Intrauterine Fetal Death

Hale Teka, M.D,
Resident Physician

• Stillbirth
̶ ACOG (US): Pregnancy loss after
• 22 weeks of gestational age
• > 500 grams
̶ Other definition in US
• > 350 grams
̶ WHO: Pregnancy loss after
• > 500 grams
̶ In Ethiopia pregnancy loss after
• > 1000 grams Hale T., M.D., Resident Physician 2Tuesday, April 3, 2018

Hale T., M.D., Resident Physician 3Tuesday, April 3, 2018

• Incidence
̶ In Ethiopia  33 per 1000 births (EDHS 2016)
̶ In US  1 in 1, 600 deliveries
̶ In the world  3.2 million (after 28 weeks gestation)
• 98% in low and middle income countries

Risk Factors
• Factors associated with increased risk of fetal death:
̶ Occurs more often in primiparous women of a given age
̶ Extremes of age
̶ Extremes of parity
̶ Offspring of subfertile couples and infertile couples conceived
through ART
̶ Previous history of IUGR delivery before 32 weeks
̶ Hispanic and black races
̶ Multiple pregnancies
̶ Previous stillbirth
̶ Previous cesarean section  controversial
̶ Obesity
̶ Smoking

Risk factors cont’d
̶ Alcohol intake
̶ Illicit drug use
̶ Low maternal education level
̶ Inadequate ANC contacts
̶ Previous history of abortion
̶ Maternal medical disorders
̶ Maternal AB blood group
̶ Not living with a partner

Genetic Factors
̶ Chromosomal abnormalities  detected in 8% to 13% of
stillbirths
̶ Amniocentesis of stillborn  80% successful culture for
chromosomal analysis
̶ The major yield of autopsy for a stillborn fetus is detection of an
unrecognized mendelian explanation

Maternal Related Causes of Stillbirth

• Infection
̶ 10-20% of stillbirths in developed countries, more on developing
̶ Infectious agents may result in stillbirth by producing
• Direct fetal infection,
• Placental dysfunction, or
• Severe maternal illness
̶ Two routes of infection
• Ascending  most common
• Hematogenous spread

Spirochetal disease
• Syphilis
• Leptospirosis
• Lyme disease
Bacterial diseases
• E-coli
• Group B-streptococci
• Ureaplasma urealyticum
• Mycoplasma hominus
• Bacteroides spps
• Gardnerella
• Mobiluncus spps and
• Various enterococci

Protozoal
• Malaria
• Toxoplasmosis
• Lysteria monocytogenes
Viral
• Parvovirus infection (Erythema
infectiosum)
• Coxackieviruses
• Echoviruses
• Cytomegaloviruses  most
common
• Ljungan virus

• Syphilis
̶ is still responsible for some stillbirths, especially in endemic areas
̶ Treponema pallidum, the causative agent, can cross the
placenta and infect the fetus after 14 weeks’ gestation, with risk
for fetal infection increasing with gestational age
̶ About 50% of infected fetuses die in utero, and an additional
27% are born with congenital syphilis

• Hypertensive disorders of pregnancy
̶ Associated with nearly 9% of all stillbirths
̶ The risk for stillbirth increases with the severity of hypertensive
disorder
̶ Women with chronic hypertension with superimposed
preeclampsia have the highest perinatal mortality rate
̶ PMR
• 21 to 22 per 1000 with severe preeclampsia or eclampsia,
• 70 per 1000 with the HELLP syndrome
• 290/1000 in one study in Ethiopia

• Diabetes Mellitus
̶ Associated with nearly 4% of all stillbirths
̶ In women with poor glycemic control, stillbirths occur most
commonly as a result of
1. Congenital abnormalities,
2. Placental insufficiency or fetal growth restriction,
3. Macrosomia or polyhydramnios, or
4. Obstructed labor (intrapartum stillbirth)

Maternal Hyperglycemia
Fetaly hyperinsulinemia
Fetal Hyperglycemia
The end result may be: Stillbirth
Insulin stimulates excessive fetal growth and
metabolic acidosis

• Thyroid Disease
̶ Graves disease,
• The most common cause of hyperthyroidism
• Results in fetal or neonatal thyrotoxicosis in about 1% of cases
 because of the transplacental passage of thyroid-
stimulating immunoglobulins
• It is associated with an increased stillbirth rate of 7%
• Fetal thyrotoxicosis can result in stillbirth as a result of
 Fetal growth restriction or
 Fetal tachycardia resulting in nonimmune hydrops

