best ivf specialist doctor dr. k.d.nayar clinic in delhi

Recurrent Pregnancy Loss

Conducting FOGSI Certified Basic & Advanced Infertility and IUI TrainingGuide 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

DR. KANAD DEV NAYARSr. Consultant & Head Of Department

Akanksha IVF CentreMata Chanan Devi Hospital , New Delhi

General Secretary :Indian Fertility Society 2016 -2018Chairman : Infertility Committee AOGD 2016-18Treasurer : LOC, IFFS World Congress INDIA, 2016

1971-1981 : M.B.B.S, D.G.O, M.D Maulana Azad Medical College, New Delhi

1997 : Diploma Obst, Royal College Of Physicians, Ireland2001 : Founded Akanksha IVF centre

AKANKSHA IVF CENTREMATA CHANAN DEVI HOSPITAL

DefinitionMiscarriage: ❖<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 Most clinicians consider RPL even if losses are not consecutiveconsecutive

Recurrent Pregnancy Loss:Recurrent Pregnancy Loss:❖Upto 28 weeksUpto 28 weeks

Pregnancy loss is greatest during the implantation phase

DefinitionMiscarriage: ❖<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 Most clinicians consider RPL even if losses are not consecutiveconsecutive

Recurrent Pregnancy Loss:Recurrent Pregnancy Loss:❖Upto 28 weeksUpto 28 weeks

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%

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

Types

❖ Primary:No viable infant❖ Secondary:After a pregnancy progressing

beyond 20 weeks❖ Tertiary:multiple miscarriages interspersed

with normal pregnancies

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

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

Immune tolerance

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

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 + 4 of a natural cycle.

Scanning electron micrograph of endometrial epithelium

on day LH + 7 of a natural cycle

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)

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.

Blastocyst invasion aided by dissolution of E cadherin

Epithelial cell adhesiveness by E-cadherin is controlled by intracellular calcium.

Rising progesterone levels induce calcitonin expression and thus increase the concentration of intracellular calcium, which then suppresses E-cadherin expression at cellular contact sites.

No progesterone

With progesterone

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.

Implantation

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.

Early Pregnancy Maintenance

Changing paradigm of Implantation

Spectrum Of Pregnancy Loss( RIF to RM)

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.

Personalized Embryo Implantation

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.

EMBRYO SELECTION AT IMPLANTATION

RECEPTIVE

SELECTIVE

• In the first trimester

– 90% karyotypically abnormal pregnancies miscarry

– 93% karyotypically normal pregnancies continue

Mcfadyen 1989

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

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

Non receptive

Receptive

selective

Endometrium

Reproductive success

• Metabollically quiet• No proteotoxic stress• Low invasive potential

• Metabolic overdrive• Proteotoxic stress• Highly invasive

Clinical consequences of embryo selection at Impantation

Lucas et al., 2016

Etiology Of Recurrent Miscarriage

Causes Of RM

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

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

Epidemiological factors: Influence of Age

• Highest risk for miscarriage if the woman is > 35 y/o and

the man is > 40 y/o.

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.

Epidemiological factors:

Environmental risks• Cigarette smoking

• Caffeine consumption

• Alcohol intake

• Video display terminal

• Anesthesia gases

• Obesity

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

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

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

Thrombophilias

• Hereditary• Protein C /Protein S deficiency• Anti thrombin III deficiency, • Factor V leiden Mutation,• MTHFR mutation

• Acquired: Antiphospholipid syndrome

Silver M et al.Obstet Gynecol 2010

Dizon et al.Obstet Gynecol 2005

De Jong et al.Sem Reprod Med 2011

ASRM 2012

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

In Inherited Thrombophilia

There is insufficient evidence to evaluate the effect of heparin in pregnancy to prevent a 1st trimester miscarriage. CHeparin therapy during pregnancy may improve the live birth rate of women with 2nd trimester miscarriage. ALMWH 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

❖ 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

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

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

❖Most common are numeric anomalies(50%-trisomy)❖Repeated aneuploidies in only 10%❖The risk of increases with advancing maternal age.❖Translocations(1.5%)❖ As the number of miscarriages increases, the risk of

euploid pregnancy loss increases

3rd miscarriage

Cytogenetic analysis of POC

Normal Unbalanced structural abnormality

Parental karyotypingGreen-top 17

Translocations❖Balanced reciprocal and Robertsonian

translocations-2-5% couples❖Structural genetic defect: genetic counseling

important❖Subsequent healthy pregnancy:Ch. Involved and

type of rearrangement

❖Cytogenetic testing is an expensive tool and may be reserved for pts who have undergone treatment in index pregnancy or have been participating in a research trial

