ABOUBAKR ELNASHAR

1. Recurrent
pregnancy
loss
Prof.
Aboubakr
Elnashar
Benha
university,
Egypt
elnashar53@hotmail.com
ABOUBAKR
ELNASHAR
DEFINITION
❑
Recurrent
pregnancy
loss
▪
2
or
more
consecutive
clinical
pregnancy
losses
until
20
w
gestation
▪
Excludes:
biochemical,
ectopic&
molar
pregnancies
(ASRM,
2013)
▪
2
or
more
pregnancy
losses
until
24
w
gestation
(including
chemical
pregnancy)
(ESHRE,
2017)
ABOUBAKR
ELNASHAR

2. ❑
RPL
or
recurrent
miscarriage?
▪
RPL
▪
Recommended
to
describe
repeated
pregnancy
demise
▪
Recurrent
miscarriage
be
used
when
all
pregnancy
losses
have
been
confirmed
as
intrauterine
miscarriages,
by
ultrasound
or
histology.
ABOUBAKR
ELNASHAR
INCIDENCE
❑Recurrent
miscarriage
▪
2
or
more:
3%
▪
of
the
population
(Regan
et
al,
2000).
▪
1
st
T:
75%
of
RM
▪
2
nd
T:
25%
ABOUBAKR
ELNASHAR

3. ❑Stress:
No
evidence
that
stress
causes
PL.
(ESHRE,
2017)
❑Age:
▪Risk
of
PL
▪lowest
between
20
to
35
ys
▪rapidly
increases
after
the
age
of
40
(ESHRE,
2017)
ABOUBAKR
ELNASHAR
CAUSES
1.
Possible
2.
Doubtful
unexplained
ABOUBAKR
ELNASHAR

4. ❑
Possible:
strong
correlation
between
the
cause
and
miscarriage
I.
Anatomic:10%
1.
Congenital
uterine
malformation.
▪
Prevalence
higher
in
2
nd
trimester
losses
▪
Septum
associated
with
poorest
outcome
▪
6-28%
fetal
survival
▪
>60%
miscarriage
rate
▪
Risk
related
to
septum
length
2.
Submucous
fibroid
3.
Cervical
incompetence
4.
Severe
IU
synechiae
ABOUBAKR
ELNASHAR
II.
Endocrine:
5%
1.Uncontrolled
DM
2.Hypothyroidism
III.
Infection:
1.
Brucellosis
2.
Bacterial
vaginosis
ABOUBAKR
ELNASHAR

5. IV.
Atiphospholipid
antibody
syndrome
V.
Paternal
causes
▪DNA
fragmentation
(Vissenberg
R,
Goddijn,
2011)
VI.
Genetic:
25%
1.
Parental
chromosomal
abnormalities
▪2–5%
of
couples
with
RM
2.
Embryonic
chromosomal
abnormalities
▪30–57%
of
further
ABOUBAKR
ELNASHAR
❑Brucellosis
&
pregnancy
outcome:
▪Higher
rate
of
▪
Abortion
▪
PTL
▪
IUFD
▪Causes
of
spontaneous
abortion
and
IUFD
▪Maternal
bacteremia
▪Toxemia
▪Acute
febrile
reaction
▪DIC
▪Diagnosis:
IgM:
1
:
160
-
non
endemic
area
1
:
320
-
endemic
area
ABOUBAKR
ELNASHAR

6. ❑
Bacterial
vaginosis
▪
Risk
factor
for
PTL
and
2
nd
TM
[Leitich
et
al,
2007]
▪
Vaginal
swabs
as
screening
tests
during
pregnancy
in
high
risk
women
with
previous
history
of
2
nd
TM.
[Trojniel
et
al,
2009]
ABOUBAKR
ELNASHAR
❑Increased
SDF
▪MA:
significant
increase
in
RM
(Robinson
et
al,
2012)
▪85%
of
u
RM
(Maynou
et
al,
2012)
▪DFI
•≥30:
male
infertility
•15-30:
RM.
•≤15:
Excellent
to
Good
fertility
potential
Assessing
sperm
DNA
fragmentation
can
be
considered
(ESHRE,
2017)
▪
An
association
between
sperm
DFI
and
RPL
(Yifu
et
al,
SR,
2020)
ABOUBAKR
ELNASHAR

