1 RECURRENT PREGNANCY LOSS Dr P M

1

RECURRENT PREGNANCY LOSS Dr. P. M. GOPINATH MD, DGO, FMMC, FICS, FICOG, MBA (HSM) Director of Social Obstetrics i/c ISO & KGH Chennai 600005

Recurrent Miscarriage-Definition • Occurrence of 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

Incidence – 15 -20% of all pregnancies – 11 -13 % in first pregnancy – 13 -17 % after first abortion – 38 % after two abortions – 55% after three abortions

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%

Anatomical Factors • What are the congenital & acquired uterine anomalies leading to RSA? • How will you manage?

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

ANATOMICAL CAUSES • • Septate uterus Intrauterine adhesions Bicornuate ut (unequal horns) Unicornuate uterus T shaped uterus Submucous fibroids Large endometrial polyps

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 • •

Septate Uterus • Most COMMON anomaly 55% • May be complete/ incomplete/segmental 25% early abortions 6. 2% late abortions & Premature labors

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

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

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 • •

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

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 • •

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

T SHAPED UTERUS- INFECTION MALA ARORA 17

Uterine Neoplasms • Endometrial Polyps

PERIOSTEALMALA ARORA ENDOMETRIAL POLYP 19 3/16/2018

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

• 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

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

HYSTEROSCOPIC CORRECTION • All of the above have a good pregnancy rate post hysteroscopic correction • Except ashermans syndrome

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

• USG follow up weekly in cases of prior 2 nd trimester loss • Funneling of >25% cervical length and/or <2. 5 cms 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

Genetic Etiology • Chromosomal 3. 5%-5% – Fetal chromosomal abnormalities – Parental balanced chromosomal rearrangement • Single gene disorders – Alpha thalassemia major – Thrombophilia – X linked dominant disorders

Risk Factors for Karyotypic abnormalities Gestational age Higher in early gestation 90% in anembryonic preg/Blighted ova 50% at 8 -11 wk 30% at 16 -19 wk 6 -12% >20 wk

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 >45 years Previous number of miscarriages 28

Spontaneous Miscarriage • 10 -15% of recognized pregnancies • Mostly sporadic ; 80% losses in 1 st 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% recurrence risk Parental Karyotypes normal Minimal

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)

In Recurrent Miscarriage • Parental chromosomal abnormality (Balanced chromosomal rearrangements) –General population 6 in 1000(0. 6%) –RM 4. 1 -11% *3 -5% of couples with RSA are carriers of balanced chromosomal rearrangements

Parental Chromosomal Abnormalities –Translocation (commonest) (1 in 500) • Reciprocal [50%] • Robertsonian [24%] –Mosaicism for a numeric aberration [12%] –Inversion 32

Translocation is exchange of chromosomal segments between two, non-homologous chromosomes. Source-Internet

Translocations Two major types Reciprocal translocation- two nonhomologous chromosomes exchange information Robertsonian translocation -two non-homologous acrocentric chromosomes break at the centromere and the long arms fuse. The short arms are often lost. Source- Emery’s book of principles of Medical Genetics

Diagnosis • Karyotype of the abortus ( fetal/placental tissue) • Peripheral blood Karyotyping of the parents in all couples with RM 35

Spontaneous abortion Recurrent Miscarriage 10 -15% 1 -3% 50 -70% abortuses 25 -30% abortuses chromosomally abnormal Couple karyotype usually Couple karyotype may be normal rearrangement carrier Recurrence risk negligible Recurrence risk upto 50%

Karyotype of Products of Conception • Successful culture requires healthy cells derived from the fetus • Unsuccessful in upto 50% of cases – Maternal overgrowth of fetal cells – Poor growth of abortus tissue esp. if there is a long time interval from the demise until the culture is performed – Poor chromosome morphology

Whether we should do POC karyotype ? ?

