OUTLINE….of RM * KNOWN KNOWNWhat we know & we DO: **KNOWN UNKNOWNWhat we know but do not do: ***UNKNOWN KNOWNWhat we know that we do not know ****UNKNOWN UNKNOWNTOTALLY NEW .. Future

1. Interesting Update
on
Recurrent
Miscarriage
for Indian Gynaecologoists
…Caring hearts, healing hands
Dr. Sharda Jain
Dr. Jyoti Agarwal

2. Our PPts on RECURRENT MISCARRIAGE
is Uploaded on slideshare.net
1. An update on recurrent pregnancy loss 2015
http://www.slideshare.net/LifecareCentre/an-update-on-recurrent-pregnancy-loss-2015
2. Recurrent pregnancy loss, thrombophilia
tests : to do or not to do.
http://www.slideshare.net/LifecareCentre/recurrent-pregnancy-loss-thrombophilia-tests
3.Recurrent Pregnancy Loss Sharing Personal
Experience (10 years)
http://www.slideshare.net/LifecareCentre/recurrent-pregnancy-loss-sharing-personal-experience-
10-years
5.Interesting Update on Recurrent Miscarriage for India Gynaecologoists

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

4. R.M.

5. RECURRENT Miscarriages
A PROBLEM OF DILEMMAS

7. * KNOWN KNOWN
What we know & we DO:
**KNOWN UNKNOWN
What we know but do not do:
***UNKNOWN KNOWN
What we know that we do not know
****UNKNOWN UNKNOWN
TOTALLY NEW .. Future
OUTLINE….of RM
…Caring hearts, healing hands

8. Still Experts
are
Evolving
Confusion is not settled as yet on CAUSES

9. Ohh No!
How I am going to come ?

10. The Known
Known
{Recurrent
miscarriages…
The Known
UnKnown

11. DEFINITION
Recurrent Miscarriage is defined as
the occurrence of three or more
consecutive spontaneous abortions
Before 20 weeks
(24 weeks in UK)

12. INCIDENCE
15-20% of clinically
detectable pregnancies abort
5% women have RPL > 2
1 % women have RPL > 3
The risk increases by about 10% with each abortion; estimated risk
being 24% after two clinically recognized losses, 30% after three losses
and 40% - 50% after four losses.

13. The ASRM has defined RPL as “a
distinct disorder defined by 2
or more failed clinical
pregnancies”
* Ectopic and Molar pregnancies
are NOT included.
DEFINITION

14. TYPES OF RPL
• PRIMARY RPL have never had a previous viable
infant.
• SECONDARY RPL woman with previous H/o
delivery beyond 20 weeks and then suffered
subsequent losses.
• TERTIARY RPL refers to those women who have
multiple miscarriages interspersed with normal
pregnancies.

15. Should we start investigating the
couple after 2nd ABORTION ??
Yes
It is Reasonable to Determine
the cause of their pregnancy loss, especially when
the woman is older than 35 years of age, or when
the couple have had difficulty in conceiving
BMJ2000;320:1708-12

16. Women with 2 LOSSES have
identifiable problems just as frequently as
women with 3 or more losses; thus,
evaluation for causes may be initiated
after 2 losses.
BMJ2000;320:1708-12

17. THREE INDEPENDENT RISK
FACTORS
• Gestational Age at abortion
• Age of the patient (Both Husband / Wife)
• History of previous abortions

18. Is Gestational Age of any importance?
Gest. Age at abortion guides us of the cause:
• 4 - 7 wks - Genetic causes
• 8 - 10 wks – APLA SYND/TB
• 10 weeks or Mid trimester - Anatomical Causes , APLA
SYND.
Yes
1

19. 12-19 year:11..15%
20 -24 year: 11 -15%
25-30 year: 12%
31-35 year: 15%
36-40 year: 25%
>40 year: 50%
45 & above :93%
Woman’s Age
2

20. AGE of parents
*MATERNAL AGE..
Advanced age declines both the
Number & Quality of Oocytes
**PATERNAL AGE:
Advanced paternal age is also a risk