7. 2.
Doubtful
causes:
weak
correlation
between
the
cause
and
miscarriage
I.
Local:
1.
Oocyte:
▪Premature
ovarian
aging:
reduced
oocyte
quality
and
quantity.
2.
Embryo
▪
Aneuploidy
ABOUBAKR
ELNASHAR
II.
Systemic
Factors
1.
Anatomic:
▪Not
a
cause
▪Arcuate
uterus
▪RVF
▪Mild
IU
adhesions
▪Subserous
fibroid
ABOUBAKR
ELNASHAR

8. ❑
Hydrosalpinx
(Harb
et
al,
2019,
SR)
▪
14
observational
studies
▪
74%
relative
increase
in
the
risk
of
pregnancy
loss
▪
Treatment:
reduction
in
pregnancy
loss
of
approximately
half
when
compared
with
no
treatment
ABOUBAKR
ELNASHAR
2.
Endocrine:
1.
PCOS
2.
Endometriosis.
3.
Inadequate
luteal
phase
4.
Hyperprolactinemia
5.
Vit
D
defficiency
6.
Obesity
or
significantly
underweight:
negative
impact
on
chances
of
a
live
birth
(ESHRE,
2017)
ABOUBAKR
ELNASHAR

9. ❑
Vit
D
deficiency
▪
High
prevalence
of
VD
insufficiency
or
deficiency
in
RPL
▪
{immunological
dysregulation}
▪
Vit
D
supplementation:
Immunological
benefits
in
the
peripheral
blood
(Gonçalves
et
al,
2018)
ABOUBAKR
ELNASHAR
3.
Inherited
Thrombophilic
Defects
1.
Factor
V
Leiden
mutation
2.
Prothrombin
gene
mutation,
3.
Protein
s
deficiency
(RCOG,
2011)
▪
Hyperhomocysteinemia
▪
Protein
C
deficiency
▪
Antithrombin
III
deficiency
ABOUBAKR
ELNASHAR

10. ▪
Inherited
Thrombophilias
are
Associated
with
Increased
Risk
of
Pregnancy
Loss
Thrombophilia
Odds
Ratio
95%
CI
Factor
V
Leiden
(early
loss)
2.01
1.13-3.58
Factor
V
Leiden
(late
loss)
7.83
2.83-21.67
Prothrombin
G20210A
2.56
1.04-29
APC
Resistance
3.48
1.58-7.69
Protein
S
14.72
0.99-218
Rey
et.
al.
Lancet
2003:361:901
.
ABOUBAKR
ELNASHAR
4.
Infections:
▪
Chronic
endometritis
▪
TORCH
test
not
recommended
(Evidence
level
II).
▪
Not
a
cause
Toxoplasmosis,
Mycoplasma
L.
monocytogenes,
C.
trachomatis
HSV,
CMV
ABOUBAKR
ELNASHAR

11. ❑Chronic
endometritis
(CE)
▪
Diagnosis:
▪
Histopatholgy:
plasma
cell
▪
Office
hysteroscopy
:
▪
Oedema
▪
Micropolyposis
▪
Hyperaemia
▪
Culture
▪High
prevalence
in
RM
(Bouet
et
al,
2016)
❑Further
research
is
needed
before
screening
for
endometritis
can
be
recommended
(ESHRE,
2017)
ABOUBAKR
ELNASHAR
5.
Immunologic
❑Autoimmune
antibodies
Immune
reaction
against
self
Antithyroid
antibodies
❑
Alloimmune
factors
immune
reaction
against
another
ABOUBAKR
ELNASHAR

