) • Abortion (< 20 wg) • Pregnancy loss (3-42 wg) • Stillbirth (20-28 wg)

5. Historical perspective • Sporadic miscarriage rate is 15% • RM rate 0.153 = 0.3-0.4%. • The actual prevalence of RM is 1-3%

6. Recurrent Pregnancy Loss (RPL) - Definition • Occurrence of 2/3 or more clinically recognized consecutive or nonconsecutive pregnancy losses before 20 weeks from last menstrual period • Primary- No previous full term pregnancy • Secondary- At least one successful pregnancy

7. Warburton D, Fraser FC: Am J Human Genet 16:1, 1964 Miscarriage Recurrence Risk

8. Maternal Age and Risk of Miscarriage • 12 – 19 years • 20 – 24 years • 25 – 29 years • 30 – 34 years • 35 – 39 years • 40 – 45 years • >45 years • 13% • 11% • 12% • 15% • 25% • 51% • 93%

9. Classification

10. Classification • Pre-implantation RPL (3-4 wg) • Implantation PL (Recurrent Implantation Failure, RIF) (4-6 wg) • Embryonic Failure (6-8 wg) • First trimester loss (8-12-14 wg) • Second trimester loss (>14 wg)

11. Mechanism miscarriage ? • Excessive oxidative stress • (Burton and Jauniaux J Soc Gynecol Investig 2004;11:342–5)

12. Recurent Miscarriage Etiology Explained • Anatomic (Sporadic) 12%-16% • Endocrine 17%-20% • Luteal phase deficiency • Uncontrolled DM • PCOS • Immunological 10%-16% • Anti phospholipid syndrome • Environmental • Alcohol, Smoking • Genetic factors 3.5-5% Un-explained 50% • Thrombophilic • Infectious factors

13. EGG 80% Venn diagram of the responsibilities of Reproductive Failure SPERM 10% UTERUS 10%

14. Causes of Recurrent Pregnancy Loss

15. Etiology - Environmental Factors • Confirmed association • Ionizing irradiation • Organic solvents • Alcohol • Mercury • Lead • Suspected association • Caffeine (> 300 mg/day) • Hyperthermia/fever • Cigarette smoking • Unknown association • Pesticides Gardella & Hill Semin Reprod Med 2000;18(4):407-424

16. Diagnostic x-rays Air travel Microwave ovens Diagnostic ultrasounds Electromagnetic fields Video display terminals Aspartame Chocolate Drinking water BGH Phytoestrogens Phthalates Herbicides Hair dyes Nail polish Saccharin Etiology - Environmental Factors

17. Anatomical Factors • What are the congenital & acquireduterine anomalies leading to RSA? • How will you manage?

18. Uterine Abnormalities • CONGENITAL (Mullerian Duct abnormalities) • UTERINE NEOPLASMS (Growth) • IATROGENIC (Acquired)

19. ANATOMICAL CAUSES • Septateuterus (early pregnancy loss) • Bicornuateut (unequal horns)(second trimester pregnancy loss) • Unicornuate uterus • T shaped uterus • Submucousfibroids • Large endometrial polyps • . . . Adenomyosis . . . . . . . • . . .Cervical insufficiency . . . • . . .Intrauterine adhesions . . .

20. 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

21. Septate Uterus • Most COMMON anomaly 55% • May be complete/ incomplete/segmental 25% early abortions 6.2% late abortions & Premature labors

22. 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

23. 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

24. 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

25. 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

26. Arcuate Uterus • Near complete resorption of u-v septum • Mild concave indentation at fundus • ? Anomaly / ? Anatomic variant • Data conflicting Abortion rates ?45% ?13% • Treatment expectant

