definition of recurrent pregnancy loss, causes , their diagnosis and management

1. RECURRENT PREGNANCY LOSS
PANEL DISCUSSION

2. DR. NIRANJAN CHAVAN
MD, FCPS, DGO, MICOG, DICOG, FICOG, DFP,
DIPLOMA IN ENDOSCOPY (USA)
Professor And Unit Chief, L.T.M.M.C&L.T.M.G.H, Sion Hospital
National Co-ordinator, FOGSI Medical in Pregnancy Committee (2019-
2021)
Chairperson, FOGSI Oncology & TT Committee (2012-2014)
Secretary MOGS (2019-2020), Premises Secretary, AFG (2019-2020)
Chair & Convenor, FOGSI Cell Violence Against Doctors (2015-2016)
Dean and Chairman, Academia of Global Obstetrician &
Gynaecologists
Chief Editors, AFG Times (2015-2016)
Course Coordinator of 11 batches Of MUHS recognised
Certificate Course of B.I.M.I.E at L.T.M.G.H (2010-2016)
Member, Oncology Committee AOFOG (2013-2015)
Member, Managing Committee, IAGE (2013-2017), (2018-2020)
Editorial Board, European Journal of Gynaec. Oncology (Italy)
Course Coordinator of 3 batches 0f Advanced Minimal Access
Gynaec Surgery (AMAS) at LTMGH (2018 -2019)

3. “………I recall nothing which in times past has caused me
more anxiety and doubt,
or
in regard to which I have found it more difficult to get
any satisfactory rules from books,
than the treatment of
Abortion.”
- T. G. Thomas (1908)

4. What are the common questions asked by
RPL patients?

5. PATIENTS QUESTIONS
Why did it
happened ?
Will it happen
again ?
How it can be
avoided ?
Could have been
avoided ?

6. What is the incidence of RPL?

7. • Spontaneous pregnancy loss is, in fact, the most common
complication of pregnancy
• About 70% of human conceptions fail to achieve viability
• estimated 50% are lost before the first missed menstrual
period
• Most of preg. Losses are unrecognized.
• Actual rate of preg. Loss after implantation is 31%(by hCG
assay)
• Clinically recognized, loss occurs in 15% before 20wks of
gestation.

8. SPONTANEOUS ABORTIONS
• Normal population
• Chromosomal abnormality --- 50%
• Trisomic --------------------- 56%
• Polyploid -------------------- 20%
• Monosomic for chromosome X-- 18%
• Unbalanced translocations ------ 4%

9. • What is the Definition of RPL?

10. • Definition : 3 or more clinically recognized pregnancy
losses before 20wks from LMP.
• Incidence: 1/300

11. • Primary recurrent pregnancy loss refers to couples that
have never had a live birth
• while "secondary RPL" refers to those who have had
repetitive losses following a successful pregnancy

12. CAUSES OF PREGNANCY LOSS
 Genetic
 Trisomies, 16, 21, 7,15
 Monosomy X, Triploidy
 Parental Structural Aberrations
 Fetal anomalies
 Any incompatible with life
 Uterine anomalies
 Septate, Bicornuate
 Fibroids
 Cervical Incompetence
 DES
 Immunological causes
 Alloimmune (cytokines,NK)
 APL (ACA,LA)
 Hereditary Thrombophilia
 APCR, FVL FII
 MTHFR, Homocysteinemia
 Pritein C, Protein S,
Antithrombin III
• Trauma
• Endocrine
• Luteal defficiency
• Thyroid dysfunction
• Diabetes
• Alloimmune
• Cytokines
• NK
• Infection
• Chlamydia
• Mycoplasma
• Toxoplasmosis
• Septic Abortion

13. PROPOSED ETIOLOGIES
• Genetic Factors 3.5-5%
• Anatomic Factors 12-16%
• Endocrine Factors 17-20%
• Infectious Factors 0.5-5%
• Immunologic Factors 20-50%
• Other Factors 10%
Novak’s Gynecology 14th ED

14. • Is it important to establish the gestational age of
these pregnancies ??

