RPL panel discussion - Recurrent Pregnancy Loss

Panel Discussion

1. RECURRENT PREGNANCY LOSS (Panel Discussion) By Dr. Vijaylakshmi Verma M.B.B.S. M.D. ( Obs /Gyn) Vijaya Maternity & Test Tube Baby Centre

2. INTRODUCTION RPL is an important reproductive health issue. It is physically and emotionally taxing for the couple and a challenge to the treating physician. So let us take up this challenge and discuss solutions to help these suffering couples.

3. Mrs. X , 26 yrs, married 2yrs, comes with history of 1st – 8 wks, missed Ab [ USG] Terminated by medical method 2nd – 5 wks ammeno . , UPT faintly + BHCG 38 mIU /ml , no Intra/Extra uterine sac on USG Diagnosis ? Advice ?

4. DEFINITION

5. Will you like to advice some tests to this patient ?

6. Advice For – -- T₃ T₄ TSH -- Rubella - IgG - IgM ____________________________________________________ F.A 3 months Counseling & Consolation

7. Mrs. YL , 30 yrs, married 3yrs, P₀L₀A₂ A₁ – 8 wks, missed Ab , medically mx [ USG] A₂ – 7 wks missed Ab , medically mx [ USG] Wants opinion - “ Doctor मेरे साथ ऐसा क्यों हो रहा है ? ”

8. CAUSES OF RPL Maternal age > 35 years. Maternal obesity BMI > 30 Paternal age. Lifestyle Factor Recurrent pregnancy loss (RPL) is a multifactorial disorder with identifiable causes in over 60% of cases. A battery of tests is recommended to rule out the various causes listed in :-

9. Hypertension Chronic renal disease Chronic pulmonary disease Heart disease Severe rhesus sensitization Systemic Conditions CAUSES OF RPL

10. Hypothyroidism/hyperthyroidism Uncontrolled DIABETES MELLITUS Hyperprolactinemia Polycystic ovarian syndrome Low Anti-mullerian Hormone (poor ovarian reserve). Luteal phase defects Hyperandrogenism Adrenal hyperplasia/Addison’s disease Deficiency of vitamin D Hormonal CAUSES OF RPL

11. Primary antiphospholipid syndrome Secondary antiphospholipid syndrome – systemic lupus erythematosus, autoimmune thyroiditis Immunological - Autoimmune APLA is positive in 15% of woman with RPL. It is the most treatable cause of RPL CAUSES OF RPL

12. Abnormalities of cytokine production – lack of shift of Th1 to Th2 response Lack of alpha V beta 3 integrin Increased uterine natural killer cells Sharing of human leukocyte antigens Increased levels of tumor necrosis factor (TNF) alpha in the endometrium Immunological - Alloimmune (Classified as unexplained) CAUSES OF RPL

13. Uterine septum : 76% risk of spontaneous pregnancy loss. Intrauterine adhesions and polyps Cervical incompetence T shaped uterus Intramural fibroid more than 5 cm size and submucous fibroid Role of Arcuate uterus is unclear Unicornuate, didelphys & Bicornuate uterus Anatomical Accounts 10-15% cases of RPL. It interrupts with the vasculature of endometrium, and thus causes abnormal & inadequate placentation. CAUSES OF RPL

14. Fetal trisomy , polyploidy, monosomy Parental balanced translocations, inversions, deletions, duplications Skewed inactivation of X chromosome Single gene defects, e.g. alpha thalassemia major, Rett syndrome, etc. Genetic Genetic causes were earlier thought to contribute in a small percentage, however they are assuming greater importance and it is believed that a large percentage of unexplained causes of RPL show subtle genetic abnormalities in the embryo . To date, genetic evaluation of the products of conception (POC) remains the most neglected yet vital investigations. There are two distinct sources of genetic abnormalities: Those that develop de novo during embryogenesis Those associated with a balanced translocation in one of the parents. Prevalence of genetic abnormalities in sporadic miscarriages is estimated to be 45% (CI 38-52%) and in recurrent miscarriages 39% (CI 29-50%) in a systematic review. Genetic Causes are: CAUSES OF RPL

