What is the management approach for a woman of reproductive age with a history of three or more consecutive pregnancy losses?

Management of Recurrent Pregnancy Loss

Screening and Diagnostic Workup

All women with three or more consecutive early pregnancy losses (before 10 weeks) must be screened for antiphospholipid antibodies (APLAs), as this is the only proven treatable cause with established therapy. 1

Essential Testing for All Patients

• Screen for antiphospholipid antibodies in all patients with ≥3 early miscarriages before 10 weeks gestation 1, 2
• Perform parental karyotyping on both partners to identify chromosomal rearrangements that could cause recurrent losses 2, 3
• Measure thyroid function tests (TSH, free T4) as thyroid dysfunction contributes to pregnancy loss and requires optimization before conception 2, 3
• Evaluate for polycystic ovary syndrome (PCOS), which is associated with higher rates of pregnancy loss 2, 3
• Begin with transvaginal ultrasound (TVUS) as the initial screening tool for uterine cavity abnormalities 2, 4
• Proceed to sonohysterography (SIS) for superior assessment of the uterine cavity compared to standard ultrasound, with 100% accuracy in classification of uterine anomalies when compared with hysteroscopy 2, 4

Male Partner Evaluation

• Evaluate the male partner in all couples with ≥2 pregnancy losses, including karyotype testing to identify chromosomal abnormalities 1, 2, 3
• Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss 1, 2, 3

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. 1, 2

• The American College of Chest Physicians explicitly recommends against screening for inherited thrombophilia in women with a history of pregnancy complications 1
• The only exception is for VTE prevention (not pregnancy loss prevention): women with homozygous factor V Leiden or prothrombin 20210A mutation AND a positive family history for VTE should receive antepartum prophylaxis with LMWH 1, 2

Treatment Based on Identified Causes

Antiphospholipid Syndrome

For women who meet laboratory criteria for APLA syndrome, treat with unfractionated heparin or LMWH plus low-dose aspirin. 2, 3

• This is the only proven-effective therapy with properly controlled trials for recurrent pregnancy loss 5

Chromosomal Abnormalities

• Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing 3
• Test products of conception when available to determine if chromosomal errors are contributing, which account for 50-60% of early losses 3

Uterine Abnormalities

• Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence 3
• 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 3

Special Genetic Considerations

• For patients with recurrent complete hydatidiform moles, consider genetic testing for mutations in NLRP7 and KHDC3L genes, which cause familial recurrent hydatidiform mole (FRHM), an autosomal recessive condition 2, 3, 4
• Patients with recurrent anembryonic pregnancies due to NLRP7 and KHDC3L gene mutations may benefit from ovum donation rather than conventional IVF 3, 4

Management of Unexplained Recurrent Pregnancy Loss

For women with two or more miscarriages but without APLA or thrombophilia, do NOT use antithrombotic prophylaxis. 1

• The American College of Chest Physicians explicitly recommends against antithrombotic prophylaxis in this population 1
• There is NO evidence supporting the use of LMWH for the sole indication of prevention of recurrent pregnancy loss outside of confirmed antiphospholipid syndrome 3
• Even after complete evaluation, the cause of RPL remains uncertain in over 50% of cases, and these patients have up to a 70% chance of success without treatment 5

Lifestyle Modifications

• Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs, as these are modifiable risk factors 2, 3, 4
• 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 2, 3, 4
• Optimize nutrition and maintain healthy weight before attempting conception 2, 3

Management of Subsequent Pregnancies

• Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected 2, 3, 4
• Provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy 2, 3, 4
• Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss 2, 3, 4
• Monitor for and promptly treat any endocrine conditions, such as thyroid dysfunction 3, 4

Common Pitfalls to Avoid

The most critical pitfall is ordering thrombophilia panels routinely, as this leads to unnecessary anticoagulation without proven benefit and potential harm. The American College of Chest Physicians provides clear guidance that inherited thrombophilia screening should not be performed in women with recurrent pregnancy loss, and antithrombotic prophylaxis should not be used in women without APLA syndrome. 1, 3