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Max Brinsmead MB BS PhDMay 2015
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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
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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%
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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
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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%
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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%
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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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