15. Antithrombin III deficiency Deficiency of protein C and protein S Activated protein C resistance Factor V Leiden mutation Methyl tetrahydrofolate gene homozygosity and hyperhomocysteinemia Prothrombin gene mutation Plasminogen activator inhibitor Inherited Thrombophilia CAUSES OF RPL

16. High sperm DNA fragmentation index Y chromosomal microdeletions Semen Factors CAUSES OF RPL

17. 0.5 – 5 % Organism speculated : Mycoplasma Ureaplasma Chlamydia trachomatis, Listeria monocytogenes, and HSV Syphlis Tuberculosis Bacterial vaginosis Malaria Infection cause pregnancy loss due to :- Placental insufficiency Direct Infection of uterus, fetus or placenta Chronic endometritis or endocervicitis Impaired endometrial receptivity & alter genes involved in implantation. Amnionitis Infections CAUSES OF RPL

18. Smoking, alcohol, drugs Exposure to irradiation Exposure to environmental toxins, pesticides , DDT, dry cleaning chemicals Exposure to anesthetic gases Environmental endocrine disrupters Miscellaneous CAUSES OF RPL

19. Epigenetic modifications of the embryo Maternal stress Idiopathic CAUSES OF RPL

20. Unknown 40-45% Hormonal 15-20% Anatomic 10-15% Infections 0.5-5% Autoimmune/Blood clotting 15-20% Genetic 2-5% Causes Of Recurrent Pregnancy Loss (Percentage-wise Distribution Of Etiology Of Recurrent Miscarriages)

21. This patient says that doctor I want all my test to be done so that I don’t abort next time. What investigations would you like to advise?

22. Investigations For RPL For Metabolic And Endocrine Factors T₃ T₄ TSH , TPO Ab Test which can be done , but not strongly recommended :  S. Insulin  S. Prolactin  AMH  Vit . D  HbA₁C (family history DM & Obese patient)

23. For Anatomical Causes 3D USG MRI HSG Hysteroscopy Lapro hystro in difficult situation Investigations For RPL

24. For Infectious Etiology TB Sure Hysteroscopy Cervical & vaginal swab culture Investigations For RPL

25. For Inherited & Aquired Thrombophilia Factor V Leiden mutation Prothrombin gene mutation Protein C , Protein S & antithrombin deficiency Investigations For RPL

26. For Immunological – Autoimmune Factor APLA syndrome panel Lupus Anticoagulant – APTT , KCT , DRVVT Anticardiolipin antibody – IgG , IgM Anti-beta-2 glycoprotein antibody – IgG , IgM ANA titer Serologic test for Syphilis (false – positive result) CBC count ( thrombocytopenia , hemolytic anemia) ACOG guideline states that any one of these lab criteria should be + ve in 2 or more occasions at least 12 weeks apart Investigations For RPL

27. For Genetic Causes FISH ( Fluorescent in situ hybridization) - can be done on nonviable chorionic tissue. - can be detect chromosomal number variations. - classically employed to detect 21, 18, 13, X & Y - extended to include 16 & 22 Conventional karyotyping - required viable chorionic tissue and hence cannot be applied to missed abortion. Microarray includes a – comparative genomic hybridization (CGH) b – single nucleotide polymorphism (SNP) Microarray – study all 24 chromosomes - does not required viable tissue - can even distinguish maternal cell contamination - can be used to detect certain genes expressed only in the placenta. - it may not detect balanced translocations and low level of mosaicism . Investigations For RPL

28. For Genetic Causes QFPCR - QFPCR is DNA based diagnostic test or we can say a small version of microarray covering 80% aneuploides contributing in RPL cases, 13, 18, 21, 15, 16, 22, X & Y chromosomes are studied - Its Economic, Rapid, Reported in just 3-4 days once sample reaches lab Next Generation sequencing a – does not require viable tissue. b – highest sensitivity to detect mosaicism . Parental karyotyping - not routinely recommended Recommendation is when : a – genetic abnormality on POC b – previous offspring with a genetic abnormality c – family history of abnormal child

