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Recurrent Pregnancy Loss

Dr. Priya Bhave ChittawarProfessor and Head,Reproductive Medicine,Sri Aurobindo Institute of Medical Sciences

Dr. Priya Bhave Chittawar

MBBS 1999( Gandhi Medical College, Bhopal): with distinction in 8 subjects and 15 gold medals. Awarded 'Dr.Vishal Vikram Singh Award' for highest marks in MBBS (1994-1999). President of India Dr. Shankar Dayal Sharma Award for the Best Outgoing student MBBS (1994-1999).

Served in various capacities in the Students Union and awarded " Dr. Suresh Kak Memorial Award for best All Rounder MBBS 1994-1999) 

Fellowship in Reproductive Medicine (Christian Medical College, Vellore) 2008-2010 : passed with distinction

Awarded by the Chief Minister Shri Shivraj Singh Chouhan in June 2008 for exemplary work in emergency Obstetrics

Best Paper award for thesis on Role of GnRH antagonists in IUI- ISAR 2010

Best Paper award in ISAR 2012 for paper on “ Hysteroscopic Management of adenomyotic myometrial cysts”

Author of Cochrane review ( Menstrual disorder and subfertility group)

Author of Cochrane sexually transmitted infections group.

Nagpur Obs Gyne society Dr. D. K. Tank Foundation AOFOG Merck Serono

Thanks!

The stories that end badly are sad, sadder still are the ones that never began….

What we know: KNOWN KNOWN

What we know we do not know: KNOWN UNKNOWN

What we know but do not do: UNKNOWN KNOWN

What we do not know that we do not know

UNKNOWN UNKNOWN

OUTLINE….

Ohh No!

{Recurrent miscarriages…

The Known Known

Three or more consecutive miscarriages

Risk of miscarriage in is 30% after 2 losses, 33% after 3 losses among patients without a history of a live birth.

15% sporadic miscarriage By chance alone 1 in 300

couples

What?

Age Genetic : embryonic and

parental Immune:

autoimmune/alloimmune Anatomic Endocrine Others

Why?

12-19 year:13% 20 -24 year: 11% 25-30 year: 12% 31-35 year: 15% 36-40 year: 25% >40 year: 50% Previous miscarriage

Age

Nondisjunction during meiosis Autosomal trisomy, monosomy

X, triplody, tetraploidy, translocations

Incidence increases with maternal age

60% of conceptus

Genetic: Embryonic

Carriers of balanced chromosomal abnormalities

3-5% of RPL couples Risk of severely handicapped child

due to aneuploidy Chances of miscarriage greater than

those of RPL couples who are not carriers ( 49% vs. 30%). (Franssen,BMJ;2006)

Genetic: paternal

Balanced translocation: carrier

{

Mechanism of abnormal embryonic karyotype in offspring of carriers of balanced translocations

Antiphospholipid antibody syndrome: 15% women with RPL vs 2% with low risk Obs. hist

ACA, LA , anti beta2 glycoprotein 1 antibody

Trophoblast function, activation complement at fetal maternal interface, thrombosis at placental villi

Without heparin, LBR<10%

Alloimmune

Septum: partial, complete Bicornuate, unicornuate uteri Poor vascularity of the septum,

disordered myometrial contractions

1.8-37% of RPL couples

Anatomic

Untreated hypothyroidism Poorly controlled diabetes

Endocrine

History including family history of miscarriages, Toxin exposure

Age, BMI,Examination; Ultrasound TSH, HbA1c, VDRL, ACA, LAC,

Anti Beta 1 glycoprotein Karyotyping Karyotyping of products of

conception

Workup

{Recurrent pregnancy loss…

The Unknown Known

What your brain does not know, your eyes cannot see…

Uterine Septum

Recurrent Pregnancy Loss..

Not a valid cause of infertility or RPL

Reflection of an inadequate follicular phase or an incompetent pregnancy (Bukulmez, OGClinNA,2004)

Luteal Phase defect

Similar rate of aneuploidy of products of conception (Lathi, JARG,2007,24; Munoz, FS,2007,94:7)

Type of aneuploidy might differ (viable autosomal trisomies( 9,13,21) and monosomy X significantly lower when no fetal pole seen

Early embryonic demise is similar event occurring earlier temporally.