12. Antibody
Possible
Pathogenic
Mechanisms
Linking
Autoantibodies
to
RPL
APL
antibodies
-Prothrombotic
-Reduced
trophoblast
differentiation
&
invasiveness
-Trophoblast
injury
&
apoptosis
-Activation
of
proinflammatory
mediators
-Stromal
inflammation
Anti
thyroid
antibodies
-Thyroid
hormone
dependent:
local
deficiency
in
thyroid
hormones,
abnormal
embryo
development
-Thyroid
hormone
independent:
Innate&
humoral
immunity
dysfunction
-Extra
thyroid
site
cross-reactivity:
changes
in
endometrial
T,
B
and
NK
cells;
altered
oocyte
quality
(antibody
expression
in
ZP)
Anti
Nuclear
antibodies
-Reduced
oocyte
quality
-Intra
placental
complement
activation
-Immune
complex
deposition
in
placental
tissue
Anti
Transglutaminase
antibodies
-Nutrient
deficiency
due
to
mucosal
damage-
zinc,
selenium,
folic
acid
-
Direct
functional
damage
to
endometrial
endothelial
&
trophoblastic
cells-
defective
placentation
D'Ippolito
S
et
al.
The
pathogenic
role
of
autoantibodies
in
recurrent
pregnancy
loss.
Am
J
Reprod
Immunol.
2019
Oct
21:e13200.
6.
Environmental&
occupational,
habits
(few
small
studies)
exposure
to
1.
Heavy
metals
2.
Solvents
&
industrial
chemicals
3.
Pesticide
:
increased
risk
of
PL
(ESHRE,
2017)
4.
Herbicide
spraying.
5.
Electromagnetic
field
6.
Radiation
7.
Anesthetic
gases
ABOUBAKR
ELNASHAR

13. ▪
Habits:
1.
Smoking
negative
impact
on
chances
of
a
live
birth
2.
Caffeine
intake
▪late
PL.
(Some
studies)
3.
Alcohol
consumption
▪risk
factor
for
▪PL
▪fetal
problems
(Fetal
alcohol
syndrome).
ABOUBAKR
ELNASHAR
EVALUATION
ABOUBAKR
ELNASHAR

14. HISTORY
❑
Obstetric
▪Gestational
age
▪
Chromosomal
and
endocrine
defects:
1
st
TM
▪
Anatomic
or
immunological:
2
nd
TM
▪
There
is
significant
overlap.
▪Embryonic/fetal
cardiac
activity
▪
Chromosomal
abnormality:
RM
prior
to
detection
of
embryonic
cardiac
activity
ABOUBAKR
ELNASHAR
❑Surgical:
uterine
instrumentation
(intrauterine
adhesions)
❑Menstrual:
▪
Irregular
menstrual
cycles
(endocrine
dysfunction).
▪
Galactorrhea
(hyperprolactinemia)
❑Family:
❑Eenvironmental
(toxins)
❑Venous
or
arterial
thrombosis
(APA
synd)
❑Previous
investigations
Laboratory
Pathology
imaging
ABOUBAKR
ELNASHAR

15. Physical
examination
❑Signs
of
endocrinopathy
▪
Hirsutism
▪
Galactorrhea
❑Pelvic
organ
abnormalities
▪
uterine
malformation
▪
cervical
laceration.
ABOUBAKR
ELNASHAR
INVESTIGATIONS
1.
Anatomical
factors
▪The
preferred
technique
(ESHRE,
2017)
▪
TV
3D
US
{1.
high
sensitivity
and
specificity
2.
distinguish
between
uterus
septum
and
bicornuate
uterus}.
▪Sonohysterography
(SHG)
▪more
accurate
than
HSG
in
diagnosing
uterine
malformations
ABOUBAKR
ELNASHAR

16. 2.
Endocrine
▪TSH
▪TSH
&
TPO-antibodies
is
recommended
▪Abnormal
TSH
and
TPO-antibody
levels
should
be
followed
up
by
T4
testing
(ESHRE,
2017)
3.
Infection
▪IgM
for
Brucellosis
ABOUBAKR
ELNASHAR
4.
Antiphospholipid
antibodies
❑Diagnosis:
2
positive
tests
at
least
12
w
apart
for
either
▪
LA
or
▪
ACL
or
▪
Anti-B2
glycoprotein-I
antibodies
of
IgG
and/or
IgM
medium
or
high
titre
over
40
g/l
or
ml/l,
or
above
the
99th
percentile.
ABOUBAKR
ELNASHAR

