Stillbirth: Definition, Evaluation and Management

SUMMARY:

Stillbirth is a devastating adverse pregnancy outcome, occurring in 1 out of 160 deliveries in the United States.  It is often associated with non-modifiable, but common, risk factors such as race and pre-existing co-morbidities. Even after thorough evaluation, often the underlying cause remains unknown.  ACOG has provided a comprehensive consensus document that addresses risk factors, causes, and management that includes bereavement support

• Background & Definition of Stillbirth
• Social and Demographic Factors Affecting Stillbirth
• Causes of Stillbirth
• Stillbirth Evaluation Algorithm
• Key Components of Stillbirth Evaluation
• Management of a Stillbirth
• Principles of Bereavement Care
• Recurrence Risk and Antepartum Surveillance

Background & Definition of Stillbirth

• Fetal death is defined by the US National Center for Health Statistics as the delivery of a fetus showing no signs of life
• Recommended to report all fetal deaths at ≥20 weeks or 350 grams (50%ile for GA 20 weeks) | Reporting varies among states
• Excluded from stillbirth statistics
  • Terminations of pregnancy for fetal anomalies
  • Pre-viable premature rupture of membranes
• From 2013
  • Overall rate 5.95 per 1,000 live births
  • Similar rate between early (3 per 1,000 for 20 to 27 weeks) and late (2.97 per 1,000 for >28 weeks)
• Rate calculation
  • Calculated via number of stillbirths per 1,000 live births plus stillbirths
  • Using a denominator of those pregnant at a given gestational age would provide clinically valuable ‘prospective fetal mortality rate’

Social and Demographic Factors Affecting Stillbirth

• Demographics
  • Race | Multiple gestations | Past history of stillbirth | Male sex of fetus | Younger (<15) or Older (>35) maternal age
  • Older age: due to lethal congenital and chromosomal abnormalities | Increased risk if nulliparous and AMA
  • Younger age: Stillbirth rate for teenagers <15 is 15.88 per 1,000 (based on large US population-based cohorts)
  • Late-term pregnancies (vs 37 weeks)
    • Relative risk at 41 weeks: 2.9
    • Relative risk at 42 weeks: 5.1
• Co-morbidities
  • Diabetes (both pregestational and GDM | Hypertensive disorders | Obesity (BMI>30) and excessive weight gain | Substance abuse | IVF | Late-term & Post-term gestational age
  • Diabetes and hypertension account for 2 to 5x increased risk
  • Thrombophilia: Acquired thrombophilia (anti-phospholipid syndrome) associated with stillbirth but inherited thrombophilias generally are not
  • Substance abuse and smoking
    • Dose-related response, especially >10 cigarettes/day
    • Significantly associated with abruption and stillbirth
• Race: Non-Hispanic Black Women
  • Rate of stillbirth is approximately twice rate of other groups (10.53 per 1,000)
  • highest discrepancy at 20 to 27 weeks of gestation
  • Causes
    • Higher rates of co-morbidities (e.g. diabetes, hypertension)
    • PROM
    • Bias and racism
• Multiple Gestations
  • Risk approximately 2.5x that of singletons (14.07 vs 5.65 per 1000)
  • Risk of stillbirth with monochorionic > dichorionic
  • Triplets: 30.53 per 1,000
  • Causes
    • Complications unique to multiples such as twin transfusion
    • Congenital anomalies
    • FGR
• Past OB History
  • Increased risk in subsequent pregnancy: Approximately 5x
  • Previous adverse pregnancy outcomes such as preterm delivery, growth restriction, preeclampsia: Increases risk 1.7 to 2x
  • Not associated with prior cesarean section

Causes of Stillbirth

Perinatal Complications

• FGR: Especially <3%tile
• Abruption: 5 to 10% of stillbirths

Infection

• 10-20% of stillbirths
  • Most common: GBS, E.coli, Listeria monocytogenesis and syphilis
• Serology for toxoplasmosis, rubella, CMV, herpes not recommended

Umbilical Cord Events

• 10% of stillbirths
  • Examples: Vasa previa | Cord entrapment | Occlusion

Note: Nuchal cord not associated with increased risk of stillbirth

Genetics

• Chromosomal anomalies
  • 6 to 13% stillbirths | >20% if anatomic abnormalities are present
  • Most common chromosomal culprits: Trisomy 21 (31%) | Trisomy 18 (22%) | Trisomy 13 (8%) | Monosomy X (22%)
  • Because cells may no longer be viable at time of test, culture failure will often occur limiting utility of standard karyotyping | Amniocentesis or CVS prior to delivery can increase chance of obtaining a result because amniocytes and placental cells may still be viable (85% vs 28% yield)
  • Microarray analysis (preferred): Based on DNA technology and therefore does not require living tissue: Increases diagnostic yield to 41.9% of all stillbirths
• Single gene disorders: Some single gene disorders are associated with stillbirth
  • Routine testing not currently recommended
  • Clinical scenario and family history are used to guide molecular testing and workup
• Birth defects
  • Dysmorphic features and/or skeletal anomalies: 20%
  • Major malformations: 15 to 20%

