What is the recommended evaluation and management for a 37‑year‑old woman with recurrent miscarriage after four prior live births?

Evaluation and Management of Recurrent Miscarriage After Four Successful Pregnancies

Begin with screening for antiphospholipid antibodies and assessment of uterine anatomy, as these represent the most treatable causes of recurrent pregnancy loss, even in women with prior successful pregnancies. 1, 2

Initial Diagnostic Workup

The evaluation should proceed systematically, focusing on identifiable and treatable causes:

Essential First-Line Testing

• Screen for antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) in all women with recurrent early pregnancy loss, as this is the most treatable cause with proven benefit for live birth outcomes. 1, 2

• Evaluate uterine anatomy starting with transvaginal ultrasound, then proceed to sonohysterography for superior assessment of the uterine cavity, as structural abnormalities may develop over time even after successful pregnancies. 1, 2

• Perform parental karyotyping on both partners to identify chromosomal rearrangements, which account for 5-7% of recurrent losses and can manifest even after prior successful pregnancies. 1, 2

• Test products of conception when available using 24-chromosome microarray analysis, as chromosomal errors account for 50-60% of early losses and this testing can provide an explanation in over 90% of cases when combined with standard workup. 1, 3

• Measure thyroid function tests (TSH, free T4) as thyroid dysfunction contributes to pregnancy loss and requires optimization before conception. 1, 2

• Assess for polycystic ovary syndrome (PCOS), which is associated with higher rates of pregnancy loss. 1, 2

• Evaluate ovarian reserve using AMH levels, as severely diminished ovarian reserve (AMH < 0.7 ng/mL) may be associated with increased miscarriage risk, particularly relevant at age 37. 1, 2

Male Partner Evaluation

• Evaluate the male partner with karyotype testing in all couples with ≥2 pregnancy losses, as male chromosomal abnormalities contribute to recurrent loss. 1, 2

• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss. 1, 2

Special Genetic Testing

• For recurrent complete hydatidiform moles specifically, test for NLRP7 and KHDC3L gene mutations, as these cause familial recurrent hydatidiform mole. 1

What NOT to Test

• Do not routinely screen for inherited thrombophilias (factor V Leiden, prothrombin 20210A) in women with recurrent loss, as evidence does not support antithrombotic prophylaxis for these conditions alone. 1

• Avoid viscoelastic testing (TEG/ROTEM) as it shows no correlation with thrombophilic defects and provides no evidence of a pro-thrombotic state in unexplained recurrent loss. 1

Treatment Based on Identified Causes

Antiphospholipid Syndrome

• For women meeting laboratory criteria for antiphospholipid syndrome, treat with unfractionated heparin or low-molecular-weight heparin (LMWH) plus low-dose aspirin throughout pregnancy. This is a Grade 1A recommendation that improves live birth rates and reduces maternal morbidity/mortality. 1, 2

Inherited Thrombophilias

• For homozygous factor V Leiden or prothrombin 20210A mutation with positive family history of venous thromboembolism (VTE), prescribe antepartum prophylactic- or intermediate-dose LMWH and continue for 6 weeks postpartum. 1, 2

• For all other thrombophilias without prior VTE and without family history of VTE, use clinical vigilance only—do NOT use antithrombotic prophylaxis. 1, 2

Chromosomal Abnormalities

• Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing, prenatal diagnostic testing, donor gametes, or adoption. 1, 2

• 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. 1, 2

Uterine Abnormalities

• Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence. 1

• History-indicated cerclage should be reserved for individuals with classic historical features of cervical insufficiency or unexplained second-trimester loss in the absence of placental abruption. 1

Critical Caveat: What NOT to Do

• For women with two or more miscarriages but without antiphospholipid syndrome or specific thrombophilia indications, do NOT use antithrombotic prophylaxis. This is a Grade 1B recommendation against treatment. 1, 2

• There is NO evidence supporting the use of LMWH for the sole indication of prevention of recurrent pregnancy loss outside of confirmed antiphospholipid syndrome. 1

Lifestyle Modifications

• Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs, as these are modifiable risk factors. 1, 2

• Encourage regular physical activity within guidelines, as it is safe and may benefit insulin resistance and obesity, which increase miscarriage risk. 1, 2

• Optimize nutrition and maintain healthy weight before attempting conception. 1, 2

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 pregnancy. 1, 2

• Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss. 1, 2

• For patients at risk of pre-eclampsia, administer low-dose aspirin throughout pregnancy starting in the second trimester. 1, 2

• Monitor for and promptly treat any endocrine conditions, such as thyroid dysfunction. 1, 2

Important Clinical Pitfalls

• Do not assume a sporadic cause when evaluating recurrent loss after prior successful pregnancies—acquired conditions (antiphospholipid syndrome, thyroid dysfunction, uterine abnormalities) can develop over time. 1

• Count anembryonic pregnancies when calculating recurrent pregnancy losses, as they represent confirmed early pregnancy losses meeting diagnostic criteria. 1, 2

• Do not omit male partner assessment—male chromosomal abnormalities and sperm DNA fragmentation are recognized contributors even when prior pregnancies were successful. 1, 2