Controversies in management of Recurrent miscarriage Aboubakr Elnashar

1. Controversies in
management of
Recurrent
miscarriage
Aboubakr Elnashar
Benha university Hospital
ABOUBAKR ELNASHAR

2. CONTENT
CONTROVERSIES
1.DEFINITION
2.MANAGEMENT OF POSSIBLE CAUSES
3.MANAGEMENT OF DOUTFUL CAUSES
ABOUBAKR ELNASHAR

3. 1. DEFINE
 3 Consecutive miscarriages
(ESHRE, 2006; RCOG, 2011)
2 Consecutive miscarriages
(ASRM, 2012)
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4. 2. MANAGEMENT OF POSSIBLE CAUSES
I. Anatomic:10% 1. Congenital uterine malformation.
2. Submucous fibroid
3. Cervical incompetence
4. Severe IU synechiae
II. Endocrine: 5% 1.Uncontrolled DM
2. Clinical and sub clinical thyroid
disorders.
III. Atiphospholipid antibody syndrome
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5. IV. Inherited Thrombophilic Defects:2nd TRM (RCOG,
2011)
1. Factor V Leiden mutation
2. Prothrombin gene mutation
3. Protein s deficiency
V. Genetic: 25%
1. Parental chromosomal abnormalities
2–5% of couples with RM
2. Embryonic chromosomal abnormalities
30–57% of further
ABOUBAKR ELNASHAR

6. ASRM
(2012)
RCOG
(2011)
ESHRE
(2006)
HSG
3DUS
MRI
2DUS
3DUS,
Hysteroscopy,
Laparoscopy
SIS and/or
HSG
Hysteroscopy
Laparoscopy
1.
Anatomical
TSH, PRL
No: T3, TPOAb
NoTFT, HA1C2.
Endocrine
LA, aCL (G&M),
aβGI
LAC and
aGL(G&/orM)
LAC and aCL3.
APS
No2nd TRM:
factor V, factor II gene
mutation
Protein S. def
RCT req4.
Thrombophil
ia
karyotype of
abortus
Parental
karyotype
If above normal:
karyotype of
abortus:abnormal:
Parental karyotype
Parental
karyotype after 2
miscarriages
5.
Genetic
ABOUBAKR ELNASHAR

7. ASRM(2012)RCOG(2011)ESHRE(2006)
RCT reqRCT req
Cx cerclage if ……
Uterine septum, s m
fibroid, severe IU
adhesions
Cx incomptence
Eltroxin;TSH:2.5
Dopamin ag
P: some benefitRCT required
GnRha: No
Met: RCT req
RCT req
Hypothyroidism
Hyperprolactinaemia
LPD
PCOS
low-dose aspirin
plus heparin
low-dose aspirin plus
heparin
RCT reqAPS
NoHeparin:
1st TRM:RCT req
2nd TRM: yes
RCT req
RCT req
Thrombophilias
Hyperhomocysteinaemia
NoNoRCT reqAlloimmune
IVF/PGD: NoIVF/PGD: NoGenetic
TCL: yesTLC: yes
IVF/PGS, Aspirin,
Heparin: No
HCG: RCT req
TLC
health
advices
Unexplained
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8. 3. MANAGEMENT DOUBTFUL CAUSES
I. ANATOMIC
 RVF, Mild IU adhesions, Subserous fibroid: Not
related to RM (ASRM,2012)
 Arcuate Uterus
1.0% to 16%.
[SugiuraOgasawara et al, 211]
 Chan et al, 2011 MA
: 2nd TRM, PTL, F malpresentation
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9. Jayaprakasan et al, 2011:
Women who are referred for ART
Arcuate uterus (11.8%) not associated with a
reduction in PR or increase in miscarriage
Further evidence is needed to recommend
hysteroscopic surgery in arcuate uterus
[SugiuraOgasawara et al, 2011] (Evidence level II).
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10. II. ENDOCRINE
Thyroid peroxidase (TPO) antibodies
Controversial
[Chen et al, 2011; Thangaratinam et al, 2012].
not linked to RM
(Yan et al, 2012}
 Linked to RM.
[Abbassi , 2011, Twig et al, 2012]
Euthyroid women with high TPO antibody
[Negr et al, 2006, RCT].
Eltroxin (50 mcg daily):
decreased
miscarriage rate (13.8 to 3.5%)
PTL (22,4 to 7%).
ABOUBAKR ELNASHAR

11.  TPO antibody screening is not recommended
(Evidence level II).
 Until strong evidence is available, thyroxine tt is
not recommended in raised thyroid antibody with
normal thyroid function tests
(Evidence level III).
 Aim: TSH < 2.5 mU/L.
ABOUBAKR ELNASHAR

12.  PCOS
linked to an increased risk of RM
Mechanism: unclear
Not a cause
1. Elevated LH (>10 IU/l): suppression of
endogenous LH release before conception: did
not improve LBR.
2. Elevated serum T (>3 nmol/l)
{Rai, 2000]
Hyperandrogenaemia: elevated FAI: RM.
3. Ovulatory PCOS: do not increase risk
ABOUBAKR ELNASHAR

