1. Max Brinsmead MB BS PhD May 2015

2. 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

3. 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%

4. 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

5. 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%

6. 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%

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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 ↑ ????  2.3-fold 2.3-fold

15. 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)

16. 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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