21. ADVANCED PARENTAL AGE
• MATERNAL AGE: increased risk of chromosomal abnormality
(Trisomy 13, 18, 21, 47XXY, 47XXX)
• PATERNAL AGE: increased risk of Autosomal dominant, X-
linked recessive Disorder

22. AGE OF THE PATIENT
Oocyte
quality and
ovarian
reserve
Decline
starts after
35 yrs
60% oocytes after 35 yrs are aneuploid

23. *Risk of miscarriage in is
20% after one loss
**30% after 2 losses
** 40% after 3 consecutive losses
among patients without a history of a
live birth.
15 to 18% sporadic miscarriage
************
What?
**Previous O.H…
is independent RISK factor**
3

24. Summary of Causes of RPL
as we view in India
AETIOLOGY
Genetic
Causes
APLA
syndrome
Uterine Causes
Cervical weakness
Inherited
Thrombophilia
?
Allo-munity
?
•Environmental
Causes
• Oxidative stress
•Psychological
•Unknown aetiology
Tuberculosis
PCOD ?
Obesity ?
LPD ?
Male factor ?
Endocrine &
Metabolic

25. DIAGNOSTIC EVALUATION
CAUSES 1 DIAGNOSIS EVALUATION THERAPY
Genetic Karyotype partners
Karype products of conception
Genetic counseling
Donor gamets, preimplantation
genetic diagnosis
Immunologic Lupus anticoagulant
Antiphospholipid antibodies
Anti – β glycoprotein
Aspirirn
Heperin + aspirin
Endocrinologic Midluteal progesterone
Thyroid – stimulating hormone
prolactin hemoglobin
A1c
Progesterone
Levothyroxin
Bromocriptine, dostinex
Metformin
Psychological Interview Support groups
Latrogenic Tobacco, alcohol use obesity
Exposure to toxins, chemicals
Eliminate Consumtion
Eliminate Exposure
Anatomic Hysterosalpingography
Hysteroscopy
Sonohysterography
Transvaginal three- dimensional
ultrasonography
Septum transaction
Myomectomy
Lysis of adhesions

26. CAUSES DIAGNOSIS
EVALUATION
THERAPY
Genetic Karyotype partners
Karype products of conception
Normal
Abnormal – karyotyping of
partners
Genetic counseling
*****
Donor gamets
****
preimplantation
genetic diagnosis
GENETIC CAUSES
WHAT WE NEED TO DO ?

27. Nondisjunction during meiosis
Autosomal trisomy, monopsony X,
triploid, tetraploidy, translocations
********
Incidence increases with maternal
age
60 -80 % of concepts
GENETIC: EMBRYONIC

28. Carriers of balanced chromosomal abnormalities
3-5% of RPL couples
*****
Risk of severely handicapped child is
due to ANEUPLOIDY &
on the size of genetic material in the relocated
segment
******
Chances of miscarriage is greater than
those of RPL couples who are not
carriers ( 50 % vs. 30%). (Franssen,BMJ;2006)
GENETIC: PATERNAL

29. BALANCED TRANSLOCATION:
CARRIER

30. Mechanism of
abnormal
Embryonic
{karyotype in
offspring of
carriers of
balanced
translocations
Most common
recurrence  25%

31. Miscarriage#1
(No action unless clinically indicated)
2nd Consecutive miscarriages*
Or
3rd Nonconsecutive Miscarriages*
Obtain Fetal POC
Karyotype
Aneuploid Karyotype
Unbalanced Chromosomal
Translocation or Inversion
Euploid Karyotype
RPL Workup
No further Evaluation
And consider
Preimplantation
Genetic diagnosis(PGD) for
Future pregnancy attempt
Perform parental
Karyotypes and offer
Preimplantation genetic
Diagnosisis (PGD) for
future
pregnancy attempts
Miscarriage is defined by the loss of a clinical pregnancy documented by
ultrasonography or histopathological examination

32. PREIMPLANTATION GENETIC DIAGNOSIS (PGD)
PGD is subdivided into 2 broad categories
* Pre - implantation genetic diagnosis (PGD)
* The purpose of PGD is to prevent the birth of
affected children from parents with a known genetic
abnormality
* PGD is widely acknowledged as acceptable for
routine clinical application
• Preimplantation genetic screening (PGS)
* attempts to identify aneuploidy in embryos to improve
pregnancy success in certain patient populations
* Parents with no identified genetic defect or disease
* PGS remains controversial for routine application
The results obtained by PGD may not always reflect the fetus genetic
composition.