15. CLINICAL PREGNANCY LOSS
PREEMBRYONIC
< 5 WKS
EMBRYONIC
< 8 WKS
FETAL
> 8 WKS

16. EARLY PREGNANCY FAILURE ( EPF)
• Anembryonic Pregnancy :
• Trophoblast has invaded the decidua
• Embryonic disc not developed/ resorbed after loss
of viability
• Embryonic / Fetal demise:
• Embryonic disc developed :: loss of viability
• USG : Emb pole> 5mm without cardiac activity

17. • On ultrasound do we have any milestones by which we
can predict the outcome?

18. THRESHOLD ???
• MSD
• 20 mm without yolk sac
• 25mm without embryo :
• TAS : anembryonic pregnancy
• Rate of increase in MSD : parameter
• < 0.6 mm/day
• Increase of <3 mm over 5 days
• Increase of < 4 mm over 7 days

19. • When shall we start investigations?

20. • Clinical Investigation should be started after two
consecutive spontaneous abortions, especially
• When fetal heart activity had been identified prior to
the pregnancy loss
• when the women is older than 35 yrs of age
• when the couple has had difficulty conceiving

21. Are there any biochemical markers to predict the
outcome?

22. BIOMARKERS
• HCG
• Progesterone
• 17 α Hydroxy progesterone
• Inhibin A
• Inhibin Pro - α C
• IGFBP I

23. CASE 1
• 24 years old Mrs. MSJ married since 5 years
• Obstetric history:
G1 – Vesicular Mole, D&E done.
G2 - Missed abortion at 7 weeks, D&E not
done, pills taken.
G3 - Missed abortion at 6 weeks, D&E done.
G4 - 6 weeks, Blighted ovum, pills given.

24. • Menstrual History: Regular
• Medical History: N.P.
• Family History: N.P.
• Clinical Findings: Normal
• Hormonal Profile: Normal
• APLA: Negative

25. KARYOTYPING:
Husband: 46XY
Wife: 46XX, t(11;22) (q24:q13)
GTG banding :
proband shows reciprocal balanced translocation
involving chr 11 & chr 22
breakage & reunion has occurred at bands 11q24 &
22q13
MFISH
balanced translocation between chr 11 & chr 22
involving breakpoints 11q24 & 22q13
respectively

26. Cytogenetic Studies of the
conceptus
Should we always do them ?

27. 13.9%5Monosomy (45XO)
66.7%24Trisomy
13.9%5Triploidy
5.5%2Structural (Unbalanced
Translocations)
ABERRATIONS IN ABORTUS
(CARP ET AL, 2002)

28. 28.0%
23.0%
63.6%
29.0%
0%
10%
20%
30%
40%
50%
60%
70%
20-30
30-40
40-45
Total
KARYOTYPE OF ABORTUS
ACCORDING TO
MATERNAL AGE
p=0.01
(Fisher’s
exact Test)
for the age
group 40-
45
compared
to the other
age groups.

29. REPEAT ANEUPLOIDY
Repeat
Aneuploidy
8/43 (19%)Carp et al, 2004
3/30 (10%)Sullivan et al, 2005
11/73 (15.1%)Total

30. • What are the RCOG guidelines?

31. RCOG GUIDELINES
 Recurrent pregnancy loss may be due to an abnormal
embryo, which is incompatible with life.
 As the number of miscarriages increases, the prevalence of
chromosomal abnormality decreases
 If the karyotype of the miscarried pregnancy is abnormal,
there is a better prognosis in the next pregnancy.
 karyotyping the products of conception provides useful
information for counseling and future management.

32. SUBSEQUENT
PREGNANCY ACCORDING
TO KARYOTYPE OF
ABORTUS
37.8%
38%
67%
62%
0%
10%
20%
30%
40%
50%
60%
70%
Euploidy Aneuploidy
Carp
Ogasawara
14/37 14/2127/71 37/60
O.R. for a live birth after
aneuploidic abortion.
3.28 (95% CI = 0.94-
11.9) Carp et al
2.62 (95% CI = 1.21-
5.67) Ogasawa et al

33. GENETIC COUNSELING
AFTER A MISCARRIAGE
• In all couples with a history of recurrent miscarriage
cytogenetic analysis of the products of conception
should be performed if the next pregnancy fails.