29. For Male Factors Testing A – recent studies point towards chromosomal abnormality of spermatozoa as cause of RPL - FISH for sperm testing can analyse a – Sperm aneuploidy b – Chromosome micro deletion & duplication B – Investigate and Interrogate for a – Cigarette smoking b – Radiotherapy c – Chemotherapy d – Varicocele e – Hyperthermia (Professional) f – ageing g – Pesticides , metal and air pollutant to DM & hypertension C – Anti sperm antibody may cause immune rejection of the embryo. Investigations For RPL

30. Now this patient’s reports are ready and her APLA panel report is : What is the treatment recommended?

31. TEATMENT For APLA + ve Patients Anticoagulants are the mainstay of treatment Low dose aspirin 75 - 150 mg/day Unfractionated heparin (UFH) dose 15,000 – 20,000 units daily in divided dose. The target aPTT is 1.5 times the normal value LMWH prophylactic dose 40 IU s/c OD & Therapeutic dose is 1 mg/kg 12 hrly or 1.5 mg/kg daily [H/O thrombo embolic events].

32. TEATMENT When to start Aspirin to be started as soon as UPT + ve LMWH started with UPT + ve or after fetal CA + ve as per RCOG guidelines When to stop Aspirin – between 36 – 38 wks of pregnancy LMWH – 12 hrs before LSCS/IOL started 12 hrs after delivery & continued till 6 wks Warfarrin is safe during lactation Can be given for 6 wks under monitoring

33. TEATMENT Adverse effects Bleeding episodes Hypersensitivity - reaction Thrombocytopenia Osteoporosis – 1 -2 % cases

34. Patient Mrs XL, P₁L₁A₂ (Both early pregnancy missed abortion on investigation presents with this report Treatment ?

35. Treatment For ANA Positive Tab HCQ 400 mg OD under monitoring

36. Mrs GP, P₀L₀A₃ all three early pregnancy missed abortion last pregnancy terminated by D&C and QFPCR on POC shows Deletion at chromosome 16 Treatment ?

37. TrEATMENT For Genetic Causes Genetic Counseling by genetic expert Detailed family history and estimate risk of recurrence of genetic disorder PGS [ Preimplantation genetic screening ] for embryo (Blastomere biopsy) has been recommended in couples with recurrent aneuploidy. PGD [ Preimplantation genetic diagnosis ] is performed for couples with known carrier state of single gene disorder i.e. Hemophilia. ART – couples who are carriers of balanced translocation will require donor gametes option for IVF & IUI can be given

38. Mrs X, P₀L₀A₂ ( Both 8 wks missed) showed this finding on 3D USG : Treatment ?

39. TEATMENT Correction Of Anatomical Causes Procedures Hysteroscopic septoplasty Hysteroscopic polypectomy Hysteroscopic or laparoscopic myomectomy Hysteroscopic adhesiolysis , metroplasty

40. Mrs RG, P₀L₀A₃ (all 3 early pregnancy missed abortions) All blood reports normal, 3D USG normal no lifestyle or systemic factor did a hysteroscopy and this is the picture : Treatment ?

41. For Infective Cause Antibiotics Clindamycin Doxycycline Erythromycin Anti TB treatment TEATMENT

42. MIDTERM RPL Mrs G , is at present 12 wks pregnant with history of 2 previous pregnancy losses at 16 wks & 18 wks How to manage ?

43. MIDTERM RPL USG finding : Cₓ length 2.5 cm int. os – 7 mm width ___________________________________________________ Cₓ encerclage  types of encerclage McDonald Shiradkor Wurm’s Followed supporting therapy

44. Mrs. XO, P₀L₀A₃ all tests mentioned till now – ve . She is 5 wks pregnant now, will you like to give immunotherapy to this patient what are the various agent used ?