17. ▪
In
2013,
in
Rio
de
Janeiro,
Brazil,
a
new
consensus
14th
International
Congress
on
Antiphospholipid
Antibodies
Task
Force
report
on
OAPS,
2014)
❑2
different
entities
▪Thrombotic
APS
▪Obstetric
APS
▪with
clinical
criteria:
▪laboratory
criteria.
ABOUBAKR
ELNASHAR
Non-criteria
O
APS
(International
Congress
on
OAPS,
2014)
ABOUBAKR
ELNASHAR

18. 5.
Assessment
of
SDF
Test
Principle
Method
TUNEL
ISNT
Incorporation
of
probes
at
the
site
of
damage
Direct
SCSA
SCD
Comet
Susceptibility
of
DBs
to
denature
in
acid
solution
Indirect
Aniline
blue
Toluidine
blue
Incorporation
of
probes
to
nuclear
proteins
Chromatin
incorporation
ISNT:
In
Situ
Nick
Translation
ABOUBAKR
ELNASHAR
ABOUBAKR
ELNASHAR
❑
Sperm
DNA
Fragmentation
(SDF)
▪
Many
methods
Sperm
chromatin
dispersion
test=
Halo
sperm
▪
depend
on
differential
response
of
fragmented
&
non
fragmented
spermatozoa
nuclei
to
an
acid&
desproteinization:
▪
Non
fragmented
spermatozoa:
peripheralm
halo
▪
Fragmented
spermatozoa:
Non
peripheral
halo

19. sperm
chromatin
dispersion
test.
Sperm
1
to
3:
Large
halo-
unfragmented
DNA.
Sperm
4
and
5:
Small
halo-
fragmented
DNA
ABOUBAKR
ELNASHAR
6.
Thrombophilias
❑Screening
for
▪factor
V
Leiden,
▪factor
II
(prothrombin)
gene
mutation
▪protein
S
deficiency
(RCOG,
2011)
▪Not
recommended
(ESHRE,
2017)
ABOUBAKR
ELNASHAR

20. 7.
Karyotyping
❑Cytogenetic
analysis
of
products
of
conception
of
3
rd
and
subsequent
consecutive
miscarriage(s).
not
routinely
recommended
but
it
could
be
performed
for
explanatory
purposes.
C
(ESHRE,
2017)
.
ABOUBAKR
ELNASHAR
❑Parental
peripheral
blood
karyotyping
of
both
partners
where
testing
of
products
of
conception
reports
an
unbalanced
structural
chromosomal
abnormality.
▪not
routinely
recommended.
▪could
be
carried
out
after
individual
assessment
of
risk.
S
(ESHRE,
2017)
.
ABOUBAKR
ELNASHAR

21. TREATMENT
ABOUBAKR
ELNASHAR
I.
Treatment
of
possible
causes
1.
Anatomical
factors
1.
Congenital
uterine
malformations
uterine
septum:
hysteroscopic
resection
septum
resection
does
not
increase
LBR
nor
does
it
decrease
the
rates
of
pregnancy
loss
or
PTB,
compared
with
expectant
management
(Rikken
et
al,
2020)
2.
Submucosal
fibroid:
Hysteroscopic
myomectomy
3.
Severe
IU
adhesions:
Hysteroscopic
surgery
ABOUBAKR
ELNASHAR

