ASRM Committee Opinion on the Evaluation and Treatment of Recurrent Pregnancy Loss

SUMMARY:

Recurrent pregnancy loss (RPL) is defined as the spontaneous loss of two or more pregnancies, excluding ectopic and molar pregnancies. Pregnancy confirmation by urine or serum hCG is sufficient. Biochemical pregnancy losses are included in the definition of RPL. Ultrasound or histopathologic confirmation is not a requirement to meet the definition.

Evaluation

Genetics

• Genetic testing of products of conception (POC) should be offered as a first step in the evaluation to all patients after a second first-trimester loss or with a history of RPL
  • Array-based technologies (e.g., SNP microarray) are preferred when available
  • Results may help direct further evaluation and identify sporadic chromosomal losses
• Rationale for genetic studies in parents
  • Peripheral karyotype is now recommended only when an unbalanced translocation is identified on POC testing, or when no POC testing is available  
• Refer to a genetic counselor if abnormal parental karyotype is present
  • Counsel patient regarding PGT or invasive diagnostic testing (CVS or amniocentesis) in future pregnancies

Note: Aneuploidy risk is lower in women with RPL vs sporadic miscarriage | In sporadic miscarriages vs RPL, 60% of early pregnancy losses have chromosomal anomalies, most of which are trisomies | Identification of aneuploidy in tissue sample may avoid expensive work-up for RPL

Antiphospholipid Syndrome (APL)

• Contributes 8 to 42% (mean 15%) of RPL cases
• Criteria for testing as follows
  • ≥3 unexplained spontaneous abortions <10 weeks
  • Single unexplained loss of morphologically normal fetus >10 weeks
  • History of a preterm delivery <34 weeks because of severe preeclampsia/placental insufficiency, in the presence of a morphologically normal fetus
• Diagnostic Criteria for APL: Requires 1 clinical and 1 laboratory criteria
  • Clinical Criteria
    • Vascular thrombosis
    • Pregnancy Morbidity (see testing criteria above)
  • Laboratory Criteria: Must occur twice ≥12 weeks apart
    • Lupus anticoagulant
    • Anticardiolipin IgG or IgM
    • Anti-beta2 glycoprotein IgM or IgG
• APL treatment includes
  • Low dose aspirin ideally started preconception
  • Prophylactic heparin, added once pregnancy is confirmed
  • Refer to hematology/rheumatology for confirmed persistent moderate-to-high antibody titers with lupus anticoagulant for long-term management

Anatomy

• Women with recurrent pregnancy loss are more than twice as likely to have a congenital uterine abnormality as women in the general population (13.3% vs. 5.5%)
• Evaluation of uterine cavity anomalies is recommended to identify congenital or acquired structural defects
• Anomalies associated with RPL
  • Septate uterus (highest risk/association) | Bicornuate | Unicornuate | Didelphic uteri
  • Arcuate uterus is considered a normal variant and is not associated with RPL
• Acquired defects
  • Submucosal fibroids | Endometrial polyps | Intrauterine adhesions | Retained products of conception
• First-line imaging: 3D transvaginal ultrasound or saline-infusion sonohysterography (SIS)
• Surgical of uterine septa or cavity-distorting acquired defects (fibroids, polyps, adhesions)
  • Recommended using shared-decision model
  • High-quality evidence showing improved live birth rates remains limited
  • No clear evidence supports surgical correction of arcuate, bicornuate, or unicornuate uteri

Inherited Thrombophilias

• Routine testing not recommended
  • Not recommended even in patients with a personal history of VTE or an affected first-degree relative
  • Anticoagulant treatment for hereditary thrombophilia or unexplained RPL is not recommended
  • High-quality evidence shows no benefit on live birth or miscarriage rate

Hormonal/Metabolic Factors

• Screen for thyroid abnormalities and diabetes
• Routine prolactin testing is not recommended
  • Prolactin testing is reserved for patients with symptoms of ovulatory dysfunction, such as galactorrhea or anovulation
  • No high-quality evidence links prolactin disturbances to RPL or supports a benefit from dopamine agonist (e.g., bromocriptine) treatment
• Screen for diabetes with Hemoglobin A1c
• Uncontrolled diabetes associated with increased pregnancy loss
  • Refer to endocrinologist
• Screen for thyroid disease with TSH testing | Treat overt thyroid disease as indicated
  • Screening for thyroid antibodies (autoimmunity) is not recommended
  • High-quality randomized trials show no benefit of levothyroxine treatment in euthyroid women with thyroid autoimmunity
• Empiric progesterone supplementation may be considered in patients with recurrent pregnancy loss
  • Evidence remains mixed and benefits appear limited to selected populations
• Metformin may be considered in women with PMOS (PCOS) who have evidence of insulin resistance and otherwise unexplained miscarriage

Etiologies not associated with RPL

• Alloimmune factors
  • Includes: CD16-NK cells (circulating and mucosal) | Embryotoxic factor | Cytokine profiles | Blocking antibodies | HLA typing | Anti-paternal leukocyte antibodies
  • Due to lack of evidence, current guidelines recommend against screening for alloimmune factors
• Ovarian reserve testing not recommended
  • Association with RPL is unclear and no proven therapeutic interventions exist
• Infection
  • Such as BV or endocervical infections