34. • What is the role of Parenteral karyotype ??

35. STRUCTURAL GENETIC
FACTOR IN EITHER
• 2.5-8% RPL couples
• Commonest :balanced reciprocal/Robertsonian translocation
• Rarer : inversion,insertions,deletions,duplications,ring
chromosome

36. Translocations
Reciprocal
translocations
Robertsonian
translocations
A translocation is the transfer of genetic material from one
chromosome to another.

37. Robertsonian translocations
occur when two chromosomes fuse
together, creating one
chromosome that contains most of
the original two.
(45 chromosomes with one variant)
Translocations
Reciprocal translocations
occur when two different
chromosomes exchange segments.
(46 chromosomes with two variants)

38. ROBERTSONIAN
TRANSLOCATION
• Robertsonian translocations between chromosomes 14 and 21,
one of the most common combinations, are of particular clinical
relevance. An individual with this translocation could have a
child with three copies of chromosome 21, resulting in Down’s
syndrome (trisomy 21).

39. NON DISJUNCTION
• Non disjunction occurs when chromosomes fail to "disjoin"
during meiosis or mitosis.

40. NON DISJUNCTION DURING
MITOSIS
The incidence of trisomies increases with
age. Trisomy 16, which accounts for 30% of
all trisomies, is the most common. All
chromosome trisomies have been reported
in abortuses except for trisomy 1.

41. DELETIONS
 Deletions are fragments of chromosomes that are
missing. They are usually lethal when homozygous
and cause abnormalities when heterozygous.
▪ Cri du Chat Syndrome
 Cri du chat syndrome is due to a deletion of a
portion of chromosome 5. Cri du chat individuals
are mentally retarded.
"Cri du chat" is French for "cry of the cat". The infants
cry sounds like a cat.

42. COUNSELING
• Cytogenetic data
• In balanced translocation there is 5-10% chance of
pregnancy with unbalanced translocation
• Important to evaluate : carriers : >70% LBR.
• Possibility of PGD

43. • All couples with a history of recurrent miscarriage should
have peripheral blood karyotyping performed. The
finding of an abnormal parental karyotype should
prompt referral to a clinical geneticist.
Genetic counseling after a
miscarriage

44. CASE 2
• 28 years old Mrs. XYZ married since 6 years G4P1L0A3
• Obstetric history:
G1 - Preterm stillbirth at 7ma abruption
G2 - Missed abortion at 6 weeks
G3 - Missed abortion at 8 weeks
G4 - Spont. Abortion at 8 weeks

45. • MENSTRUAL HISTORY:
4-5/28 Regular, Moderate, Painless
• MEDICAL HISTORY:
History of childhood Asthma
History of DM and HT in family

46. TORCH
• ROUTINE INVESTIGATONS
• WNL
 Toxo - IgG +ve, IgM -
ve
 Rubella - IgG Low +ve,
IgM -ve
 CMV - IgG Mod +ve,
IgM -ve
 Herpes - IgG mild +ve,
IgM -ve

47. AUTOIMMUNE PROFILE
• BT - 3’ 05”, CT - 4’ 25”,
• Platelets - 1.2 lac/cmm
• PT - 13 sec (T) 11 sec ( C )
• ACL - IgG - high +ve (181U)
- IgM - high +ve (221U)
• LA - high +ve
• dsDNA +ve

48. TORCH
• Toxoplasmosis
• Other infections – parvovirusB19, HIV, Syphillis,
hepatitis, varicella
• Rubella
• Cytomegalovirus
• Herpes Simplex infections

49. DISTINCTIVE FEATURES
Intracranial calcifications (Toxo, CMV)
Cataracts (Rubella, HSV)
Chorioretinitis (Toxo, CMV)
Bone lesions (Syphilis, Rubella)
Congenital heart disease (Rubella)
Microcephaly (CMV)
Hydrocephalus (Toxo)
Vesicles (HSV, VZV, Syphilis)

50. RCOG GUIDELINES FOR TORCH
• For an infective agent to be implicated in the aetiology
of repeated pregnancy loss, it must be capable of
persisting in the genital tract and avoiding detection or
must cause insufficient symptoms to disturb the
women.
• Toxoplasmosis, rubella, cytomegalovirus, herpes and
listeria infections do not fulfill these criteria and routine
TORCH screening should be abandoned.

