What are the treatment options for recurrent pregnancy loss in patients with Polycystic Ovary Syndrome (PCOS)?

Treatment of Recurrent Pregnancy Loss in PCOS Patients

For women with PCOS experiencing recurrent pregnancy loss, initiate weight loss of at least 5% body weight through lifestyle modification as the foundational treatment, followed by metformin to improve insulin sensitivity and reduce miscarriage risk, particularly in those with insulin resistance or obesity. 1, 2, 3

Preconception Management Strategy

Weight Loss as Primary Intervention

• Loss of just 5% of initial body weight significantly improves both metabolic and reproductive abnormalities, including pregnancy outcomes in PCOS. 1, 2
• Target a 30% energy deficit or 500-750 kcal/day reduction through any balanced dietary approach that creates an energy deficit. 4, 2
• Implement regular exercise programs, which show positive effects even without weight loss. 1, 2
• Weight loss specifically reduces miscarriage rates in PCOS patients by improving insulin sensitivity and reducing hyperandrogenism. 3

Metabolic Screening Before Conception

• Screen all PCOS patients attempting pregnancy for metabolic abnormalities: fasting glucose, 2-hour glucose tolerance test, and lipid profile before conception. 2, 5
• Identify insulin resistance, as it is a key modifiable risk factor for recurrent miscarriage in PCOS. 3, 6
• Assess hyperandrogenism (elevated testosterone), which correlates with higher abortion rates—62.5% of PCOS patients with raised testosterone experienced miscarriage in one study. 6

Pharmacological Treatment

Metformin as Key Intervention

• Metformin improves insulin sensitivity, reduces ovarian androgen production, and appears safe during pregnancy, making it the primary pharmacological option for reducing miscarriage risk in PCOS. 2, 3
• Metformin is particularly indicated in obese PCOS patients with insulin resistance, where 75% of abortions occur among those with insulin resistance. 6
• Continue metformin through early pregnancy, as it reduces insulin levels and subsequently decreases ovarian androgen production. 2
• The American Diabetes Association supports metformin use to improve insulin sensitivity and reduce metabolic risk factors. 4

For Achieving Pregnancy (If Not Yet Conceived)

• Use clomiphene citrate as first-line ovulation induction, with 80% ovulation rate and 50% conception rate among those who ovulate. 1, 2
• If clomiphene fails, use low-dose gonadotropin therapy rather than high-dose to minimize ovarian hyperstimulation risk. 1
• Consider letrozole as first-line pharmacological treatment for anovulatory infertility in PCOS per recent evidence. 5

Pregnancy Monitoring Protocol

Enhanced Surveillance

• Provide preconception counseling about increased pregnancy risks specific to PCOS. 2
• Monitor blood pressure, kidney function, and proteinuria regularly throughout pregnancy. 2
• Prescribe low-dose aspirin from week 12 to week 36 to reduce preeclampsia risk. 2
• Repeat glucose screening at 24-28 weeks if initial screening was normal. 5

Mechanism-Based Rationale

The three primary mechanisms by which PCOS causes recurrent miscarriage are hyperandrogenemia, obesity, and hyperinsulinemia. 3 Addressing these through weight loss and metformin directly targets the pathophysiology rather than treating symptoms alone.

Critical Pitfalls to Avoid

• Do not neglect metabolic screening even in normal-weight PCOS patients, as insulin resistance can occur independent of obesity. 4
• Do not use thiazolidinediones in pregnancy, as their effects on early pregnancy are poorly documented compared to metformin. 1
• Do not exceed recommended clomiphene dosage and duration. 4
• Do not delay lifestyle intervention—it must be implemented first as the foundation, not as an afterthought. 2

Alternative Considerations

• Laparoscopic ovarian drilling may reduce miscarriage rates but has undetermined benefit according to ACOG. 1, 3
• Inositol shows promise but lacks specific ACOG recommendations for pregnancy use in PCOS. 7
• GLP-1 agonists (semaglutide, liraglutide) show promise for weight reduction when combined with lifestyle interventions, though pregnancy-specific data are limited. 4