Stillbirth Evaluation  Algorithm

• All stillbirths
  • Fetal autopsy (can include imaging) | Provides additional clinical information in approximately 30% of cases   
  • Placental pathology (gross and microscopic) including cord and membranes | Provides additional clinical information in approximately 30% of cases
  • Genetics | Abnormalities seen in 8% of cases
• If no other cause identified – add
  • Antiphospholipid antibody testing
  • Fetal-maternal hemorrhage testing
  • Other tests as indicated
• FGR or hypertensive disorder – add
  • Antiphospholipid antibody testing
  • Fetal-maternal hemorrhage testing
  • Other tests as indicated
• Suspected fetal anomaly – add
  • Other testing including molecular genetics based on findings
• Intrapartum stillbirth – add
  • Antiphospholipid antibody testing
  • Fetal-maternal hemorrhage testing
  • Other tests as indicated
• Preterm labor | Chorioamnionitis | PPROM | Other Clinical scenarios – add
  • Other tests as indicated based on clinical scenario
  • “Remaining tests of limited utility”

KEY POINTS:

Key Components of Stillbirth Evaluation

• Fetus & Placenta
  • Weight | HC | Fetal length | Placenta weight
  • Document abnormalities
• Obtain genetics consent: Collect ≥1 of the following specimens in sterile tissue medium of LR (not formalin fixative)
  • Amniotic fluid (preferred if delivery not imminent)  
  • Placental block 1cm x 1cm taken from below cord insertion site
  • Umbilical cord segment of 1.5cm
  • Internal fetal specimen – costochondral junction or patella | Do not send skin (cells usually will not grow)
  • Obtain consent for fetal autopsy
    • If consent not given: Limit investigation to external evaluation (by trained perinatal pathologist)
    • May include photographs and imaging (X-ray, ultrasound)
  • Maternal evaluation
    • Obstetric history (previous and present)
    • Comorbidities
    • Exposures: Smoking | Alcohol | Drug or medication use
    • Genetics work-up including 3 generation pedigree
    • Personal or family history: Arrhythmias | Including sudden death (e.g. for for prolonged QT syndrome)
  • Lab testing
    • Kleihauer-Betke or flow cytometry at time of stillbirth
    • Syphilis  
    • Lupus anti-coagulant | Anticardiolipin | Beta-2 glycoprotein IgG and IgM antibodies (retest at 12 weeks if positive)
    • Based on clinical indication: Indirect Coombs | Glucose screening for LGA | Toxicology if abruption or suspected drug use

Management of a Stillbirth

• Method and timing of delivery depend upon gestational age and maternal preference
  • Timing of delivery is not critical because coagulopathies uncommon
• Second trimester
  • Medical induction of labor: D&C may be necessary for placental removal
  • D&E: May limit efficacy of autopsy
• <20 weeks
  • Mifepristone: 200 or 600mg PO plus misoprostol
    • Evidence limited between 24 and 28 weeks
• <28 weeks gestation
  • Vaginal misoprostol: 400 to 600mcg q3 to 6 hours | <400mcg associated with decreased efficacy
  • Addition of mifepristone 200 or 600mg PO 24 to 48 hours before misoprostol
    • <20 weeks: Good evidence to add  
    • 24 to 28 weeks: Evidence limited | reduces time to delivery but doesn’t improve overall efficacy compared to misoprostol alone
  • ≥28 weeks: Use standard obstetric induction protocols
• Prior uterine scar
  • < 24 weeks: Vaginal misoprostol
  • 24 to 28 weeks: Further research required to determine safety and optimum dose “in whom lower doses of misoprostol (200 micrograms per dose) may be preferred”
  • ≥28 weeks: Use standard obstetric induction protocols including cervical ripening with Foley
  • Women with increased risk of uterine rupture (e.g. classical): “Repeat cesarean delivery is a reasonable option” | Discuss risks and benefits

Principles of Bereavement Care

• Support services: Consider referral to a bereavement counselor, peer support group, or mental health professional
  • Feelings of guilt and/or anger are common
• Additional considerations
  • Good communication | Shared decision making | Recognition of parenthood | Acknowledge grief
  • Be aware of
    • Options including burials, cremation, and funerals | Emotional and practical support | Health professionals trained in bereavement care | Importance of self-care for health professionals