22. 4.
Cervical
incompetence
▪Cervical
cerclage:
▪Indication:
1.
one
or
more
2
nd
TM
or
PTL
before
24
w.
TVS:
cervix
is
25
mm
or
less
2.
Three
or
more
previous
PTL
and/or
2
nd
TM.
ABOUBAKR
ELNASHAR
2.
Treatment
of
hypothyroidism:
❑Eltroxin
▪Objective:
TSH:
2.5
mIU/L
▪Dose
▪
Non
pregnant:
▪
1.7
μg/kg/d
or
▪
25
μg/d
adjusted
by
25
μg/d
every
2
to
4
ws
until
euthyroid
state
is
achieved.
▪
Pregnant:
▪
Increase
30%
ABOUBAKR
ELNASHAR

23. Given
its
potential
to
reduce
the
miscarriage
rate,
LT4
supplementation
is
recommended
for
infertile
women
with
SCH
and/or
TAI
who
are
undergoing
IVF/ICSI
(Rao
et
al,SR,
2018)
ABOUBAKR
ELNASHAR
▪Thyroid
autoimmunity
▪TSH
level
should
be
checked
in
early
gestation
(7-9w)
▪Eventual
hypothyroidism
should
be
treated
with
levothyroxine.
GPP
(ESHRE,
2017)
▪Euthyroid
women
with
thyroid
antibodies
insufficient
evidence
to
support
treatment
with
levothyroxine.
C
(ESHRE,
2017)
ABOUBAKR
ELNASHAR

24. 3.
Treatment
of
Infection
❑Brucellosis
•
Rifampin:
900
mg
once
daily
for
6
w
•
Rifampin:
900
mg
once
daily
plus
trimethoprim-Sulphmethoxazole
(TMP-SMX;
5
mg/kg
of
the
trimethoprim
component
twice
daily)
for
4
w
ABOUBAKR
ELNASHAR
❑Asymptomatic
abnormal
vaginal
flora
and
bacterial
vaginosis
▪Oral
clindamycin
•early
in
2
nd
T:
•300mg
PO
BID
x
7
days
▪
Significantly
reduces
▪
late
miscarriage
and
▪
spontaneous
PTL
(Evidence
II).
ABOUBAKR
ELNASHAR

25. 4.
Antiphospholipid
syndrome
▪Low-dose
aspirin
plus
heparin
▪reduces
the
miscarriage
rate
by
54%
▪No
difference
in
efficacy
and
safety
between
unfractionated
heparin
and
LMWH
when
combined
with
aspirin
▪Low
dose
Asprin
no
adverse
fetal
outcomes
ABOUBAKR
ELNASHAR
ABOUBAKR
ELNASHAR

26. 5
Increased
SDF
1.
Oral
antioxidant
have
not
been
shown
to
improve
the
chance
of
a
live
birth
(ESHRE,
2017)
2.
Life
style
modifications:
stop
smoking
and
wt
loss
3.
Identify
and
tt
underlying
condition:
GTI
and
varicocele
4.
Consider
TESA-ICSI
ABOUBAKR
ELNASHAR
6.
Genetic
factors
Abnormal
parental
karyotype:
I.
Referral
to
a
clinical
geneticist.
1.
Prognosis
for
the
risk
of
future
pregnancies
with
an
unbalanced
chromosome
complement
2.
Familial
chromosome
studies.
3.
Proceeding
to
a
further
natural
pregnancy
with
or
without
a
prenatal
diagnosis
test
ABOUBAKR
ELNASHAR

27. II.
PGD/IVF
a.
For
translocation
carriers.
▪
be
aware
of
▪
financial
cost
▪
implantation
and
LBR
following
IVF
▪
higher
(60%)
chance
of
a
healthy
live
birth
in
future
untreated
pregnancies
following
natural
conception
than
achieved
after
PGD/IVF
(30%).
B.
For
unexplained
RM:
does
not
improve
LBR.
ABOUBAKR
ELNASHAR
II.
Treatment
of
doubtful
causes
1.
PCOS
▪Metformin:
debatable.
▪MA:
preconception
Met
did
not
reduce
RM
▪Small
retrospective:
reductions
in
RM.
(Glueck
etal,
2001;
Jakubowicz
et
al,
2001)
▪Insufficient
evidence
to
recommend
metformin
ABOUBAKR
ELNASHAR