33. • Modern Treatment of balanced translocation is PGD
with IVF. But most Indian patients say that they readily
conceive & find IVF & PGD very expensive.
• Antenatal genetic testing includes time – tested
diagnostic evaluations such as chorionic villus sampling
or amniocentesis. In addition, newer minimally invasive
testing modalities( NIPT) are currently being developed
and applied..
• Benefit seen over 50% which is more than IVF & PGD
PARENTAL CHROMOSOMAL
ABNORMALITIES (3-5%)
What we do in India

34. CAUSE DIAGNOSIS EVALUATION THERAPY
APLA
Syndrome
Lupus anticoagulant
Antiphospholipid Antibodies
IgM , IgG
Anti – β glycoprotein
IgM , IgG
Aspirin
Heparin + aspirin
APLA SYNDROME

35. INCIDENCE of Antiphospholipid antibody
syndrome: 15% in women with RPL vs
2% with low risk Obst .
********
Causes of RM / Preterm Birth /IUD / IUGR
ANTIPHASPHOLIPID SYNDROME [APS]

36. ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
• Anticardiolipin antibodies
• Lupus anticoagulant
• B2 Glycoprotein antibodies
ANTIPHOSPHOLIPID ANTIBODIES –
inhibit the trophoblastic differentiation,
cause inflammatory response,
in later pregnancy, cause thrombosis in the placenta
vasculature.

37. Clinical and laboratory criteria established for the
research of definite antiphospholipid
syndrome: the Sydney criteria 2010
Note : at least 1 clinical and 1 laboratory criterion
must be present for definite APS.
CLINICAL CRITERIA
1. VASCULAR THROMBOSIS
One or more clinical episodes of an arterial,
venous , or small vessel thrombosis confirmed by
imaging or doppler studies or histopathology,
without significant evidence of inflamation in the
vessel well.
Clin onstet gynecol 2010;53:617-27

38. Clinical and laboratory criteria established for the
research of definite antiphospholipid
syndrome: the Sydney criteria
2. OBSTETRIC MORBIDITY
• One or more unexplained demise of a morphologically normal
fetus at or beyond 10 week of gestation, or
• One or more premature birth of a morphologically normal fetus
at or before 34 weeks of gestation, caused by severe
preeclampsia or severe placental insufficient, or
• At least 3 unexplained , consecutive miscarriages of less than 10
weeks of gestation with no known factors associated with
recurrent miscarriages including parental genetic, anatomic and
endocrinologic factor. Clin onstet gynecol 2010;53:617-27

39. LABORATORY CRITERIA
1. aCL --- IgG and / or IgM in blood , present in
medium or high titers (greater than 40 PL or MPL or
greater than the 99th percentile) on 2 or more occasions
at least 12 weeks apart measuresd by a standardized
ELISA
2. Anti –B2 Gp1 Antibody -- of IgG and /or IgM isotype in
blood (greater than the 99th percentile) or 2 or more
occasions at least 12 weeks apart measured by a
standardized ELISA
3. Lupus anti coagulant
Clin onstet gynecol 2010;53:617-27

40. TREATMENT
Pregnant women with Apla syndrome should
be treated with LOW – DOSE ASPIRIN plus
HEPARIN to prevent further miscarriage This
treatment is initiated, early .
This treatment combination significantly
reduces the miscarriage rate by >50%

41. TREATMENT
Without treatment only 10% of
pregnancies in women with
recurrent miscarriage and
APLA Synd. will be live born.
Antiphospholipid antibodies inhibit the
trophoblastic differentiation, cause inflammatory
response, and , in later pregnancy, cause
thrombosis in the placenta vasculature.
These effects reversed by heparin