45. Immunotherapy In RPL Immunomodulatory Therapies Suggested Are : Paternal Leukocyte Immunization – may enhance maternal recognition of paternal alloantigens and prevent RPL IV Immunoglobulin – No standardization of dose regim High cost Possibilities of adverse effect Anti-TNF- α Drugs – ( Tumor necrosis factor-alpha) Granulocyte Colony Stimulating Factor – (G-CSF) Intralipids – 250 ml on the day of OPU improved result in RPL patients in few studies Corticosteroids – Prednisolone is shown to reduce uNK cells in few studies In some patient evidences to recommend routine use of drugs

46. TEATMENT Endocrine & Medical Treatment Hypothyroid , Hyperthyroid , Subclinical hypothyroid , DM [ HBA₁C < 6.5 ] Hypertension Obesity [ ? If possible] Hyperprolactinemia Role of Vit D supplement Correction of hyperhomocysteinemia Role of folic acid, Vit B₆ , B₁₂ supplement Correction of Luteal phase deficiency Treatment of PCOD

47. TEATMENT Life Style Management Alcohol Smoking Caffeine ( not more than 3 cups a day) Nicotin ( Panmasala , Zarda & Tobacco)

48. Role of progesterone Recommendation is : Dydrogestrone 10 mg BD till 20 wks Natural micronized progesterone a. 400 mg vaginally till 20 wks b. Can be given oral with poor absorption c. Injectable for poor pt compliance

49. Progesterone and Early Pregnancy 49 Progesterone is produced by corpus luteum after ovulation Prepares endometrium for implantation Fertilization successful Corpus luteum persist & secrets progesterone Failure in fertilization Corpus luteum degenerates; inovulation occurs

50. Importance of Progesterone in Early Pregnancy 50 Progesterone is essential for pregnancy maintenance Endogenous progesterone rises sharply after ovulation and peaks the following week Progesterone is produced by placenta later in pregnancy through hCG regulation

51. Progesterone Induces Secretory Changes in Endometrium Maturation of endometrium Stabilization of endometrium Implantation of embryo Regulation of inflammatory mediators Adequate positive immune response in early pregnancy, preventing pregnancy loss

52. Immunomodulatory Properties of Dydrogesterone in Early Pregnancy Dydrogesterone Decreases pro-inflammatory cytokines and increases anti-inflammatory cytokines in early pregnancy

53. Choosing the Right Progestogen for Treatment of Recurrent Pregnancy Loss

54. 2015 European Progestin Club Guidelines 2015 European Progestin Club Guidelines for the Treatment of Recurrent Miscarriage For women presenting with a clinical diagnosis of recurrent miscarriage, 3 or more, there is a reduction in the rate of miscarriage with the use of dydrogesterone Recommendation

55. Recurrent Miscarriage Oral Vaginal Dydrogesterone Micronized Progesterone 10 mg BD till 20 weeks of pregnancy 400 mg/day vaginally till 20 weeks of pregnancy FOGSI - Good Clinical Practice Recommendations: Use of Progestogens in Early Pregnancy

56. 2017 ESHRE Guidelines for Recurrent Pregnancy Loss 2017 ESHRE Guidelines for Recurrent Pregnancy Loss Consensus-based Recommendation There is some evidence that oral dydrogesterone treatment,initiated when fetal heart action can be confirmed, may be effective but more trials are needed Conditional Recommendation Vaginal progesterone does not improve live birth rates in women with unexplained RPL

57. Benefits of Oral Dydrogesterone Compared to Micronized Progestogen

58. Oral Bioavailability Oral Dose Dydrogesterone Micronized Progesterone 28% <5% 10 mg 100–300 mg Dydrogesterone has ~5.6 times better oral bioavailability than progesterone Dydrogesterone requires a 10–20 times lower oral dose than micronized progesterone, providing clear clinical benefits Dydrogesterone vs. Micronized Progesterone: Bioavailability and Oral Administration

59. Dydrogesterone has high oral bioavailability , which together with its activity and high specificity for progesterone receptors causes endometrial transformation at a dose 10–20 times lower than that of MCP. Minimizes side-effects and reduces the likelihood of altered liver function Oral administration strategy promises compliance and convenience for the patient . Dydrogesterone Is Superior to Micronized Progesterone

60. Thank you……