28. 2.
Euthyroid
women
with
high
serum
thyroid
peroxidase
antibody
RCT
:
[Negr
et
al,
2006].
levothyroxine
(50
mcg
daily):
decreased
▪
Miscarriage
rate
(13.8
to
3.5%)
▪
PTL
(22.4
to
7%).
ABOUBAKR
ELNASHAR
3.
Hyperprolactinemia
▪RCT
[Hirahara
et
al,
1998].
Bromocriptine
significantly
higher
rate
of
successful
pregnancy
(86
Vs
52%)
▪
Bromocriptine
is
recommended
to
increase
LBR
(ESHRE,
2017)
ABOUBAKR
ELNASHAR

29. 4.
Vit
D
insuffiecncy:
▪Preconception
counseling
▪
include
the
general
advice
to
consider
prophylactic
vit
D
supplementation
ABOUBAKR
ELNASHAR
5.
Chronic
endometritis
❑Regimen:
▪Ofloxacin:
400
mg
daily
for
2w
▪Doxycycline:
100
mg
twice
daily
for
2
w
❑Persistent
CE:
Ciprofloxacin:
500mg
and
Metronidazole:
500
mg
twice
daily
for
2
w.
ABOUBAKR
ELNASHAR

30. 6.
Inherited
thrombophilias
Heparin
▪
R
1
st
TM
insufficient
evidence
▪
R
2
nd
TM
improve
the
LBR
(RCOG,
2011)
▪Not
to
use
antithrombotic
prophylaxis
unless
in
the
context
of
research.
C
(ESHRE,
2017)
ABOUBAKR
ELNASHAR
7.
Hyper
Hcyt
▪In
the
absence
of
consistent
evidence
for
an
association
between
HHcy
and
RPL
▪Assessing
Hcy
levels
is
not
routinely
recommended.
▪However,
if
HHcy
is
detected
▪
treatments
are
available
that
can
lower
Hcy
levels
and
possibly
improve
the
chance
of
LBR
ABOUBAKR
ELNASHAR

31. 1.
Lifestyle
2.
TLC
3.
Progesterone
III.
Treatment
of
unexplained
RM
▪
No
evidence-based
tt.
▪
Low
risk,
simple,
and
cheap
4.
Ineffective
1.
Aspirn
2.
Heparin
3.
Combined
therapy
4.
HCG
5.
HMG
6.
Immunptherapy
7.
Endometrial
scratch
8.
PGD
&
ICSI
ABOUBAKR
ELNASHAR
1.
Lifestyle
modification
▪
Stop
smoking
▪
Minimize
caffeine:
Less
than
200mg/d
▪
Minimize
alcohol:
<3
drinks
per
week
▪
Reduction
BMI
(for
obese
women).
▪
No
RCT.
ABOUBAKR
ELNASHAR

32. 2.
Psychological
supportive
care/TLC.
▪
Early
&
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%
▪Multiple,
non-randomized
studies
show
benefit
of
TLC
on
pregnancy
outcome
(Stray-Pedersen
et
al,
1984;
Liddell
et
al,
1991;
Clifford
et
al,
1997)
ABOUBAKR
ELNASHAR
3.
Progestogen
❑Cochrane
Database
S
R.
2013
▪4
trials,
225
women
El-Zibdeh
2005
Goldzieher
1964
Le
Vine
1964
Swyer
1953
180
54
56
113
▪10
mg
bid
oral
Dydrogesterone,
5000
IU
IM
hCG/4d
▪Duration:
12
th
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

33. ❑
≥3
consecutive
miscarriages
of
unknown
cause.
(Roepkke
et
al,
SR
&MA,
2018)
❑
21
RCT
regarding
❑
No
significant
difference
in
LBR
▪
acetylsalicylic
acid
▪
LMWH
▪
IV
Img
▪
leukocyte
immune
therapy
❑
Treatment
with
progesterone
▪
starting
in
luteal
phase
effective
in
increasing
LBR
▪
RR
1.18
(95%
CI1.09-1.27)
but
not
when
started
after
conception.
ABOUBAKR
ELNASHAR
▪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

