The document addresses the complex management of recurrent pregnancy loss (RPL), defining types of RPL, potential causes, and treatment recommendations for affected couples. It emphasizes the importance of genetic counseling, investigation of underlying conditions like thrombophilia, and the role of hormonal treatments such as progesterone, while discussing various therapeutic approaches. In addition, it highlights the significance of assessing uterine anomalies and the impact of maternal age on miscarriage rates.

1. MANAGEMENT OF RPL
Dr. Sunita Khedkar
M.B.B.S , DGO (Mumbai )
Consultant , Khedkar
Maternity hospital,
Aurangabad

2. RECURRENT PREGNANCY LOSS
(RPL)
 ≥3 consecutive miscarriages before the age of fetal
viability*
*Weight <500 gram, GA- ≤22 weeks (WHO), ≤24 weeks (RCOG)
1. Primary RPL- No previous successful pregnancy
2. Secondary RPL- Previous ≥1 successful pregnancy

3. 2 OR 3- NUMBER GAME?
After 2 loss-
 Loss of subsequent pregnancy similar
 Significant chance of detecting cause
 Especially- if subfertility or >35 years
 Avoid 3rd
potential psychological trauma
 Women starting reproductive career late
 Patient → Impatient

4. PARENTERAL AGE AND RPL
Recommendations
 Women should be sensitively informed that the risk of
pregnancy loss is lowest in women aged 20 to 35 years.
Strong ⊕⊕
 Women should be sensitively informed that the risk of
pregnancy loss rapidly increases after the age of 40.
Strong ⊕⊕
 Male age
Most studies evaluating male age have reported a
significant association between increasing male age
and the incidence of miscarriage (Sharma et al., 2015)

5. 5
STRESS
 Changes Th2 response in endometrium to Th1 response
 Affects HPO axis
 Adrenaline release reduces placental blood flow

6. IF DEFINITE CAUSE OF RPL IS
FOUND
 Targeted Therapy
 Explain- the role of chance
factors

7. CAUSES
fetal
 chromosomal
abrasions-
accounts for 43% of
losses
maternal
 abnormal tropoblast
invasion and development
sec to
1. Endocrine
2.
immunological-local/syste
mic reaction
3. anatomical abrasions

8. RPL WITH GENETIC BACKGROUND
 Genetic abnormalities of conceptus-
- recognised cause of sporadic , recurrent
pregnancy loss.
 Prevalence of chromosomal abnormality in single
sporadic miscarriage- 45%

9.  Common abnormalities that occur in early losses
–developmental and genetic
 Most pregnancies – embryo morphologically
abnormal (86-91% where embryo is present)
 Genetically abnormal embryos -Phenotypically
abnormal /normal (some)

10. POC KARYOTYPING
RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of
Couples with Recurrent First trimester and Second-trimester Miscarriage
•Chromosomal anomaly of the embryo- Commonest cause
of single sporadic miscarriage
•Provides opportunity to offer genetic counselling
•Prognosis for future pregnancy is BETTER if the
karyotype of POC abnormal
•Chance of aneuploidy DECREASES as the number of
miscarriage increases

11. CHOROMOSOMAL ANALYSIS-
PARENTS
 Not Routine
 Only if karyotyping of POC - unbalanced structural
abnormalities
 If karyotype of POC not done

12. .All couples with abnormal foetal /parental karyotype -genetic
councilling , discuss possible Rx options- pros n cons
1.PGT-A( preimplantation genetic testing for aneuploidy)
Embryos in IVF cycle are biopsied and screened for
chromosomal abnormalities prior to implantation.
2.FISH- with embryo biopsy @ D3 ,looks at specific number of
chromosome ,at early stage when mosaicism is higher.
3.Whole genome teqniques-
* Array CGH(Comparative genomic hybridisation )
* NGS( next generation sequencing),
more accurate screening teqniques( biopsy taken at blastocyst
stage, looking at all chromosomes)

13.  Clinical outcomes are improved in couples with
PGS.
-Costly
 3rd
party reproduction
 adoption

14. THROMBOPHILIA ( HEREDITORY/ AQUIRED)
Predisposes patient to venous thromboembolism
Hereditory thrombophilia-
 Factor V Leiden mutation
 Prothrombin mutation
 Protein C, Protein S, Antithrombin deficiency
 MTHFR gene mutation
(methylene tetrahydrofolate reductase)