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

Karyotype of Products of Conception Normal Abnormal (trisomy or chromosomal rearrangement) Both requires parental karyotype Direct parental karyotype is more cost effective No need for first abortion

Why Karyotype of the Parents ? ? • Individuals with Balanced Chromosomal Rearrangement usually phenotypically normal • Are at risk of having conceptus with – normal – balanced phenotypically normal – unbalanced • spontaneously aborted • phenotypically malformed

Single Gene Disorders in RM • • Second and 3 rd trimester losses Alpha Thalassemia Myotonic dystrophy X linked Dominant disorder – – – Incontinentia Pigmenti Chondrodysplasia punctata Focal dermal hypoplasia of Goltz Rett Syndrome Aicardi Syndrome 42

Single Gene Disorders in RM • Hereditary thrombophilia • • • – First and later trimester losses – Microthrombosis in placenta ; Impaired uteroplacental circulation Factor V Leiden gene mutation Evidence based Prothrombin G 20210 A mutation inc. risk Protein C, S deficiency Antithrombin III No significant association MTHFR C 677 T mutation Combination of any of above-Increased risk 43

Genetic Evaluation and Testing Recommendation • History of – Recurrent miscarriage – Clotting disorder – Still birth/neonatal death – Babies with dysmorphic features – Infertility – Mental retardation /developmental delay – Inherited disorder (J Gen Counsel ; 14(3)2005) 44

Karyotypic abnormalities in couples with Recurrent abortions Total Couples n=742(1484 cases) Duration -12 years Chromosomal rearrangements = 52 (7% ) Structural aberrations 22 (2. 9%) – Reciprocal (6, 8, 11, 18)=15 (68. 2%) – Robertsonian (21, 22, 13, 14)=4 (18. 1%) – Inversion(4)=1 (9%) – Deletion=2 • Numerical anomalies (mosaics with XO, XXX, XXY)= 9 (1. 2%) • • • Chromosomal variants (para centromeric heterochromatin/fragile sites) = 21 (3. 2%) Dubey et al. Ind J Hum Genet 2005

Role of Infections

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

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

Its time to say goodbye to TORCH tests……. TORCH T ESTS Cochrane Review has categorically proven in multiple meta-analysis that none of the “TORCH” group of infections are responsible for RECURRENT SPONTANEOUS ABORTIONS

So which infections, if any are responsible for RSA? Female • Viral infections ? ? – Coxasackie B – Parovo-virus B • Bacterial infections – Bacterial Vaginosis – Tuberculosis – Chlamydia trachomatis Male factors: • Semen infections can cause anueploidy and be the reason of RSA

Genitourinary diseases prior spontaneous abortion as a risk factor for RSA Concluded “infections of the maternal and/or paternal genitourinary system may be the causal factor for recurrent pregnancy loss and can also pre-determine women that are of greater susceptibility to preterm pregnancy” • Culić V, Konjevoda P, et al. Coll Antropol. 2009 Mar; 33(1): 187 -92 • Kamilova N, Sultanova I, et al. Georgian Med News. 2008 Nov; (164): 23 -7

Bacterial Vaginosis • Commonest cause of vaginitis • Amsel's criteria for diagnosis of BV – Thin, homogeneous discharge – Release of an amine (putrescine, cadaverine, & trimethylamine) or fishy odor on addition of KOH is to vaginal discharge – "Clue cells" (Vaginal epithelial cells coated with coccobacilli) – Vaginal p. H > 4. 5 • Nugent score: Gram Stain of vaginal swab Bacterial Vaginosis 50% Trichomona Candida s vaginalis albicans 25%

BV and RSA • BV one of the most frequently founded cause of spontaneous abortions and prematurity birth • Diagnostics is easy and not expensive • High vaginal p. H is diagnostic • Treatment is simple using Metronidazole/Clindamycin 1. Damianov L, Damianova V. Akush Ginekol (Sofiia). 2004; 43 Suppl 2: 26 -7. 2. Mania-Pramanik J, Kerkar SC, et al. J Clin Lab Anal. 2008; 22(5): 375 -9. 3. Li TC, Makris M, et al. Hum Reprod Update. 2002 Sep-Oct; 8(5): 463 -81

The influence of Chlamydia trachomatis infection on RSA Specific anti-chlamydial antibodies in 3 groups of women • Ig. A class – 7. 9% (p=0. 082) in group 1 (RSA group), – 4. 5% (p=0. 236) in group 2 (1 abortion) – 0% in group 3 ( no abortions) • Ig. G class in 21. 1% (p=0. 024), 36. 4% (p=0. 000) and in 4. 4%, respectively. CONCLUSIONS: • C. t. infection is an important causative agent in RSA • Anti-Chlamydial antobodies included in screening tests Wilkowska-Trojniel M. Adv Med Sci. 2009; 54(1): 86 -90 Kavalier F, BMJ. 2005 Jul 16; 331(7509): 121 -2.