RCOG❖If the evaluation of RPL identifies a remedial cause, cytogenetic

analysis of subsequent losses can be employed to evaluate whether the event was random and not a failure of treatment per se. ASRM

Testing of POC’s may be of psychological value to the couple…..pitfalls being

❖maternal contamination of the specimen❖failure to seek other causes if karyotype is abnormal

PGD & IVFThe role of pre-implantational genetic diagnosis (PGD) with

IVF has been reviewed, and it has been found not to be cost-effective in the management of RPL. (C)

In patients with RPL the spontaneous birth rate is still 50%; with PGD the miscarriage rate may be decreased, but only 33% of women become pregnant after each PGD/ IVF cycle

5. Anatomical Factors

• Congenital Uterine MalformationsPrevalence 1.8-37.6%More common in 2nd trimester pregnancy loss Acien P. Hum Reprod 1997:12; 1372-76

• Cervical weakness (Incompetent Cervix)True incidence is unknownDiagnosis is based mainly on history of spontaneous ROM or painless cervical dilatation.

Anatomical

• Congenital uterine anomaly• Leiomyoma• cervical incompetence• Intrauterine Adhesions

Uterine Abnormalities

• All women : 1 – 5% • RPL: 2-35%.• etiological role is controversial• associated with 2nd-trimester loss • some of these are due to associated cervical

incompetence.• the role of uterine malformations in first-

trimester RPL is debatable

All women with RPL should have a pelvic USG

Suspected uterine anomalies may be confirmed by:❖ hysteroscopy/laparoscopy ❖ 3D pelvic ultrasound.❖ sonohysterography❖ hysterosalpingography (HSG) ❖ magnetic resonance imaging (MRI)-debatable

ASRM 2012No conclusive evidence in reducing risk of RPL

by treatment of

• Asherman’s syndrome

• intrauterine synechiae

• uterine fibroids

• uterine polyps

CONSENSUS

• Correction of significant uterine cavity defects(septa/fibroids)

• Reconstructive surgery :secondary adhesions and uterine rupture in subsequent pregnancy

• Irreparable:IVF/surrogacy

Cervical Incompetence❖ recurrent , painless second-trimester

losses❖ no gold standard for non-pregnant

diagnosis❖ Serial USG follow up is offered when not

undergone cerclage. B❖ Consensus is to insert a cervical suture if

there is a suggestive history and the cervix is <25 mm in length before 24 weeks. B

❖ But some patients will miscarry despite surveillance

6. Endocrine Factors

• Luteal Phase defect

• Diabetes MellitusHigh HA1c leads to 1st trimester miscarriage Hanson U. Diabetologia 1990;33,100-104

• Thyroid dysfunction Anti-thyroid antibodies Abalovich Thyroid 2002; 12; 63-68

• PCOSAttributed to insulin resistance, hyperinsulinemia and hyperandrogenemia Rai R, Human Reprod 2000; 15; 612-615

PCOSInsufficient evidence for

Suppression of high LH A

Metformin in PCOS C

RCOG 2011

Endocrine Causes

• Women with diabetes who have high haemoglobin A1c levels in the first trimester are at risk of miscarriage and fetal malformation

• Meticulous control of blood sugars

• There is a weak association with thyroid disorder but screen & treat only hypo or hyperthyroidism

7. Infectious Agents

• To implicate an infective agent, it must persist in the genital tract relatively undetected and asymptomatic.TORCH screening should be abandonedBacterial vaginosis (mainly 2nd trimester losses)Emerging role of Mycoplasma

Regan et al Infection and Pregnancy 2001; 291-304 Ralph et al. BMJ 1999; 319; 220-223

Infective AgentsFor an infective agent to be implicated in the aetiology of repeated pregnancy loss

•Capable of persisting in the genital tract • avoiding detection• insufficient symptoms to disturb the woman.None of the organisms in TORCH fulfil these criteria and routine TORCH screening should be abandoned.Level 3

No convincing data that infections cause RPL

Bacterial Vaginosis

• Risk for 2nd trimester miscarriage and delivery.

• Treatment with oral clindamycin

Tuberculosis??

Literature review does not list tuberculosis as a cause for RSMIn Indian settings it has been evaluated as a cause and treated

Male Factors• Standard semen

parameters(sperm morphology) are not predictive of RPL

• Sperm aneuploidy and DNA Fragmentation

• Contradictory data for causal effect b/w pregnancy loss and sperm DNA Fragmentation

• Routine testing for spermploidy or DNA Fragmentation is not recommended.

