Threatened and unexplained repeated miscarriages

1. Aboubakr Elnashar
Threatened and
unexplained repeated miscarriages
Prof. Aboubakr Elnashar
Banha university, Egypt

2. THREATENED MISCRRAIGE
Vaginal bleeding < 20 ges ws
commonest complication in pregnancy, occurring
in 1/5 of cases.
(Johns et al, 2003).
vaginal bleeding
cervical os is closed,
but the diagnostic criteria for spontaneous abortion
have not been met.
ABOUBAKR ELNASHAR

3. Adverse effects
low likelihood
At 8 w if FH +ve: 90% will not miscarry.
Prognosis
Good:
bleeding light
limited to early pregnancy ≤6 w
Bad:
bleeding is heavy
extends into 2nd T
ABOUBAKR ELNASHAR

4. ABOUBAKR ELNASHAR

5. Management
No effective interventions
NICE, 2015
ABOUBAKR ELNASHAR

6. Progestins
Most promising tt
The rate of spontaneous miscarriage was
statistically significantly lower with progestin tt
compared with either placebo or no tt
(14 vs 26%; relative risk 0.53, 95% CI 0.350.79).
(Cochrane SR, 2011)
ABOUBAKR ELNASHAR

7. Progestins were administered either orally or
vaginally, and a subgroup analysis found a
significant decrease in the rate of miscarriage only
for oral progestins; the analysis of vaginal
progestins lacked sufficient statistical power to
detect a difference.
There was no significant increase in congenital
anomalies or PIH in the progestin group.
(Cochrane SR, 2011)
ABOUBAKR ELNASHAR

8.  Oral progestin dydrogesterone , compared with
placebo or supportive care (eg, bed rest)
significant decrease in the rate of miscarriage in
the progestin group (13 vs 24%; odds
ratio [OR] 0.47, 95% CI 0.310.7).
[Carp, 2012 MA].
Limitation:
small number of participants and events
poor methodologic quality of studies
ABOUBAKR ELNASHAR

9. 2015 European Progestin Club Guidelines
Schindler et al.2015.
Recommendation
Grade and
Reference
For women presenting with a
clinical diagnosis of threatened
miscarriage, there is a
reduction in the rate of
spontaneous miscarriage with
the use of dydrogesterone
Consensus-
based
recommendation
References:
Wahabi 2011,
Carp 2012

10. .
Many miscarriages are caused by genetic
abnormalities in the conceptus. It is unlikely that
progestins could prevent a miscarriage of this
etiology.
The data are insufficient to make a
recommendation for or against progestins for
women with threatened abortion.
ABOUBAKR ELNASHAR

11. Other medications
HCG
Uterine muscle relaxants: tocolytics, betaagonists
Vitamin supplementation
Chinese herbal medicine
high quality data do not support their use
ABOUBAKR ELNASHAR

12. Bed rest
commonly recommended
unnecessary and will not affect outcome
RCT: bed rest at home or in the hospital is not
beneficial in preventing fetal loss
[Aleman et al, 2005].
Abstinence from sexual intercourse and physical
exertion
typically advised
no data to support this.
ABOUBAKR ELNASHAR

13. Unexplained
Recurrent miscarriage
Prof. Aboubakr Elnashar
Banha university, Egypt

14. CONTENTS
1. DEFINITION
2. INCIDENCE
3. TYPES
4. CAUSES
5. PROGNOSIS
6. TREATMENT
CONCLUSION
Aboubakr Elnashar

15. 1. INCIDENCE
Recurrent miscarriage
2 or more: 3%
3 or more: 1%
of the population
(Regan et al, 2000).
1st T: 75% of RM
2nd T: 25% of RM
Can be established in:
50% (ACOG,2001)
Aboubakr Elnashar

16. 2. DEFINITION
Miscarriage
Spontaneous loss of pregnancy before the fetal viability.
includes all pregnancy losses from the time of conception
until 24w.
ectopic and molar pregnancies are not included.
Recurrent
3 or more consecutive
2 or more
(ASRM, 2008)
Aboubakr Elnashar

