Recurrent

miscarriage
Prof. Aboubakr
Elnashar
Benha university, Egypt

elnashar53@hotmail.com
ABOUBAKR ELNASHAR
 Contents
Introduction
Causes
Evaluation
Treatment
Conclusion

ABOUBAKR ELNASHAR
 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 miscarriage
3 or more consecutive pregnancies
(RCOG, 2011)
2 or more
(ASRM, 2008)

ABOUBAKR ELNASHAR
 CAUSES
1. Possible
2. Doubtful
unexplained

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 Possible: strong correlation between the cause and
miscarriage

I. Anatomic:10%
1. Congenital uterine malformation.
2. Submucous fibroid
3. Cervical incompetence
4. Severe IU synechiae

II. Endocrine: 5%
1.Uncontrolled DM
2.Uncontrolled thyroid disease

ABOUBAKR ELNASHAR
III. Infection:
1. Brucellosis

2. Bacterial vaginosis
IV. Atiphospholipid antibody syndrome
V. Inherited Thrombophilic Defects
1. Factor V Leiden mutation
2. Prothrombin gene mutation,
3. Protein s deficiency
VI. Genetic: 25%
1. Parental chromosomal abnormalities
2–5% of couples with RM
2. Embryonic chromosomal abnormalities
30–57% of further

ABOUBAKR ELNASHAR
Brucellosis and 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
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]

ABOUBAKR ELNASHAR
2. Doubtful causes: weak correlation between the cause and
miscarriage
I. Local:
1. Oocyte:
Premature ovarian aging: reduced oocyte
quality and quantity.
2. Sperm: Paternal causes
DNA fragmentation
(Vissenberg R, Goddijn, 2011)
3. Embryo
 Aneuploidy
4. Endometrium
Normal endometrium can distinguish between
good-quality and poor-quality embryos.
(Teklenburg etal, 2010)
Chronic endometritisABOUBAKR ELNASHAR
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

ABOUBAKR ELNASHAR
II. Systemic Factors
1. Anatomic:
 Arcuate uterus
 Not: RVF, Mild IU adhesions, Subserous
fibroid
2. Endocrine:
1. PCOS
2. Endometriosis.
3. Inadequate luteal phase
4. Hyperprolactinemia
5. Obesity
3. Thrombophilia
1. Hyperhomocysteinemia
2. Protein c def
3. Antithrombin ABOUBAKR
III def ELNASHAR
4. Infections:
 Chronic endometritis
 TORCH test
not recommended
(Evidence level II).
 Not:
Toxoplasmosis, Mycoplasma
L. monocytogenes, C. trachomatis
HSV, CMV

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Chronic endometritis (CE)
Diagnosis:
Histopatholgy: plasma cell
Office hysteroscopy :
Oedema
Micropolyposis
Hyperaemia
Culture

High prevalence in RM.

(McQueen et al, 2015; Bouet et al, 2016)

ABOUBAKR ELNASHAR
5. Immunologic
Autoimmune antibodies
Immune reaction against self
Antithyroid antibodies
 Alloimmune factors
immune reaction against another

ABOUBAKR ELNASHAR
6. Environmental:
1. Alcohol & smoking
2. Herbicide spraying.
3. Electromagnetic field
4. Radiation
7. Inhalation of anesthetic gases
8. Exposure to solvents, heavy metals & industrial chemicals.

ABOUBAKR ELNASHAR
EVALUATION

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 HISTORY
 Obstetric
Gestational age
Chromosomal and endocrine defects: 1st TM
Anatomic or immunological: 2nd 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

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 Physical examination
Signs of endocrinopathy
Hirsutism
Galactorrhea

Pelvic organ abnormalities

uterine malformation
cervical laceration.

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 INVESTIGATIONS
1. Anatomical factors
Pelvic ultrasound and/or HSG or
sonohysterography
initial screening test
Hysteroscopy, laparoscopy or 3DUS
definitive diagnosis.

