There appears to be an association between PCOS and RPL,4 however the presence of confounding factors within the PCOS population such as obesity, hyperinsulinaemia, LH hypersecretion, hyperandrogenism and thrombophilia, which are also known to impact reproductive outcomes, makes it difficult to establish a direct causal relationship.

Introduction 

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder affecting up to 15% of women of reproductive age.1 The presence of PCOS is associated with several pregnancy complications including gestational diabetes, pre-eclampsia, pregnancy-induced hypertension and pre-term birth.2,3  

There appears to be an association between PCOS and RPL,4 however the presence of confounding factors within the PCOS population such as obesity, hyperinsulinaemia, LH hypersecretion, hyperandrogenism and thrombophilia, which are also known to impact reproductive outcomes, makes it difficult to establish a direct causal relationship.5 In a small cohort study, Sagle et al. demonstrated that PCOS was significantly more prevalent in women with RPL (82% vs. 18%, P<0.001).6  

PCO morphology does not appear to be predictive of live birth rate in women with RPL, however.2,7 In a cohort study, Rai et al. demonstrated a live birth rate of 60.9% (142/233) in women with PCOS compared to 58.5% (148/253) in women without PCOS.7  

Metformin and myoinositol treatment 

Metformin treatment has been shown to improve insulin resistance through the inhibition of glucagon and hepatic gluconeogenesis. Exposure to metformin during the first trimester of pregnancy has not been shown to increase the risk of birth defects.9 However, metformin is associated with gastrointestinal side effects.10 Indirect evidence outside of the field of RPL points to the benefit of metformin in improving live birth rates in women with polycystic ovary syndrome (PCOS). However, the lack of large-scale studies in women with RPL and PCOS leaves the benefit of metformin treatment on live birth rate and miscarriage rates in the RPL population uncertain.11   

In women with PCOS, metformin treatment has been shown to significantly reduce the rate of miscarriage.11,12 A prospective cohort study demonstrated an 8.9% rate of early pregnancy loss in the metformin group compared to 36% in the control group (P<0.001).12 A high quality randomised controlled trial and individual patient data meta-analysis found that metformin commenced in first trimester in women with PCOS may reduce the risk of late miscarriage and pre-term birth.13 

In women with anovulatory PCOS undergoing ovulation induction, metformin has been shown to improve live birth rates (odds ratio [OR] 1.59, 95% CI 1.00 to 2.51; I2 = 0%; 4 studies, 435 women; low‐quality evidence) compared with placebo.10 No significant differences in miscarriage rates were demonstrated, however (OR 1.08, 95% CI 0.50 to 2.35; I2 = 0%; 4 studies, 748 women; low‐quality evidence).10 

The benefit of metformin in women with RPL and PCOS is unknown, however in view of the possible benefits seen in the non-RPL population, women with a diagnosis of PCOS should be offered metformin pre-conception and continued through pregnancy. Further high-quality studies are needed in this area.4  

Myoinositol is a sugar alcohol that has been suggested as a treatment for PCOS. To date, there have been no studies investigating the effectiveness of myoinositol to prevent miscarriage in women with RPL and PCOS, and existing meta-analyses are uncertain of an effect on sporadic miscarriage.14   

 

Bullet point guidance 

Investigations 

  • Women should be advised that both transabdominal and transvaginal ultrasonography will be performed to assess pelvic anatomy.
  • While there appears to be an association between PCOS and RPL, PCO morphology does not seem to be predictive of live birth rate in women with RPL.4
  • Women should be appropriately assessed, using strict Rotterdam criteria, before making a diagnosis of PCOS.
  • The Rotterdam criteria are the following:
  • PCO morphology on transvaginal pelvic ultrasound (ovary measuring ³10 ml and/or ³20 antral follicles [2-9 mm] per ovary)
  • Oligo and/or anovulation
  • Biochemical (raised serum testosterone, DHEA-S or androstenedione) and/or clinical signs of hyperandrogenism (acne, hirsutism, alopecia or acanthosis nigricans).4,8