51. INFECTIONS & RECURRENT
PREGNANCY LOSS
• Tuberculosis
• Listeriosis
• Bacterial vaginosis
• TORCH infections
• Chlamydiae
• Syphilis
• Mycoplasmas
Note : Late rather than early abortions
Doubtful role of antibiotic prophylaxis

52. GENITAL TUBERCULOSIS AND
RPL
Genital tuberculosis ?
Latent GTB
Immunological Basis-
↑ Cytokines; ↑ Th1 : Th2 i.e changes ratio of cytokines
towards an increase in abortogenic milieu
Implantation failure-
due to fibrosis & inflamation

53. Does APLA cause early pregnancy loss ????

54. MECHANISM
• Inhibition of cytotrophoblast
• invasion
• Differentiation
• Thrombosis: platelets, fibrinolysis & coagulation
cascade
• Arachidonic acid release blocked hence PGI 2
decreased
• Anticytokines action against IL3
• Placental cell Apoptosis

55. CHARACTER OF PREGNANCY LOSS
 Typical presentation is growth retardation probably
leading to fetal death in the second or third trimesters
(Lockshin, 1993).
 APS in 10% of unselected patients with RPL (Tincani et al
1987)
 APS in 30% (Drakely et al 1998) of patients with
recurrent second trimester pregnancy loss.

56. OTHER IMMUNOLOGICAL DISORDERS
• SLE
• Higher rate of RPL
• APLA : 37% ≈ poor outcome
• Lupus flares / renal disease
• Counseling
• RAFS: (Reproductive
autoimmune Failure
Syndrome)
• 90% Cannot be dete
cted by routine
antibody estimate

57. THERAPY IN IMMUNOLOGICAL
DISORDERS
• Aspirin & Low Molecular Heparin
• Antipaternal cell antibodies
• IV IG

58. MANAGEMENT
 Aspirin: 75 mg / day
 Prednisolone: 60 mg /day.
Side effects- cushingoid features,
Immunosuppressant (miliary
tuberculosis),glucose intolerance,
HT, IUGR.
 Heparin: 5000 IU BD subcut
side effects- osteoporosis,
thrombocytopenia, hemorrhage.
 LMWH: Low molecular weight Heparin
(Dalteparin, Enoxaparin)

59. ROLE OF IVIG IN RPL
• 45% of miscarriages and 95% of late pregnancy losses
from women experiencing RPL are chromosomally
normal.
• Large data suggestive of the causes being
immunological.

60. IMMUNOTHERAPY
• Passive, with immunoglobulin
• NK Cells down-regulated by IVIG
(Ruiz et al, 1996)
• Down regulation associated with improved outcome
• Cytokine balance altered by IVIG
(Bakimer, et al, 2000)

61. 48%
32%
0%
10%
20%
30%
40%
50%
IVIG
33/70
Controls
23/71
IVIG AFTER > 5 ABORTIONS
(CARP ET AL, 2007)
OR = 2.1 (95% CI 1.01-
4.37)

62. DEFECTS IN COAGULATION FACTORS

63. Thrombophilia Nonpregnant
Risk of DVT
Method of testing
Factor V Leiden
(G1691A)
3 to 8 fold DNA analysis
Factor II
Prothrombin (20210A)
3 fold DNA analysis
Protein S deficiency 2 fold Activity assay
Antithrombin deficiency 25 to 50 fold Activity assay
Protein C deficiency 10 to 15 fold Activity assay
Acquired activated
Protein C resistance
1.7 fold Anti coagulant response
With activated protein C
MTHFR
(C677t or A1298C)
Questionable Fasting homocysteine
If +ve DNA testing
Acquired
hyperhomocysteinemia
2.5 to 4 fold Fasting homocysteine
Ormethionine loading

64. TREATMENT STRATEGY
• Correction of hyperhomocysteinemia
• LMWH

65. CASE 3
• 35 yrs, A3 with history of previous 3 missed abortions
• A1- 8 weeks missed abortion
• A2- 7 wks missed aboretion
• A3-10 wks missed abortion

