Max Brinsmead MB BS PhDMay 2015

A summary of...

RCOG Green-top Guideline number 17 April 2011 “The Investigation and Treatment of

Couples with Recurrent First-trimester and Second-trimester Miscarriage”

RCOG Scientific Advisory Committee Opinion Paper 26 June 2011 “The Use of Antithrombotics in the

Prevention of Recurrent Pregnancy Loss” Plus some empiric recommendations

based on my own personal experience

Definition of Recurrent Miscarriage (RM)

Loss of three or more consecutive pregnancies at <20 (24) weeks gestation Some distinguish between primary and

secondary RM Without or with prior live birth

Incidence: Overall 15% of clinical pregnancies end in

miscarriage 5% of couples will experience two consecutive losses 1 – 2% will experience three consecutive losses But thereafter the chance of successful livebirth is ≈

40%

Factors Associated with Miscarriage

Maternal age (Paternal age) Alcohol abuse Smoking Excessive caffeine consumption Maternal obesity Anaesthetic gases – data incomplete Visual Display Units - no effect

Maternal Age and Risk of Miscarriage

12 – 19 years 20 – 24 years 25 – 29 years 30 – 34 years 35 – 39 years 40 – 45 years >45 years

13% 11% 12% 15% 25% 51% 93%

Possible Causes of Recurrent Miscarriage

Antiphospholipid Syndrome Parental Chromosome Rearrangement Uterine Abnormalities Cervical Incompetence Endocrine abnormalities in the

mother Infective agents Immune factors Inherited Thrombophilias Idiopathic/Unknown

>50%

Antiphospholipid Syndrome

Found in ≈ 15% couples Characterised by the identification of

lupus anticoagulant and/or anticardiolipin antibodies

May or may not be associated with clinical maternal autoimmune disease

Responds to a combination of Aspirin and Heparin But not aspirin alone Either unfractionated heparin or LMW heparin

in non heparinising doses Pregnancies remain at risk of pre eclampsia,

IUGR and pre term delivery

Parental Chromosomal Rearrangements 1-2% of couples will have a balanced

translocation of chromosomes Best identified by screening the

chromosomes of the 3rd spontaneous miscarriage Because of the high cost of chromosome

analysis A medical geneticist can provide a risk

of recurrence Management options include

Use of donor gametes IVF and pre implantation genetic diagnosis

Uterine Abnormalities

Can be found in 1 – 5% of all women And 2 – 35% of couples with recurrent

miscarriage Thus their aetiological roles is

controversial Probably associated with 2nd-trimester loss And some of these are due to associated

cervical incompetence Reconstructive surgery carries risks of

secondary adhesions and uterine rupture in any subsequent pregnancy

But there is a role for the hysteroscopic resection of uterine septa And fibroids that distort the uterine cavity

Cervical Incompetence

Associated with recurrent , painless second-trimester losses

The diagnosis is easy with a classical history

But there may be a spectrum of disorder And there is no gold standard for non-

pregnant diagnosis Consensus is to insert a cervical suture

if there is a suggestive history and the cervix is <25 mm in length before 24 weeks

But some patients will miscarry despite surveillance

Infective Agents

Untreated Syphilis and HIV no question

But Toxoplasmosis, Herpes, CMV and Listeria fail Koch’s postulates

There is an association between recurrent pregnancy loss/pre term labour and bacterial vaginosis (BV)

And a RCT of treatment BV with oral Clindamycin suggests benefit

So screening for BV is worthwhile

Endocrine Causes

Meticulous control of blood sugars reduces the risk of miscarriage & congenital malformations in known diabetics

But any role for Metformin in patients with suspected insulin resistance e.g. PCO, obesity or gestational diabetes is unproven

There is a weak association with thyroid disorder but screen & treat only hypo or hyperthyroidism

Any role for Progesterone Support or HCG therapy remains unproven

Immune Factors

The role of HLA-compatibility (or incompatibility) between partners remains unproven So immunomodulation with paternal/donor

leukocyte/trophoblast immunisation is not indicated

There may be role played by uterine Natural Killer (uNK) cells

There may also be a relative deficiency of anti inflammatory cytokines (Interleukin 4, 6 and 10) But empiric therapies with corticosteroids have

proved disappointing

Inherited Thrombophilias

Abnormality ↑RR of Miscarriage Stillbirth

Factor V Leiden Activated Protein C

resist. Protein S deficiency Protein C deficiency Antithrombin III

deficiency Homocysteinuria Prothrombin gene

mutations

2-fold 8-fold

3.5-fold 14-fold

7-fold Not ↑ Not ↑ ? ? 2.3-fold 2.3-fold

Recommended Investigations for RM HIV and Syphilis serology

Lupus anticoagulant (Russell Viper inhibition) and anticardiolipin antibodies (EIA) ± ANA

Karyotyping miscarriage tissue number 3 Ultrasound of the uterus (or HSG)

Follow up with hysteroscopy ± Laparoscopy 3-D ultrasound or MRI

Thrombophilia screen Factor V Leiden Protein S deficiency Prothrombin gene mutation only (others if there is a history of

thromboembolism)

Management of Unexplained RM

There is no place for empiric low-dose aspirin May actually ↑risk of miscarriage

RCT’s of antithrombotic therapy show no benefit And make no sense because there is no

intervillous blood flow before 10 – 12 w Non RCT’s of “close supportive care”

have a 75% live birth rate This can be done with early monitoring

of S. Progesterone and vaginal Progesterone support for <30 nmol/L

Plus early ultrasound for encouragement

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