In a reproductive‑age woman with two consecutive miscarriages, what is the burden of recurrent pregnancy loss (RPL) and what evaluation and first‑line treatment are recommended?

Burden and Management of Recurrent Pregnancy Loss

Epidemiologic Burden

Recurrent pregnancy loss (RPL) affects approximately 2-5% of reproductive-aged couples, representing a significant reproductive health challenge with profound physical and psychological consequences. 1, 2, 3

• RPL is traditionally defined as two or more consecutive pregnancy losses before 20 weeks of gestation, with most current guidelines recommending evaluation after the second clinically recognized first-trimester loss 4, 5, 1, 2
• The condition poses serious threats to women's physical and mental health, requiring compassionate and psychologically sensitive care across all stages 2, 3
• Even after comprehensive evaluation, the cause remains unexplained in 50-75% of cases, which presents a major clinical challenge 6, 7, 3
• Despite the diagnostic uncertainty, patients with unexplained RPL have a 60-70% chance of successful subsequent pregnancy without specific treatment, which provides important prognostic reassurance 6, 2

Cardiovascular and Long-term Health Implications

• Women with history of miscarriage demonstrate increased cardiovascular risk in later life, with associations to ischemic heart disease (OR 1.45,95% CI 1.18-1.78) 8
• Stillbirth history is associated with both non-fatal cardiovascular disease (OR 1.49,95% CI 1.08-2.06) and fatal events (OR 2.23,95% CI 1.90-2.62) 8

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Initial Diagnostic Evaluation

Essential Testing for All Patients

Screen all women with ≥2 clinically recognized pregnancy losses for antiphospholipid antibodies (APLAs), as this represents the most treatable cause with proven benefit for maternal-fetal outcomes. 4, 5, 1

• Perform parental karyotyping on both partners to identify chromosomal rearrangements (translocations, inversions), which account for 5-7% of RPL cases and are inherited in families 4, 5, 1
• Test products of conception when available to determine if chromosomal errors are contributing, as these account for 50-60% of early losses 4, 3
• Measure thyroid function tests (TSH, free T4) as thyroid dysfunction contributes to pregnancy loss and requires optimization before conception 4, 5, 1
• Evaluate for polycystic ovary syndrome (PCOS), which is associated with higher rates of pregnancy loss 4, 5
• Assess ovarian reserve using AMH levels, as severely diminished ovarian reserve (AMH <0.7 ng/mL) may increase miscarriage risk, especially in women <35 years 4

Anatomical Assessment

• Begin with transvaginal ultrasound (TVUS) as the initial screening tool for uterine cavity abnormalities 4, 5, 9
• Proceed to sonohysterography (SIS) for superior assessment of the uterine cavity, as structural abnormalities are identified in up to 38% of women with recurrent miscarriage 5, 9, 1
• Three-dimensional SIS demonstrates 100% accuracy in classification of uterine anomalies when compared with hysteroscopy 9

Male Partner Evaluation

Evaluate the male partner in all couples with ≥2 pregnancy losses, as male factors are now recognized as significant contributors. 4, 5

• Perform karyotype testing to identify chromosomal abnormalities in the male partner 4, 5
• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss 4, 5

Special Genetic Considerations

• For patients with recurrent complete hydatidiform moles, test for mutations in NLRP7 and KHDC3L genes, which cause familial recurrent hydatidiform mole (autosomal recessive condition) 4, 5, 9
• Women with confirmed NLRP7 or KHDC3L mutations should be offered ovum donation rather than conventional IVF, as the likelihood of achieving normal pregnancy with autologous oocytes is extremely low 4, 9

Important: What NOT to Test

Do NOT routinely screen for inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency) in women with recurrent pregnancy loss. 4, 5

• The only exception: women with homozygous factor V Leiden or prothrombin 20210A mutation AND positive family history for VTE should receive antepartum LMWH prophylaxis—but this is for VTE prevention, not pregnancy loss prevention 4, 5
• Avoid viscoelastic testing (TEG/ROTEM) as it shows no correlation with thrombophilic defects and provides no evidence of a pro-thrombotic state in unexplained RPL 4, 9

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First-Line Treatment Based on Identified Causes

Antiphospholipid Syndrome (Most Important Treatable Cause)

For women who meet laboratory criteria for antiphospholipid syndrome, treat with unfractionated heparin or low-molecular-weight heparin (LMWH) plus low-dose aspirin throughout pregnancy. 4, 5, 1, 6

• This is the only treatment with Grade 1A evidence from properly controlled trials demonstrating improved live-birth rates and reduced maternal morbidity/mortality 4, 6
• There is NO evidence supporting the use of LMWH for prevention of recurrent pregnancy loss outside of confirmed antiphospholipid syndrome 4

Chromosomal Abnormalities

• Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing (PGT-A), prenatal diagnostic testing, donor gametes, or adoption 4
• The recurrence risk for unbalanced offspring is approximately 50% when a balanced translocation is identified 4

Uterine Abnormalities

• Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence 4, 6, 2
• History-indicated cerclage should be reserved for individuals with classic historical features of cervical insufficiency or unexplained second-trimester loss (not for early first-trimester losses) 4, 5

Progesterone Supplementation

• Vaginal progesterone supplementation may be considered in patients experiencing vaginal bleeding during the first trimester 2

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Lifestyle Modifications (Evidence-Based)

Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs, as these are modifiable risk factors. 4, 5, 1

• Regular physical activity within guidelines is safe and unlikely to increase pregnancy loss risk; it may actually benefit insulin resistance and obesity, which increase miscarriage risk 4, 5
• Optimize nutrition and maintain healthy weight before attempting conception 4, 5

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Management of Subsequent Pregnancies

Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected, and provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy. 4, 5, 9

• Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss 4, 5, 9
• Monitor for and promptly treat any endocrine conditions, such as thyroid dysfunction 4, 9
• For patients at risk of pre-eclampsia, administer low-dose aspirin throughout pregnancy starting in the second trimester 4

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Critical Clinical Pitfalls to Avoid

• Do not assume a sporadic cause when a family history is present; the prevalence of inherited chromosomal rearrangements rises from 3.6% to 5-7% when family history is documented 4
• Do not omit male partner assessment; male chromosomal abnormalities and sperm DNA fragmentation are recognized contributors 4, 5
• Anembryonic pregnancies (blighted ovum) should be counted when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses meeting diagnostic criteria 9
• Do not use anticoagulation therapy in women with inherited thrombophilias alone (without APS or VTE history), as evidence does not support this practice 4