66. INVESTIGATIONS
• Hb - 10 gm%
• Urine R/M-N
• LFT, RFT - N
• VDRL, HIV -ve
• Bl gr - O +ve, husband - B +ve
• Day 2 progesterone levels- 2ng/ml
• Day 8 progesterone level—8.7ng/ml

67. • Endometrial biopsy done which was suggestive of
endometrial lag of >3 days
• USG suggestive of lack of endometrial echogenicity on 7th
postovulatory day and leutinised unruptured follicle and
leuteal cyst formation

68. • What is luteal phase defect?
• Diagnostic criteria for leuteal phase defect?
• Role of progesterone and HCG?
• Other hormonal defects to cause RPL?

69. • Role of Endocrinologic factors ???

70. LUTEAL PHASE DEFECT
• LPD
• Lag of 2days in histological development of
endometrium
• Mid luteal Progesterone < 10ng/Ml
• Abnormal expression of endometrial progesterone
receptors or αVβ3 integrin : biomarker of uterine
receptivity : D20-21
• Progesterone
• Clomiphene
citrate

71. ROLE OF PROGESTERONE & HCG
• Conversion of TH1 to TH2 response
• Progesterone induced blocking factor
(PIBF)
• Reduction of NK cells activity

72. DEFECTIVE OVARIAN FUNCTION
High D 3 FSH > 20 IU/L
Low D 3 inhibin B < 0.6
units/ml
Low D 3 Estradiol < 20 pg / ml
Low antral follicle count < 5
Low antimullerian hormone < 15pmol /L

73. • Other hormonal defect responsible for RPL?

74. HYPOTHYROIDISM
• Untreated hypothyroidism
• Sensitive TSH assay
• Antibodies ►►
• Antimicrososmal
• antithyroglobin
R/O
hypothyroidism
During
Pregnancy
hypothyroidism

75. HYPERPROLACTINEMIA
• Dopamine agonistsInsufficient
folliculogenesis
 Oocyte
maturation
LPD
H
P
O
A
X
I
S

76. INSULIN RESISTANCE
• DM
• Poor glycemic control
• PCOD
• Increased insulin
resistance

77. CASE 4
• 29 year old Mrs. X working as computer
professional married since last 5 years
• History of primary infertility, K/c/o PCOS, conceived
after ovulation induction with clomiphene citrate
and IUI

78. • Past obstetric history - G3P0L0A3
G1 - Missed abortion at 2 ma
2 years back
G2 - Spont. Ab at 3 ma 1 year back
G3 - Spont. Ab at 3 ma 6 months back
• Menstrual History
4-5/30 Regular, moderate, painful

79. INVESTIGATIONS
• Hb - 9.8 gm%
• Urine R/M - NAD
• FBS - 92 mg%, PLBS - 104 mg%
• RFT, LFT - WNL,
• Pap smear - N
• XRC - NAD
• HSA- 20 million per cc, 60- 70% motility

80. USG
• Uterus: Anterior wall intramural fibroid measuring
1.5 X 1.2 cm,
• Submucosal fibroid from posterior wall
2.1 X 2.2 cm
• ET - 7 mm
• Rt Ovary - N
• Lt Ovary clear cyst 3 X 4 cm,
• POD - N

81. • AUTOIMMUNE PROFILE:
Platelets - 2 lacs, BT CT - N, LA - N,
ACL-N
• Diagnostic Laparoscopic findings -
Uterus - N
Rt. Ovary - N
Lt. Ovary - cyst,
B/L Fallopian tubes - patent

82. DIAGNOSTIC HYSTEROSCOPY
FINDINGS
Submucosal fibroid

83. Dr. Sanjay Gupte
• What is the role of other Anatomical factors?

84. ANATOMIC FACTORS
 Mullerian
anomalies
 Septum
 Bicornuate
 unicornuate
 IU Adhesions
 Submucous fibroid
 Intramural fibroid ???
Small uterine cavity