Early fetal demise vs. early embryonic demise

Recommended in third miscarriage ( Greentop no 17)

Maternal tissue contamination ( Jarret,AJOG,2001)

Failure to grow ( 20-30%) Failure to look for other causes Abnormal embryonic dev reported with normal

karyotype ( dimorphic embryos) with embryoscopy.

Villi have to separated from maternal tissue Microsatellite analysis: differentiate from

maternal tissue

Karyotyping of POC

Only if karyotyping of POC reveals unbalanced numerical defects ( Greentop)

In all cases of RPL ( ASRM) In couples at high risk of being carriers (

risk=>2.2%) (ESHRE)

Parental Karyotyping

Low maternal age at second miscarriage,

A history of three or more miscarriages A history of two or more miscarriages in

a brother or sister A history of two or more miscarriages in

the parents of either partner increase the probability of carrier status( Jauniaux, HR,2006)

Parental Karyotyping

1. Normal karyotype in the conceptus 2. Carrier status of same balanced structural abnormality 3. Unbalanced structural abnormality1% ( Miscarriage, Stillbirth, child with handicap)chances of having a healthy child are as high as for non-carrier couples (over 80%)Chances of subsequent miscarriage higher (50%) compared to non carrier couples with RPL (30%)(Franssen,BMJ;2006)

Consequences of carrier state

LBR in PGD group 31% LBR in natural conception

55.5% Miscarriage rate in PGD group

0-50% ( median 0%) Miscarriage rate in natural

conception 34%( Franssen, HR,2011)

PGD for carrier couples

Cochrane: A statistically significant benefit in using hCG (risk ratio (RR) 0.51, 95% confidence interval (CI) 0.32 to 0.81; five studies, 302 women ( Jan 2013)

HCG for RPL

{Generate evidenceEvaluate evidenceApply evidence

Read the fine print!

High heterogeneity ( 39%) After excluding data from

poorly designed studies, revised RR 0.74 (CI 0.44 to 1.23).

Small numbers Chromosomal analysis not

carried out

HCG for RPL

PROMISE trial underway 760 women randomised Immunomodulatory action:

upregulate TGF-β secretion in response to trophoblast, blocks Thl immunity to trophoblast.

Upregulates STAR Myometrial relaxation

Progesterone for RPL

Three small non randomized trials (Stray-Pederson, Liddel 1991, Clifford 1997)

Control groups not matched and small

No testing for APS Livebirth rates claimed to

increase by 50% for groups receiving TLC

Tender loving care…

Combined aspirin/heparin treatment versus placebo in women with unexplained RM ( Kaandorp2010, NEJM)

NO difference in LBR Significant side effects in

treatment group

Anticoagulation for unexplained RPL

HepASA trial: no difference in LBR between ASA alone versus ASA and heparin (Laskin, Journal of Rheumatology,2009)

Trial stopped prematurely due to equivalent LBR in both groups.

Anticoagulation for RPL with ANA/thrombophilia

{Recurrent pregnancy loss…

The Unknown Unknown..

“Real knowledge is to know the extent of one’s ignorance”

Luteal phase defect Early fetal demise and early embryonic

demise Karyotying of POC Parental karyotyping HCG and progesterone for RPL TLC Anticoagulation for unexplained RPL Anticoagulation for ANA/thrombophilia

Type 1 unexplained RPL: occurring by chance

Type 2 unexplained RPL: due to an underlying pathology that is not currently identified by routine clinical investigations or due to significant environmental and lifestyle risk factors. Younger women, higher order miscarriages

(Saravelos, HR2012)

Unexplained RPL

Now we know.. What we don’t know…

Think septum! A good 2D TVS. HSG/office hysteroscopy LBR 85% after septal

resection.

Doing what we know…

Pool our knowledge and patient base

Well designed RCT looking at treatments for RPL

Multicentric

Trying to know the unknown..

When you know something, to hold that you know it. When you do not know a thing, to allow that you do not know it, this is knowledge

Confuscious

THANKS !!!