42. CAUSE DIAGNOSIS EVALUATION THERAPY
Anatomical Hysterosalpingography
Hysteroscopy
Sonohysterography
Transvaginal three- dimensional
ultrasonography
Septum transaction
Myomectomy
Lysis of adhesions
ANATOMICAL CAUSES

43. ANATOMIC CAUSES OF RM
1. Congenital malformations of the reproductive
tract
*Septum: partial, complete
**Bicornuate,
***unicornuate uteri
2. Intrauterine adhesions
3. Intrauterine masses, including fibroids or polyps
4. Cervical weakness

44. UTERINE MALFORMATIONS
Usually coincidental , rather than the cause.
Present in 2% of women with normal
reproductive history .
Prevalence higher -5 to 25% in women with
second trimester miscarriage

45. CERVICAL WEAKNESS
Exact incidence unknown but is a recognized
cause of second – trimester miscarriage
diagnosis is based on clinical history of
second – trimester miscarriage,
preceded by SROM or
painless cervical dilatation
Serial cervical Sonography surveillance or cervical
cerclage may be offered to women with a history
of second – trimester miscarriage where cervical
weakness is suspected

48. *Poor vascularity of the
septum, *disordered
myometrium
*uterine contractions
Anatomic - - Septum
PARTIAL & COMPLETE

49. Septate Uterus
• Most COMMON anomaly 55%
• May be complete/ incomplete
•25 % early abortions
•5 - 7% late abortions & Premature labors

50. ANATOMIC CAUSES (22.4%)
Congenital Anomalies
Septum = 2.05 %
Bicornuate Uterus = 2.7 %
Acquired Abnormalities
Synaechie = 3.5% + more
Submucous Myoma = 4 %
Endometrial Polyp = 4.5%??
Experience
Some cases had more than 1 cause

51. UTERINE ABNORMALITIES
Treatment SUMMARY as practiced in
• Uterine septum: GnRH analogue and hysteroscopic
septal resection and given the practice of
temporary intrauterine device.
• Intrauterine adhesions : hysteroscopic division and
temporary intrauterine device: postoperative
course of cyclic estrogen and progesterone therapy.
• Fibroids: GnRH analogue and myomectomy

52. *Untreated hypothyroidism
**Poorly controlled diabetes
ENDOCRINAL CAUSES
(Accepted)

53. HYPOTHYROIDISM / ANTIBODIES
• Thyroid gland function is critical in the maintainence
of early pregnancy.
• Overt or Sub clinical hypothyroidism is co – related
with poor pregnancy outcome
• Antithyroid antibodies (thyroglobulin and thyroid
peroxidase) are raised in euthyroid recurrent
aborters.
• Thyroid hormone replacement therapy along with
careful monitoring prior to
pregnancy & early pregnancy periods is associated
with improved outcomes

54. DIABETES MELLITUS
• Diabetic women with good metabolic control are
probably no more likely to miscarry than non-
diabetic women.
• Diabetic women with raised glycosylated Hb
concentrations in first trimester are at increased risk.
• Diabetic patients should be euglycaemic before
attempting a pregnancy
Kalter et al Am.J.O.G.,

55. THE UNKNOWN
KNOWN
{Recurrent
pregnancy loss…

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

57. • GENITAL TUBERCULOSIS
• Luteal phase defect
• PCOD
• Obesity
• Thrombophilia
• Male Factor
• HCG and progesterone for RPL
• TLC
• Anticoagulation for unexplained RPL
• Anticoagulation for ANA/thrombophilia

58. READ THE FINE PRINT!
Generate evidence
{Evaluate evidence
Apply evidence

59. Infections are RARE cause of RPL
according to world literature

60. Microbiologic Agents
<1%
Organisms implicated in causing Recurrent Abortion include:
Chlymadia
Mycoplasma
Ureaplasma
Herpes
Cytomegalovirus
Toxoplasma
TORCH is a useless
Investigation
DILEMMA