34. ❑Coomarasamy
et
al,
2015:
NEMJ
PROMISE
STUDY:
836
patients
▪Multicenter,
double-blind,
placebo,
RCT
▪Vaginal
suppositories:
400
mg
micronized
progesterone
in
1
st
T
did
not
result
in
a
significantly
higher
LBR
among
women
with
a
history
of
unex
RM.
ABOUBAKR
ELNASHAR
ABOUBAKR
ELNASHAR

35. 4.
Ineffective
1.
Aspirin
▪No
improvement
▪
LDA
have
a
beneficial
effect
on
PTL
in
low
resource
country
(Lancet,
2020)
ABOUBAKR
ELNASHAR
2.
Heparin
▪Insufficient
evidence
(Mantha
et
al,
2009,
MA)
▪No
support
of
the
use
of
anticoagulants
in
women
with
unRM
(Cochrane
Database
Syst
2014)
▪
Daily
LMWH
injections
do
not
increase
ongoing
pregnancy
or
LBR
in
women
with
unexplained
RPL.
▪
Given
the
burden
of
the
injections,
they
are
not
recommended
for
preventing
miscarriage
(Schleussner
et
al,
2015.)
ABOUBAKR
ELNASHAR

36. 3.
Combination
therapy
▪observational
study
before
&during
pregnancy
with
▪
Prednisone:
20
mg/
▪
Dydrogesterone:
20
mg/d
▪
Aspirin:
100
mg/d
▪
Folate:
5
mg/second
day
[Tempfer
et
al,
2006].
▪In
treated
group:
1
st
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.
ABOUBAKR
ELNASHAR
4.
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)
insufficient
evidence
to
recommend
the
use
of
hCG
(ESHRE,
2017
ABOUBAKR
ELNASHAR

37. 5.
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
6.
Immunotherapy
▪
Paternal
cell
immunisation
▪
third-party
donor
leucocytes
▪
trophoblast
membranes
▪
IVIG
in
women
with
previous
uRM
does
not
improve
LBR
(RCOG,
2011)
▪Immunotherapy
should
not
be
advised
[Porter
etalm
2006]
▪
IVIG:
confirmed
this
conclusion
▪
Expensive
▪
Serious
adverse
effects:
transfusion
reaction,
anaphylactic
shock
and
hepatitis.
(Stephenson
et
al,
2010MA)
ABOUBAKR
ELNASHAR

38. ❑
Intralipid
Therapy
▪should
not
be
used
for
improving
LBR
{it
could
be
harmful
for
the
mother}
(ESHRE,
2017)
ABOUBAKR
ELNASHAR
7.
Endometrial
scratching
no
evidence
to
recommended
(ESHRE,
2017)
When:
✓cycle
preceding
the
actual
treatment
cycle(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).
✓Not
on
the
day
of
OR:
significantly
reduce
CPR
(Nastri
et
al,
2012)
ABOUBAKR
ELNASHAR

39. 8.
ICSI
&
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
ASSESSING
PROGNOSIS
OF
A
COUPLE
WITH
RPL
I.
FACTORS
AFFECTING
PROGNOSIS
1.
Reproductive
history
▪
The
number
of
prior
pregnancy
losses
▪
important
factor
for
chance
of
live
birth
▪
2
nd
unexplained
RPL
▪
only
consecutive
pregnancy
losses
after
the
birth
influenced
the
subsequent
prognosis
▪
while
the
number
of
losses
prior
to
the
birth
did
not
affect
the
prognosis
in
the
next
pregnancy
ABOUBAKR
ELNASHAR

