What are the causes of intrauterine fetal death (IUFD)?

Causes of Intrauterine Fetal Death (IUFD)

The causes of IUFD are multifactorial, with placental pathology being the most common identifiable cause (found in up to 65% of cases when investigated), followed by umbilical cord abnormalities (particularly hypercoiling), fetal genetic abnormalities, infections, and maternal conditions—though up to 60% remain unexplained when comprehensive investigation is not performed 1.

Major Categories of IUFD Causes

Placental Causes (Most Common)

Placental pathology represents the leading identifiable cause when properly investigated:

• Maternal vascular malperfusion (MVM): The most frequent placental lesion (30% of cases), including placental infarction, retroplacental hematomas, and features of uteroplacental insufficiency 2
• Placental abruption: Accounts for approximately 7% of term IUFDs 3
• Combined maternal and fetal vascular malperfusion: Found in 10% of cases 2
• Placental infections: Can cause vascular damage leading to hypoxia 4

The high diagnostic yield of placental pathology (64.6% usefulness) makes it the single most valuable investigation 1.

Umbilical Cord Abnormalities (Second Most Common)

Cord abnormalities are present in up to 72.9% of term IUFD cases and represent 27-54% of identifiable causes:

• Hypercoiling: The most frequent specific cord finding (28.6% of cases) 3, 5
• Umbilical cord constriction/true knots: Increasingly recognized as a cause 5
• Velamentous cord insertion: Less common but significant 5
• Cord entanglement: Particularly in cases with reduced fetal movement 3

Important caveat: The prevalence of cord abnormalities as a cause has been relatively increasing in recent years (from 30% to 54.5%), likely due to improved prenatal detection of other causes like fetal anomalies 5.

Fetal Genetic and Structural Abnormalities

• Chromosomal abnormalities: Genetic testing has 11.9% diagnostic usefulness 1
• Congenital malformations: Previously the leading cause (43% in 2001-2007), now reduced to 8.6% due to improved prenatal diagnosis and termination options 5, 6
• Non-lethal malformations may be discovered at postmortem even when another clear cause exists 1

Maternal Medical Conditions

Key maternal factors associated with IUFD include:

• Hypertensive disorders: Preeclampsia present in 39% of IUFD cases 7
• Diabetes: Both pre-gestational and gestational diabetes (glucose screening has only 1.6% diagnostic yield) 1, 7
• Obesity: Significant independent risk factor 7
• Antiphospholipid antibodies: Testing has 11.1% diagnostic usefulness; acquired thrombophilia shows stronger association than heritable thrombophilia 1

Infectious Causes

Common infectious organisms in developed countries include 1:

• Escherichia coli
• Klebsiella pneumoniae
• Group B Streptococcus
• Enterococcus
• Mycoplasma/Ureaplasma
• Haemophilus influenzae
• Chlamydia
• Viral infections (HSV, CMV) can cause placental vascular damage 4

However, infectious screening has low diagnostic yield (parvovirus 0.4%, syphilis 0.2%) 1.

Feto-Maternal Hemorrhage

• Kleihauer test has 6.4% diagnostic usefulness 1
• Should be performed but rarely identifies the cause

The Problem of Unexplained IUFD

Critical limitation: Conventional diagnostic systems fail to identify a specific cause in approximately 50-60% of IUFDs 1, 3. This high rate of "unexplained" deaths primarily reflects:

• Inadequate investigation: In one recent study, only 47.1% of cases had placental pathology performed, yet 61.4% were classified as "unknown cause" 3
• Lack of comprehensive postmortem examination
• Absence of standardized classification systems

When comprehensive investigation is performed (postmortem + placental histology), a possible or probable cause can be identified in up to 75% of cases 1.

Gestational Age Patterns

The causes vary by gestational age:

• Early preterm (<34 weeks): MVM predominates (23% of cases) 2
• Late preterm (34-37 weeks): MVM remains most common (5% of cases) 2
• Term (≥37 weeks): Idiopathic causes become most common, followed by cord abnormalities 2
• Most term IUFDs occur at 38-39 weeks gestation 3, 7

Clinical Presentation

Reduced fetal movement is reported in 61.4% of IUFD cases and represents a critical warning sign 3.

Essential Diagnostic Approach

All women with late IUFD should be offered three core investigations 1:

1. Placental pathology (highest yield: 64.6%)
2. Postmortem examination (42.4% yield)
3. Genetic testing (11.9% yield)

Secondary investigations with lower but meaningful yield:

• Antiphospholipid antibody testing (11.1%)
• Kleihauer test for FMH (6.4%)

The distinction between underlying cause (disease process), mode of death (e.g., asphyxia), and classification (e.g., growth restriction) is important for accurate diagnosis and future pregnancy counseling 1.