61. TUBERCULOSIS Is a BIG Cause
of RPL (Good 1/3 cases)
&
Is extensively studied both by
Dr. Sharda Jain (Lifecare Centre Team)
& Dr. Sonia Malik
In Indian RPL Patients
Majority of Indian Obstetrician
Do Endorse the same
Our PPT Ref. http://www.slideshare.net/LifecareCentre/genital-tb-in-infertility-
our-experience-dr-sharda-jain-dr-jyoti-agarwal-dr-jyoti-bhaskar?qid=a22f617e-cb42-4e86-87bd-07deac56e48f&v=qf1&b=&from_search=5
Slideshare.net

62. LUTEAL PHASE DEFECT
• Not a valid cause of infertility or
RPL
• Difficult to Diagnose
(Bukulmez, OGClinNA,2004)

63. PCOD & RM

64. PCOS – the risk of recurrent miscarriage is
attributed to
* insulin resistance, ** Hyperinsuliaemia
and *** Hyperandrogenism
There is insufficient evidence to advocate the use of progesterone or matformin in
women with recurrent miscarriage
Free testosterone
Reverse FSH / LH ratio
USG picture

65. O
B
E
S
I
T
Y

66. OBESITY – Risk of sporadic and RM is
increased
Patients of BMI > 27.5 kg/m2
are likely to take longer to conceive
So it is good to lose weight by
structured weight loss programme
Over weight BMI > 22.5
Obese BMI > 27.5
Severe Obese BMI > 32.5
Morbid Obesity BMI >37.5

67. The current 2014 march guidelines on RPL do not
recommend screening for
Thrombophilia
unless a personal history of
Venous thromboembolism is present.
Key point & Recommendation
ACOG 2014
Obstet. & Gynae clinics of north america
March 2014-volume 41 – number 1

68. INHERITED THROMBOPHILIA
Few important points in treatment
• Factor V Leiden. Factor ii (Prothrombin) gene
mutation, and protein S deficiency
• There is insufficient evidence to advocate
heparin in pregnancy in women with recurrent
first – trimester miscarriage associated with
inherited thrombophilia.
• Heparin therapy during pregnancy may improve
the live birth rate of women with
SECOND – TRIMESTER miscarriage associated
with inherited thrombophilia

69. Anticoagulation for
unexplained RPL
• Combined aspirin/heparin
treatment versus placebo in women
with unexplained RM
( Kaandorp2010, NEJM)
• NO difference in LBR
• Significant side effects in treatment
group

70. Anticoagulation for RM with
ANA/ Thrombophilia
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.

71. MALE FACTOR
Sperm DNA Fragmentation Test

72. Unexplained Infertility
& Recurrent Pregnancy Loss
• there is enough evidence that test of sperm DNA
damage may be predictor of failed natural
pregnancy out come in Unexplain infertility
• Couple with Recurrent pregnancy loss.
there is enough evidence that high level DNA
damage are associated with R.M.
*****
At Lifecare Centre we are routinely screening

73. Diagnostic Cutoff Point
of sperm DNA fragmentation
DFI Fertility potential
<15% Excellent
15% - 30% Good
>30% Poor

74. TREATMENT

75. HCG for RPL
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)

76. HCG for RPL
• High heterogeneity in RM population ( 39%)
• After excluding data from poorly designed
studies, revised RR 0.74 (CI 0.44 to 1.23).
• Still Small number of cases.
• Chromosomal analysis not carried out.

78. PROGESTERONE for RPL
encouraging results
• PROMISE trial underway
• 760 women randomised
• Immunomodulatory action:
upregulate TGF-β secretion in
response to trophoblast,
• Blocks Th-l immunity to trophoblast.
• Myometrial relaxation

79. Tender loving care…
• 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

80. GREAT FACT
A significant proportion of cases of recurrent
miscarriage remains unexplained despite detailed
investigation.
• These women can be reassured that the prognosis for
a successful future pregnancy with supportive care
alone is in the region of 65%.
However prognosis does worsen with increasing age and
number of previous miscarriages

81. We Run Dedicated
Recurrent Pregnancy Loss Clinic
since 2003
Our Experience of 753 Recurrent
Consecutive Miscarriages – Updated
(31st July 2016)
FOCUS IS ON CAUSES

82. Etiology
The causes are complex and
obscure with more than one
factor operating in many cases.
Factor may be recurrent or non –
recurrent.

