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

• Risk and dosage for women undergoing EPL
  • Risk is low
  • ‘Consider’ for women undergoing EPL, especially later in first trimester
  • If given, administer ‘at least’ 50 micrograms Rh(D)-immune globulin within 72 hours

Note: In the case of medical management, the ACOG Guideline states that “Women who are Rh(D) negative and unsensitized should receive Rh(D)-immune globulin within 72 hours of the first misoprostol administration”

• Surgical
  • Higher risk of alloimmunization
  • Patients ‘should receive’ at least 50 micrograms Rh(D)-immune globulin

Learn More – Primary Sources:

ACOG Practice Bulletin 200: Early Pregnancy Loss 

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