Recurrent pregnancy loss

{
Recurrent Pregnancy
Loss
Dr. Priya Bhave Chittawar
Professor 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….

{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…

 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 evidence
Evaluate evidence
Apply 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 !!!

Recurrent pregnancy loss

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Recurrent pregnancy loss