13. May be:
Insulin resistance: hyperinsulinaemia
 independent factor of RM
{Chakraborty et al, 2013].
 one of the direct causes: RM.
[Li et al, 2012; Hong et al, 2013]
ABOUBAKR ELNASHAR

14. GnRHa
Suppress LH secretion prior to ovulation induction:
no difference in outcome
 Metformin
To reduce RM: debatable.
MA: preconception metformin did not reduce RM
Small retrospective study: reductions in RM.
(Glueck etal, 2001; Jakubowicz et al, 2001)
 Metformin is not recommended as a tt of RM
(Evidence level III).
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15.  HYPERPROLACTINEMIA
In early pregnancy were significantly greater in
women who miscarried .
[Hirahara et al, 1998].
: RM
{alterations in the hypothalamic pituitary ovarian
axis: impaired folliculogenesis and oocyte
maturation, and/or a short luteal phase}.
ABOUBAKR ELNASHAR

16. Serum prolactin
(ASRM, 2012)
 Normalization of prolactin levels with a
dopamine agonist : decrease in RM.
[Hirahara et al, 1998, RCT].
Treatment of hyperprolactinemia associated with
RM is recommend
(ASRM, 2012, Up to date, 2013)
ABOUBAKR ELNASHAR

17.  LUTEAL PHASE DEFECT
 Short luteal phase: pregnancy loss but the
assessment and interpretation of a putative
LPD is problematic.
 The use of histological and biochemical
endpoints as diagnostic criteria for endometrial
dating are unreliable
(Evidence level III).
ABOUBAKR ELNASHAR

18. Progestagen supplementation
Cochrane Database Syst Rev. 2013
4 trials, 225 women
: statistically significant decrease in miscarriage rate
compared to placebo or no tt
(Peto OR 0.39; 95% CI 0.21 to 0.72).
However, these 4 trials were of poor methodological
quality.
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19. III. INFECTIONS
 TORCH test
not recommended
(Evidence level II).
Bacterial vaginosis
 Risk factor for PTL and 2nd TM
[Leitich et al, 2007]
 Vaginal swabs as screening tests during
pregnancy in high risk women with previous
history of 2nd TM.
[Trojniel et al, 2009]
Oral clindamycin early in 2nd T: significantly reduces
rate of 2nd TM and PTL
[Leitich et al, 2007] (Evidence II).
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20. IV. THROMBOPHILIAS
 Controversial.
[McNamee et al, 2012]
 Methylene tetrahydrofolate mutation:
Hyperhomocysteinemia,
Protein C deficiency,
Antithrombin deficiency: Not associated with RM
 The evidence is conflicting on
hyperhomocysteinaemia as a risk factor for RM:
testing for MTHFR mutation is not a part of
routine evaluation for RM.
(Evidence level II).
ABOUBAKR ELNASHAR

21. Hyperhomocysteinemia
High dose folic acid (5 mg) and vit B12 (0.5 mg)
once daily: reduce levels of homocysteine
No evidence to support usage of 5 mg folic acid
from prepregnancy stage purely to reduce the risk
of RM
(Evidence level III).
ABOUBAKR ELNASHAR

22. V. ALLOIMMUNE FACTORS
No clear evidence related to RM.
1. human leucocyte antigen incompatibility
between couples
2. absence of maternal leucocytotoxic antibodies
3. absence of maternal blocking antibodies.
4. altered peripheral blood NK cells
5. raised uNK cell numbers
: should not be offered routinely in the investigation
of RM.
(RCOG, 2011)
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23. Intralipid:
Evidence does not support
[Shreeve , Sadek, 2012}
Paternal cell immunization, third party donor
leukocytes, trophoblast membranes, and IV IG: Not
beneficial
.[Chochrane SR, 2006]
Criticized {not dd between primary and 2nd y RM}
 IVIG increased LBR in 2nd ry RM
insufficient evidence for its use in primary RM
[Hutton etl, 2007, MA]
Immunotherapy should not be advised.
[Porter etalm 2006] (Evidence level II)
ABOUBAKR ELNASHAR

24. VI. PATERNAL CAUSES
Significant increase of RM in patients with high
DNA damage compared with those with low DNA
damage
(Robinson et al, 2012, MA)
Significant association between SDF and
pregnancy loss after IVF or ICSI
(Zini, 2008, MA)
85% of u RM
(Maynou et al, 2012)
ABOUBAKR ELNASHAR

25. Several tests are available
but no consensus:
most predictive test?
Cut off level?
DFI ≥30: male infertility
15-30: RM
≤15: fair
ABOUBAKR ELNASHAR

26.  Insufficient evidence (Level C) to recommend
routine SDF testing to predict pregnancy loss.
(ASRM, 2013)
For diagnostic test
1. Results must be reproducible
2. Applicable to a given patient
3. Change management of patient
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27. Thank youABOUBAKR ELNASHAR