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

Managing Early Pregnancy Loss

CLINICAL ACTIONS:

Early Pregnancy Loss (EPL) describes a nonviable intrauterine pregnancy identified prior to 13 weeks gestation, often a consequence of significant fetal chromosome abnormalities incompatible with life.  Frequency of EPL increases with maternal age.

Expectant Management

• Limit expectant management to the first trimester
• Spontaneous complete expulsion will occur in 80% of women with EPL ≤8 weeks gestation
• Educate patient on moderate-to-heavy bleeding and cramping
• Provide support and pain medications as needed
• Ultrasound expulsion criteria
  • Absence of gestational sac and endometrial thickness <30 mm (common criteria)
    • No evidence of increased morbidity with thicker endometrium

Medical Management

• Prior to medical management, ensure patient does not have
  • Infection
  • Severe anemia
  • Hemorrhage
  • Bleeding disorder
• Misoprostol 800 micrograms vaginally
  • Repeat once, as needed, no earlier than 3 hours and within 7 days if no response
• Consider mifepristone (if available) 200 mg orally 24 hours before misoprostol (see ‘Note’ and ‘Related ObG Topics’ below)
  • Mifepristone is limited by FDA restrictions
  • ACOG supports “improving access to mifepristone for reproductive health indications”
• Counsel patient about bleeding and cramping
  • If soaking >2 maxipads/hour for > 2 hours, surgical intervention may be indicated
• Use ultrasound to document expulsion or serial quantitative HCGs if ultrasound is unavailable
• In case of failure, patient can still consider expectant management (see above) or surgical intervention

Note: Research (RCT) demonstrates the administration of 200 mg mifepristone followed by 800 micrograms misoprostol improves outcomes

• 83.8% of women in the mifepristone-pretreatment group vs 67.1% in the misoprostol-alone group experienced complete expulsion (see summary in ‘Related ObG Topics’, below)

Surgical management

• Suction curettage in office or ambulatory surgery setting with local anesthesia/sedation
• May be preferred treatment by women who want a faster and more controlled treatment path
• ACOG recommends a single preoperative dose of doxycycline to prevent infection following surgical management
  • 200-mg dose of doxycycline 1 hour prior to surgery (consensus and expert opinion)
• Surgical intervention is management of choice in the following scenarios
  • Hemorrhage
  • Infection
  • Hemodynamic instability

SYNOPSIS:

Expectant, medical or surgical management to treat miscarriage are considered equivalent.  Unless there is a change in clinical status (e.g. hemorrhage or infection), patient preference can guide decision making.

KEY POINTS:

• Risk of serious complications after treatment of EPL are rare, and comparable for all three treatment types
• Medical management compared to expectant management
  • Increases time to complete expulsion
  • Does not increase need for surgical intervention
• Medical management with misoprostol appears to be the most cost-effective treatment of EPL
• Women should avoid intercourse for 1-2 weeks after passage of pregnancy tissue is complete

Rh(D)-immune Globulin (RhIg)

• There are multiple conflicting society guidelines on whether to administer RhIg after early pregnancy
• ACOG suggests
  • Forgoing routine Rh testing and RhIg prophylaxis for patients at <12w0d of gestation who are undergoing abortion (managed with uterine aspiration or medication) or experiencing pregnancy loss (spontaneous or managed with uterine aspiration or medication)
  • Rh testing and RhIg administration can be individualized based on shared decision-making 
• SMFM recommends
  • If RhD testing and RhIg administration are feasible, offer RhD testing and RhIg administration in RhD negative patients
  • Based on evidence analysis, “Data on the risks of alloimmunization after early preg nancy loss or induced abortion do not convincingly demonstrate the safety of forgoing RhIg”

Learn More – Primary Sources:

ACOG Practice Bulletin 200: Early Pregnancy Loss 

ACOG Clinical Practice Update: Rh D Immune Globulin Administration After Abortion or Pregnancy Loss at Less Than 12 Weeks of Gestation

SMFM: RhD immune globulin after spontaneous or induced abortion less than 12 weeks of gestation

Manual vacuum aspiration: an outpatient alternative for surgical management of miscarriages. 