Male Evaluation

• Sperm DNA fragmentation (SDF) testing may be considered for the following
  • Oherwise unexplained RPL
  • Recurrent miscarriage with concomitant infertility
• Further research is needed to determine whether SDF improves outcomes

Preimplantation Genetic Testing for Aneuploidy (PGT-A)

• Not shown to reduce miscarriage or improve live birth rate in RPL compared vs expectant management 
• May be discussed via shared decision-making in women >40 years with a documented aneuploid miscarriage to reduce miscarriage risk
• No evidence currently demonstrates that PGT-A shortens time to pregnancy or raises live birth rate 

Other Considerations

• Encourage lifestyle modifications
  • Smoking cessation
  • Decrease alcohol consumption if >3 to 5 drinks per week
  • Decrease caffeine consumption if >3 cups coffee/day
  • Weight loss if obese
  • Counseling on illicit drug use
• Patients should be offered psychological support and counseling
• Chronic Endometritis
  • May be considered in selected patients with unexplained RPL
  • Evidence remains limited and routine screening is not recommended for all patients
  • No proven benefit of doxycycline treatment for chronic endometritis in RPL patients
• Emotional support and comprehensive health assessment
  • Provide psychological support and counseling throughout evaluation and treatment
  • Discuss future health risks associated with RPL and optimize overall health prior to conception such as
    • CVD | Diabetes | Autoimmune Disorders | Mental Health Disorders

KEY POINTS

Overall Evaluation

• Lifestyle modifications
• Peripheral karyotypic analysis for both parents when indicated (unbalanced translocation on POC testing, or no POC testing available)
• Lupus anticoagulant testing
• Evaluation of structures via sonohysterogram, hysterosalpingography, and/or hysteroscopy
• Screen for thyroid abnormalities (TSH) | Prolactin testing only if symptomatic
• Offer genetic testing of products of conception at the second loss or in patients with RPL using array-based technology as a first step in the evaluation
• Pregnancy losses do not need to be consecutive to warrant evaluation
• Biochemical pregnancy losses count toward the diagnosis of RPL
• If unexplained RPL, approximately 50% to 80% of patients will ultimately have a successful future pregnancy even without specific intervention
• Routine testing for thrombophilia and ovarian reserve is not recommended

Do not screen for

• Infection
• Ovarian reserve
• Alloimmune factors
• Thyroid antibodies

Learn More – Primary Sources

ASRM Committee Opinion: Recurrent pregnancy loss

FIGO: Good Practice Recommendations on the use of progesterone in the management of recurrent first-trimester miscarriage

How Effective are Treatments for Unexplained Recurrent Miscarriage?

BACKGROUND AND PURPOSE: 

• Recurrent pregnancy loss (RPL) is unexplained in approximately 50% of cases  
  • RPL is estimated to vary between 0.5% and 2.3% in different populations 
  • RPL definitions are not consistent as some define RPL as ≥3 losses before gestational week 22 while some use ≥2 losses  
• Evidence based treatment is limited but there have been several suggested treatments that includes  
  • Acetylsalicylic acid | Low molecular weight heparin | Progesterone | Intravenous immunoglobulin | Corticosteroids | Leukocyte immune therapy | Pre-implantation genetic screening | tender loving care  
• Roepke et al. (Acta Obstetricia et Gynecologica Scandinavica, 2018) contrasted treatment efficacies in women with unexplained recurrent pregnancy loss

METHODS: 

• Systematic review and meta-analysis 
• Literary search included 21 randomized controlled trials (RCTs) with women who had ≥3 miscarriages and treated with one of the following 
  • Acetylsalicylic acid 
  • Low molecular weight heparin 
  • Progesterone 
  • Intravenous immunoglobulin 
  • Leukocyte immune therapy 
• Outcomes 
  • Live birth; at gestational age ≥ 22 completed weeks 
  • Complications or side effects 
• Only studies with outcome of live birth and/or complication were included 
• The study quality was assessed and data was extracted independently by at least two authors 

RESULTS: 

• There was no significant difference in live birth rates between acetylsalicylic acid, low molecular weight heparin or placebo 
• Meta-analysis of low molecular weight heparin vs. control found no significant differences in live birth rate 
  • Risk ratio (RR) 1.47 (95% CI, 0.83-2.61) 
• Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate 
  • RR 1.18 (95% CI 1.09-1.27)  
  • There was no benefit to progesterone when started after conception 
• Intravenous immunoglobulin showed no effect on live birth rate compared with placebo 
  • RR 1.07 (95% CI 0.91-1.26) 
• Paternal immunization compared with autologous immunization showed a significant difference in outcome, although the studies were small and at high risk of bias 
  • RR 1.8 (95% CI 1.34-2.41) 

CONCLUSION: 

• While the studies had strengths, the authors acknowledge that  
  • Not including large RCTs that used a ≥2 losses definition rather than 3 could impact results  
  • Overall, studies suffer from low quality and bias   
  • Progesterone administered at ovulation and continued through the luteal phase was the only significant treatment for idiopathic recurrent pregnancy loss 
• They suggest that treatments for recurrent pregnancy loss should be used within the context of RCTs 

Learn More – Primary Sources: 

Treatment efficacy for idiopathic recurrent pregnancy loss – a systematic review and meta-analyses.