Fawaz Edris MD, RDMS, FRCSC, FACOG, AAACS

1. RECURRENT PREGNANCY LOSS Fawaz Edris MD, RDMS, FRCSC, FACOG, AAACS

2. INTRODUCTION  • Emotionally traumatic, similar to stillbirth or neonatal death • Etiology is often unknown • Primary or secondary • Live birth occurred at some time in secondary • Better prognosis with secondary

3. DEFINITION • ≥ 3 consecutive losses of clinically recognized pregnancies < 20 week gestation • Ectopic, molar, and biochemical pregnancies not included • 15 % experience sporadic loss of clinically recognized pregnancy • 2 % experience 2 consecutive losses • 0.15 x 0.15 = 0.0225 = 2 % • 0.4 to 1 % experience 3 consecutive losses • 0.15 x 0.15 x 0.15 = 0.003 = 0.3 %  observed frequency is higher than expected by chance alone

4. RISK FACTORS AND ETIOLOGY • Only in 50 %, the cause can be determined • Etiological categories: • Uterine • Immunologic • Endocrine • Genetic • Thrombophilic • Environmental

5. UTERINE FACTORS • Acquired or congenital anomalies • Congenital anomalies: 10 -15 % in ♀ with RPL vs. 7 % in all ♀ • Abnormal implantation: • ↓ vascularity (septum) • ↑ inflammation (fibroid) • ↓ sensitivity to steroid hormones

6. SEPTATE UTERUS • Most common • Poorest outcome • Miscarriage > 60 % • Fetal survival with untreated cases 6 to 28 % • The longer, the worse • The mechanism • Not clearly understood • Poor blood supply  poor implantation

7. LEIOMYOMA • Submucous • The mechanism • Their position • Poor endometrial receptivity • Degeneration with increasing cytokine production

8. OTHER UTERINE CAUSES • Endometrial polyps • Rx: Polypectomy • Intrauterine adhesions • Curettage for pregnancy complications (4/52) • Traumatize basalis layer  granulation tissue • Insufficient endometrium to support fetoplacental growth • Menstrual irregularities (hypomenorrhea, amenorrhea), cyclic pelvic pain, infertility.

9. OTHER UTERINE CAUSES • Cervical insufficiency • Recurrent mid-trimester loss • Other uterine anomalies • Impaired uterine distention

10. IMMUNOLOGIC FACTORS • Antiphospholipid syndrome (APAS) • 5 - 15 % of ♀ with RPL may have APAS • Other immunological factors • Not well defined

11. ENDOCRINE FACTORS • Luteal phase defect • Progesterone is essential for implantation and maintenance of pregnancy • A defect in C.L.  impaired progesterone production • Controversies: • Does this defect really exists? • If it does, is related to miscarriage? • No consensus on method of diagnosis • No consensus on method of treatment

12. ENDOCRINE FACTORS • Diabetes mellitus • Poorly controlled  early (and late) loss • No ↑ risk with well-controlled • Mechanism • Hyperglycemia • Maternal vascular disease • Immunologic factors (possible)

13. ENDOCRINE FACTORS • Insulin resistance • No strong evidence • PCOS • Miscarriage 20 - 40% vs. baseline rate 10 - 20% • Mechanism is unknown • ↑ LH, Testosterone, and androstenedione  adversely affect the endometrium

14. ENDOCRINE FACTORS • Thyroid disease and antibodies • Poorly controlled hypo- or hyper-thyroidism • Infertility & pregnancy loss • ↑ thyroid antibody, even if euthyroid. • No strong evidence • Hyperprolactinemia • Rx  ↑ successful pregnancy (86 vs. 52%) • BUT, need correct diagnosis • At what level to treat?

15. GENETIC FACTORS  • ↑ RPL in 1st degree relatives of ♀ with unexplained RPL • Shared HLA types, coagulation defects, immune dysfunction, other undefined heritable factors • Chromosomal rearrangements • 5 % of couples with RPL have major chromosomal defects (vs. 0.7 %) • Balanced translocation or an inversion • Even if present, may not be the cause  complete evaluation of RPL is indicated

16. 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

17. MISCELLANEOUS • Environmental chemicals & stress • Anesthetic gases (nitrous oxide), formaldehyde, pesticides, lead, mercury • Sporadic spontaneous loss • No evidence of associations with RPL • Personal habits  • Obesity, smoking, alcohol, and caffeine • Association with RPL is unclear • May act in a dose-dependent fashion or synergistically to ↑ sporadic pregnancy loss • Exercise • does not ↑ sporadic or RPL

18. MISCELLANEOUS • Male factor • Trend toward repeated miscarriages with abnormal sperm (< 4% normal forms, sperm chromosome aneuploidy) • ICSI • Paternal HLA sharing not risk factor for RPL • Advanced paternal age may be a risk factor for miscarriage (at more advanced age than females) • Infection • Listeria, Toxoplasma, CMV, and primary genital herpes • Cause sporadic loss, but not RPL

19. MISCELLANEOUS • Decreased ovarian reserve • Quality and quantity of oocytes decrease • ♀ with unexplained RPL have a higher D3 FSH and E2 than ♀ with known cause • Celiac disease • Untreated & even subclinical, associated with pregnancy loss, menstrual disorders, and infertility • Treatment prevent these problems • No evidence that it causes RPL