Immune Factors

Th1 Cytokines vs. Th2 Cytokines

Th1 Cytokines Th2 Cytokines

(Success)(Miscarriage)

IL 3, IL 4, IL 5IL 6, IL 10, IL 13

Th1 & NK Cells(IL 2, IFNγ, TNF)

1

Pro-inflammatory Anti-inflammatory

Peaceful balance must exist between the “bad” Th1 and the “good” Th2 cytokines. If Th1 cytokines overpower Th2, this leads to miscarriage while Th2 predominance ensures a successful pregnancy.

Allogenic Immune Response

Immunosuppressive Factors(physiologic progesterone concentration)

Decidua

PGE2

↓Th1 & NK Cells(IL2, IFNy, TNF)

Humoral Immunity

PBMCPIBF ImmunotrophicFactor

CSF1, GM-CSF

Th2 cytokines(IL 4,

5,6,9,10,13)

IG Asymmetric Antibodies

Pregnancy MaintenancePregnancy Maintenance

2

• Role of Natural Killer (NK) cells is important but pbNK are different from uNK cells. Current focus is on uNK cells

Le Boutellier P. AJRI 2008; 59, 401-406

• Cytokines (predominantly Th1) are believed to be responsible in causing miscarriage.

Szeres Bartho. AJRI 2002;

Essential Immunomodulation:Core Property of Progesterone

A. Progesterone – Beneficial immunomodulation in RPL

1. Th2/Th1 cytokines profile2. Increased PIBF level3. Effect on NK cell activity4. Homing of NK cells in Endometrium5. Effect on various protein release

B. Progesterone effect on TNF-alpha & IL-10

Alloimmune FactorsNo clear evidence to support the hypothesis

of :

• HLA incompatibility between couples,

• the absence of maternal leucocytotoxic antibodies or

• the absence of maternal blocking antibodies.

Uterine NK cells

• Raised uNK cell numbers in women with recurrent miscarriage was not associated with an increased risk of miscarriage.

• This remains a research field and testing for uNK cells should not be offered routinely in the investigation of recurrent miscarriage.

Tuckerman et al.Hum Reprod 2007.

Proposed immunological treatment

• G-CSF • Lipid infusions• Lymphocyte immuno-therapy• Intravenous human immunoglobin• Corticosteroids• Anti – TNF drugs• Seminal plasma suppositories

Unexplained RPL• No apparent Causative factor in 50-75%

couples of RPL

• Chances of future successful pregnancy can exceed 50-60% depending on maternal age and parity.

• supportive care alone in the setting of a dedicated early pregnancy assessment unit should be offered. B

• Method: Participants were randomly assigned in a 1:1 ratio to receive vaginal suppositories containing either 400 mg of micronized progesterone (Utrogestan, Besins Healthcare) twice daily or matched placebo from a time soon after receiving positive results on a urinary pregnancy test (and no later than 6 weeks of gestation) through 12 completed weeks of gestation (or earlier if an ectopic pregnancy was diagnosed or miscarriage occurred before 12 weeks)

• Conclusion, our trial showed no significant increase in the rate of live births with the use of vaginal progesterone in the first trimester of pregnancy among women with recurrent miscarriages. Our results do not support the earlier findings of a Cochrane review4 that suggested a benefit of progesterone therapy in the first trimester among women with recurrent miscarriages.

• 4 July 2014, de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S

• There is a limited number of studies on the efficacy and safety of aspirin and heparin in women with a history of at least two unexplained miscarriages with or without inherited thrombophilia.

• Of the nine reviewed studies quality varied, different treatments were studied and of the studies at low risk of bias only one was placebo-controlled.

• No beneficial effect of anticoagulants in studies at low risk of bias was found. Therefore, this review does not support the use of anticoagulants in women with unexplained recurrent miscarriage. The effect of anticoagulants in women with unexplained recurrent miscarriage and inherited thrombophilia needs to be assessed in further randomised controlled trials; at present there is no evidence of a beneficial effect.

Management of Unexplained RM

• RCT’s of antithrombotic therapy and empiric low does aspirin show no benefit

• Non RCT’s of “close supportive care” have a 75% live birth rate

• This can be done with early vaginal Progesterone support

• Early ultrasound for encouragement

Initial Evaluation of Early RPL

Work up of early RPL

Diagnosis & Management

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