85. HSG OF UNICORNUATE UTERUS

86. A : before surgery
B : after surgery
HSG OF BICORNUATE
UTERUS

87. Partial septate uterus
Complete septate uterus
HSG OF SEPTATE UTERUS

88. UTERINE LEIOMYOMA II
 Sx
- asymptomatic
- menorrhagia
pelvic pain or pressure
 Dx
- bimanual examination
- USG or HSG
 Tx
- myomectomy
under laparotomy
- hysteroscopic myomectomy

89. HSG OF DES EXPOSURE

90. CASE 5
• 33 year old married since 10 years
• G5 P0 L0 A4
• 6 weeks amenorrhea
• Family and personal history not contributory

91. OBSTETRIC HISTORY
• G1-2ma missed abortion S/E done 9 yrs
back
• G2- 2ma MTP done i/v/o h/o antimalarial
drugs taken 8 years back
• G3 - 2ma missed abortion S/E done 2 years
back
• G4 - 2ma missed abortion S/E done 1 1/2
years back
• G5 - PP

92. INVESTIGATION
• Hb - 10 gm%
• Urine R/M-N
• LFT, RFT - N
• VDRL, HIV -ve
• Bl gr - O +ve, husband - B +ve
• HSA - N

93. HYSTEROSCOPY- ASHERMAN’S
SYNDROME

94. ASHERMAN’S SYNDROME:
UTERINE SYNECHIAE
 Ex
- mechanical trauma
- infection
- estrogen deficiency (?)
 Sx
- mestrual disorder
- infertility
- pregnancy loss
 Dx : HSG or Hysteroscopy
 Tx
- hysteroscopic dissection
- IUD or pediatric Foley catheter
- estrogen-progesterone
HSG before Tx
HSG after treatment

96. CASE-6
 History indicated:
h/o repeated STL (second trimester losses) or PTB,
Painless cervical dilatation,
Precipitate labor
 USG indicated:
cervical length < 15 mm?
cervical length reduction 1 mm / week
 Physical examination indicated:
shortening of cervix detected on manual
examination in 2nd trimester

97. INCOMPETENT CERVIX

98. Dr Shirodkar said that
cerclage is for “women
who abort repeatedly
between the forth and
seventh month… where
one can by repeated
internal
examinations…find that
the cervix is gradually
yielding”

99. CONCLUSION
• Cerclage is beneficial in 2 or more STL/PTB
• Beneficial if cervical length is 15mm or less or
internal os > 5 mm
• Not useful in twins or placenta previa

100. CERCLAGE
NOMENCLATURE
Old nomenclature New nomenclature
- Prophylactic-Elective - History indicated
- Therapeutic-Salvage - Ultrasound indicated
- Rescue-Emergency - Physical examination
- Urgent - Combined

101. INTERVENSIONS

102. CLINICAL PROTEOMICS IN
SPONTANEOUS ABORTIONS

103. PROGESTERONE
• Temptations of its use
• RU486
• Immunomodulatory action ????
• Pregnancy support

104. ROLE OF NK CELLS
• RPL: high activity of NK cells at the uterine lining as
well as peripheral blood
• NK cells lead to release of pro-inflammatory
cytokines.
• These lead to placental blood vessel clotting and
subsequent pregnancy loss.
• CD8 type T cells Th2 cytokines are protective against
NK cytokine-dependent miscarriage.

105. • How does the fetus escape rejection by NK
cells??

106. • Following trophoblastic invasion the fetal semi-
allograft induces PgR in γ/δ T cells.
• This enhances the interaction with high levels of
progesterone
• Progesterone causes expression of PIBF

107. PIBF
• Inhibits
• NK-cell cytologic activity
• Th1 cytokines(IL2 and interferon γ )
• Favors
• Th2 cytokines(IL4, IL5 and IL10)
• This inhibits cellular immune response and
promotes humoral response

108. SUPPORTING EVIDENCE
• Much less PIBF expression was found in women
who eventually lost their pregnancies than in
healthy pregnant women*
• However no such difference was found in aborters
or non-aborters in patients aggressively treated
with progesterone **
* Liddell HS et al * * Brigham SA et al

109. DIFFICULTIES…..
• Determining the role of progesterone in
preventing RPL is difficult due to difficulty in
determining who has progesterone deficiency
• When does the problem start ??? Luteal phase or
will the need of progesterone increase with
advancement of pregnancy

