Best Ivf Doctor Dr. K.D.Nayar Clinic in Delhi

1. Recurrent Pregnancy Loss

2. DR. KANAD DEV NAYAR Sr. Consultant & Head Of Department Akanksha IVF Centre Mata Chanan Devi Hospital , New Delhi Conducting FOGSI Certified Basic & Advanced Infertility and IUI Training Guide for one year Fellowship in Clinical ART , IFS accredited centre 11 International presentations in ASRM meetings since 2006 and more than 30 National presentations and publications in reputed journals

3. AKANKSHA IVF CENTRE MATA CHANAN DEVI HOSPITAL

4. Definition Miscarriage: • <20 weeks(WHO) • <500 gm Recurrent Miscarriage: • Loss of 3 or > consecutive pregnancies(RCOG) • 2 or > failed pregnancies documented by ultrasound or histopathological examination(ASRM) • Most clinicians consider RPL even if losses are not consecutive Recurrent Pregnancy Loss: • Upto 28 weeks

5. Pregnancy loss is greatest during the implantation phase

7. Definition Miscarriage: • <20 weeks(WHO) • <500 gm Recurrent Miscarriage: • Loss of 3 or > consecutive pregnancies(RCOG) • 2 or > failed pregnancies documented by ultrasound or histopathological examination(ASRM) • Most clinicians consider RPL even if losses are not consecutive Recurrent Pregnancy Loss: • Upto 28 weeks

8. Introduction • 15-25 % - clinically recognized pregnancy loss • 0.6-2.3%-RPL • 5% of couples will experience two consecutive losses • 1 – 2% will experience three consecutive losses • But thereafter the chance of successful live birth is ≈ 40%

9. Difficulty in diagnosis • Differentiate sporadic pregnancy losses from RPL • Only 71% of self-reported clinical pregnancy losses could be verified in hospital records • ASRM: Clinical pregnancy documented by ultrasonography or histopathological examination

10. Types • Primary:No viable infant • Secondary:After a pregnancy progressing beyond 20 weeks • Tertiary:multiple miscarriages interspersed with normal pregnancies

11. Whom to evaluate? • A threshold of three or more losses should be used for epidemiological studies • Clinical evaluation may proceed after two losses • Women without any co-morbid medical conditions should not undergo extensive investigations after a single miscarriage ASRM 2012

12. Epidemiology • The earlier the gestation the higher the risk of miscarriage, majority of it ocurring in the first trimester. • The prevalence of miscarriage increases with advancing maternal age • Both retrospective and prospective studies have shown that the risk of another miscarriage increases after each subsequent pregnancy loss

13. Immune tolerance Successful mammalian pregnancy depends upon immune tolerance of a genetically incompatible fetus by the maternal immune system.

14. Scanning electron micrograph of endometrial epithelium on day LH + 4of a natural cycle. Nikas G: Endometrial Receptivity: Changes in Cell-Surface Morphology.Semin Reprod Med 18(1):229-236, 2000 Scanning electron micrograph of endometrial epithelium on day LH + 7of a natural cycle

15. Nikas G: Endometrial Receptivity: Changes in Cell-Surface Morphology.Semin Reprod Med 18(1):229-236, 2000 • The human implantation window (day 20-21/28 day cycle) is determined by the formation of pinopodes. • The formation of pinopodes is progesterone-dependent (inhibited by the administration of the anti-progestin mifepristone). • Examination of endometrial biopsy specimens for pinopodes is a potential test in infertility evaluation for the optimization of embryo transfer and implantation. ? (ESHRE 2012)

16. Ovulation to implantation Chemokines and cytokines guide embryo to optimal implantation spot Integrins and cadherins attach blastocyst to pinopods Hanna Achache and Ariel Revel. Endometrial receptivity markers, the journey to successful embryo implantation. Human Reproduction Update, Vol.12, No.6 pp. 731–746, 2006.