15. MX
RPL+ Thrombophilia- treatment to prevent thromosis
1. Anthithrombotic agents –aspirin
2. Anticoagulants – heparin(UFH/LMWH)
3. IVIG, Steroids –to suppress immune system, improve
pregnancy outcome
4. FA, vit B6, vit B12- reduce homocystein level
MTHFR mutation +/hyperhomocysteinemia

16. In women with hereditory thrombophilia + RPL
antithrombotic prophylaxis is NOT recommended
Exept
in context of clinical research /
VTE Prevention .
Screening for hereditory thrombophilia-
not recommened.

17. APS -ANTIPHOSPHOLIPID
SYNDOME
 Persistent presence of antiphospholipid antibodies +
vascular thrombosis +/ pregnancy complications.
 3/more losses excluding
-Miscarriages before 10 weeks
-Maternal anatomic/hormonal abnormalities
-Maternal and paternal chromosomal causes
Is one of the clinical criteria –diagnosis of APS

18. 3 CLINICALLY RELEVENT ANTIBODIES
( ASSOCIATED WITH THROMBOSIS)-
 Lupus Anticoagulant (LAC)-
Positive
 Anti-Cardiolipin Antibody
(ACL)
IgG/ IgM-
Moderate to High Titre (>40
IU/L)
 Anti- 2-glycoprotein 1
ẞ
IgG/ IgM
Moderate to High Titre
 Considerable laboratory
variations and lack of
standardization
 LAC- dRVVT (with
platelet neutralization)-
better than aPTT
 ACL and 2-
ẞ
glycoprotein- ELISA
 In 2 occasions ≥12
weeks apart

19. Mx APS-
1.Anticoagulants –
For prevention of thrombosis LMWH is prefered
over UFH-
- less risk of osteoporosis,
heparin induced thrombocytopenia
2.Steroids- prednisolone has been evaluated in Rx
of RPL + APS - no e/o benefit
Adverse effects --eg.risk of GDM,
risk HT, preclampsia,
LBW, NICU admission

20. 3. IVIG-superior to prednisolone
birth wt
number of miscarriages
PTL
4. Hydrxy chloroquine- immunomodulator-
inhibits antigen presentation and B, T cell activation.
Safe ,effectve in preventing obs complications in APS.
Further studies- RPL and APS

21.  LDA (75 mg/day) after
+ve UPT
 LMWH- after
confirmation of fetal
cardiac activity
 IVIG/Corticosteroid-
Not effective in
primary APS
Prophylactic Dose
No intervention Antithrombotics
Live Birth rate 10% 80%
Improvement 54%

22. ESHRE-RPL –GUIDELINE-(NOV 2017)
 Women who satisfy lab criteria of APS
and h/o 3/more pregnancy losses
- low dose Aspirin ( 75-100mg/day),
starting before conception,
-Prophylactic dose of heparin( UFH/LMWH)
from positive UPT.
Anticoagulant Rx with 2 losses ,only for clinical research
(GDG)

23. METABOLIC AND ENDOCRINE
ABNORMALITIES
Overt Hypothyroidism
-Associated with poor pregnancy outcomes
Risk of miscarriage, preterm delivery,LBW,
poor fetal neurodevelopment.
*increase daily dose T4 d/t physiological
changes.
*TSH levels – early pregnancy( 7-9 weeks)

24. SUBCLINICAL HYPOTHYROIDISM -
SCH
 Acc.to American Thyroid association- treat if
1. TSH >10mU/L
2. TPO antibodies +ve and TSH above
trimester specific range.
1st
trimester- 2.5mU/L
2nd
trimester- 3mU/L
3rd
trimester- 3.5mU/L
Reduction in risk of abortion with T4 supplementation

25. LUTEAL PHASE INSUFFICIENCY
 Consecutive short leuteal phase( Normal-11-16days)-
S/O insufficient progesterone– abortion.
--One of the reasons for implantation failure-
miscarriage
unsuccessful assisted reproduction
Associated with PCOS, thyroid, prolactin disorder and poor
ovarian function ( age, AMH, AFC).
 Progesterone
 HCG

