Workup of Recurrent Pregnancy Loss
Screen for antiphospholipid antibodies (APLAs) in all patients with recurrent early pregnancy loss (three or more miscarriages before 10 weeks), perform parental karyotyping, evaluate uterine anatomy with imaging, assess thyroid function and PCOS, and evaluate the male partner—but do NOT routinely screen for inherited thrombophilias. 1, 2, 3
Initial Laboratory Evaluation
Mandatory Testing
Antiphospholipid antibody screening is the single most important test, recommended for all women with three or more early pregnancy losses (before 10 weeks gestation). 1
- This is the only thrombophilia screening recommended, as inherited thrombophilias should NOT be routinely tested in women with pregnancy complications. 1
Parental karyotyping should be performed on both partners to identify chromosomal rearrangements that could cause recurrent losses. 2, 4, 5
Endocrine Assessment
Thyroid function tests (TSH, free T4) are essential, 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
Assess ovarian reserve with AMH levels, particularly in older women, as severely diminished ovarian reserve (very low AMH) may be associated with increased miscarriage risk. 2, 6
Anatomical Evaluation
Imaging Studies
Transvaginal ultrasound (TVUS) is the initial screening tool for uterine cavity abnormalities. 2, 3
Sonohysterography (SIS) provides superior assessment of the uterine cavity compared to standard ultrasound. 2, 3
- Three-dimensional SIS has demonstrated 100% accuracy in classifying uterine anomalies when compared with hysteroscopy. 3
Hysterosalpingography (HSG) is an alternative imaging modality to identify structural abnormalities. 2
Look specifically for Müllerian anomalies, intrauterine synechiae (Asherman syndrome), and cervical incompetence, all of which can interfere with implantation. 2
Male Partner Evaluation
Evaluate the male partner in all couples with two or more pregnancy losses, as this is now a guideline recommendation. 2, 3
Consider karyotype testing of the male partner to identify chromosomal abnormalities. 2, 3
Sperm DNA fragmentation testing should be considered, as increasing evidence links elevated sperm DNA fragmentation with recurrent pregnancy loss. 2, 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, 6
- These patients may benefit from ovum donation rather than conventional IVF. 3
What NOT to Test
Inherited Thrombophilias
Do NOT routinely screen for inherited thrombophilias (factor V Leiden, prothrombin G20210A mutation, protein C/S deficiency) in women with recurrent pregnancy loss. 1
- This is a critical pitfall to avoid, as many clinicians over-test for thrombophilias despite clear guideline recommendations against routine screening. 1
The only exception: If a woman has homozygous factor V Leiden or prothrombin 20210A mutation AND a positive family history for VTE, she should receive antepartum prophylaxis with LMWH, but this is for VTE prevention, not pregnancy loss prevention. 1, 2, 6
Do NOT use antithrombotic prophylaxis in women with inherited thrombophilia and pregnancy complications, as there is no evidence of benefit. 1
Other Tests to Avoid
Do NOT use antithrombotic prophylaxis (heparin or aspirin) in women with two or more miscarriages who do not have APLA or confirmed thrombophilia. 1
Low-molecular-weight heparin should NOT be used solely for prevention of recurrent fetal growth restriction. 2
Important Definitions and Counting Losses
Anembryonic pregnancies (blighted ovum) should be counted when calculating recurrent pregnancy losses for workup purposes, as they represent confirmed early pregnancy losses. 3
- An anembryonic pregnancy is defined as a gestational sac ≥25 mm without an embryo, or absence of an embryo on serial examinations. 3
Current guidelines recommend evaluation after two clinically recognized first-trimester pregnancy losses, not waiting for three losses as was previously standard. 5
Management of Confirmed Conditions
Antiphospholipid Syndrome
- For women who meet laboratory criteria for APLA syndrome, treatment with unfractionated heparin or LMWH plus low-dose aspirin is recommended. 1, 4
Lifestyle Modifications
Counsel on smoking cessation, alcohol avoidance, and elimination of recreational drugs, as these are modifiable risk factors. 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
Optimize nutrition and maintain healthy weight before attempting conception. 3
Monitoring Subsequent Pregnancies
Confirm viable intrauterine pregnancy with early ultrasound as soon as pregnancy is detected. 2, 3
Provide regular prenatal visits with serial ultrasound monitoring throughout the pregnancy. 2, 3
Screen for gestational diabetes in current pregnancies, as glucose intolerance may contribute to pregnancy loss. 3
Consider vaginal progesterone supplementation if the patient experiences vaginal bleeding during the first trimester. 5
Prognosis and Counseling
Most patients with RPL, including those without identifiable risk factors, are expected to achieve a live birth within 5 years from initial evaluation. 5
Prognosis depends on maternal age and number of previous losses, with younger women and those with fewer losses having better outcomes. 7
Provide psychological support, as RPL is highly distressing and couples require compassionate care and accurate information about their chances of success. 7, 5