Recurrent Miscarriage

1. Max Brinsmead PhD FRANZCOG June 2011 Recurrent Miscarriage

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. Paternal 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

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 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?

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 ↑ • 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

17. For copies of this PowerPoint go to www.brinsmead.net.au and follow the links to “Students” Any Questionsor Comments?