̶ Overt hypothyroidism places women at increased risk for
• pregnancy-induced hypertension,
• SGA infants, and
• stillbirth with a rate of 12/1000 to 20/1000
̶ Controversial
• Subclinical hypothyroidisim (defined as TSH values at the
97.5th percentile and normal free thyroxine)
• Euthyroid women with high serum antithyroid peroxidase
(TPO) antibody concentrations

• SLE
̶ Stillbirth rate 40-150 per 1000
̶ Fetal prognosis appears to depend primarily on maternal
disease activity and is increased with active renal disease
̶ Another cause of stillbirth is neonatal lupus erythematosus
congenital AV block
• This occurs in 1% to 5% of infants born to women with
autoantibodies to SSA/Ro and SSB/La as a result of their
transplacental passage which can cause permanent
destruction of the AV conduction system and scarring of the
endocardium
• Associated with the development of hydrops in up to 40% of
cases detected in utero, with a third resulting in stillbirth

̶ The presence of antiphospholipid antibodies and a prior fetal
loss are also significant predictors of subsequent stillbirth in
women with SLE
̶ Antiphospholipid antibodies are present in over a third of
patients with SLE and are associated with an increased risk for
thrombosis and damage to the uteroplacental vasculature
• A review of 554 women with SLE found that fetal death was
more common in those with antiphospholipid antibodies (38%)
than in those without antibodies (16%).

• Renal Disease
̶ Depends on the severity of renal impairment and the presence
of hypertension
̶ Maternal creatinine levels
• < 1.4 and 1.4 – 2.4  9%
• > 2.4  36%
̶ Presence of hypertension raises stillbirth rate by 10 fold
• Renal disease  50%
• Renal disease with hypertension  80%
̶ Only 52% live birthrate in women who required dialysis
̶ Outcomes improved if renal transplant before pregnancy

• Intrahepatic Cholestasis of Pregnancy
̶ The most common form of noninfectious liver disease
̶ Stillbirth rate 12-30 per 1000

• Thrombophilias
̶ APAS
• In a study of 366 high-risk women with a history of two
pregnancy losses and no more than one live birth, more than
80% of APLA-positive women experienced at least one fetal
death (at ≥10 weeks of gestation), whereas only 24% of APLA-
negative women experienced a fetal death
̶ Heritable thrombophilias
• FVL mutation
• Deficiencies of the anticoagulant proteins antithrombin and
protein C and S
• Increased levels of maternal von Willebrand factor

Fetal Related Causes of Stillbirth

Conditions Related to the fetus
• Red Cell Alloimmunization
̶ Now decreasing because of anti-D
̶ Sesitization to non-D antigen continues to occur
• Platelete Alloimmunization
̶ When severe, fetal alloimmune thrombocytopenia (platelet count <50
× 109/L) results in intracranial hemorrhage and stillbirth
• Chromosomal Abnormalities
̶ Overall, fetal cytogenetic abnormalities account for 6% to 13% of all
stillbirths
̶ Distribution of chromosomal abnormalities associated with stillbirths (in
a study):
• Trisomy 21, 31%; monosomy X, 22%; trisomy 18, 22%; trisomy 13, 6%;
and other chromosomal abnormalities, 19%

̶ Confined placental mosaicism (CPM)
• Spontaneous abortion, stillbirth, and fetal growth restriction,
occurs in 15% to 20% of affected pregnancies
̶ Fetal single-gene and mendelian disorders may also result in
stillbirth
• Autosomal recessive disorders such as hemoglobinopathies
(e.g., α-thalassemia);
• Metabolic diseases such as
Smith-Lemli-Opitz syndrome;
Glycogen storage diseases; peroxisomal disorders; and
amino acid disorders have all been associated with
stillbirth by different mechanisms
• X-linked dominant mutations may be lethal in male fetuses.