Early Pregnancy Loss: How to Make the Ultrasound Diagnosis

CLINICAL ACTIONS:

Early Pregnancy Loss (EPL) is defined as a nonviable intrauterine pregnancy identified before 13 weeks gestation. ACOG states that ultrasound is the “preferred modality to verify the presence of a viable intrauterine gestation.” The AIUM Practice Parameter (see ‘Learn More – Primary Sources’ below) states

With transvaginal imaging, cardiac motion is usually observed when the embryo is 2 mm or greater in length. If an embryo less than 7 mm in length is seen without cardiac activity, a subsequent scan in 1 week is recommended to determine viability

Ultrasound Guidelines: The following criteria are derived from the 2012 Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy

Diagnostic Criteria (Transvaginal)

• CRL of ≥7 mm and no heartbeat
• Mean sac diameter of ≥25 mm and no embryo
• Absence of embryo with heartbeat ≥2 weeks after a scan showing a gestational sac without a yolk sac
• Absence of embryo with heartbeat ≥11 days after a scan showing a gestational sac with a yolk sac

Suggestive, But Not Diagnostic (Transvaginal)  – Follow up at 7-10 days

• CRL <7 mm and no heartbeat
• Mean sac diameter of 16 to 24 mm and no embryo
• Absence of embryo with heartbeat 7 to 13 days after an ultrasound showing a gestational sac without a yolk sac
• Absence of embryo with heartbeat 7 to 10 days after an ultrasound scan showing a gestational sac with a yolk sac
• Absence of embryo for ≥6 weeks after last menstrual period
• Empty amnion: Amnion seen adjacent to yolk sac, with no visible embryo
• Enlarged yolk sac: >7 mm
• Small gestational sac in relation to the size of the embryo
  • <5 mm difference between mean sac diameter and CRL

SYNOPSIS:

Early pregnancy loss may present with clinical symptoms such as cramping and bleeding.  However, these findings can be present in normal, ectopic or molar pregnancies.  Ultrasound, if available, is a critical diagnostic modality but must be used in combination with clinical and laboratory findings, particularly serum β-hCG. For more information on recommended management when pregnancy location cannot be confirmed, see ‘Related ObG Topics’ below.

KEY POINTS:

• Document presence or absence of cardiac activity with M‐mode imaging or a 2D video clip
  • Pulsed Doppler ultrasound should not be used in the first trimester to “hear” the heartbeat
• ACOG highlights the limitations of the above guidelines including
  • Cut-offs may be overly conservative based on available evidence
• When taking care of patients with potential miscarriage
  • Consider a patient’s desire to have certainty of the loss prior to intervention
  • Discuss benefits of alternatives to surgical intervention as well as associated risks including
    • Spontaneous, unplanned passage of POCs
    • Potential anxiety
• Additional ACOG ‘suggestive’ criteria (not diagnostic) that also require follow up at 7 to 10 days
  • Slow fetal heart rate: <100 bpm at 5 to 7 weeks
  • Subchorionic hemorrhage

Learn More – Primary Sources:

ACOG Practice Bulletin 200: Early Pregnancy Loss 

AIUM Practice Parameter for the Performance of Limited Obstetric Ultrasound Examinations by Advanced Clinical Providers

Diagnostic criteria for nonviable pregnancy early in the first trimester. Society of Radiologists in Ultrasound Multispecialty Panel on Early First Trimester Diagnosis of Miscarriage and Exclusion of a Viable Intrauterine Pregnancy.

FDA Reviews Fluconazole in Pregnancy

SUMMARY:

Following a Danish study in 2016 by Nielsen et al. (JAMA, 2016), which concluded that fluconazole was associated with miscarriage, the FDA undertook a review to determine the safety of fluconazole in pregnancy. The FDA concluded (October 2019) that 

Based on our reviews of several studies, FDA has determined that the available data do not provide conclusive evidence of an increased risk of miscarriage or stillbirth with a single 150 mg dose of oral fluconazole (Diflucan)

We reviewed the 2016 study cited in this DSC and four additional epidemiological studies

We approved updated prescribing information in 2018 to include all available information on the use of fluconazole in women who are pregnant or breastfeeding

It adequately addresses the potential risk of harm to unborn babies

•  

CDC 2015 Sexually Transmitted Diseases Treatment Guidelines: Vulvovaginal Candidiasis

Vulvovaginal candidiasis occurs frequently during pregnancy. Only topical azole therapies, applied for 7 days, are recommended for use among pregnant women

• Imidazoles inhibit the enzyme that converts lanosterol to ergosterol, disrupting the structure and function of the fungal membrane
• Azole options can be found below in the ObG Related Entry ‘Diagnosis and Treatment of Vulvovaginal Candidiasis’ 

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Learn More – Primary Sources:

ACOG Practice Bulletin 215: Vaginitis in Nonpregnant Patients 

Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth

Use of oral fluconazole during pregnancy and the risk of birth defects

Exposure to fluconazole and risk of congenital malformations in the offspring: A systematic review and meta-analysis 

Fluconazole use and birth defects in the National Birth Defects Prevention Study

Does Antibiotic Use Increase Risk of Spontaneous Abortion?