17. Aboubakr Elnashar
Unexplained:
Possible (definite or probable) causes (Good
correlation between the cause & RM) are excluded
by basic investigations
OR
No more than 2 doubtful causes
(Christiansen et al, 2008)

18. 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
ABOUBAKR ELNASHAR

19. 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

20. Basic investigations
1. Pelvic US (or HSG or SIS)
2. Antiphospholipid Ab:
LA
ACL
Anti-ß2 glycoprotein-I
3. TSH
4. Thombophylia screen:
Factor V Leiden mutation
FactorII(prothrombin) gene mutation
Protein S deficiency
5. If the above examinations are normal:
karyotype of the abortus: abnormality:
Parental karyotype

21. 3. TYPES
(Saravelos and Regan,2013)
Classified type I and type II
Type I: chance alone
Type II: genuine abnormality.
Help in selecting investigation and tt: improve
cost-effectiveness and overall clinical care.
Aboubakr Elnashar

22. I. Type I.
The Factor of Chance
No abnormality other than embryonic aneuploidy
which may not have been tested before the referral to a
specialist clinic.
Healthy women
Prognosis: very good in their future pregnancy
without the need for surgical or pharmacologic
intervention.
Aboubakr Elnashar

23. II. Type II.
Genuine pathology (other than embryonic aneuploidy): that
cannot be identified by the current investigations:
Typically younger
Higher order of miscarriages (4, 5, or more)
Prognosis: Worse. Underlying causes;
Past studies: systemic endocrine and immunologic
Recent studies: on spermatozoal, embryonic, and
endometrial
Management:
Difficult {no evidence-based tt}.
well-designed trials investigating novel disorders and tt.
Aboubakr Elnashar

24. 4. CAUSES
1. Oocyte:
Premature ovarian aging: reduced oocyte quality
and quantity.
Oocyte quantity and quality cannot be easily
assessed
Aboubakr Elnashar

25. 2. The Sperm: Paternal causes
Original reports:
Y-chromosome microdeletions
sperm oxidative stress
sperm concentration, morphology, and function.
DNA fragmentation
(Vissenberg R, Goddijn, 2011)
SDF is significantly associated with miscarriage
Methods to select sperm without DNA damage:
reduce miscarriage in ART.
(Robinson et al, SR, 2012)
Aboubakr Elnashar

26. 85% of uRM
(Maynou et al, 2012)
Advanced paternal age: Risk factor for miscarriage
{SDF: increases}
important to evaluate sperm DFI in uRM
Methods:
DFI
≥30: male infertility
15-30: RM.
≤15: Excellent to Good
fertility potential
Aboubakr Elnashar

27. Aboubakr Elnashar

28. sperm chromatin dispersion test.
Sperm 1 to 3: Large halo- unfragmented DNA.
Sperm 4 and 5: Small halo- fragmented DNA
Aboubakr Elnashar

29. ASRM Guidelines 2012:
Insufficient evidence (Level C) to recommend
routine SDF testing to predict pregnancy loss.
Aboubakr Elnashar

30. Evgni et al, 2014: Clinical indications for
SDF tests
1.Prolonged idiopathic infertility
2.Low fertilization rate or bad quality embryos in
IVF
3.Implantation failure following IVF
4.Repeated abortions
5.Prolonged exposure to toxic environmental
conditions affecting fertility
6.Conventional seminal parameters found below
the reference range
7.Advanced male partner age
8.Varicocele patients
9.Cancer patients
Aboubakr Elnashar

31. 3. The Embryo
 ART, and PGS of the embryo for aneuploidy in
women with uRM, may improve the prognosis
Aboubakr Elnashar

32. 4. The Endometrium
Normal endometrium can distinguish between good-
quality and poor-quality embryos.
(Teklenburg etal, 2010)
RM:
{increased levels of proimplantation cytokines}.
(Salker et al, 2010)
: disables the natural selection of healthy embryos:
implantation of poor-quality embryos: miscaraige.
Aboubakr Elnashar

33. 5. Systemic Factors
Until these conditions are proved to have a causal
effect, most women with these abnormalities may still
be diagnosed as having uRM.
Aboubakr Elnashar

34. Aboubakr Elnashar
I. Anatomic
Arcuate Uterus

35. Aboubakr Elnashar
II. Endocrine:
1. Inadequate luteal phase
 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).

36. 2. Thyroid antibodies:
have been associated with miscarriage
(MA, Thangaratinam et al, 2011)
[Chen et al, 2011; Thangaratinam et al, 2012]
 Not linked to RM
{in uRM is not higher than in the general
population,
does not have a prognostic value regarding the
outcome of a subsequent pregnancy
(Yan et al, 2012)}
high risk of developing hypothyroidism in 1st T
autoimmune thyroiditis postpartum: should be
followed appropriately
[Marcus, 1999]. Aboubakr Elnashar

37. 3. PCOS:
linked to an increased risk of M
(Smith and Schust, 2011)
Mechanism: unclear
Not a cause
1. Elevated LH
2. Elevated serum testosterone levels
3. Ovulatory PCOS: No increase risk
May be:
1. Insulin resistance hyperinsulinaemia
2. Hyperandrogenaemia: elevated FAI: RM.
Metformin to reduce RM: debatable.
MA: preconception metformin did not reduce RM
Small retrospective: reductions in RM.
(Glueck etal, 2001; Jakubowicz et al, 2001)

38. 4. Obesity
increases the risk of both sporadic and RM
independent factor: increased risk of miscarriage in
couples with uRM.
(Lo et al, 2012).
Aboubakr Elnashar

39. 5. Hyperprolactinemia
Normal PRL:
important in maintaining early pregnancy.
High Prolactin:
In early pregnancy: significantly increase M
[Hirahara et al, 1998]. RCT
Bromocriptine: significantly higher rate of
successful pregnancy (86 Vs 52%)
TT of hyperprolactinemia and RM is recommend
(Up to date, 2013)
Low prolactin:
increased risk of M
(Li et al, 2013) Aboubakr Elnashar

40. 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).
ABOUBAKR ELNASHAR

41. 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

42. 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

43. 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)
ABOUBAKR ELNASHAR

44. 5. PROGNOSIS
Traditional View
uRM: excellent prognosis in subsequent pregnancies
without the need for any surgical or pharmacologic
intervention.
Psychological supportive care: tender love and
care (TLC):
:reduction in RM up to 50%
(Pedersen et al, 1984 Clifford et al, 1997)
limitations in these trials.
No enough investigations
Small number
High drop out
Difficult to examine the mechanism through which it
operates.
(Li et al, 2002)
Aboubakr Elnashar

45. Novel Views
Favorable prognosis in uRM: not due to TLC.
(Saravelos and Li, 2012)
{Significant proportion of uRM are type I:
Favorable prognosis without any intervention}
General
population
Untreated
unRM
12-25%14-26%subsequent
pregnancy loss
Aboubakr Elnashar

46. 6. TREATMENT
 No evidence-based tt.
 Low risk, simple, and cheap
1. Psychological supportive care/TLC.
 Early and frequently repeated ultrasounds
βHCG monitoring
practical advice concerning life style and diet,
emotional support in the form of counselling,
Clear policy for the upcoming 12 w and medication.
 Chance of a live birth is good: over 50%
Aboubakr Elnashar

47. 2. Lifestyle modification
 Stop smooking, alcohol
 Caffeine reduction
 Reduction BMI (for obese women).
 No RCT.
Aboubakr Elnashar

48. 3. Decrease SDF
1. Oral antioxidant
2. Life style modifications: stop smoking and wt
loss
3. Identify and tt underlying condition: GTI and
varicocele
4. Consider TESA-ICSI
Aboubakr Elnashar

49. 4. Progestogen
Cochrane Database S R. 2013
4 trials, 225 women
El-Zibdeh
2005
Goldzieher 1964Le Vine
1964
Swyer
1953
1805456113
10 mg bid oral
Dydrogesterone,
5000 IU IM
hCG/4d
Duration: 12th w
10 mg/d oral
Dydrogesterone,
Duration: not
stated.
500 mg/w
IM
17 oh PC
Duration:
until 36 w
6 x 25 mg
progesterone
pellets
Duration: unclear.
Aboubakr Elnashar

50. 3 or more consecutive miscarriages
Progestogen tt:
significant decrease in miscarriage rate compared
to placebo or no tt
(Peto OR 0.39; 95% CI 0.21 to 0.72).
2 prior miscarriages.
a trend but not a significant reduction in miscarriage
rates
(Peto OR 0.68; 95% CI 0.43 to 1.07).
Limitations of MA:
these 4 trials were of poorer methodological quality.
Aboubakr Elnashar

51. Carp et al, 2015, SR and MA
509 women
10.5% miscarriage rate after dydrogesterone
administration vs 23.5% in control women (odds ratio for
miscarriage 0.29 [confidenceinterval 0.13–0.65] and
13% absolute reduction in the miscarriage rate
significant reduction of 29% in the odds for
miscarriage when dydrogesterone is compared to
standard care bed rest or placebo
Aboubakr Elnashar

52. 2015 European Progestin Club Guidelines
Schindler, 2015. .
Recommendation Grade and Reference
For women presenting with a
clinical diagnosis of recurrent
miscarriage, 3 or more, there is
a reduction in the rate of
miscarriage with the use
of dydrogesterone
Consensus-
based
recommendation
References:
Haas 2013,
Kumar 2014

53. Mechanism:
Immmunomodulatory actions by
Decreasing proinflammatory and
increasing anti-inflammatory cytokines in early
pregnancy
[Choi et al, 2000].
Duration:
Start: 3 days after the LH surge {not to inhibit
ovulation}
Continue: until 10 w
{placental progesterone production fully functional}
Aboubakr Elnashar

54. 5. Aspirin with or without heparin
No improvement
Insufficient evidence to support the routine use of
LMWH to improve pregnancy outcomes in women
with a history of pregnancy loss.
(Mantha et al, 2009, MA)
No support of the use of anticoagulants in women
with unRM.
(Cochrane Database Syst 2014)
Aboubakr Elnashar

55. 6. Combination therapy
An observational study
before and during pregnancy with
Prednisone (20 mg/day),
Progesterone (20 mg/day),
Aspirin (100 mg/day) and
Folate (5 mg every second day)
[Tempfer et al, 2006].
In treated group:
1st T M : 19% Vs 63% (not statistically significant).
LBR: 77 Vs 35%, respectively (P = 0.04).
The nonrandomized design and small number of cases
also limits the usefulness of this study.

56. 7. HCG
During early gestation may be useful in
preventing miscarriage
{endogenous hCG plays a critical role in the
establishment of pregnancy }
The evidence: equivocal
(Chochrane S R, 2013)
Aboubakr Elnashar

57. 8. HMG
observational study:
effective for tt of endometrial defects in women with
RPL
[Li et al, 2001].
Mechanism:
correction of a luteal phase defect
stimulation of a thicker endometrium: better implantation
site.
Clinical experience supports the efficacy of this
treatment
(Tulandi et al, 2013).
Aboubakr Elnashar

58. 9. Immunotherapy
Paternal cell immunisation
third-party donor leucocytes
trophoblast membranes
IVIG in women with previous uRM
does not improve LBR
(Cochrane systematic review, 2006 ; RCOG, 2011)
IVIG:
confirmed this conclusion
Expensive
Serious adverse effects: transfusion
reaction, anaphylactic shock and hepatitis.
(Stephenson et al, 2010MA)
Aboubakr Elnashar

59. 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

60.  Intralipid Therapy
Form:
20% IV administered fat emulsion routinely used as a
source of fat and energy for patients in need of extra intake
Composed of :
purified soybean oil, purified egg phospholipids,
glycerol, and water.
Some evidence effective in
1. RM due to immunologic causes, particularly
elevated natural killer cells or other unidentified
immunologic causes.
2. uRM
3. uRIF
Aboubakr Elnashar

61. In vitro studies:
Intralipid suppress Natural Killer cell cytotoxicity:
decreases the number of natural killer cells.
Administration:
IV infusion in an office setting.
100 mls of Intralipid are mixed with 500 mls NS.
60-90 minutes.
TT start at the start of the IVF cycle
continued monthly should a positive pregnancy test
result until the 24th w of pregnancy.
Side effects
No
Aboubakr Elnashar

62.  Endometrial scratching
 When:
cycle preceding the actual treatment cycle.
(Friedler et al., 1993; Barash et al., 2003; Raziel et al., 2007; Zhou et al.,
2008).
7 days prior to the onset of menstruation,
immediately before the start of ovarian stimulation
for IVF tt.
In the follicular phase of the index cycle : no
benefit
(Karimzade et al., 2010; Zhou et al., 2008).
Not on the day of OR:
significantly reduce CPR
(Nastri et al, 2012)
Aboubakr Elnashar

63. How and results:
biopsy/scratch or hysteroscopy: CPR doubled.
(Raziel et al., 2007 ; Narvekar et al, 2010)
CPR: twice as high with biopsy/scratch as
opposed to hysteroscopy
(Potdar et al, 2012)
(2 syst reviews: Potdar et al, 2012; El-Toukhy et al, 2013)
Uses:
RIF
Un-infertility
UnRM
Aboubakr Elnashar

64. (A) First, the pipelle sample is inserted until it reaches the fundus.
(B) The inner plunger is withdrawn to apply a suction force to the endometrial cavity.
(C) Endometrial scratch of the superficial layer of the endometrium is performed with the
use of a ‘hoovering’ movement, combining a rotational and in-and-out movement of the
pipelle sampler several times.
Aboubakr Elnashar

65.  Mechanisms:
1. lower the number of NK cells.
2. Induce decidualization of the endometrium
3. Provoke wound healing, involving secretion
cytokines and growth factors
(Li and Hao, 2009).
4. Recruit stem cells to the endometrium, creating a
partially new endometrium free of epigenetic defects
(Taylor, 2004; Du and Taylor, 2007).
Aboubakr Elnashar

66. 10. ICSI and PGD
Evidence is lacking: Similar results.
(Pellicer et al, 1999)
Not recommend
(Visenberg, 2012)
SR (Musters et al, 2011):
Miscarriage rates following PGS may be slightly
lower , but
lack of RCTs
invasiveness of ART
relatively good prognosis of women with uRM and
natural conception
: this tt is inappropriate.Aboubakr Elnashar

67. Thank you
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4884091351/

68. CONCLUSION
RM is unexplained when the possible causes are
excluded by basic investigations:
1. Pelvic US (or HSG or SIS)
2. Antiphospholipid antibodies
3. TSH
4. Thrompophelia screen (3 only), and
5. if the above examinations are normal: karyotype
of the abortus: abnormal: parental karyotype

69. UnRM is classified into
Type I (by chance alone)
Type II (genuine abnormality).
: helps to select investigation and tt.
Past studies:
Systemic endocrine
Immunologic causes
Recent studies:
Sperm
Embryo
Endometrial.

70. No evidence-based tt. Trials of tt:
TLC
Lifestyle modification
Decrease SDF
Progestagen
Aspirin with or without heparin
Combination therapy
HCG
HMG
Intralipid
Endometrial scratching

71. Thank you
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4884091351/