40. 2.
Family
history
▪
sporadic
or
recurrent
(≥2)
pregnancy
loss
is
more
common
among
RPL
patients’
first-degree
relatives
than
controls,
approximately
a
doubled
incidence
or
per
pregnancy
loss
rate
3.
Female
age.
ABOUBAKR
ELNASHAR
II.
PROGNOSTIC
TOOLS
•
Lund
&
Brigham
▪
RPL
couples
have
a
good
prognosis
for
a
next
live
birth,
especially
if
▪
Female
age
▪
Number
of
previous
miscarriages
are
low.
ABOUBAKR
ELNASHAR

41. Number
of
Prior
Pregnancy
Losses
Age
(years)
2
3
4
5
20
92
90
88
85
25
89
86
82
79
30
84
80
76
74
35
77
73
68
62
40
69
64
58
62
45
60
54
48
42
▪
Predicted
success
(%)
in
future
pregnancy
for
patients
with
prior
pregnancy
loss
Prospective
study
of
325
women
with
prior
idiopathic
pregnancy
loss;
pregnancy
outcomes
in
225/326
(70%)
in
subsequent
pregnancy
followed.
Brigham
SA
et
al,
Hum
Reprod
1999;
11:
2868-2871.
ABOUBAKR
ELNASHAR
▪
Prognosis
▪
Spontaneous
LBR
after
4
th
loss
is
relatively
high
(60%)
▪
Secondary
RPL
better
prognosis
▪
If
normal
RPL
workup
→
77%
LBR
▪
If
abnormal
RPL
workup
→
71%
LBR
(Laufer
et
al
1994)
▪
Risk
of
miscarriage
highest
until
gestational
age
of
previous
miscarriage.
▪
Loss
risk
after
documentation
of
fetal
cardiac
activity
only
3%
(Brigham
et
al,
1999)
▪
83%
chance
of
healthy
child
in
couples
with
balanced
translocation
(Franssen
et
al.
BMJ
2006)
ABOUBAKR
ELNASHAR

42. ❑Investigations:
After
2
consecutive
miscarriages:
I.
Recommended:
1.
3DUS
or
Sonohysterography)
2.
TSH,
TPO
3.
Brucellosis
IGM
4.
Antiphospholipid
antibodies
II.
Considered:
1.
Factor
V
Leiden,
factor
II
(prothrombin)
gene
mutation
and
protein
S.
(RCOG,
2011)
2.
SDF
testing
ABOUBAKR
ELNASHAR
❑Treatment
of
possible
causes
1.Uterine
septum,
submucous
fibroid,
severe
IU
adhesions:
Hysteroscopic
surgery.
2.
Cervical
incompetence:
cervical
cerclage
3.
Subclinical
hypothyroidism:
Eltroxin
4.
Brucellosis:
Rifamycin
5.
APA:
Low
dose
aspirin
&
heparin.
6.
Inherited
thrombophilias:
Heparin
7.
Karyotyping
abnormalities:
Clinical
geneticist.
ABOUBAKR
ELNASHAR

43. ❑
Treatment
of
doubtful
causes
1.
PCOS
2.
Autoimmune
thyroid
3.
Hyperprolactnaemia
4.
Chronic
endometritis
ABOUBAKR
ELNASHAR
❑
Treatment
of
Unexplained
miscarriage
1.
TLC
2.
Life
style
modification
3.
Progestagen
4.
Ineffective
treatment
1.Combination
treatment
2.Aspirin
3.Heparin
4.HCG,
5.HMG
6.Intralipid,
7.Endometrial
scraching
8.PGS
ABOUBAKR
ELNASHAR

44. You
can
get
this
lecture
from:
1.
My
scientific
page
on
Face
book:
Aboubakr
Elnashar
Lectures.
https://www.facebook.com/groups/2277448840913
51/
2.
Slide
share
web
site
3.
elnashar53@hotmail.com
4.
My
clinic:
Elthwara
St.
Mansura
ABOUBAKR
ELNASHAR
CONCLUSIONS
ABOUBAKR
ELNASHAR

45. ABOUBAKR
ELNASHAR
ABOUBAKR
ELNASHAR

46. Etiology
of
RPL
Kutteh
et.
Al.
Ob
Gyn.
1999;93:42S
ABOUBAKR
ELNASHAR