110. SPECTRUM THEORY ???
• The spectrum of progesterone deficiency
• Prevention of embryonic implantation
• Early loss : chemical pregnancy
• Blighted ovum
• Viable but missed before 1st trimester
• 2nd trimester loss
• Preterm delivery

111. BENEFITS OF
PROGESTERONE
It is better to treat a woman with a benign treatment that
is later found not to be effective than not treat her, have
her miscarry and later find studies showing unequivocally
that with such treatment definitely reduces the risk of
miscarriage.
-Shulman (2008 yearbook)

112. • ROLE OF HCG ??

113. INTERVENTION : HCG
• HCG is the hormone responsible for CL support
in early pregnancy
• If pregnancy is failing levels of HCG may be low
resulting in low progesterone.
• Rather than giving progestrone HCG could be
used directly in order to stimulate natural
hormone to reduce ab normal fetal effects.

114. EVIDENCE
Study Treatment Control Odds ratio
Quenby &
Farquharson
6/41 10/39 0.39(0.13-1.20)
Svigos 1/13 9/15 0.11(0.02-0.05)
Harrison 0/10 7/10 0.05(0.01-0.32)
Harrison 6/36 8/31 0.58(0.18-1.87)
Total 13/95 34/85 0.26(0.14-0.52)
• Early smaller studies showed HCG to be beneficial
• Larger trials : weaknesses
HCG v/s placebo for recurrent miscarriages :
miscarriages per treated pregnancy

115. • HCG is not a panacea to all patients of RPL
• Beneficial in particular group
• How to diagnose these patients?
• irregular cycles : more benefits
• HCG or Pr : HCG more natural

116. COMPARISON OF PROTOCOLS
Investigation/ treatment RCOG ACOG ESHRE
 Progesterone/
HCG supplement ---insufficient evidence---
 Bacterial vaginosis ---insufficient evidence---
 Thrombophilias ---insufficient evidence---
 Anticoagulant for ---insufficient evidence---
Thrombophilia
 TFTs NR NR R
 OGCT NR NR R
 TORCH NR NR NR
 Immunotherapy NR NR insuf.evidence

117. Summary of Evaluation And
Management of RPL

118. EVALUATION AND MANAGEMENT
RPL 1
Factor Diagnostic
Evaluation
Abnormal
result
Therapy
Immunologic LA,AC IgG / M
ß2GlyproI
Phosphotydylserine
Embryotoxicity assay
Immunophenotyping
15- 20% ASA
Heparin
IV
Immunoglobulin
Parental
structural
chromosome
rearrangement
Cytogenetic analysis of
both the partners
2.5% -8% Genetic
counseling
Donor gametes
PGD

119. EVALUATION AND MANAGEMENT
RPL 2
Factor Diagnostic
Evaluation
Abnormal
result
Therapy
Endocrinologic Endometrial biopsy
Midluteal
Progesterone
TSH ,PRL,FBSL
8-12% Progesterone
Levothyroxine
Bromocrytine/caber
goline,metformin
,insulin
Anatomic Hysteroscopy
HSG
sonohysterography
15-20% Hysteroscopic
metroplasty
Adhesiolysis
myomectomy

120. EVALUATION AND MANAGEMENT
RPL 3
Factor Diagnostic
Evaluation
Abnorma
l result
Therapy
Thrombophili
c
Factor V Leiden
Prothrombin gene
Fasting homocysteine
Antithrombin activity?
Protein C activity?
Protein S activity?
8-12%? Low
molecular
weight or
fractionated
Heparin
Folic acid
Microbiologic Endometrial
biopsy
Cervical /vaginal
cultures?
8-10 % Antibiotics

121. EVALUATION AND MANAGEMENT
RPL 4
Factor Diagnostic
Evaluation
Abnormal
result
Therapy
Psychologic Mental status
evaluation
Support group
Counseling
psychiatrist
Iatrogenic Review tobacco
,alcohol, caffeine
use
Review exposure to
toxins,chemicals
5% Genetic
counseling
Donor gametes
PGD

122. THANK YOU