PURPOSE:

This study by Muanda et al. (CMAJ, 2017) aimed to determine if antibiotic use during pregnancy is associated with spontaneous abortion.

METHODS:

Nested Case-Control Study

RESULTS:

Each case of spontaneous abortion (<20 weeks’ gestation) was matched for gestational age and year against 10 randomly selected controls.  Antibiotic use was compared to non-exposure and exposure to penicillins or cephalosporins. After adjusting for potential confounders, multiple types of antibiotic use were associated with an increased risk of spontaneous abortion: azithromycin (adjusted odds ratio 1.65, 95% CI 1.34-2.02) clarithromycin (adjusted odds ratio 2.35, 95% CI 1.90-2.91), metronidazole (adjusted odds ratio 1.70, 95% CI 1.27-2.26), sulfonamides (odds ratio 2.01, 95% CI 1.36-2.97), tetracyclines (adjusted odds ratio 2.59, 95% CI 1.97-3.41) and quinolones (adjusted odds 2.72, 95% CI 2.27-3.27).  These findings held whether comparing against non-exposure or exposure to penicillins or cephalosporins.  The authors note that one potential confounder, that of severity of infection, could not be assessed in this study. Nevertheless, they do suggest that macrolides (excluding erythromycin) quinolones, tetracyclines, sulfonamides and metronidazole may be associated with miscarriage prior to 20 weeks and policies may need to update guidelines to reflect these findings.

Learn More – Primary Sources:

Use of antibiotics during pregnancy and risk of spontaneous abortion

Is HPV Vaccination During Pregnancy Safe?

PURPOSE:

This study by Scheller et al. (NEJM, 2017) aimed to determine if exposure to the quadrivalent HPV vaccine during pregnancy leads to adverse outcomes.

METHODS:

Matched case control study

RESULTS:

Data from pregnant women in Denmark between 2006-2013 were extracted from national registries. Women who had been vaccinated during pregnancy were matched against women who had not been vaccinated in a 1:4 ratio. No increased risk was found for birth defects, spontaneous abortion, preterm birth, low birth weight, small size for gestational age or stillbirth. The authors conclude that exposure of quadrivalent HPV vaccine in pregnancy is safe and not associated with higher risk for adverse outcomes.

Learn More – Primary Sources:

Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes

Conceiving After Pregnancy Loss – Is Waiting Beneficial?  

FINDINGS:

A common question for providers following an early pregnancy loss is how long to wait before trying to conceive again.  The authors performed a secondary analysis of a previous randomized controlled trial (RCT) to determine if there is any benefit to waiting after miscarriage by comparing time to pregnancy and live birth among couples based upon the time interval from fetal loss to attempting to conceive.

The authors found that in women who tried to conceive within a 3 month interval rather than waiting:

• There was a statistically significant higher pregnancy rate – 68.9% compared to 51.1% (P< 0.01)
• There was a statistically significant higher live birth rate – 53.2% compared to 36.1% (P<0.001)
• After adjusting for age, race, BMI, education and subfertility, the 0-3 month group had a shorter time to achieve a pregnancy and shorter time to a pregnancy that resulted in a live birth
• Waiting longer than 12 months may increase time to achieve pregnancy
• There were no increased pregnancy complications in the 0 to 3 month group

SYNOPSIS:

The authors of this study (Obstet Gynecol, 2016) analyzed data from a well designed RCT that looked at the effects of preconception-initiated aspirin in women with prior losses (Lancet, 2014). In this present study the authors were able to compare 765 couples who attempted conception within 3 months to 233 couples who waited longer.  The authors did adjust for aspirin therapy, although results did not show any significant effect.

KEY POINTS:

• This results of this paper do not support delaying pregnancy after a loss
• The decision to conceive after loss may involve issues beyond physiological factors, which should be included in the informed decision making process between provider and patient
• Diagnosis code: N96

Learn More – Primary Sources:

Trying to conceive after an early pregnancy loss: an assessment on how long couples should wait

Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial