Recurrent Pregnancy Loss-LPD

1. Recurrent Pregnancy Loss-LPD Dr. USHA REDDY MRCOG

2. ? Why LPD

3. Abortion & Infertility Profound personal tragedy a formidable challenge to physician.

4. Human Reproduction Woefully inefficient 15 % of ova exposed to sperm fail to divide 15% fail to implant & 41% of implanted pregnancy are lost41% implanted pregnancy are lost of which 2/3 after Hcg secretion and 1/3 even beforeThus finally only 30% → Viable Preganancy

5. Hormonal bio essays Imaging techniques Newer surgical endoscopic procedure Pharmaceutical treatment ▼ Successful management of this heterogeneous disorder and endowing the blessing of parenthood to many a despondent couple

6. Spontaneous Abortion Incidence 16% of all clinically recognised pregnancies but 55% after 3 consecutive Spontaneous Abortions (in patients with Habitual/Recurrent Abortion) Vlaandeeren W 1987

7. Endocrine etiologies Luteal phase defect Thyroid dysfunction Uncontrolled diabetes mellitus Immune-based Uterine anatomic anomalies Endometrial infections Antiphospholipid syndrome Inherited thrombophilias & Alloimmune causes Parental chromosomal abnormalities Proposed causes of RSA Lee RM, Silver RM 2000 Recurrent pregnancy loss: summary and clinical ecommendations. Semin Reprod Med 18:433–440

8. Pregnancy & Immunomodulation

9. Endocrine - Immuno Interaction Duphaston modulates the mother ‘s-to- be immune response from Rejection Protection to

10. Spontaneous Recurrent Abortion Causes Explainable 50-60% Genetic Infectious Endocrine Autoimmune - SLE, Anticardiolipin Antibodies Unexplained 40-50% Allogenic Immune Response to Paternal Antigens R Raghupathy 1999

11. Formation of the Zygote

12. In Pregnancy…... FETUS Mother Father Own Foreign Antigens Mother’s Body Foreign Antigens Mother’s Body

13. We all agree that ……. Material from Father…………………. …………. Is Foreign to Mother Therefore … Mother’s body will recognize it as An Antigen & set up an Immune reaction to Fetus

14. What follows is……. Foreign Antigens T & B cells T helper 1 cell response T helper 2 cell response Antibodies Response to Fetus is same as that to any Foreign Antigen

15. Immune Reaction During Pregnancy Fetus with Paternal Antigens T helper 1 cell response T helper 2 cell response Protection of the Fetus Abortion of the Fetus

16. Pregnancy protective Immunomodulation starts... ...Pre-embryo‘s journey in the Fallopian Tubes 30-36h day 3-4 2 cells 4 cells 8 cells Morula day 5-6 Blastocyst

17. Four cell stage of Embryo Start of feto-maternal crosstalk...

18. From days 15-16 ... maternal blood circulates... within the intervillous space

20. How does T helper 1 response cause Abortion? Fetus T helper 1 cell response NK LAK cells Release harmful cytokines Symmetric Antibodiesby B cells Bind with Antigen TNF ά IFNγ IL2 IL12 IL18 Activation of Complement Phagocytic & Cytotoxic reactions Inflammation Abortion of Fetus

21. Let us look at each of these reactions in detail now…………..

22. Cytokines …... Fetus T helper 1 cell response activated Tumor Necrosis Factor ά Interferon γ Interleukin 2 Interleukin 12 Interleukin 18 Harmful cytokines Inflammation Abortion of Fetus

23. Symmetric Antibodies…... Symmetricity b/w binding surfaces.. Maternal Antibody Paternal Antigen Exact alignement b/w binding surfaces Lock-n-Key pattern Antigen-Antibody binding Activation of Complement Cascade Abortion of the Fetus

24. Binding of Antigen & Antibody

25. The Complement Cascade

26. Destruction of Cell by Complement

27. LAK cells …... Fetus T helper 1 cell response activated Harmful cytokines Tumor Necrosis Factor ά Interleukin 2 Natural Killer cells Lymphokine Activated Killer cells Abortion of Fetus

28. Having shown the immune response in Abortion Let us see what happens in a successful Pregnancy

29. In successful Pregnancy Embryo protective Immunomodulation takes place

30. Embryo Protective Immunomodulation -What is it? 3 positive responses NK Activity T helper 2 cell response Asymmetric Antibodies Protective cytokines No binding with Antigen IL 3 IL 4 IL 5 IL 6 IL 10 IL 13 No activation of Complement Cascade Protection of Fetus

31. Embryo Protective Immunomodulation - How is this brought about ? Normal Pregnancy Progesterone (P) Receptor Activation Progesterone Induced Blocking Factor (PIBF) Embryo Protective Immunomodulation Protection of Fetus

32. Embryo Protective Immunomodulation in Successful Pregnancy PIBF NK Activity T helper cell 2 response Asymmetric Antibodies Protective cytokines No binding with Antigen IL 3 IL 4 IL 5 IL 6 IL 10 IL 13 No activation of Complement Cascade Protection of Fetus

33. Unfortunately ….. As we have seen …. In up to 50 % of women with Recurrent Abortion, Embryo-protective Immunomodulation does not take place

34. In these women with Recurrent Abortion duphaston is the key to Embryo survival

35. Let us see….. How duphaston ensures Embryo protective Immunomodulation

36. Embryo Protective Immunomodulation - Role of duphaston duphaston Progesterone (P) Receptor Activation PIBF Embryo Protective Immunomodulation Protection of Fetus

37. Treatment of LPD Treatment of LPD can be by any of the following : • Progesterone • Non luteolytic progestogen • hCG

38. Recent Indian Data Report of the study undertaken by Dr. Sonia Malik, MD, Sr. Consultant, Obstet & Gynaecology, Infertility & IVF, New Delhi in the year 1998-1999, publihed in Obs & Gynae Today, August 2000 : 497-501 • Aim - To study the effect of duphaston (dydrogesterone) on the endometrium in case of luteal phase insufficiency. • Patients and Methods - 25 patients undergoing infertility investigations were identified as having luteal phase insufficiency according to the following criteria -. • an endometrial biopsy on day 21 showing a lag of 3 days or more. • A serum progesterone concentration of < 10 ng/ml. • An ultrasound scan showing either poor endometrium or corpus luteum. …contd.

39. Advantages of Dydrogesterone over other Progestogens Androgenic - + + No side effects like acne, activity hirsutism, voice changes Impairment of - + + Safe in diabetics and in carbohydrate post menopausal women metabolism Impairment of - + + Decreases risk of CVD lipid metaboilsm Virlization of - + + No adverse effects on foetus female foetus Anabolic effects - + + No weight gian / increased BP Thermogenic effect - + + No masking of the BBT Parameters Dydrogesterone Nonrethisterone MPA Clinical advantages of Dydrogesterone

40. Human Chorionic Gonadotrophin • HCG stimulates cells of the corpus luteum to produce progesterone. In the normal corpus luteum, the luteal cells are adequate in number and have adequate capacity to produce progesterone. • However, malfunctioning corpus luteum has less number of luteal cells. Also, the capacity of each luteal cell to produce progesterone in response to HCG is compromised ( decreased ) in luteal phase defect . Therefore progesterone production via stimulation of malfunctioning corpus luteum by HCG will be less. ( ref. Momoeda et al, Human Reproduction, 1998, July; 13 (7), 1907-11 ) …contd.

41. Stimulatory effect of exogenous HCG on progesterone production is minimal on malfunctioning corpus luteum. This suggests that LPD does not benefit from HCG administration. ( ref. Momoeda et al, Human Reproduction, 1998, July; 13 (7), 1907-11 ) …contd.

