In a reproductive‑age woman (20‑35 years) with polycystic ovary syndrome (PCOS) who has experienced two or more consecutive spontaneous abortions, what is the relationship between PCOS and recurrent pregnancy loss (RPL) and what first‑line evaluation and management should be pursued?

Relationship Between PCOS and Recurrent Pregnancy Loss

Women with PCOS who experience recurrent pregnancy loss face a significantly elevated miscarriage risk driven by multiple interconnected mechanisms including insulin resistance, hyperandrogenemia, hyperhomocysteinemia, and thrombophilia—requiring comprehensive metabolic screening and targeted interventions with lifestyle modification, metformin, and consideration of anticoagulation therapy. 1, 2, 3

Understanding the Mechanistic Link

The relationship between PCOS and RPL is multifactorial and well-established:

• PCOS patients demonstrate a 40% recurrent miscarriage rate compared to 12% in non-PCOS infertile women, representing more than a three-fold increase in risk 2
• Insulin resistance occurs in 56-70% of PCOS women with RPL, and 75% of abortions occur specifically in PCOS patients with documented insulin resistance 1, 2
• Hyperhomocysteinemia affects 70.63% of PCOS women with RPL versus 57.26% in non-PCOS controls, with probabilistic modeling identifying it as the strongest plausible factor for RPL diagnosis (43.32% probability) 1
• Hyperandrogenemia contributes independently, with 62.5% of abortions occurring in PCOS women with elevated testosterone levels 2

First-Line Evaluation Protocol

Mandatory Metabolic Screening

All PCOS patients with RPL require comprehensive metabolic assessment before attempting subsequent pregnancy: 4, 5

• Fasting glucose and 2-hour glucose tolerance test 4, 5
• Fasting lipid profile 4, 5
• Fasting insulin levels to document insulin resistance 1, 2
• Serum homocysteine levels 1, 3
• Testosterone and DHEA-S levels 3

Thrombophilia Workup

PCOS patients with RPL demonstrate significantly higher rates of thrombophilic abnormalities requiring targeted evaluation: 3

• Plasminogen activator inhibitor activity (PAI-Fx) - significantly elevated in PCOS with RPL 3
• Activated protein C ratio (APCR) - higher proportions in PCOS with RPL 3
• Factor V Leiden mutation screening - higher prevalence in PCOS with RPL 3
• Protein C, protein S, and antithrombin III levels 3
• Prothrombin G20210A mutation 3
• MTHFR gene mutations 3

Additional Ovarian Reserve Assessment

Consider evaluating ovarian reserve markers, as diminished ovarian reserve independently increases miscarriage risk: 6

• Anti-Müllerian hormone (AMH) levels - women with AMH <0.7 ng/ml show slightly higher miscarriage risk 6
• Antral follicle count (AFC) via transvaginal ultrasound - particularly relevant in women <35 years 6

Evidence-Based Management Strategy

Foundation: Lifestyle Modification (Mandatory First-Line)

Weight loss of just 5% of initial body weight must be the foundation of treatment, as it improves both metabolic and reproductive outcomes: 4, 5

• Target 500-750 kcal/day energy deficit (total intake 1,200-1,500 kcal/day) 5
• Prescribe ≥150 minutes/week moderate-intensity exercise or 75 minutes/week vigorous activity 5
• Exercise provides metabolic benefits even without weight loss 5

Pharmacologic Interventions

Metformin 500-2000 mg daily should be initiated in PCOS patients with documented insulin resistance and RPL: 7, 4, 5

• Metformin improves insulin sensitivity, reduces ovarian androgen production, and appears safe during pregnancy 7, 4
• The American Diabetes Association supports its use for improving ovulation frequency 4
• Continue metformin through early pregnancy given its safety profile 7

For patients attempting conception with documented thrombophilia: 3

• Consider low-dose aspirin from week 12 to week 36 of pregnancy 4
• Evaluate for low-molecular-weight heparin (LMWH) in combination with aspirin for those with documented thrombophilic abnormalities 8

Clomiphene citrate 50-150 mg daily for ovulation induction (if anovulatory): 7, 4

• First-line agent with 80% ovulation rate and 50% conception rate among ovulators 7, 4
• Limit to six total cycles 5

Emerging Therapies with Mechanistic Promise

N-acetylcysteine and other antioxidants show promise for targeting oxidative stress pathways: 8

• Dual metabolic-immune effects may address immunometabolic crosstalk underlying PCOS-related pregnancy loss 8

GLP-1 receptor agonists may be considered for patients with obesity or elevated cardiovascular risk when lifestyle and metformin are insufficient: 5

• Show promise for weight reduction and metabolic improvement 5

Preconception Counseling Requirements

All PCOS patients with RPL require comprehensive preconception counseling about increased pregnancy risks: 4

• Higher rates of gestational diabetes, preeclampsia, and pregnancy complications 4
• Need for closer monitoring throughout pregnancy with regular blood pressure, kidney function, and proteinuria assessment 4
• Importance of achieving metabolic optimization before conception 4, 5

Critical Pitfalls to Avoid

Do not delay lifestyle intervention - it must be implemented first regardless of other treatments 4, 5

Do not assume normal weight excludes metabolic dysfunction - screen all PCOS patients with RPL regardless of BMI, using ethnic-specific cutoffs for Asian, Hispanic, and South Asian populations 5

Do not overlook hyperhomocysteinemia - it represents the strongest plausible factor for RPL in PCOS (43.32% probability) and requires specific evaluation and treatment 1

Do not miss thrombophilia screening - PCOS patients with RPL have significantly higher rates of APCR, Factor V Leiden mutations, elevated PAI-Fx, and hyperhomocysteinemia compared to non-PCOS RPL patients 3

Do not use spironolactone in patients attempting to conceive - it is contraindicated in pregnancy 5

Do not combine multiple insulin-sensitizing agents during pregnancy without medical supervision 7

Ongoing Pregnancy Management

Once pregnancy is achieved, implement enhanced surveillance: 4

• Regular monitoring of blood pressure, kidney function, and proteinuria 4
• Low-dose aspirin from week 12 to week 36 to reduce preeclampsia risk 4
• Consider continuation of metformin through early pregnancy given safety profile 7, 4