Recurrence Risk and Antepartum Surveillance

• Evidence is limited however appears to be increased risk for recurrence
• Antepartum surveillance
  • Comorbidities: Use recommended management guidelines
  • Obesity: Prepregnancy BMI of 35.0 to 39.9, consider beginning weekly antenatal fetal surveillance by 37w0d | prepregnancy BMI ≥40, consider beginning weekly antenatal fetal surveillance by 34w0d (ACOG PB 230)
  • Previous stillbirth ≥32w0d: Once or twice weekly beginning  at 32w0d or 1 to 2 weeks prior to gestational age of last stillbirth
  • Previous stillbirth <32w0d:  Individualize | Consider potential morbidity and cost for delivery due to false positive results
  • Growth ultrasound at 28 weeks to screen for fetal growth restriction
• Fetal kick counts
  • Encourage awareness of fetal movement patterns
  • Shared decision making recommended due to lack of data to make specific recommendations
• Timing of delivery
  • 39w0d
  • If other comorbidities present: Time delivery as recommended for particular complication (see ‘Related ObG Entries’ below)
  • Maternal anxiety may warrant early term delivery (37 0/7 to 38 6/7) in women who are educated regarding increased fetal risks
  • Amniocentesis to confirm fetal lung maturity is generally not recommended

Note: While screening for acquired thrombophilia (lupus anticoagulant, IgG and IgM for both anticardiolipin and β2-glycoprotein antibodies) is recommended, routine aspirin use to prevent stillbirth is not advised due to lack of evidence for efficacy

Learn More – Primary Sources:

ACOG: Obstetric Care Consensus No 10: Management of Stillbirth

ACOG Practice Bulletin 230: Obesity in Pregnancy

NICHD: Working to Address the Tragedy of Stillbirth

COVID-19 and Risk for Stillbirth and Preterm Birth

PURPOSE:

• Khalil et al. (JAMA, 2020) analyzed the association between COVID-19 and risk for stillbirth and preterm delivery        

METHODS:

• Retrospective cohort study
  • St George’s University Hospital, London (UK)
• Compared 2 time periods
  • Prepandemic: October 1, 2019, to January 31, 2020
  • Pandemic (following first reported cases in UK of COVID-19): February 1, 2020, to June 14, 2020
• Outcomes
  • Stillbirth | Preterm birth | Cesarean delivery | NICU admission
  • Repeat analysis performed with exclusion of terminations for fetal anomalies (IN UK, stillbirth includes late termination ≥24 weeks)

RESULTS:

• Prepandemic
  • 1681 births | 1631 singletons | 22 twins | 2 triplets
• Pandemic period
  • 1718 births: 1666 singleton | 26 twins
• Nulliparity was less common during the pandemic period (P < .001)
  • Prepandemic: 52.2%
  • Pandemic: 45.6%
• Fewer pregnancies were complicated by hypertension during the pandemic period (P = .005)
  • Prepandemic: 5.7%
  • Pandemic period: 3.7%
• Stillbirth incidence was increased during the pandemic period
  • Prepandemic: 2.38 per 1000 births (n=4)
  • Pandemic: 9.31 per 1000 births (n=16)
  • Difference: 6.93 per 1000 births (95% CI, 1.83-12.0; P = .01)
• Stillbirth incidence remained elevated after exclusion of terminations for anomalies
  • Prepandemic: 1.19 per 1000 births
  • Pandemic: 6.98 per 1000 births
  • Difference: 5.79 (95% CI, 1.54-10.1; P = .01)
• There were no significant differences identified for the following outcomes
  • Preterm deliveries (<37 weeks)
  • NICU admission
• No cases of stillbirth were associated with COVID-19
  • None of the mothers had symptoms associated with COVID-19
  • No placental or postmortem exams suggested of COVID-19
  • Note: Universal testing for SARS-CoV-2 only began May 28, 2020

CONCLUSION:

• Stillbirth rates were increased during the pandemic vs prepandemic period
  • One important limitation noted by authors is lack of data on cause of the stillbirth
• Possible reasons for increase in stillbirth rate
  • Increase may still be due to SARS-CoV-2 infection in asymptomatic women (who would not have been tested)
  • Women may have deferred care due to COVID-19 concerns (e.g. delaying care to avoid infection)
  • Possible change in practice resulting in fewer antenatal visits or ultrasound assessments
  • Chance: Study time frame was short | If study was longer, difference perhaps would resolve
  • Hospital may have received more referrals 

Learn More – Primary Sources:

Change in the Incidence of Stillbirth and Preterm Delivery During the COVID-19 Pandemic