Recurrent Pregnancy Loss: Evaluation and Treatment
Initial Diagnostic Workup
For women with recurrent pregnancy loss (defined as two or more clinically recognized pregnancy losses), begin with a systematic evaluation that includes parental karyotyping, antiphospholipid antibody screening, anatomical assessment, thyroid function testing, and male partner evaluation. 1, 2, 3
Essential Laboratory Testing
Screen for antiphospholipid antibodies (APLAs) in all patients with three or more miscarriages before 10 weeks of gestation, as this represents one of the few treatable causes with proven interventions 4, 1, 3
Perform parental karyotyping on both partners to identify chromosomal rearrangements that could cause recurrent losses, as chromosomal errors account for 50-60% of early pregnancy losses 1, 2, 3
Measure thyroid function tests (TSH, free T4) since thyroid dysfunction contributes to pregnancy loss and requires optimization before conception 1, 2, 3
Evaluate for polycystic ovary syndrome (PCOS), which is associated with higher rates of pregnancy loss 1, 2, 3
Test products of conception when available to determine if chromosomal errors are contributing 3
Anatomical Evaluation
Begin with transvaginal ultrasound (TVUS) as the initial screening tool for uterine cavity abnormalities 1, 2, 3
Proceed to sonohysterography (SIS) for superior assessment of the uterine cavity compared to standard ultrasound, with three-dimensional SIS showing 100% accuracy in classification of uterine anomalies when compared with hysteroscopy 1, 2
Hysterosalpingography (HSG) serves as an alternative imaging modality to identify structural abnormalities 1
Male Partner Evaluation
Evaluate the male partner in all couples with two or more pregnancy losses, as this is now a guideline recommendation that addresses a previously overlooked contributor to recurrent pregnancy loss 4, 1, 2, 3
Perform karyotype testing of the male partner to identify chromosomal abnormalities 4, 1, 2, 3
Consider sperm DNA fragmentation testing, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss 4, 1, 2, 3
Special Genetic Considerations
- For patients with recurrent complete hydatidiform moles, perform genetic testing for mutations in NLRP7 and KHDC3L genes, which cause familial recurrent hydatidiform mole (FRHM), an autosomal recessive condition 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, as there is no evidence supporting antithrombotic prophylaxis for pregnancy loss prevention in these conditions 4, 1, 3
The only exception: Women with homozygous factor V Leiden or prothrombin 20210A mutation AND a positive family history for VTE should receive antepartum prophylaxis with prophylactic- or intermediate-dose LMWH, but this is for VTE prevention, not pregnancy loss prevention 4, 2
Evidence-Based Treatment Strategies
For Confirmed Antiphospholipid Syndrome
For women who meet laboratory criteria for APLA syndrome, treat with unfractionated heparin or LMWH plus low-dose aspirin, as this represents one of the few interventions with proven efficacy 4, 1, 3, 5
For Genetic Causes
Couples with parental chromosomal rearrangements require genetic counseling regarding options including preimplantation genetic testing 3
Patients with recurrent anembryonic pregnancies due to NLRP7 and KHDC3L gene mutations may benefit from ovum donation rather than conventional IVF 2, 3
For Anatomical Abnormalities
Surgical correction may be appropriate for certain uterine malformations, intrauterine synechiae, or cervical incompetence 3, 6
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
For Unexplained Recurrent Pregnancy Loss
For women with two or more miscarriages but without APLA or thrombophilia, do NOT use antithrombotic prophylaxis, as there is no evidence supporting this intervention 4, 3
Vaginal progesterone supplementation may be considered in patients experiencing vaginal bleeding during the first trimester 6
Most people with RPL, including those without identifiable risk factors, are expected to achieve a live birth within 5 years from initial evaluation 6
Lifestyle Modifications
Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs, as these are modifiable risk factors 1, 2, 3
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 1, 2, 3
Optimize nutrition and maintain healthy weight before attempting conception 1, 3
Management of Subsequent Pregnancies
Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected 1, 2, 3
Provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy 1, 2, 3
Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss 1, 2, 3
Monitor for and promptly treat any endocrine conditions, such as thyroid dysfunction 2, 3
Important Clinical Caveats
Anembryonic pregnancies (previously termed blighted ovum) should be counted when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses meeting diagnostic criteria 2, 3
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
The psychological impact of recurrent pregnancy loss is significant, and clinicians should provide compassionate and supportive care across all stages, recognizing that multiple pregnancy losses can have a substantial psychological toll on affected couples 6, 7, 8