83. LIFECARE GUIDELINES
1. THE COMPLETE EVALUATION
* Genital Tuberculosis (MTBC / PCR)
* Genetic
* Anatomical
*APLA syndrome
* Endocrinology
* * Iatrogenic
should be initiated when the decision to evaluate
a couple is made.
2. A complete evaluation for RPL shows possible
causes in good 80%of cases in contrast to 60% quoted in world
literature

84. Lifecare RPL clinic’s Break – up of Causes
In
50%
More
Than
1
cause
GENETIC 2.8 % 3.8%
ENDOCRINE CAUSES
- ↑ Glycosylated HB 16%
15%
- S/C Hypothyrodism 26 % 21%
- Thyroids Anti Bodies + 9 % 11%
- LPD 22% 17%
- PCOD – ↑ LH 14% 20%
TUBERCULOSIS
39 % 36%
TB + TNF a ↑ 31% 35%
Apla Syndrome 6% 10%
Thrombophilia 3 % 7% Now we have
stopped investigating
Alloimmunity
TNF a, and / or NK Cells
8 % 5% Stopped investigating
ANATOMICAL /UTERINE 22.4 % 24%
Jan 2013 July 2016 No. 753

85. Recommended
diagnostic evaluation
BASIC BLOOD TESTS
. Haemogram
. Glycosylated HbA1c
. TSH ,Anti TPO
TRANS VAGINAL ULTRASOUND
2D, If needed 3D Hysteroscopy
Tubercular DIagnostic Tests..
Endometrial Biopsy for TB PCR or MTBC
Blood tests for APLA syndrome
Genetic screening - Parents / POC Karyotyping
* Anticardiolipin antibodies
* Lupus anticoagulant
* B2 Glycoprotein antibodies

86. MANAGEMENT TIPS
• TLC .. Tender Loving Care
. COUNSELLING
. Specific Cause Related Treatment
.. Aspirin and LMWH for APLA Syndrome
.. PGS/PGD for genetic abnormalities after
counseling otherwise Antenatal Fetal Screening
.. Surgical Treatment only for Uterine Septum with
history of Recurrent Miscarriage
• Anti – oxidant , HCG & liberal vaginal Progesterone

87. Now we know..
What we did not know…

88. Keep Trying to know
the unknown..
DOING WHAT WE KNOW…
DEDICATED RM CLINIC

89. The Unknown Known
Unknown Unknown
{Recurrent
Pregnancy Loss…

90. UNEXPLAINED RM
• Type 1 unexplained RM: occurring by
chance
• Type 2 unexplained RM: due to an
underlying pathology that is not
currently identified by routine clinical
investigations or due to significant
environmental and lifestyle risk
factors. eg. Younger women, higher order
miscarriages
(Saravelos, HR2012)

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

92. THANKS !!!
*When you know something & it is
experience too--to hold on
that you know it.
** When you do not know - a thing,
….Please do admit & allow that you do
not know it,
this is gateway to knowledge
Confucius

93. Useful PRAYER – for both
Patients and Doctors !
“God grant me the serenity to accept the
things I cannot change;
The courage to change the things I can;
And the WISDOM to know the
difference”.

95. ADDRESS
11 Gagan Vihar, Near Karkari Morh
Flyover, Delhi - 51
Helpline
9650588339,
9599044257
011-22414049, 011-22058865
WEBSITE :
www.drshardajain.com
www.lifecarecentre.in
www.lifecareivf.com
www.globalstemgenn.com
www.lifecareaesthetics.com
E-MAIL ID
Sharda.lifecare@gmail.com
Lifecarecentre21@gmail.com
info@lifecareivf.com
…Caring hearts, healing hands