Hattori Y, Nakanishi T. Am J Reprod Immunol. 2007 Oct; 58(4): 350 -7. • Uterine cervical inflammatory cytokines, interleukin 6 and -8, as predictors of RSA • Both IL-6 and IL-8 in cervical mucus were significantly higher in patients who miscarried subsequently than in those who had a live birth.

Other rare viruses Coxsackie B virus (CBV) & RSA Parvovirus B 19

Is it time to look at the sperm?

Consequences of fertilisation by sperm with nuclear DNA damage No DNA Repair Fertilisation Failure Partial DNA Repair Fertilisation Normal offspring ? Abnormal offspring

SEMEN CULTURE • Male accessory gland infection with E coli / Staph aureus / • Bacteria ride on the sperm tails into uterine cavity • Produce low grade endometritis

Possible role of male factors in recurrent pregnancy loss • Amongst male partners of women with RSA 3 (4%) had varicocele, 23 (30. 6%) had infection, 1 (1. 3%) immunological and 1 (1. 3%) had genetic abnormality • Sperm motility, viability and sperm function tests were significantly lower in the RPL group as compared to the control group (P = 0. 000) • Male factor might be a contributing factor towards RPL • Both the partners should be evaluated • Infection treated in both Saxena P, Misro MM et al. Indian J Physiol Pharmacol. 2008 Jul-Sep; 52(3): 274 -82

Conclusion Problems of Research in RSA • The cause of individual abortion may be different • More than one factor may exist • Thorough investigation often fails to reveal a cause • Infections must be ruled out Fertil Steril. 2010 Mar 1; 93(4): 1234 -43. Epub 2009 Mar 31

Conclusions • TORCH group DOES NOT cause RSA • Infections in both partners need to be evaluated in cases of RSA • Therefore the genetic counseling of couples should include thorough medical examination and evaluation for infections

Antiphospholipid Antibody Syndrome and Recurrent Pregnancy Loss 63

Autoimmune etiology • Secondary to autoimmune disease such as SLE, Polyarteritis nodosa, etc • Primary Antiphospholipid Syndrome (PAPS) refers to the association of adverse pregnancy outcome and presence of antiphospholipid antibodies 64

Which antibodies ? • A number of antibodies have been studied • The antibodies with the greatest significance and association with obstetric events are – Lupus anticoagulant (LA) – Anticardiolipin antibodies (ACL Ig. G and ACL Ig. M) • Others have such as β 2 glycoprotein-I, antiphosphatidylserine antibodies, annexin, etc may not be obstetrically significant 65

Incidence • About 1% of couples have recurrent miscarriages • Antiphospholipid antibodies are found in about 2% of a Caucasian population. Not studied in a general Asian / Indian population • 5 – 20% of women with recurrent miscarriages have antiphospholipid antibodies Mac. Lean AS et al, BJOG 1994 Rai RS et al, Hum Reproduction 1995 Balasch J et al, Hum Reproduction 1996 66

Statistical Distribution • Prevalence of antiphospholipid antibodies in various categories of women was studied Women with 3 or more early fetal losses Women with normal pregnancy outcome Women who have not been pregnant (includes women not desiring pregnancy and infertile women) 16% 7% 3% Parke AL et al, Arch Rheumat 1991 67

Diagnosis of PAPS • Based on clinical and laboratory criteria • One obstetric or thrombotic criteria and one laboratory criteria should be present to diagnose PAPS • Other autoimmune disease has to be ruled out to make the diagnosis of PAPS Wilson A et al, International Consensus statement on APS, Arthritis Rheumatol 1999 68

Obstetric Criteria • Three or more consecutive spontaneous abortion before the 10 th week of gestation • One or more unexplained fetal death at or beyond the 10 th week of gestation • Severe preeclampsia or placental insufficiency (IUGR) necessitating birth before the 34 th week of gestation 69

Vascular Thrombosis Criteria • Unexplained venous thrombosis • Unexplained arterial thrombosis • Small vessel thrombosis in any tissue or organ, without significant evidence of inflammation of the vessel wall 70

Laboratory Criteria • Anticardiolipin antibody Ig. G or Ig. M isotype in medium to high titers by standardized ELISA assay • Lupus anticoagulant present • A positive test has to be repeated on at least one more occasion six weeks apart to fulfill the laboratory criteria 71

Lupus anticoagulant testing • Screen with demonstration of prolonged phospholipid dependent coagulation screening test (eg: activated partial thromboplastin time, kaolin clotting time, diluted Russell’s viper venom time, dilute prothrombin time) • Failure to correct the prolonged screening test by mixing with normal platelet-poor plasma • Shortening or correcting the prolonged screening test by addition of excess phospholipids • Exclusion of other coagulopathies if clinically 72 indicated