2. Endocrine
TSH
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.

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 5. Thrombophilias
Screening for
factor V Leiden,
factor II (prothrombin) gene mutation
protein S deficiency

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 6. Karyotyping
Cytogenetic analysis of products of conception
of 3rd and subsequent consecutive
miscarriage(s).

Parental peripheral blood karyotyping

of both partners where testing of products of
conception reports an unbalanced structural
chromosomal abnormality.
.

ABOUBAKR ELNASHAR
TREATMENT

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 I. Treatment of possible causes
1. Anatomical factors
1. Congenital uterine malformations
uterine septum
hysteroscopic resection

2. Submucosal fibroid:
Hysteroscopic myomectomy

3. Severe IU adhesions:
Hysteroscopic surgery

ABOUBAKR ELNASHAR
4. Cervical incompetence
Cervical cerclage:
Indication:
1. one or more 2nd TM or PTL before 24 w.
TVS: cervix is 25 mm or less
2. Three or more previous PTL and/or 2nd TM.

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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%

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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 2nd T:
•300mg PO BID x 7 days

significantly reduces the rate of late miscarriage

and spontaneous preterm birth in a general
obstetric population
(Evidence II).

ABOUBAKR ELNASHAR
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
5. Inherited thrombophilias
Heparin
R 1st TM
insufficient evidence may improve LBR for
these women
R 2nd TM
improve the LBR

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
 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)

ABOUBAKR ELNASHAR
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%)
Treatment of hyperprolactinemia and RM, even in
the absence of overt hypogonadism : recommend
(Up to date, 2013)

ABOUBAKR ELNASHAR
4. 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 weeks.
 III. Treatment of unexplained RM

 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
2. Lifestyle modification

 Stop smoking, alcohol

 Caffeine reduction

 Reduction BMI (for obese women).

 No RCT.

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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
 4. Progestogen
Cochrane Database S R. 2013
4 trials, 225 women

Swyer Le Vine Goldzieher 1964 El-Zibdeh

1953 1964 2005
113 56 54 180
6 x 25 mg 500 mg/w 10 mg/d oral 10 mg bid oral
progesterone
pellets IM Dydrogesterone, Dydrogesterone,
Duration: unclear. 17 oh PC Duration: not 5000 IU IM
Duration: stated. hCG/4d
until 36 w Duration: 12th w

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
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)
Daily LMWH injections do not increase ongoing pregnancy or livebirth
rates in women with unexplained RPL. Given the burden of the
injections, they are not recommended for preventing miscarriage
Schleussner et al, 2015.

ABOUBAKR ELNASHAR
6. Combination therapy
An observational study
before and during pregnancy with
Prednisone: 20 mg/d
Dydrogesterone: 20 mg/d
Aspirin: 100 mg/d
Folate: 5 mg/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.
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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
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
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)
Immunotherapy should not be advised.
[Porter etalm 2006] (Evidence level II)
IVIG:
confirmed this conclusion
Expensive
Serious adverse effects: transfusion
reaction, anaphylactic shock and hepatitis.
(Stephenson et al, 2010MA)

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 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
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
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  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)

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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
CONCLUSIONS

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Investigations
After two or three consecutive miscarriages:
1. Pelvic US (or HSG or Sonohysterography)
2. TSH
3. Brucellosis IGM
4. Antiphospholipid antibodies
5. Factor V Leiden, factor II (prothrombin) gene
mutation and protein S.
6. If the above examinations are normal: karyotype of
the abortus: unbalanced structural chromosomal
abnormality: Parental karyotype
ABOUBAKR ELNASHAR
Treatment of possible causes
1. Uterine septum, submucous fibroid, severe IU
adhesions: Hysteroscopic surgery.
Cervical incompetence: cervical cerclage
2. Subclinical hypothyroidism: Eltroxin
3. Brucellosis: Rifamycin
4. APA: Low dose aspirin & heparin.
5. Inherited thrombophilias: Heparin
6. Karyotyping abnormalities: Clinical geneticist.

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 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. Decrease SDF
4. Progestagen
5. combination
6. Aspirin, Heparin
7. HCG, HMG
8. Intralipid, Endometrial scraching
9. PGS

ABOUBAKR ELNASHAR
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