20. CANDIDATES FOR EVALUATION  • Evaluate and Rx ≥ 2 or 3 consecutive losses • Most have good prognosis for a successful pregnancy, even when no Dx or Rx • The minimum workup: • Complete medical, surgical, genetic, and family history • Physical examination

21. HISTORY  • GA & characteristics (anembryonic pregnancy, live embryo) of all previous pregnancies • RPL typically occurs at a similar GA • Most common causes of RPL vary by trimester • Chromosomal & endocrine earlier than anatomic or immunological causes • Uterine instrumentation  intrauterine adhesions • Menstrual cycles regularity  endocrine dysfunction • Galactorrhea, Headache, Visual disturbances hyperprolactinemia

22. HISTORY  • Thyroid related symptoms • Hx of congenital or karyotypic abnormalities  heritable • Was cardiac activity detected? If not  suggests chromosomal abnormality • Does F.Hx display patterns of disease consistent with strong genetic influence? consanguinity • Exposure to environmental toxins • Hx venous thrombosis  thrombophilia or APAS • Information from previous laboratory, pathology, and imaging studies

23. PHYSICAL EXAMINATION • General physical • Signs of endocrinopathy (hirsutism, galactorrhea, thyroid) • Pelvic organ abnormalities (uterine malformation, cervical laceration)

24. LABORATORY EVALUATION  • Karyotype (Parental) • Low yield & limited prognostic value  only if the other work-up was negative • Karyotype (Embryonic) • Not really needed • May consider after 2nd loss • If abnormal karyotype + normal parents  “bad luck”

25. UTERINE ASSESSMENT • Sonohysterography (SIS) • More accurate than HSG • Differentiate septate & bicornuate uterus • Hysterosalpingogram (HSG) • Does not evaluate outer contour • Not ideal for the cavity • Hysteroscopy • Gold standard for Dx + Rx intrauterine lesions • Cannot differentiate septate from bicornuate • Reserved for when no Dx is made

26. UTERINE ASSESSMENT • Ultrasound • Presence and location of uterine myomas • Associated renal abnormalities • MRI • Differentiate septate from bicornuate • Hysteroscopy, laparoscopy, or MRI  second-line tests when additional information is required

27. APAS • Dx: one lab & one clinical criteria are met • Clinical criteria: • Venous or arterial thrmobosis • RPL • Laboratory criteria • Lupus anticoagulant • Anticardiolipin antibody (IgG and IgM) • Medium or high titers of both • Low to mid positive can be due to viral illness • Repeat twice, 6-8 weeks apart

28. THROMBOPHILIA • Contradictory literature • Evaluate if loss > nine weeks + evidence of placental infarction or maternal thrombosis

29. THYROID • TSH +/- FT4 & FT3 • More important in ♀ with clinical manifestations but even in asymptomatic • Thyroid peroxidase antibody

30. OVARIAN RESERVE • D3 FSH +/- D3 E2 in ♀ of any age or ¼ would be missed • Clomiphene challenge test

31. NONE USEFUL TESTS • Routine cervical cultures for Chlamydia, Mycoplasma & vaginal evaluation for BV & toxoplasmosis serology • ANA • Screening for DM • Immune function (HLA typing, etc) • Progesterone level (Single or multiple) • Endometrial biopsy

32. MANAGEMENT • Prognosis for successful future pregnancy is good • live birth rates after normal and abnormal diagnostic evaluations, 77 and 71 percent, respectively • Emotional support is important and enhance success

33. PARENTAL KARYOTYPE ABNORMALITY • Refer for genetic counseling • Information for probability of a chromosomally normal or abnormal conception • May undergo prenatal genetic studies • Amniocentesis • CVS • IVF with PGD

34. UTERINE ABNORMALITIES • Managed hysteroscopically • Septum, adhesions, submucosal myoma • Cervical cerclage • Second trimester loses

35. MANAGEMENT • Antiphospholipid syndrome • Aspirin & Heparin • Suspected immunologic dysfunction  • Several immunologic Rx advocated • None effective • Some are harmful • DM • Controlled at least 6/12 prior to conception • Thyroid • Hyper and Hypo thyroid should be controlled • Euthyroid with ↑ peroxidase antibody may benefit from treatment

36. MANAGEMENT • Polycystic ovary syndrome  • No agreed upon protocol • Metformin just as effective when stopped at diagnosis of pregnancy or 12/52 gestation • Hyperprolactinemia  • Normal levels play important role in maintaining early pregnancy (in RPL) • Thrombophilia  • Anticoagulation if loss > 9/52

37. UNEXPLAINED RPL  • 50% of RPL remain unexplained • Prognosis is still good • >50 % live birth even without intervention

38. UNEXPLAINED RPL  • Lifestyle modification  • Eliminating use of tobacco, alcohol, and caffeine & reduction in BMI (for obese women). • Progesterone • Widely used but studies on its efficacy are lacking • Vaginally or IM • Human menopausal gonadotropin • Correcting LPD or creating thicker endometrium • Clinical experience supports the efficacy • IVF +/- PGD • Mixed results • Promising

39. UNEXPLAINED RPL  • Useless interventions: • hCG • CC • Pregnancy issues  • Increased risk of : • IUGR • PTD • No increased risk of: • PIH • GDM

40. Thank you