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

ABOUBAKR ELNASHAR

ABOUBAKR ELNASHAR

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)

ABOUBAKR ELNASHAR

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

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

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.

ABOUBAKR ELNASHAR

Other medications

HCG

Uterine muscle relaxants: tocolytics, betaagonists

Vitamin supplementation

Chinese herbal medicine

high quality data do not support their use

ABOUBAKR ELNASHAR

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

Aboubakr Elnashar

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

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

ABOUBAKR ELNASHAR

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.

Aboubakr Elnashar

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

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

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)

Aboubakr Elnashar

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.

Aboubakr Elnashar

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].

Aboubakr Elnashar

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).

Aboubakr Elnashar

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

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

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

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

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

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

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

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

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

Aboubakr Elnashar

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.

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

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

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

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)

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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)

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)

IVIG:

confirmed this conclusion Expensive

Serious adverse effects: transfusion reaction, anaphylactic shock and hepatitis. (Stephenson et al, 2010MA)

Aboubakr Elnashar

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

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

Aboubakr Elnashar

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

Aboubakr Elnashar

(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

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

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

Thank you

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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

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4884091351/