17. Epithelial cell adhesiveness by E-cadherin is controlled by intracellular calcium. Blastocyst invasion aided by dissolution of E cadherin With progesterone No progesterone Rising progesterone levels induce calcitonin expression and thus increase the concentration of intracellular calcium, which then suppresses E-cadherin expression at cellular contact sites. Hanna Achache and Ariel Revel. Endometrial receptivity markers, the journey to successful embryo implantation. Human Reproduction Update, Vol.12, No.6 pp. 731–746, 2006.

18. Implantation

19. The feto-maternal interphase • Tolerance is now believed to depend in part on the interactions of cytokines secreted by maternal and fetal cells at the site of implantation.

20. Early Pregnancy Maintenance

21. Changing paradigm of Implantation

22. Spectrum Of Pregnancy Loss( RIF to RM)

23. Embryo invasion or decidual encapsulation? • Once the blastocyst has breached the luminal epithelium it becomes quickly embeded in the uterine mucosa • This concept of passive decidua and invasive embryo is being challenged. • Active decidual cell migration and encapsulation of the conceptus are integral steps in implantation process.

24. Personalized Embryo Implantation

25. Emerging Concept: Embryo Recognition & Selection • Human endometrial stromal cells become biosensors of embryo quality but only upon differentiation into decidual cells. • Cyclic dedidualisation not only enables rapid embryo encapsulation but also recognition & selection • The purpose of a tailored maternal response is either to support further development of high-quality embryos by secretion of key implantation factors ( IL-1, Heparin binding EGF, LIF) or to trigger early disposal of an unwanted conceptus by activating serine protease and rendering them prone to oxidative stress.

26. RECEPTIVE EMBRYO SELECTION AT IMPLANTATION SELECTIVE

27. • In the first trimester – 90% karyotypically abnormal pregnancies miscarry – 93% karyotypically normal pregnancies continue Mcfadyen 1989

29. Selectivity Vs Receptivity • The Biphasic transition of decidual cells from the proinflammatory initiation phase ( Receptive) to a fully secretory anti-inflammatory ( Selective) phenotype (marked by expansion of decidual ER, up regulation of various molecules, HSPA8 ) the ability of cell to sense and respond to embryonic signals in a tailored fashion balances the receptivity versus selectivity traits of the human endometrium. • An excessive decidual response (increased selectivity) will curtail the window of receptivity and increase the disposal efficacy of embryos, thereby reducing the incidence of miscarriages but also increasing the likelihood of conception delay or recurrent implantation failure after IVF. • Conversely, a disordered decidual response will increase the likelihood of both pregnancy as well as miscarriage by facilitating out-of-phase implantation

31. Selectivity Vs Receptivity • To be reproductively successful, the maternal endometrium must be receptive as well as selective, meaning acquiring the ability to mount a secretory response that is tailored to an individual embryo. • The purpose of a tailored maternal response is either to support further development of high-quality embryos or to trigger early disposal of an unwanted conceptus • Unrestrained endometrial receptivity and lack of embryo selection both contribute to subsequent pregnancy failure • Conversely, premature or excessive decidualization will increase the barrier function of the endometrium and reduce the likelihood of pregnancy. Notably, as maternal age advances, the incidence of embryonic aneuploidy increases, thus requiring a greater need for endometrial selection in order to avoid recurrent pregnancy failure

32. Clinical consequences of embryo selection at Impantation • Metabollically quiet • No proteotoxic stress • Low invasive potential Endometrium Non receptive selective Reproductive success Receptive • Metabolic overdrive • Proteotoxic stress • Highly invasive Lucas et al., 2016

33. Etiology Of Recurrent Miscarriage

34. Causes Of RM

35. 1. Epidemiological factors:Influence of Maternal Age • 15-19 • 20-24 • 25-29 • 30-34 • 35-39 • 40-44 • 45 and older • 9.9 • 9.5 • 10.0 • 11.7 • 17.7 • 33.8 • 55.2 Fertility and Sterility: vol.46, p 989; 1986

36. Epidemiological factors:Influence of Maternal Age • 12-19 • 20-24 • 25-29 • 30-34 • 35-39 • 40-44 • 45 & older • 13 • 11 • 12 • 15 • 25 • 51 • 93 BMJ v 320, 1708-1712, 2000

37. Epidemiological factors: Influence of Age • Highest risk for miscarriage if the woman is > 35 y/o and the man is > 40 y/o.