42. Among the characteristics of LPD in women is the inability of the corpus luteum to respond appropriately to LH/HCG. This defect may be caused by inappropriate formation of new LH/HCG receptors. ( Felig P, Endocrinology & Metabolism, 1995, third edition, 994 ) • HCG will not correct the luteal phase defect in patients with inadequate ovarian LH/HCG receptors. ( Mishell’s Text Book of Infertility, Contraception and Reproductive Endocrinology, 1997, Fourth edition, 739-40 ) • There is a risk of ovarian hyperstimulation syndrome ( OHSS )associated with hCG use. …contd.

43. Micronised progesterone…NATURAL? • The term natural progesterone ( as used to describe micronised progesterone ) is misleading. Diosgenin ( plant source - Dioscorea villosa ) Micronised Progesterone Dydrogesterone Either both are natural or both are synthetic. ( Ref: : Peterson C M, Clinical Obstetrics and Gynecology, 1995, 38 ( 4 ) : 819; http://www.skinbiology.com/menopause&aging.html; data on file ) Synthetic Steps

44. DIOSGENIN the same natural source of dydrogesterone and micronised progesterone What is the difference between dydrogesterone and micronised progesterone?

45. COCH3 CH3 COCH3 CH3 The difference is in the structure. • This structural difference brings about the difference in the metabolism. (ref. Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184 ) CH3 CH3 H H O O O dydrogesterone progesterone

46. Dydrogesterone’s different metabolism... • The metabolites of dydrogesterone retain 4,6- diene-3-one structure. The major metabolite of dydrogesterone retains progestational activity. Hence, it is orally effective . • Dydrogesterone has very good oral bioavailability. • It brings about 100% conversion to secretory endometrium ( Identical endometrial histological appearance as seen in natural cycles ). (ref. Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184; Malik S, Nagpal S, Obs & Gynae Today, August 2000, V ( 8 ) : 497-501 )

47. Oral micronised progesterone’s different metabolism • The metabolites of progesterone do not retain 4 - ene - 3-one structure. Hence, it is not orally effective. • 95% of micronised progesterone administered orally was converted to inactive metabolites due to first pass effect. • Incomplete secretory conversion of endometrium has been reported with oral micronised progesterone. (ref. Amsterdam P H et al, European J of Drug Metabolism and Pharmacokinetics, 1980, 5 (3): 173-184 ; Levine H L, Watson N A, Abstract presented at the 8th International Congress on the menopause, Sydney, Australia,November 3-7, 1996; )

48. Safety ...Dydrogesterone vs micronised progesterone • Unlike oral micronised progesterone, dydrogesterone does not cause hepatotoxicity, natriuresis. • Unlike progesterone, dydrogesterone does not cause impairment of carbohydrate metabolism. ( Ref. - AICOG News, December 2000, ; Martin A J, Supplement to Modern Medicine, December , 1986, 31(12) ).

49. Dydrogesterone vs vaginal micronised progesterone • Vaginal administration of progesterone is complicated by a marked variability within and among patients. • Side effects include vaginal irritation, discharge, monilial vaginitis. • Dydrogesterone being administered by oral route, the above limitations, side effects are not observed. • Vaginal micronised progesterone is found to deter embryo implantation and decrease pregnancy rates. Dydrogesterone maintains implantation site and achieves good pregnancy rates. ( Maxson W S , Clin Exp Obst & Gyn, June 1987, 30(2):470, Wang H S, Soong Y K, Gynecol Endocrinol, 1996, 10(5): 349-355 )

50. Efficacy of Dydrogesterone comparable with parenteral progesterone • The implantation rate and pregnancy rate with dydrogesterone was similar to intramuscular progesterone injection in IVF programme. • Pregnancy rate in oocyte donation programme using dydrogesterone is comparable to that reported with natural products. • The activity of dydrogesterone is comparable to that of parenterally administered progesterone. { ref. : Jan Domitrz et al Ginekol Pol 1999 Jan 70 (1) : 8-12; Abu Musa, Clin Exp Obst & Gyn, 1998, XXV (3 ) : 84; Gelfand M M et al, Menopause: The J of North American Menopause Society, 1997, 4(1): 11 ;