26. PROGESTERONE- WHICH
MOLECULE?
NMP Dydrogesterone
Selectivity to P4
receptor
More selective
Route Oral, vaginal, IM Oral
Bioavailability Better
Metabolism May increase risk of
obstetric cholestasis
Less metabolic load
on liver

27. Oral Vaginal IM
•Easiest way •Higher uterine
concentration
•Optimum blood
level
•Can be taken
anywhere
•Needs privacy •Extremely painful
• acceptable and
tolerable to women
•10% may have
vaginal dryness/
irritability
•Abscess
formation
Route of administration- Does NOT affect the outcome
•Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10: CD003511
•Van der Linden et al. Cochrane Database of Systematic Reviews 2015

28. IS PROGESTERONE SAFE?
 No significant differences in the rates of preterm birth,
neonatal death, or fetal genital anomalies- between
progestogen therapy vs placebo/control.
 No studies reported adverse maternal effects.
Haas DM, Ramsey PS. Cochrane Database Syst Rev 2013 Oct 31; 10:
CD003511.

29. IS PROGESTERONE EFFECTIVE IN RPL
Wahabi HA, et al. 2011 The evidence suggesting benefit of
progestins for women with RPL and with
threatened miscarriage, remains preliminary
Haas DM, Ramsey PS.
2013
Sub-group analysis - women with
RPL,when supplemented with progesterone
shows the odds of miscarriage are
significantly decreased .
Carp H. 2015 Although all the predictive and
confounding factors could not be controlled
, significant reduction ( 29% )in the odds
for miscarriage was found when
dydrogesterone is compared to standard
care

30. PROMISE TRIAL
FIRST TRIMESTER PROGESTERONE THERAPY IN WOMEN WITH A HISTORY OF
UNEXPLAINED RECURRENT MISCARRIAGE
Coomarasamy A., et al. N Eng J Med 2015;373:2141-8

31. PROMISE TRIAL-
 Progesterone therapy in
the 1st
trimester of
pregnancy did not result
in a significantly higher
rate of live births among
women with a history of
unexplained recurrent
miscarriages

32. RCOG Green Top
Guidelines No 17. April
2011. The Investigation and
Treatment of Couples with
Recurrent First trimester and
Second-trimester Miscarriage
Insufficient evidence to
recommend progesterone
supplementation in recurrent
miscarriage
FOGSI Position
Statement 2015
No evidence of harm , some e/o
benefit ,
Decision should be based on
clinician’s discretion .

33. FOGSI POSITION STATEMENT 2015
• No statistically significant difference in congenital
abnormalities seen in clinical studies between
newborns of mothers who received progesterone &
those who did not
• caution in patients with cardiovascular diseases ,
impaired liver function & cholestasis.

34. HCG AND OESTROGEN
hCG
 Insufficient evidence
 RCOG Green Top Guidelines No 17. April 2011. The
Investigation and Treatment of Couples with Recurrent First
trimester and Second-trimester Miscarriage
 Higher risk of OHSS
 Van der Linden et al. Cochrane Database of
Systematic Reviews 2015
 Smaller placebo controlled study
cited hCG benefit confined to a
small subgroup of patients with
RPL & oligomenorrhoea.
 Quenby S, Farquharson RG. Human chorionic
gonadotropin supplementation in recurring pregnancy
loss: a controlled trial. Fertil Steril 1994;62:708–10.
Oestrogen
 no
improvement
in outcomes
 Van der Linden et al.
Cochrane Database
of Systematic Reviews
2015

35. PCOS
 Prevalence of PCOS in pts of RPL- 50-60%

Thrombotic association
 high LH , androgen levels
insulin resistance, hyperinsulinemia, glucose intolerence
ovulatory dysfunctions ( endocrino- metabolic)

36. METFORMIN / INSULIN
 PCOS, Insulin resistance, GDM
 Treatment reduces risk of miscarriage and
improves pregnancy outcomes.
 Metformin- low risk ,effective oral hypoglycemic
agent for type 2DM.
Safe and effective in gestational DM.
corrects glycemic abnormalites.

37. 1. Suppression of high LH- does not improve live
birth- Grade A
2. Metformin- Insufficient evidence- Grade C
3. Laparoscopic Ovarian Drilling- ?