38. Epidemiological factors:Previous reproductive history • Risk of further miscarriage increases with each successive pregnancy loss (~40% after 3 consecutive miscarriages) and the prognosis worsens with increasing maternal age.

39. Epidemiological factors:Environmental risks • Cigarette smoking • Caffeine consumption • Alcohol intake • Video display terminal • Anesthesia gases • Obesity

40. 2 Thrombophilias2A. Antiphospholipid syndrome • Present in 15% of women with RM vs. <2% in low risk women • Highly-treatable! • APAS refers to association between antiphospholipid antibodies (Lupus anticoagulant, anti-cardiolipin and anti-B2glycoprotein 1) and adverse pregnancy outcome or arterial thrombosis. J Thrombo Haemost 2006;4;295-306

41. Antiphospholipid syndrome • Adverse outcome • >3 miscarriages < 10 weeks AOG • >1 Morphologically normal fetal loss after 10 weeks AOG) • >1 Preterm deliveries < 34 weeks AOG • Mechanisms for Morbidity • inhibits trophoblastic differentiation / function • Activates complement pathways leading to a local inflammatory reaction • Thrombosis of the uteroplacental vasculature. Bose et al: Amer J Obstet Gynecol 2005; 192; 23-30

42. 2B. Inherited thrombophilias • Factor V Leiden, Protein C/S and AT III deficiency, Prothrombin gene mutation and Hyperhomocystenemia  systemic and utero-placental thrombosis. • Meta-analysis showed losses in the 2nd trimester were greater than the 1st trimester losses. Rey E. Lancet 2003; 361; 901-908

43. Thrombophilias • Hereditary • Protein C /Protein S deficiency • Anti thrombin III deficiency, • Factor V leiden Mutation, • MTHFR mutation • Acquired: Antiphospholipid syndrome

45. Prospective cohort studies have failed to confirm an association between hereditary thrombophilias and fetal loss • Routine testing for inherited thrombophilias in RPL is not recommended Silver M et al.Obstet Gynecol 2010 Dizon et al.Obstet Gynecol 2005 De Jong et al.Sem Reprod Med 2011 ASRM 2012

46. In Inherited Thrombophilia There is insufficient evidence to evaluate the effect of heparin in pregnancy to prevent a 1st trimester miscarriage. C Heparin therapy during pregnancy may improve the live birth rate of women with 2nd trimester miscarriage. A LMWH has proven efficacy in single miscarriage >10 weeks in women with: • FVLM • Prothrombin gene mutation • Protein S deficiency • LBR 86% for enoxaparin Vs 29% for aspirin alone

48. Low does aspirin (42.9% LBR) • With heparin(74.3% LBR) • Neither corticosteroids nor intravenous immunoglobulin therapy improve the live birth rate compared with other treatment modalities; their use may provoke significant maternal and fetal morbidity.A

49. 3. Genetic Factors • Parental chromosomal rearrangement • 2-5& of couples with RM have a balanced chromosomal anomaly (reciprocal or Robertsonian translocation) • Couples appear normal but have increased rates of miscarriage or congenital anomalies / mental retardation depending on the genetic content of the re-arranged chromosomes • Hum Reprod 2006: 21; 1076-1082 • BMJ 2006; 352; 759-763

50. Genetic • Embryonic chromosomal abnormalities (structural and numerical) may account for 30 - 57% of miscarriages. • Parental chromosomal rearrangements are the cause of RPL in 3 - 5% of couples. The most common abnormalities are balanced reciprocal or Robertsonian translocations