Controversies in

management of

Recurrent

miscarriage

Aboubakr Elnashar Benha university Hospital

ABOUBAKR ELNASHAR

CONTENT CONTROVERSIES

1.DEFINITION

2.MANAGEMENT OF POSSIBLE CAUSES

3.MANAGEMENT OF DOUTFUL CAUSES

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1. DEFINE

3 Consecutive miscarriages (ESHRE, 2006; RCOG, 2011)

2 Consecutive miscarriages (ASRM, 2012)

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2. MANAGEMENT OF 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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ASRM

(2012)

RCOG

(2011)

ESHRE

(2006)

HSG

3DUS

MRI

2DUS

3DUS,

Hysteroscopy,

Laparoscopy

SIS and/or

HSG

Hysteroscopy

Laparoscopy

1.

Anatomical

TSH, PRL

No: T3, TPOAb

No TFT, HA1C 2.

Endocrine

LA, aCL (G&M),

aβGI

LAC and

aGL(G&/orM)

LAC and aCL 3.

APS

No 2nd TRM:

factor V, factor II gene

mutation

Protein S. def

RCT req 4.

Thrombophil

ia

karyotype of

abortus

Parental

karyotype

If above normal:

karyotype of

abortus:abnormal:

Parental karyotype

Parental

karyotype after 2

miscarriages

5.

Genetic

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ASRM(2012) RCOG(2011) ESHRE(2006)

RCT req RCT req

Cx cerclage if ……

Uterine septum, s m

fibroid, severe IU

adhesions

Cx incomptence

Eltroxin;TSH:2.5

Dopamin ag

P: some benefit

RCT required

GnRha: No

Met: RCT req

RCT req

Hypothyroidism

Hyperprolactinaemia

LPD

PCOS

low-dose aspirin

plus heparin

low-dose aspirin plus

heparin

RCT req APS

No Heparin:

1st TRM:RCT req

2nd TRM: yes

RCT req

RCT req

Thrombophilias

Hyperhomocysteinaemia

No No RCT req Alloimmune

IVF/PGD: No IVF/PGD: No Genetic

TCL: yes TLC: yes

IVF/PGS, Aspirin,

Heparin: No

HCG: RCT req

TLC

health

advices

Unexplained

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3. MANAGEMENT DOUBTFUL CAUSES

I. ANATOMIC

RVF, Mild IU adhesions, Subserous fibroid: Not related to RM (ASRM,2012)

Arcuate Uterus

1.0% to 16%. [SugiuraOgasawara et al, 211] Chan et al, 2011 MA

: 2nd TRM, PTL, F malpresentation

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Jayaprakasan et al, 2011:

Women who are referred for ART

Arcuate uterus (11.8%) not associated with a

reduction in PR or increase in miscarriage

Further evidence is needed to recommend

hysteroscopic surgery in arcuate uterus [SugiuraOgasawara et al, 2011] (Evidence level II).

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II. ENDOCRINE

Thyroid peroxidase (TPO) antibodies

Controversial [Chen et al, 2011; Thangaratinam et al, 2012].

not linked to RM (Yan et al, 2012}

Linked to RM. [Abbassi , 2011, Twig et al, 2012]

Euthyroid women with high TPO antibody [Negr et al, 2006, RCT].

Eltroxin (50 mcg daily):

decreased

miscarriage rate (13.8 to 3.5%)

PTL (22,4 to 7%).

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TPO antibody screening is not recommended (Evidence level II).

Until strong evidence is available, thyroxine tt is

not recommended in raised thyroid antibody with

normal thyroid function tests (Evidence level III).

Aim: TSH < 2.5 mU/L.

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PCOS

linked to an increased risk of RM

Mechanism: unclear

Not a cause

1. Elevated LH (>10 IU/l): suppression of

endogenous LH release before conception: did

not improve LBR.

2. Elevated serum T (>3 nmol/l) {Rai, 2000]

Hyperandrogenaemia: elevated FAI: RM. 3. Ovulatory PCOS: do not increase risk

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May be:

Insulin resistance: hyperinsulinaemia

independent factor of RM {Chakraborty et al, 2013].

one of the direct causes: RM. [Li et al, 2012; Hong et al, 2013]

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GnRHa

Suppress LH secretion prior to ovulation induction:

no difference in outcome

Metformin

To reduce RM: debatable.

MA: preconception metformin did not reduce RM

Small retrospective study: reductions in RM. (Glueck etal, 2001; Jakubowicz et al, 2001)

Metformin is not recommended as a tt of RM (Evidence level III).

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HYPERPROLACTINEMIA

In early pregnancy were significantly greater in

women who miscarried . [Hirahara et al, 1998].

: RM {alterations in the hypothalamic pituitary ovarian axis: impaired folliculogenesis and oocyte maturation, and/or a short luteal phase}.

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Serum prolactin (ASRM, 2012)

Normalization of prolactin levels with a

dopamine agonist : decrease in RM. [Hirahara et al, 1998, RCT].

Treatment of hyperprolactinemia associated with

RM is recommend (ASRM, 2012, Up to date, 2013)

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LUTEAL PHASE DEFECT

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).

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Progestagen supplementation

Cochrane Database Syst Rev. 2013 4 trials, 225 women

: statistically significant decrease in miscarriage rate

compared to placebo or no tt (Peto OR 0.39; 95% CI 0.21 to 0.72).

However, these 4 trials were of poor methodological

quality.

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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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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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VI. PATERNAL CAUSES

Significant increase of RM in patients with high

DNA damage compared with those with low DNA

damage (Robinson et al, 2012, MA)

Significant association between SDF and

pregnancy loss after IVF or ICSI (Zini, 2008, MA)

85% of u RM (Maynou et al, 2012)

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Several tests are available

but no consensus:

most predictive test?

Cut off level?

DFI ≥30: male infertility

15-30: RM

≤15: fair

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Insufficient evidence (Level C) to recommend

routine SDF testing to predict pregnancy loss. (ASRM, 2013)

For diagnostic test 1. Results must be reproducible 2. Applicable to a given patient 3. Change management of patient

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Thank you ABOUBAKR ELNASHAR