Pitfalls in diagnosis of PAPS • Usually an overdiagnosed syndrome • Not meeting clinical and the strict laboratory criteria • Not repeating the laboratory test at 6 weeks • Non standardized ELISA for ACL antibodies • Interlaboratory variations for phospholipid dependent coagulation tests used for screening for lupus anticoagulant 73

False results in PAPS • Improperly collected and processed samples • Temporal and trimester wise fluctuations • VDRL positive patients who may or may not have syphilis • General infections and inflammations • Coagulopathies and anticoagulant medication users (including aspirin, heparin) 74

Goals for treating PAPS • Avoid early pregnancy loss • Normalize placental and fetal circulations to prevent early birth from obstetric complications such as preeclampsia and growth restriction • Prevent maternal vascular thrombosis in pregnancy and postpartum 75

Women with PAPS without a history of thrombotic events (most women with RPL) Women with PAPS with history of thrombotic events (past or present) Prophylactic therapies Full anticoagulation with such as aspirin, heparin in heparin (or warfarin) in pregnancy and 6 to 8 pregnancy and postpartum weeks postpartum 76

Aspirin alone v/s Aspirin + Heparin • Recent metaanalysis shows that the combination of Aspirin + Heparin is better than Aspirin alone in achieving live births in women with recurrent pregnancy loss and antiphospholipid antibodies Mak A et al, Rheumatology (Oxford) 2010 77

Is Heparin + Aspirin really better? • The metaanalysis was based on data from five trials involving 334 patients across non uniform care platforms • Overall live birth rates were 74. 27 and 55. 83% in the combination and aspirin alone groups – RR 1. 301; 95% CI 1. 040, 1. 629 – Number needed to treat is 5. 6 • There is no placebo group for comparison • Another metaanalysis showed that LMW heparin + Asprin does not significantly improve birth rates. The benefits is present only with unfractionated heparin Zikas PD et al, Obstet Gynecol 2010 78

Clinical Tips for using Heparin • There is controversy as to whether LMW Heparin is effective in preventing recurrent pregnancy loss • Consider costs, convenience and compliance before initiating therapy • Therapy should be started when fetal cardiac activity is demonstrated and continued throughout pregnancy and postpartum • Heparin in prophylactic doses needs to be stopped for about 24 hours around the time of labor and delivery 79

Clinical Tips for using Heparin • Heparin in prophylactic doses can not be monitored and does not require monitoring by coagulation parameters • Do a platelet count at 3 days, 1 week and bimonthly when the patient is on heparin • Standard doses – Unfractionated heparin – 5000 units sc bd – Enoxaparin – 40 mg sc daily or in two doses 80

Full Anticoagulation : Practical • Preconception : Warfarin • Switch to Heparin when fetal cardiac activity is demonstrated • Warfarin should be considered in the second trimester • Switch back to Heparin at 34 to 36 weeks • After delivery : Warfarin 81

What not to do for PAPS • Steroid therapy should be avoided for PAPS because it significantly increases morbidity (hypertension, diabetes, preterm births) without any demonstrable benefit • Immunoglobulin therapy is experimental and not for clinical use at present 82

RECOMMENDED INVESTIGATIONS Grade A (FOR ALL PATIENTS) 1. Hysterosalpingography/ Hysteroscopy 2. APTT/ d. RVVT/ Lupus anticoagulant 3. Ig. G & Ig. M anticardiolipin antibodies 4. TSH / Prolactin / Testosterone / Hb. A 1 C/ 2 hrs Post Prandial INSULIN 5. Karyotyping of both parents & 6. If possible abortus

RECOMMENDED INVESTIGATIONS Grade B (FOR SELECTED PATIENTS) 1. ANDROGENS, LH, FSH IN PATIENTS WITH IRREGULAR MENSTRUATION 2. SERUM PROGESTERONE 3. EB FOR DATING & TB PCR, CULTURE 4. SERUM HOMOCYSTEINE LEVELS / THROMBOPHILIA SCREEN 5. HVS / WET PREP & p. H / KOH Whiff test 6. SEMEN CULTURE / TB PCR

ANTI PHOSPHOLIPID SYNDROME LOW DOSE ASPIRIN preg clinic HEPARIN after ultrasound viability Low molecular weight heparin Intravenous immunoglobulins Corticosteroids only used in aps associated with sle • Warfarin if previous arterial thrombosis in second & third trimester • • •