 

Treatment 

  • Pregnant women in the first trimester, and those trying to conceive, should be advised that a balanced diet is crucial to support embryo/fetal development and maternal wellbeing.
  • Women and men with RPL should strive for a healthy BMI (19-25 kg/m2).4 
  • In women with PCOS with BMI >25 kg/m2, a weight loss of 5-10% has been shown to improve reproductive outcomes, although this has not specifically studied in women with RPL and PCOS.8
  • Currently the benefit of metformin treatment in women with RPL and PCOS is unknown.
  • Evidence outside of the RPL field has shown metformin treatment may improve pregnancy outcomes in women with PCOS.
  • In view of the available evidence, women with a diagnosis of PCOS and RPL should be offered metformin 500 mg once daily (OD). Doses should be titrated, as tolerated, up to 500 mg three times daily (TDS).
  • The use of metformin should be recommended to women throughout pregnancy, although obstetric teams may opt to amend that plan locally.
  • Women should be warned of the associated gastrointestinal side effects, including heartburn, stomach pain, nausea and vomiting.
  • In women who experience significant side effects of metformin, the dose should be reduced as tolerated to a minimum of 500 mg OD. Alternatively, a modified release (MR) formulation may be prescribed. If adverse symptoms persist at this lowest dose or while taking a MR preparation, consideration should be given to discontinuation of metformin.
  • Contraindications to metformin: acute metabolic acidosis (including lactic acidosis and diabetic ketoacidosis). Caution should be exerted when risk factors for lactic acidosis are present (e.g., chronic stable heart failure, concomitant use of drugs that can acutely impair renal function).

References 

  1. Quenby S, Gallos ID, Dhillon-Smith RK, et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet 2021; 397(10285): 1658-67.
  2. Liddell HS, Sowden K, Farquhar CM. Recurrent miscarriage: screening for polycystic ovaries and subsequent pregnancy outcome. Australian and New Zealand Journal of Obstetrics and Gynaecology 1997; 37(4): 402-6.
  3. Boomsma CM, Eijkemans MJ, Hughes EG, Visser GH, Fauser BC, Macklon NS. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Human Reproduction Update 2006; 12(6): 673-83.
  4. Bender Atik R, Christiansen OB, Elson J, et al. ESHRE guideline: recurrent pregnancy loss. Human Reproduction Open 2018; 2018(2): hoy004.
  5. Homburg R. Pregnancy complications in PCOS. Best Pract Res Clin Endocrinol Metab 2006; 20(2): 281-92.
  6. Sagle M, Bishop K, Ridley N, et al. Recurrent early miscarriage and polycystic ovaries. British Medical Journal 1988; 297(6655): 1027-8.
  7. Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and recurrent miscarriage–a reappraisal. Human Reproduction 2000; 15(3): 612-5.
  8. Teede HJ, Misso ML, Costello MF, et al. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Human Reproduction 2018; 33(9): 1602-18.
  9. Andrade C. Major malformation risk, pregnancy outcomes, and neurodevelopmental outcomes associated with metformin use during pregnancy. Journal of Clinical Psychiatry 2016;77: e411-414.
  10. Sharpe A, et al. Metformin for ovulation induction (excluding gonadotrophins) in women with polycystic ovary syndrome. The Cochrane Database of Systematic Reviews 2019; 12: Cd013505.
  11. Khattab S, et al. Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecological Endocrinology 2006;22: 680-684. 
  12. Al-Biate MA. Effect of metformin on early pregnancy loss in women with polycystic ovary syndrome. Taiwanese Journal of Obstetrics and Gynecology 2015;54: 266-269.
  13. Lovvik A, et al. Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinology 2019;7(4): 256-266.
  14. Showell, M.G., et al., Inositol for subfertile women with polycystic ovary syndrome. The Cochrane database of systematic reviews, 2018. 12(12): p. CD012378-CD012378.