Complete over view of the causes diagnosis management of Recurrent Pregnancy Loss it is a personal experience of treating recurrent miscarriages with excellent result

1. Recurrent Pregnancy Loss
Sharing Personal Experience (10 years)
Dr. Sharda Jain
Director :-
Sec General : Delhi Gynae Forum

3. RECURRENT PREGNANCY LOSS
Dr. Sharda Jain
Dr. Jyoti Agarwal
Dr. Jyoti Bhaskar

4. How much is the problems of
Abortion / RM
60% of embryos never yield a live birth
Edmonds et al,1982
30% of “Implanting embryos” miscarry, often
before the woman realizes she is pregnant
Miller et al ,1980
15-20% of clinically detectable pregnancies
abort
5% women have RM > 2
1 % woman have RM > 3

5. Should we start investigating the
couple after 2nd
abortion ??
Yes

6. What is the role of RPL Clinic ?
Yes

7. RECURRENT PREGNANCY
LOSS
A PROBLEM OF DILEMMAS

8. How
To
Manage
R
E
C
U
R
R
E
N
T
Abortion

10. Causes - Biggest DILEMMAS
Uterine Causes
Anatomical Causes
AETIOLOGY
Infectious Causes ?
TB Genetic Causes
AUTO IMMUNOLOGIC
CAUSES
APLA syndrome
Endocrine causes ?
Thrombophilia
Allo-munity
•Environmental
Causes
• Oxidative stress
•Psychological
•Unknown aetiology

11. Summary
of Cochrane Review
• Parental Chromosomal rearrangements
• Anatomic defect of the uterine fundus and
cervix,
•APLA Sydr. (phospholipid antibodies)
• Thrombophilia activated protein C
resistance, factor V and II gene mutation –
Play definite Role

12. The majority of cases are due to repeated
fetal chromosome abnormalities
occurring
consecutive by chance.
Summary of
Cochrane Review
Karyotype POC

13. • Progesterone deficiency, hypersecretion of LH,
infective agents, and immune rejection are not
currently considered causes of RM.
• Empirical treatment with progesterone , high LH
suppression , or immunotherapies are of no
proven benefit.
• Subclinical/ overt
thyroid disorder or diabetes mellitus are rare
Summary of
Cochrane Review

14. We Run Dedicated
Recurrent Miscarriage Clinic
since 2003
Our Experience of 680 Recurrent
consecutive Miscarriages – Updated
(30th
June 2013)

15. ANATOMICAL /UTERINE 22.4 %
INFECTIONS – Tuberculosis 39 %
TB + TNF a ↑ 31%
GENETIC 2.8 %
Karyotype (Products of Conceptions) 66 % (219/348)
ENDOCRINE CAUSES
- ↑ Glycosylated HB 16%
- S/C Hypothyrodism 26 %
- Thyroids Anti Bodies + 9 %
- PCOD – ↑ LH 14%
- LPD 22%
AUTOIMMUNITY
Apla Syndrome 6%
Thrombophilia 3 %
Alloimmunity
TNF a, and / or NK Cells
8 %
Diagnosis and management of recurrent Pregnancy Loss
(Since 2003 – June 2013)
In
50%
More
Than
1
cause

16. My AIM
Is
Share Our Experience last 10 years with RM,
Clinical tips & management strategy

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 underline cause
• 4 - 6 wks Alloimmunity & LPD
• 5 - 7 wks - Genetic causes
• 8 - 10 wks - Immunological Causes
• Mid trimester - Anatomical Causes , APLA
Yes

19. 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 Ds

20. Age of the patient.
Oocyte
quality and
ovarian
reserve
Decline
starts after
35 yrs
60% oocytes after 35 yrs are aneuploidic

21. Remember
Women who have had at least
one live born infant :- Good Prognosis
a. with no prior fetal losses - recurrence risk is 12 % for next preg
•
b. With atleast 1 prior fetal loss - recurrence risk is 24 % for next preg
•
c. With two prior fetal losses - recurrence risk is 26 % for next preg
• d. With three prior fetal losses - recurrence risk is 32 % for next preg
WOMEN WHO HAVE NOT HAD ATLEAST ONE LIVEBORN
infant with 2 or more fetal losses –
Recurrence Risk for the next pregnancy is 40 - 45 % .