38. PCOS
 Recommendation
Assessment of PCOS,
fasting insulin and fasting glucose
is not recommended in women with RPL to
improve next pregnancy outcome.
 Strong ⊕⊕

39. HYPERPROLACTINEMIA
 insufficient folliculogenesis, short luteal phase
 Prolactin disorders are associated with PCOS,
luteal phase deficiency, stress and obesity
 Recommendation
 Prolactin testing is not recommended in
women with RPL in the absence of clinical
symptoms of
hyperprolactinemia(oligo/amenorrhea).
Conditional ⊕

40. HYPER PROLACTINEIA MX
 Prolactin testing if clinical symptoms of it-
oligo/amenorrhoea.
 Dopamine agonist therapy-bromocriptine
-cabergoline
Bromocriptine- 2.5-5 mg/day (depending upon response)
before conception till 9 weeks- better pregnancy
outcomes.
Bromocriptine can be considered in RPL with
hyperprolactinemia .

41. VITAMIN D
 Vit D deficiency-
Affects growth and development of foetus.
Risk factor for DM, pre-eclampsia, SGA infants
 Supplement reduce the abnormal cellular immune
response.
Reduced risk of preterm delivery and LBW babies.
 Recommandation- Preconception counciling in RPL,
prophylactic vit D supplementation could be
considered.

42. HYPERHOMOCYSTEINEMIA-HHCY
 Increased homocysteine levels –RPL
 Folic acid Rx reduce homocysteine levels
Greatest results in MTHFR mutations
 High dose of FA (15mg) x 3mths
f/b FA 5mg + vit B6 ( 750mg)/day x 3mths --
improvement in live birth rate.
*Aspirin +LMWH after CA -- improve LBR

43. ENDOCRINE THERAPY
If endocrine
abnormalities
detected
 L-thyroxine
 Insulin sensitizers
 Dopamine agonists Treatment of
presumed LPD
 Progesterone
 hCG
 Oestrogen

44. RPL- IMMUNOLOGICAL
BACKGROUND
 Presence of immune biomarkers in
peripheral blood
/ endometrium / decidua -- RPL

45. Fetus with
Paternal
antigens
T helper 1
cell response
Miscarriage of
The Fetus
T helper 2
cell response
Protection of
The Fetus
Immunology

46. . IMMUNOLOGICAL BIOMARKERS
 .1 Human leukocyte antigen (HLA)
 .2 Anti-HY antibodies
 .3 Cytokines
 .4 Natural killer cells (NK cells)
 .5 Antinuclear antibodies (ANA)
 Antithyroid antibodies
 Antiphospholipid antibodies
No immunological biomarker has been documented to definitely
cause RPL.
*Trails of anticoagulation –No improvement in LBR
*no immunological biomarker( exept APS) can be used for specific Rx.

47. RX OPTIONS
In patients with auto /
alloantibodies ,endometrial NK cell
abnormalities ,
 Lymphocyte immunisation(LIT)
 , paternal leucocyte immunisation
 Ivig infusions
 Intralipid therapy
 filgrastim
 Prednisone

48. IMMUNE THERAPY
 Immunotherapy is expensive
has potentially serious adverse effects
• RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment
of Couples with Recurrent First trimester and Second-trimester Miscarriage

49. UTERINE ANOMALIES
 Congenital- Mullerian tract malformations
1. Septate utrus
2. Bicorporeal uterus with normal Cx (bicornuate uterus)
3. Bicorporeal uterus with double Cx (Didelphic uterus)
4. Hemiuterus (Unicornuate uterus)
 Well documented association between congenital uterine
malformations and RPL.