ANATOMICAL CAUSES • Hysteroscopic evaluation • Intrauterine adhesiolysis • Septum resection • Removal of submucous fibroids and polyps • CERVICAL CERCLAGE if indicated

INFECTVE CAUSES • Screening and treatment of bacterial vaginosis • Screening and treatment of occult genital tuberculosis • Chlamydia screening & treatment

ENDOCRINAL FACTORS • Polycystic ovaries ? metformin • Luteal phase defects progesterone / Duphaston • Thyroid replacement therapy • Optimising Hb. A 1 c levels • Correct hyperprolactinaemia

THROMBOPHILIA SCREEN POSITIVE • LOW MOLECULAR WEIGHT HEPARIN • UNFRACTIONATED HEPARIN (From 6 weeks to 36 weeks of pregnancy)

HAEMATOLOGICAL • Folic acid, vitamin b 6, vitamin b 12 in hyperhomocystinaemia • Low dose aspirin • Heparin or LMWH • Full dose heparin in case of DVT • WARFARIN if arterial thrombosis 90

ALLOIMMUNE CAUSES Progesterone therapy Evidence for use

Dydrogesterone in the reduction of recurrent spontaneous abortion El-Zibdeh MY. Dydrogesterone in the reduction of recurrent spontaneous abortion. J Steroid Biochem Mol Biol 2005; 97: 431 -434 Methods Treatment • Randomised, controlled study Women randomised to: • Pregnant women (< 35 years old) who had – Oral dydrogesterone 10 mg b. i. d. experienced at least 3 consecutive – Intramuscular human chorionic miscarriages with the same partner gonadotrophin (h. CG) • Only women for whom no explanation 5000 IU every 4 days could – No additional treatment be found for their recurrent miscarriages • Randomisation according to the day of were included. the week they attended clinic • Treatment started as soon as possible 180 Women of which: after confirmation of pregnancy and – 82 Received dydrogesterone continued until 12 th gestational week – 50 Received h. CG • All women received standard supportive – 48 Received no additional treatment care: multivitamin supplements and (control) recommended bed rest

Dydrogesterone in the reduction of recurrent spontaneous abortion El-Zibdeh MY. Dydrogesterone in the reduction of recurrent spontaneous abortion. J Steroid Biochem Mol Biol 2005; 97: 431 -434 Results Conclusion Dydrogesterone reduced the chances of spontaneous pregnancy loss in women with recurrent miscarriage Dydrogesterone was well tolerated and had no unwanted effects on the delivery or outcome of pregnancy

EVIDENCE - Dydrogesterone Progressive increase in PIBF cells with increasing concentrations of dydrogesterone. Dydrogesterone Progesterone (P) Receptor Activation ↑Progesterone Induced Blocking Factor Embryo Protective Immunomodulation J Szekeres Bartho 9 th World Congress of Gynecological Endocrinology, Hong Kong, December 2001 Dydrogesterone inhibits the production of the Th 1 cytokines IFN-g and TNF-a from lymphocytes and up-regulates the production of the Th 2 cytokines IL-4 and IL-6, inducing a Th 1 to Th 2 cytokine shift. Protection of Fetus Th 1 Raj Raghupathy et al. BJOG 2005; 112: 1 -6 Dydrogesterone has an immunomodulatory capability and appears to induce a maternal cytokine shift from Th 1 cytokine dominance towards a Th 2 bias. Raj Raghupathy et al. BJOG 2005; 112: 1 -6 F TN Th 2 4 IL- 0 1 IL- α IFN γ 1 IL-

ROLE OF TENDER LOVING CARE

DESTRESS & REASSURE • Psycho-neuro-immunology • Stress affects immune system • Changes th 2 response in endometrium to th 1 response • Hypothalamus affects endocrine system • Adrenaline release reduces placental blood flow

DIAGNOSTIC IVF / ICSI with PGD PICKS UP ANEUPLOIDY IN EMBRYOS

SURROGACY n If diagnostic IVF & PGD confirm normal gametes / embryos n All treatment modalities have failed

Conclusion / Problems of RPL • The cause of individual abortion may be different • More than one factor may exist • Thorough investigation often fails to reveal a cause Fertil Steril. 2010 Mar 1; 93(4): 1234 -43. Epub 2009 Mar 31

THANK YOU for your valuable time