What is the recommended evaluation and management for a reproductive‑age woman with polycystic ovary syndrome and recurrent pregnancy loss (≥ 2 consecutive miscarriages)?

PCOS and Recurrent Pregnancy Loss: Evaluation and Management

Women with PCOS and recurrent pregnancy loss should undergo metabolic screening (fasting glucose, 2-hour OGTT, lipid panel) and thrombophilia evaluation, followed by preconception weight optimization targeting ≥5% loss, metformin 1500–2550 mg daily to address insulin resistance and potentially reduce miscarriage risk, and consideration of ovarian drilling if medical management fails. 1, 2, 3, 4, 5

Essential Diagnostic Workup

Metabolic Assessment

• All women with PCOS require comprehensive metabolic screening at diagnosis, including fasting glucose, 2-hour oral glucose tolerance test (75g load), fasting lipid profile, BMI, and waist-hip ratio. 1, 2
• Screen for type 2 diabetes and glucose intolerance given the 31–35% rate of impaired glucose tolerance and 7.5–10% rate of diabetes in obese PCOS patients, with progression rates of 5–15% within 3 years. 3
• Repeat cardiovascular risk screening (weight, blood pressure, lipids, glycemic control) every 6–12 months regardless of body weight. 2

Thrombophilia and Coagulation Evaluation

• Consider thrombophilia screening in women with PCOS and recurrent pregnancy loss, as familial protein S deficiency and hypofibrinolysis (particularly 4G4G PAI-1 polymorphism) may contribute to thrombosis-mediated uteroplacental insufficiency. 4
• Women with PCOS have 1.5-times higher baseline risk of venous thromboembolism compared to non-PCOS women. 3

Endocrine and Reproductive Assessment

• Measure total testosterone or bioavailable/free testosterone to confirm hyperandrogenism, TSH to exclude thyroid disease, and prolactin to rule out hyperprolactinemia. 1
• Evaluate for other infertility factors including semen analysis and tubal patency assessment before initiating treatment. 3, 6
• Perform transvaginal ultrasound and endometrial biopsy if persistent bleeding occurs to exclude pregnancy or uterine pathology. 3

Preconception Management Algorithm

First-Line: Lifestyle Modification and Metabolic Optimization

• Target ≥5% weight loss through a structured program with 500–750 kcal daily deficit, as even modest weight reduction significantly improves ovulation rates, fertility potential, insulin sensitivity, and reduces miscarriage risk. 1, 2, 3
• Weight loss of as little as 5% can restore regular menses and improve response to fertility medications. 3
• Implement regular exercise programs, which provide metabolic benefits even without weight loss. 2
• Screen and treat hypertension and diabetes prior to attempting conception, as women with PCOS have elevated risk for gestational diabetes, pre-eclampsia, and placental abruption. 3

Second-Line: Metformin for Metabolic and Reproductive Benefits

• Initiate metformin 1500–2550 mg daily (typically 1000–1500 mg in divided doses) to improve insulin sensitivity, reduce androgen levels, and potentially decrease miscarriage risk in women with PCOS and recurrent pregnancy loss. 7, 4, 5
• Metformin normalizes PAI-1 activity (a marker of hypofibrinolysis), insulin levels, androstenedione, and testosterone while promoting weight loss. 4
• Evidence suggests metformin may reduce miscarriage rates in PCOS patients, though this remains an area requiring further study. 5
• Metformin appears safe during pregnancy with a favorable safety profile, though current practice typically advises discontinuation upon positive pregnancy test unless another indication exists (e.g., type 2 diabetes). 7, 8

Ovulation Induction When Attempting Conception

• Clomiphene citrate 50–150 mg daily for 5 days is the first-line ovulation induction agent, producing approximately 80% ovulation rates and 50% conception among ovulators. 7, 3, 9, 6
• Letrozole (aromatase inhibitor) is an alternative first-line option for ovulation induction. 3, 9
• If clomiphene fails, use low-dose gonadotropin therapy rather than high-dose protocols to reduce ovarian hyperstimulation risk. 7
• Metformin alone is not recommended as monotherapy for ovulation induction in normoglycemic PCOS patients without insulin resistance. 7

Third-Line: Surgical Intervention

• Ovarian drilling by laparoscopy or transvaginal hydrolaparoscopy is an option when medical treatment fails, aiming to enhance ovulation and pregnancy rates while potentially reducing miscarriage risk. 6, 5
• Consider this approach before proceeding to assisted reproductive technology. 6

Management During Pregnancy

Monitoring and Complications

• Screen for gestational diabetes appropriately, as women with PCOS have multiple risk factors including high prevalence of impaired glucose tolerance. 3
• Monitor for hypertension, pre-eclampsia, and placental complications given the increased metabolic syndrome prevalence. 3
• Women with PCOS are at risk for microvascular complications of diabetes during pregnancy. 3

Medication Considerations

• The decision to continue or discontinue metformin during pregnancy should be individualized based on metabolic status and prior miscarriage history. 7, 8, 4
• Combined oral contraceptives should be discontinued when attempting conception. 2

Critical Pitfalls to Avoid

• Do not delay metabolic screening—insulin resistance and glucose intolerance are present regardless of BMI in PCOS patients, affecting both lean and overweight women. 1, 3
• Do not overlook thrombophilia evaluation in recurrent pregnancy loss, as familial protein S deficiency and PAI-1 polymorphisms may be reversible contributors to pregnancy loss. 4
• Do not use metformin as sole therapy for ovulation induction without addressing lifestyle factors and considering clomiphene as first-line. 7, 6
• Do not ignore psychological comorbidities (anxiety, depression, eating disorders), as these are prevalent in PCOS and can impede effective weight management and treatment adherence. 2
• Be aware that PCOS women using oral contraceptives have 3.7-fold greater risk of venous thromboembolism compared to non-PCOS OCP users. 3

Evidence Quality Considerations

The strongest guideline-level evidence supports clomiphene as first-line for ovulation induction and metformin for metabolic management. 1, 7, 2 The link between PCOS and recurrent miscarriage remains incompletely understood, with hyperandrogenemia, obesity, and hyperinsulinemia as the most likely mechanistic candidates. 5 The role of thrombophilia is supported by case reports and small studies but lacks large-scale validation. 4 Weight loss recommendations are based on consistent observational evidence showing reproductive and metabolic benefits. 1, 2, 3