Threatened and unexplained repeated miscarriages
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Transcript of Threatened and unexplained repeated miscarriages
Aboubakr Elnashar
Threatened and
unexplained repeated miscarriages
Prof. Aboubakr Elnashar Banha university, Egypt
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
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
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Management
No effective interventions
NICE, 2015
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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)
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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)
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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
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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
.
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.
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Other medications
HCG
Uterine muscle relaxants: tocolytics, betaagonists
Vitamin supplementation
Chinese herbal medicine
high quality data do not support their use
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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
Unexplained
Recurrent miscarriage Prof. Aboubakr Elnashar
Banha university, Egypt
CONTENTS 1. DEFINITION 2. INCIDENCE 3. TYPES 4. CAUSES 5. PROGNOSIS 6. TREATMENT CONCLUSION
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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)
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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)
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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)
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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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
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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
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.
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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.
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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.
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4. CAUSES
1. Oocyte:
Premature ovarian aging: reduced oocyte quality
and quantity.
Oocyte quantity and quality cannot be easily assessed
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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)
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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
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sperm chromatin dispersion test. Sperm 1 to 3: Large halo- unfragmented DNA. Sperm 4 and 5: Small halo- fragmented DNA
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ASRM Guidelines 2012:
Insufficient evidence (Level C) to recommend routine SDF testing to predict pregnancy loss.
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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
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3. The Embryo
ART, and PGS of the embryo for aneuploidy in
women with uRM, may improve the prognosis
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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.
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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.
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I. Anatomic
Arcuate Uterus
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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).
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].
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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)
4. Obesity
increases the risk of both sporadic and RM independent factor: increased risk of miscarriage in
couples with uRM. (Lo et al, 2012).
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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)
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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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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).
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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).
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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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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)
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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
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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%
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2. Lifestyle modification
Stop smooking, 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
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4. 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: 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.
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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.
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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
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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
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
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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)
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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.
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)
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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).
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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)
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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)
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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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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
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(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.
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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).
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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.
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Thank you
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4884091351/
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
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.
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
Thank you
https://www.facebook.com/groups/22774
4884091351/