27. 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

28. Uterine Neoplasms • Endometrial Polyps

29. Leiomyomas (Fibroids) most common…. 20-50% of reproductive women When will you considerfibroids responsible ?

30. 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

31. Iatrogenic… Intrauterine adhesions ,“Asherman’s Syndrome” • Lead to Poor implantation, • Decreased blood supply , • infection Abortion rates 40% Preterm labour 23% Management :-Hysteroscopic excision of adhesions

32. HYSTEROSCOPIC CORRECTION • All of the above have a good pregnancy rate post hysteroscopic correction • ExceptASHERMANS SYNDROME

33. Cervical insufficiency - Causes Congenital • Mullerian tube defects (bicornuate uterus, septate uterus, unicornuate uterus) • Diethylstilbestestrol exposure in utero • Abnormal collagen tissue (Ehlers Danlos syndrome, Marfans syndrome ) Acquired • Forceful mechanical cervical dilatations • Cervical lacerations • Cervical cone or LEEP procedure (IATROGENIC) Alimentary/Life style Smoking Cu, vit C deficiency

34. Anatomical Factors • When will you label a patient as a case of incompetent Cervix? • What are the different surgical procedures? • Role of prophylactic surgery?

35. USG follow up weekly in cases of prior 2nd trimester loss • Funneling of >25% cervical length and/or <2.5 cm cervical length before 24 weeks of pregnancy • Cervical cerclage reduces the rate of preterm birth Carp et al, 2007 • Emergency cerclage: beneficial if no infection or uterine contractions

36. What is the miscarriage rate in patients with ADENOMYOSIS? • 11% • Mechanism: Nitric Oxide

37. Genetic Etiology • Chromosomal 3.5%-5% • Fetal chromosomal abnormalities • Parentalbalanced chromosomal rearrangement • Single gene disorders • Alpha thalassemia major • Thrombophilia (fetal) • X linked dominant disorders

38. Risk Factors for Karyotypic 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

39. Risk Factors for RM • 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

40. Spontaneous Miscarriage (sporadic) • 10-15% of recognized pregnancies • Mostly sporadic; 80% losses in 1st 12 wks • 50-70% due to chromosomal anomalies • Autosomal trisomy 50-60% • 13,16,18,21,others • Monosomy X-20% • Triploidy –15% • Tetraploidy-5% • Unbalanced translocation-3-5%

41. In Recurrent Miscarriage (RM) • Fetal chromosomal abnormality in only 25-32% of product of conception (POC) • 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)

42. In Recurrent Miscarriage • Parental chromosomal abnormality (Balanced chromosomal rearrangements) • General population 6 in 1000 (0.6%) • RM4.1-11% *3-5% of couples with RSA are carriers of balanced chromosomal rearrangements

43. Parental Chromosomal Abnormalities • Translocation (commonest) (1in 500) • Reciprocal [50%] • Robertsonian [24%] • Mosaicism for a numeric aberration[12%] • Inversion

44. Diagnosis • Karyotype of the abortus ( fetal/placental tissue) • Peripheral blood Karyotyping of the parents in all couples with RM

46. Karyotype of Products of Conception • 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

47. Single Gene Disorders in RM • Second and 3rd trimester losses • Alpha Thalassemia • Myotonicdystrophy • X linked Dominant disorder • IncontinentiaPigmenti • Chondrodysplasiapunctata • Focal dermal hypoplasia of Goltz • Rett Syndrome • Aicardi Syndrome

48. Single Gene Disorders in RM • FETUS thrombophilia • First and later trimester losses • Microthrombosis in placenta; Impaired uteroplacental circulation • Factor V Leiden gene mutation Evidence based Prothrombin G 20210A mutation inc. risk • Protein C,S deficiency • Antithrombin III No significant association • MTHFR C677T mutation • Combination of any of above-Increased risk

49. Role of Infections

50. Doubtful causes of RPL • TORCH infections • Endocrine and metabolic disease • Untreated adrenal hyperplasia, hypothyroidism & diabetes mellitus. • Exogenous causes • Environmental factors, alcohol, street drugs, anesthesia gases etc