22. Management Tips
Which would be of significance to
you in the management of
subsequent pregnancy.
DILEMMA of our Role
2nd Abortion under our care

23. • Document Pattern and Trimester of the pregnancy loss and
whether a live embryo or a fetus was present. Clinical / USG
• Carefully document any suspected uterine abnormally at surgical
evaculation.
• Send product of conception for HPE , TB & karyotype,
At the time 2nd
& 3rd
Miscarriage
The TLC approach is important to
(see couple together, sympathy, sensitivity)

24. History and examination for
• Causative Factors
• Associated Factors
• Obstetric history Confirm true diagnosis of
• Pregnancy : biochemical , Ultrasonography
• Gestation of former losses
• “RM” - pattern of losses
RM Assessment and Evaluation
Counseling after the 2nd
and 3rd
Abortion

25. Family History : of RM , PCOD, Diabetes, Genetic disorder,
Thrombophilia - early onset cardiovascular disease or stroke (<50 yr)
Physical examination : identify signs of endocrine / Gynae Disease
• Oppurtunistic screening (BP , Pap smear, Rubella IgG),
RM Assessment and Evaluation
Counseling after the 2nd
and 3rd
Abortion

26. Investigations of RM
All Patients
• PELVIC USG
• PARENTAL, KARYOTYPE
• Miscarried tissues Karyotype
• Early follicular phase ,LH,FSH, testosterone (Day 2-3)
• APLA / APS
Lupus anticoagulant and ACL
• Thrombophilia
- Activated protien C resistance
- Factor V leiden gene mutation
- Prothrombin gene mutation
• Glucose tolerance test or glycoselated HB
• Thyroid – TSH / Antibodies TPO
• TNF a
• Serology for rubella
• Blood group and rhesus type
• Viral Markers optional
TB , Mx Test, Latent TB, MTBC,TB PCR

27. Selected Investigations of RM
• Uterine Factor
- HSG/Hysteroscopy/laparoscopy
- Three – dimensional pelvic ultrasound ?
• Full Thrombophilia Screening
In additional to those taken in all patients - protein C,
protein S, antithrombin III, MTHER, factors XII and VIII
Personal Family History of vascular thrombosis
Autoimmune disease – Jt Pain , Skin rash , allergy
APS – Migraine ,epilepsy, Jt pain, vascular thrombosis

28. TVS
DILEMMAS

29. • TUBERCULOSIS
• Uterine Malformations
• Evaluating the uterus/cervix
• Evaluating the ovaries /endometrium
• Evaluating the corpus luteum
• Evaluating the pregnancy.
TVS

30. • Persistently
THIN
Endometrium
Is a common finding
In TB

31. •Endometrium
hardly 2-3 mm.
•Endometrial
lining appears
broken, bright
echogenic.
In TB

32. •Peri ovarian
inflammation
and spec’s of
calcification on
ovarian surface.
In TB

33. • PID with no pain is
most important
symptom/ sign.
• It may present as -
• Fluid collection in
cul-de-sac
• Fluid collection in
endometrial cavity.
• Fluid collection inside
the tubes (if adhesions
at fimbrial end, fluid
shows a definite
oblong expansion
In TB

34. • T-O mass are seen as
unilocular or multilocular
thick walled mass with diffuse
internal echoes.
• Layering effect seen when
debri settles down.
• Outer margins poorly
delineated if adhesions present
• Restricted mobility (Frozen
pelvis)
In TB

35. Uterine Artery Doppler
The chance for
pregnancy is
almost zero if the PI
is more than 3.019
on the day of hCG
administration
Patients who get
pregnant have a lower
RI (0.53 vs 0.64)