̶ Lastly, autosomal dominant disorders caused by spontaneous
mutations (e.g., skeletal dysplasias) or inherited parental
mutations (e.g., prolonged QT interval) may contribute to
stillbirth
̶ High levels of circulating progesterone, a hormone that prolongs
the QT interval, may contribute to higher lethality of these
mutations in affected fetuses

• Structural Anomalies
̶ About 25% of stillborn have detectable structural anomalies as
fetal causes of death
̶ Of particular note, amniotic band sequence is a sporadic
condition of uncertain etiology that refers to the entrapment of
fetal parts by disrupted amnion and often results in stillbirth
̶ Findings are variable and include amputations, constrictions,
clefts, and deformations

• Fetomaternal Hemorrhage
̶ Fetomaternal hemorrhage, the transplacental passage of fetal
blood cells to the maternal circulation, has been attributed as
the cause of about 4% of stillbirths
̶ Acute fetomaternal hemorrhage leads to severe fetal anemia,
ultimately resulting in cardiovascular decompensation, stroke,
disseminated intravascular coagulation, and stillbirth
̶ A large fetomaternal hemorrhage will cause severe fetal
anemia and in some cases fetal death due to exsanguination
̶ A transfusion of more than 25% of fetal blood volume (20 mL/kg
or greater) has been associated with high rates of stillbirth (26%)
as well as with neonatal anemia requiring transfusion (21.7%)

• Fetal Growth Restriction
̶ Fetal growth restriction (FGR) is not an actual cause of stillbirth;
̶ Pathologic associations IUFD and stillbirth exist
̶ Most pregnancies complicated by FGR result in live births, so
FGR is a risk factor rather than a cause of stillbirth
̶ It is a clue that should prompt evaluation for associated
conditions, such as preeclampsia or placental insufficiency,
rather than being a diagnosis itself

Placental Related Causes of Stillbirth

• Placental etiology
̶ Beyond uteroplacental insufficiency associated with FGR, other
placental causes of stillbirth include developmental
abnormalities such as placenta previa, vasa previa, and
neoplasms
̶ Vasa previa occurs when submembranous fetal vessels cross the
endocervical os, and it may cause stillbirth as a result of rupture
of fetal vessels during labor or rupture of membranes, leading to
fetal exsanguination
̶ Fetal blood may pass through the vagina rather than entering
the maternal circulation
̶ Histologic evaluation of the placenta and cord confirms the
diagnosis

̶ Acute circulatory disorders of the placenta associated with
stillbirth may be on the maternal or fetal side
̶ A major maternalside circulatory disorder is abruptio placentae,
which may be considered a cause of death when there are
clinical signs of a large abruption or when histopathologic
examination of the placenta shows extensive signs of abruption
• The adjusted RR was 8.9 (95% CI, 6.0 to 13.0) for stillbirth in a
cohort of women with abruption
• The subset of women with greater than 75% placental
separation had an adjusted RR for stillbirth of 31.5 (95% CI, 17.0
to 58.4)

Umblical Cord Related Causes of Stillbirth

• Umblical Cord Pathology
̶ Umbilical cord abnormalities account for 3% to 15% of stillbirths
̶ Velamentous insertion of the umbilical cord occurs when vessels
insert on the membranes rather than on the placenta
̶ It may cause stillbirth if it leads to a vasa previa
̶ With furcate insertion of the umbilical cord, the umbilical cord
blood vessels lose the protective cover of Wharton’s substance
before entering the chorionic plate
̶ Because of splaying of the vessels and their wide distribution,
they are exposed to external trauma
̶ During labor and delivery they may rupture and twist,
consequently compromising the placental circulation and
resulting in stillbirth

Villamentous cord insertion Villamentous cord insertion

̶ Umbilical cord occlusion results in cessation of blood flow to the
fetus
̶ The mechanisms whereby cord accidents could lead to stillbirth
include:
• Intermittent disruption of blood flow such as cord prolapse,
• Fetal blood loss through cord hemorrhage,
• Intrinsic cord abnormalities, and
• Entanglement of the cords in the case of monochorionic twins
̶ Umbilical cord prolapse is an obstetric emergency that causes
stillbirth and is defined as presentation of the cord in advance of
the presenting fetal part

̶ Umbilical cord torsion has been reported as a cause of fetal
death and is seen most frequently at the fetal end of the cord
̶ If the torsion occurred before the death, the cord should remain
twisted after separation of the fetus from the placenta
̶ The involved cord is congested and edematous, often with
evidence of thrombosis of the cord vessels
̶ Other, uncommon causes of death include rupture, strictures,
and hematomas of the umbilical cord

̶ Cord entanglement in the form of nuchal cords occurs in up to
30% of uncomplicated pregnancies
̶ Examination of a tight knot may show:
• Grooving of the cord
• Constriction of the umbilical vessels in long-standing cases,
• Edema, congestion, or thrombosis in more acute ones
̶ It is difficult to attribute any adverse outcome to the presence of
a knot in the absence of such changes
̶ Thus, the isolated finding of a nuchal cord or a true knot at the
time of birth is insufficient evidence that cord accident is the
cause of the stillbirth

• Complications of Multifetal Gestation
̶ 8-10 fold higher in multiples
• TTTS
• TRAP
• MCMA placentation
• Preterm birth,
• Growth impairment,
• Malformations,
• Genetic abnormalities, and vascular anastomoses.