50.  All women with RPL should be assessed for uterine
anomaly (congenital/ acquired)
 Septate Uterus- RPL in 1st
Tm
 Bicornuate/ Arcuate Uterus- RPL in 2nd
Tm
RCOG Green Top Guidelines No 17. April 2011. The Investigation and Treatment of Couples with Recurrent First
trimester and Second-trimester Miscarriage
Initial Screening
• 2D USG
• HSG/ SSG
Further Testing
• 3D USG
• Hystero/Laparoscopy
• MRI

51. SEPTATE UTERUS-
 Associated with poor pregnancy outcome
 Hysterscopic metroplasty –Rx of choice
easy, less morbidity, less risk of IU adhesions.
After Rx - higher pregnancy rates
reduced miscarriage rates

52. BICORPOREAL UTERUS , NORMAL CX
Metroplasty (trans abdominal / laproscopic)
Reduce preterm birth ,LBW
But no strong evidence in RPL
–not recommanded for RPL
.
Bicorporeal uterus ,double Cx
Laproscopic unification has been described
Doubtful efficacy in improving LBR

53. T shaped uterus -No e/o to support Rx
Hemiuterus ( unicornuate uterus)
- Uterine reconstruction –not recommanded
- Irreparable anatomic abnormality + RPL
- IVF and surrogacy can be offered.

54. ACQUIRED IU MALFORMATIONS
-Not clearly associated RPL
 Endometrial polyps – hysteroscopic removal , if >1cm.
 Fibroids-
1.Submucosal-
myomectomy- reduce miscarriage rates in selected
cases with RPL.
2. Intramural-
fibroids that do not distort uterine cavity- no Sx
needed
3. Subserosal- less likely to cause RPL

55. HYSTEROSCOPIC MYOMECTOMY-
Post- op complications –may affect future fertility
intra-uterine adhesions
Risk of rupture during future pregnancy
.
INTRA UTERINE ADHESIONS- IUA
RPL- more predisposed to IUA d/t prev D n C
exessive, overzealous curratage.
Rx-Surgical adhesiolysis
care to prevent recurrence of adhesions.

56.  RCOG Green Top Guidelines No 17. April 2011. The Investigation and
Treatment of Couples with Recurrent First trimester and Second-trimester
Miscarriage
 Role of Fibroid resection- ?

57. CERVICAL INSUFFICIENCY
 Recurrent 2nd
trimester abortions
 Cervical encirclage- to prevent preterm birth –
prev 2nd
tri loss
Short cervix on USG

58. CERVICAL ENCERCLAGE
 No role in repeated 1st
trimester miscarriages
 Not indicated in uterine anomalies or cervical surgeries
(multiple D/C)
RCOG Green Top Guidelines No 17. April 2011. The Investigation and
Treatment of Couples with Recurrent First trimester and Second-
trimester Miscarriage

59. UNEXPLAINED / IDEOPATHIC RPL
• Counsel them and explain the chances
• Reassure that she is in safe hands
• Give psychological support
• Respect the couple’s concerns and decisions

60. FACTS AND FIGURES
Background Risk 10-20%
By chance 0.34 %
Rec Miscarriage 1 %
No cause found 50 %
Successful preg 75%
Subsequent Pregnancy
After one Miscarriage Pregnancy loss Live birth
One 20% 80%
Two 25% 75%
Three 30% 70%
Four 40% 60%
Six 50% 50%

61. TENDER LOVING CARE (TLC)
• RCOG Green Top Guidelines No 17. April 2011. The Investigation and
Treatment of Couples with Recurrent First trimester and Second-trimester
Miscarriage
75% will have live-birth, with supportive care alone
•Brigham SA,Conlon C, Farquharson RG.A longitudinal study of pregnancy
outcome following idiopathic recurrent miscarriage.Hum Reprod 1999;14:2868–71.

62. MISCELLANEOUS RX
 Vitamin B12 + Folate + Pyridoxine- to
reduce homocysteine level
 Antioxidants
 Empirical antibiotics
 Probiotics
 Nitric Oxide donors – as vasodilator
Reported in small studies but
no RCT available
Life Style Changes
• Weight Control
• Smoking Cessation
• Reduce alcohol, exessive caffine
. Avoid recreational drugs
Stress reduction
Can be helpful

63. TAKE HOME MESSAGES
 The pathophysiology of RPL is little understood
 Only tests required- APLA screening, pelvic USG and
selective karyotyping
 Treatment should be offerred for these abnormalities only
 Unexplained RPL is an enigma for gynaecologists
 Gain the confidence of the patients
 Tender Loving Care is all that is needed
 RPL patients carry risk of developing atherosclerotic
disease in later life ( d/t chronic activation of pro-
inflammatory pathways)