36. MID LUTEAL DOPPLER ASSESSMENT OF
UTERINE ARTERY BLOOD FLOW IN RPL
• Increased resistance to uterine artery blood
flow may be an important contributing factor
to some causes of RPL and may represent
an independent indication of risk of
pregnancy loss.
Natalia Lazarin et al fertil steril june 2007
TVS doppler of uterine arteries during
midluteal phase of untreated cycles

37. • Which are the defects max asso. with
RSA
• Best diagnostic tool
ANATOMIC FACTOR
DILEMMA

38. Incidence of term pregnancy before
and after treatment
Sepate Uterus
2.05% N = 14
15% >80% after
surgery
Bicornuate Uterus
2.7% N = 18
60% 80 (with TLC)
Didelphic Uterus
N = 2
Infertility
10%
Surgery not
indicated
Our Experience

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

40. SEPTAL DEFECT in our experience
• Diagnosed on
USG/HSG/HYSTEROSCOPY
• Correctable with
Hysteroscopic
Metroplasty
Personal Experience - We had 14 cases
Term pregnancy 7/14

41. Bicornuate Uterus
• 10% of anomalies
• Incomplete fusion of Uterine horns at level of fundus
• Two separate but communicating endometrial cavities
• Abortion rate 30%
• Preterm labour 20%
• Strassman Metroplasty ???
Successful Pregnancy
are well known

42. 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
Successful Pregnancy
are well known

43. Uterus Didelphys
• Least common anomaly -5-7%
• Abortion rate 43%,Premature birth rate 38%
Resection of Vaginal septum if there is difficulty in intercourse / vaginal
delivery Strassmann Operation not indicated. Once pregnancy is there with
IUI - there is no difficulty . Personal experience of two cases.

44. Arcuate Uterus
No Role

45. T shaped Uterus
Never seen
• Diethylstilbestrol treatment for Premature labour
started 1940 Banned 1970

46. Uterine Causes (22.4%)
Congenital Anomalies
septum = 2.05 %
Bicornuate Uterus = 2.7 %
Acquired Abnormalities
Synaechie = 3.5% + more
Myomas submucus = 4 %
Endometrial Polyp = 14.5%??
Cervical incompetence = 6%
Experience

47. Cervical Incompetence
6 %

48. When do you think it is advisable
to give a cerclage?
• Cervical length<2.5cms
• Internal os width>1.5cm
• Available closed cervical length >1/2
Timing of cerclage:
Any time between 12 wks to
28 wks

49. FIBROIDS & RSA
• Do FIBROIDS cause
Recurrent pregnancy loss?

50. Sub mucus fibroids may be asso. With RPL should be removed hysteroscopically
Intramural and subserous do not require removal.

51. Intra Uterine
Synechia
3.5% (24)
Number is much More

52. Uterine Abnormalities
Treatment SUMMARY
• Uterine septum: GnRH analogue and
hysteroscopy septal resection and temporary
intrauterine device.
• Intrauterine adhesions : hysteroscopic
division and temporary intrauterine device:
postoperative course of cyclic estrogen and
progesterone therapy.
• Fibroids: GnRH analogue and myomectomy

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

54. Clarifying Tubercular
Endometritis in RM

55. Tubercular Endometritis
in RM
Are we justified in starting ATT on the
basis of a positive molecular (PCR) test,
Histochemistry positive test (MTBC) with
no other obvious clinical features
?

56. Yes
Tubercular Endometritis

57. We Run Dedicated
Rec. Miscarriage Clinic
since 2003
Our Obsession with TB started in 2005
Our Experience of 680 Recurrent
consecutive Miscarriages – Updated
(30th
June 2013)

58. 2005 IVF Failure -13
7 Cases positive for MBTC (EB)
4 Cases Conceived on their own
3 required Lit Therapy
All had Threatened Abortion
Eye opener experience of LIFECARE

59. INFECTIONS –
Tuberculosis
TB + TNF a ↑
39 %
31%
Diagnosis and management of RM
(Since 2003 – June 2013) & 680 Cases
Diagnosis :- TB Gold Test , MTBC, TB PCR

60. Treatment and Results Tubercular
Endometritis in RM is very satisfying
37 % - 3 months
16 % - IUI
32% - IVF

61. • Almost all chromosomally abnormal
conception spontaneously abort. 70% of
abortuses are chromosomally abnormal.
• Over 90% of conception having normal
karyotype continue
Miscarriage may be viewed as nature’s
quality control process.
Genetic Causes & RM

62. KARYOTYPE OF PARTNERS
• MANDATORY
• About 5% of the couples with RM are carriers of
balanced translocations.
• They themselves are healthy but during gametogenesis
there is malsegregation of chromosomes ,resulting in
either monosomy or trisomy.
The chances of RM with one partner with balanced
translocation is 30%
Difficult to convince patients – Cost
DILEMMA

63. KARYOTYPE OF POC
Aneuploidies of conceptus are
a well recognised cause of
sporadic abortion.
Trisomies affecting
chromosomes 13, 16, 18, 21, 22
constitute the largest group.
Strong association with
advanced maternal age.
Monosomy X is the single most
common chromosomal
abnormality in sporadic
abortions. No age association.

64. KARYOTYPE OF POC
• May be advised
• Not always successful to culture
• FISH can be done
• Often reveals aneuploidy which is not a cause of
RPL
• Does have a role in directing the management.
• Women who abort chromosomally normal
pregnancies should be investigated for causes other
than genetic.
• If abortus does show unbalanced translocation then
could point to parents being balanced carriers

65. Genetic in Male
• Both abnormal sperm morphology and ↑DNA
fragmentation increase recurrent pregnancy loss.
• Carrell and colleagues found higher rates of sperm
DNA fragmentation in couples with recurrent early
pregnancy loss following spontaneous conception.
(Arch Androl 2003;49:49-55)

66. Autoimmune Causes
15%
Immune system has ability to discriminate
between self and non-self.
The failure of self tolerance is called
“autoimmunity”.
SLE associated with increased abortion.
Antiphospholipid antibodies– associated in
pregnancy loss in healthy women.
DILEMMA

67. APS / APLA
ANTIPHOSPHOLIPID ANTIBODY SYNDROME
• CHARACTERISED BY CIRCULATING
ANTIBODIES AGAINST MEMBRANE
PHOSPHOLIPID (LA. ACA….)
• LUPUS ANTICOAGULANT IS most important
• Thrombosis / Placental infarction
9-10 wks
2nd
Trim. More frequent

68. THROMBOPHILIA-Associated with RM
How common?
• About 50% to 60% of patients with
recurrent miscarriages harbor a
coagulation defect.
• Identification of the defect, followed by
appropriate therapy, will lead to normal-
term delivery in 98%.
Roger L.Bick, Dec. 2004 Medscape

69. ACQUIRED AND CONGENITAL
THROMOBOPHILIAS
• 66% of RPL cases have atleast one
thrombophilic defect compared to 28%
controls.
• Two defects found in 21% of patients
Sarig G etal fertil steril 2002
These datas suggest that
hypercoagulable states might be an
important Factor for RPL

70. Apla Syndrome,
Thrombophilia - Complications
Abortion IUFD PIH
APLA Syndrome ++ ++ ++
Factor V Leiden mut. ++ ++ ++
APC Resistance + ++ ++
Hyperhomocysteinemia. + + +
Antithrombin III def. ++ ++ +
Protein C deficiency + ++ +
Protien S deficiency + ++ +

71. Other APL’s anti bodies
• Whether other APL’s such as
antiphosphatidylserine and
antiphosphatidylethanolamine,should be
looked for and whether anticoagulation
treatment should be given.
Results from one study suggested that APL’s other than LAC
and ACA are associated with RPL and will benefit from
anticoagulant therapy
Franklin RD human reprod 2002

72. APLA
Therapeutic Options
Antiaggregants
Aspirin
Anticoagulants
Heparin / LMWH
Immunosuppression
Corticosteroids
IVIG
Other tt options
Plasmapheresis
Azothiaprin

73. THERAPY
• LOW DOSE ASPIRIN AND HEPARIN /
LOW MOLICULAR WEIGHT
HEPARIN ARE THE FIRST LINE
THERAPY
• PREDNISONE OR IMMUNOGLBULINS CAN BE ADDED IN REFRACTORY CASES
• PREDNISONE THERAPY IS ASSOCIATED WITH INCREASED INCIDENCE OF PRETERM
DELIVERIES
• DUE TO OSTEOPENIC EFFECTS OF PREDNISONE AND HEPARIN ,CALCIUM
SUPPLEMENTATION IS MUST

74. Alloimmune Causes – Why Is The
Baby Not Rejected?
• Unique Phenomenon
• Shuts off Rejection
immunity of Uterus
+
• Growth / Development of fetus

75. 1In a normal pregnancy the father’s DNA in the baby tells
the mother ‘s body to set up a protective reaction around
the developing embryo.
• If the father’s DNA is too closely matched to the mother,
there is a good chance that the embryo created by them is
unable to differentiate itself from the mother’s body.
This results in a lack of blocking antibody to pregnancy,
and the pregnancy fails.
2 TNF a (TH type – I)
Role of
Absent Anti Paternal Lymphocytotoxic
Antibodies (Blocking AB)

76. NK cell measurement and NK cytotoxicity are two
measurements for assessing cellular immune response.
In most cases, Natural Killer Cells are good for
the body because they prevent cancer. However
in excess they kill the embryo and interfere with
the endocrine system that produces hormones
essential for pregnancy.
Lit therapy ↓ TNF a / NK cell cytotoxicity.
Natural Killer (NK) Cells
& NK Cytotoxicity , TNF a

77. “Alloimmunity”
SYSTEMATIC COCHRANE REVIEW
EMPHASIS THAT NONE OF THESE
IMMUNOTHERAPIES,
IV IMMUNOGLOBULINS, HAVE NO SIGNIFICANT ROLE TO
PLAY
?

78. ENDOCRINE Causes
↑ Glycosylated HB 16%
S/C Hypothyrodism 26 %
Thyroid Anti Bodies + 9 %
PCOD – ↑ LH 14%
LPD 22%

79. Hypothyroidism / Antibodies
No definite evidence that hypothyroidism
causes sporadic or recurrent abortion.
Antithyroid antibodies(thyroglobulin and thyroid
peroxidase) are raised in euthyroid recurrent
aborters.
Antibody Abortion(%)
Absent 8.4
Present 17.0
Stagnaro-Green,JAMA,

80. Diabetes MellitusDiabetes 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.,

81. PCOD – Raised LH
Abortion observed in
patients with raised LH
levels (D5/6 levels > than
10 IU/L)
DILEMMA
LH levels Abortion(%)
N 12
Raised 65
Regan et al

82. DOES DOWN REGULATION
OF LH LEVELS HELP IN
DECREASING THE
ABORTION RATES ?
PCOD – Raised LH

83. HARDY et al compared embryo quality in
PCOS &others undergoing IVF and found
no difference
PCOD – Raised LH

84. LH may exert deleterious effect by
increasing
androgens,suppressing granulosa cells
Or by decreasing endometrial receptivity by
disordered prostaglandin synthesis Franks
PCOD – Raised LH

85. Results of Prospective Randomised
Study – St Mary’s Hospital ,
London By (Clifford.k)
No benefit from suppressing LH levels.

86. Luteal Phase Defect
Incidence varies from 10-60%.
Evaluated by mid-luteal progesterone and
late luteal endometrial biopsy
META-ANALYSIS of Six RCT of use of
progesterone during pregnancy –
Use of Progesterone or HCG does not reduce
miscarriage.
Daya, Br.J.O.G.,
Goldstein Br.J.O G.
DILEMMA

87. PROGESTERONE HELPS !!!
When should the supplementation start ?
• RPL progesterone
supplementation should
be started day after
ovulation to cause
effective secretory
changes for implantation
and effective
immunomodulation to
prevent embryonic
rejection.

88. Uterine Specificity In Vaginal administration
Ensures efficacy Where it matters

89. OXIDATIVE STRESS AND ROLE OF
ANTIOXIDANTS in RM
What is Their EffectivenessWhat is Their Effectiveness
on Pregnancy outcomeon Pregnancy outcome
??
??

90. • Multiple micronutrients offered
• Folic acid, calcium,iron beneficial
• Vit E,C, carotenoids, carotene,L-Arginine
• Magnesium, zinc, need further elucidation
• Lycopene, Lyco-O-Mato,Green Tea extracts,
etc
?

91. Psychological
• RM is associated with significant
psychological morbidity.
• Role of psychological stress is unclear

92. Tender Loving Care
• Even after three miscarriages the
chance of success without treatment is
approximately 60% except for women
with antiphospholipid syndrome and
thrombophilia in which success rates
are lower

93. Diagnosis and management of recurrent Pregnancy Loss
(Since 2003 – June 2013)
ETIOLOGY DIAGNOSTIC
EVALUATION
TREATMENT
Genetic 2.8% Karyotype of partners
POC ?
genetic counseling / donor
gametes
ANATOMIC 22.4% USG/ HSG/ MRI
Endoscopy
Surgical Correction
Septate S/M firoids & adhesions
Infections TB 39% TB Gold ,MTBC,,
TB PCR
ATT
AUTOIMMUNE
Apla Syndrome 6%
Thrombophilia 3%
LA, ACL Aspirin / Heparin
ALLOIMMUNE 8% TNF a , NKCell Paternal leukocyte therapy
Endocrine
PCOD, ,LPD,Hypothyroid. 14%
Diabetes Mellitus
Progesterone 21 / EB,
↑ LH, TSH, Glyco. Hb
Hormonal Therapy
TLC

94. Management Options
In Next Pregnancy
Approach
Do Not advocate “Unproven” treatment

95. Recommends
• TLC Approach
• Liberal use of vaginal progesterone
• Serial Scan to reassure
• Counseling , Acupuncture, Diet

96. • Offer Low Dose Aspirin And Heparin to women with APS
• Offers low – dose heparin to women with thrombophilia
• Patients with diabetes mellitus : good matabolic control
• Patient with hypothyrodism – TSH < 2.5
• Paternal Lit therapy ?
↑ TNF a, TB ?
• Low mol. Wt heparin ??
Idiopathic , TB , ↑ TNF a, , APLA

97. Second Trimester
• Primary cervical carclage with suspected
cervical incompetence
• Serial cervical Ultrasonography with
insertion of cervical suture with evidence
of shortening / funneling
• Serial vaginal swab for Bacterial vaginosis
Diet Advice & LAMART’S Classes

98. RM is associated - Low birth wt
- ↓ Liquor
- Early IUGR
- IUD
Injection medroxy prog. Acetate if required
Low Mol. wt Heparin if required
Arnine Sachet / 4 L fluid if required
Third Trimester
Level 3NURSERY

99. Importance of Abortion / RM
Key Message Lifecare34
60% of embryos never yield a live birth
Edmonds et al,1982
30% of “Implanting embryos” miscarry, often
before the woman realizes she is pregnant
Miller et al ,1980
15-20% of clinically detectable pregnancies
abort
5% women have RM > 2
1 % woman have RM > 3
In INDIA Genital TB is major cause (2/5), Uterine – 1/5
Paternal Karyotype , Thrombophilia & TNF a
need to be Evaluated More & More

100. LOGICAL TO OFFER ART?
• IVF WITH EMBRYO BIOPSY
• DONOR OOCYTES IN OLDER AGE GROUPS
• DONOR OOCYTES FOR RECURRENT
HYDATIDIFORM MOLE
• DONOR SPERM IN PT WITH Y CHROMOSOME
DELETIONS
• DONOR EMBRYOS IN MOTHERS WITH BALANCED
TRANSLOCATION
• SURROGACY UTERINE FACTOR
D
a
y
1
Day 5
Day 4Day 3
Day 2

101. Thank You