Intrapartum Stillbirth
• Incidence
̶ 1 in 1000 in developed countries
̶ 7.5 in 1000 in developing countries
̶ 20 – 25 in 1000 in sub-Saharan countries
̶ 1/10th of stillbirths in high income countries intrapartum
̶ 50% of stillbirths in low income countries intrapartum

Causes of Stillbirth
• Cause
̶ Causes of stillbirth are catergorized as:
• Probable
• Possible
• Present
̶ Probable cause of stillbirth if it had a high likelihood of directly
causing the fetal death;
̶ if a condition was not a direct cause of the stillbirth, but possibly
involved in a pathophysiologic sequence that led to the fetal
death, it was considered a possible cause of death
̶ Potentially important conditions that were present but did not
meet criteria for probable or possible causes of death were
recorded as present

̶ A probable cause of death was found in 60.9% of stillbirths, and
possible or probable cause was found in 76.2% when a
complete evaluation was performed.
• The distribution of causes of death were as follows:
̶ Obstetric conditions, 29.3%;
̶ Placental abnormalities, 23.6%;
̶ Fetal genetic/structural abnormalities, 13.7%;
̶ Infection, 12.9%;
̶ Umbilical cord abnormalities, 10.4%;
̶ Hypertensive disorders, 9.2%; and
̶ Other maternal medical conditions, 7.8%.

Diagnosis and Evaluation of Stillbirth

Diagnosis and Evaluation
• Details of the Pregnancy
̶ Gestational age at death (based on accurate dating criteria
and determination of timing of death)
̶ Medical conditions complicating pregnancy
• Hypertensive disorders
• Gestational diabetes
• Cholestasis of pregnancy
• Viral illness

̶ Pregnancy complications
• Multiple gestation
• Preterm labor
• Rupture of membranes
• Fetal structural or chromosomal abnormalities
• Infections
• Trauma
• Abruption
̶ Maternal serum marker screen, ultrasound findings

• Maternal Medical History
̶ Chronic disease
̶ Diabetes
̶ Hypertension
̶ Autoimmune disease (systemic lupus erythematosus)
̶ Cardiopulmonary disease
̶ Thyroid disease
• History of pertinent acute conditions
̶ Prior venous thromboembolism
̶ Cigarette, alcohol, or substance use
• Known genetic abnormalities
̶ Balanced translocations
• Single gene mutations

• Pregnancy History
̶ Pregnancy losses
̶ Previous stillbirth or neonatal death
̶ Previous pregnancy complicated by
• Fetal growth restriction
• Congenital anomalies
• Abruption
• Hypertension

• Family History
̶ Stillbirth or recurrent miscarriage
̶ Genetic syndromes
̶ Developmental delay or mental retardation
̶ Significant medical illnesses (pulmonary embolism, deed venous
thrombosis)

Hale T., M.D., Resident Physician 50
Evaluation of a Stillbirth
Tuesday, April 3, 2018

Prediction of Stillbirth
• Maternal
̶ Race
̶ Parity
̶ Advanced maternal age
̶ BMI
• Biochemical markers
̶ Low PAPP-A
̶ Elevated MSAFP
̶ elevated β-human chorionic gonadotropin (β-hCG)
• Imaging
̶ Doppler imaging of the uterine artery
̶ Detection of FGR

Prevention of Stillbirth
• Managing maternal medical disorders
• Low dose asprin, prophylactic heparin (LMWH)
• Weight reduction to achieve a normal BMI

MANAGEMENT OF SUBSEQUENT PREGNANCY AFTER STILLBIRTH

Reference
1. Robert K. Creas, et al., CREASY & RESNIK'S MATERNAL-FETAL
MEDICINE Principles and Practice 7ed2014: Saunders, an imprint of
Elsevier Inc.
2. Gabbe, et al., Obstetrics: Normal and Problem Pregnancies
7ed2017: Elsevier, Inc.
3. CUNNINGHAM, et al., Williams Obstetrics 24 ed2014: McGraw-Hill
Education.

Thank you for listening!
60Hale T., M.D., Resident PhysicianTuesday, April 3, 2018

Intrauterine Fetal Death

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