Max Brinsmead MB BS PhD May 2015

RECURRENT MISCARRIAGE

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 3 rd 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 2 nd -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

       Factor V Leiden Activated Protein C resist.

Protein S deficiency Protein C deficiency Antithrombin III deficiency Homocysteinuria Prothrombin gene mutations

↑ RR of Miscarriage Stillbirth

       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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