Causes of Missed Miscarriage
Chromosomal abnormalities are the primary cause of missed miscarriage, accounting for approximately 67% of cases, with trisomy 16, monosomy X (Turner syndrome), and triploidy being the most common abnormalities. 1
Chromosomal and Genetic Causes
The most frequent underlying etiology involves embryonic chromosomal defects. Among numerical abnormalities, trisomy 16 is the most prevalent, followed by 45,X (Turner syndrome) and triploidy. Structural chromosomal abnormalities, particularly deletions, also contribute significantly 1. Single gene mutations may additionally play a role, with variants in genes critical for early embryonic development—including those involved in chordate embryonic development, cell proliferation, and forebrain development—identified through whole-exome sequencing 2. Specific insertional translocations, such as between chromosomes 1 and 7, have been documented as inherited causes across multiple generations 3.
Maternal Risk Factors
Metabolic and Endocrine Factors
- Advanced maternal age (>35 years) increases risk substantially (AOR: 4.23) 4
- Obesity (BMI ≥30 kg/m²) shows strong association (AOR: 3.67) 4
- Being underweight or overweight independently increases chromosomal abnormality risk 1
- Gestational diabetes mellitus significantly elevates risk (AOR: 3.89) 4
- Elevated thyroid-stimulating hormone levels correlate with increased embryonic chromosomal abnormalities 1
- Vitamin D deficiency or insufficiency (25-hydroxyvitamin D levels) represents an independent risk factor 1
Anatomical and Hormonal Factors
- Genital abnormalities compromise embryonic development 5
- Luteal insufficiency impairs early pregnancy maintenance 5
Infectious Causes
While the 1995 CDC guideline mentions uterine infection (chorioamnionitis) as a possible cause after invasive procedures like CVS or amniocentesis, infection rates are extremely low (<0.1%) in these contexts 6.
Reproductive History
- Previous spontaneous abortion history 5
- Primiparity 5
- History of placental dysfunction in prior pregnancies increases recurrence risk 7
Paternal Factors
- Spouse semen abnormalities contribute to embryonic developmental failure 5
Lifestyle and Environmental Exposures
- Smoking 5
- Alcohol consumption 5
- Perming or dyeing hair during pregnancy 5
- Radiation overload 5
- Excessive intimate contact with pets 5
Psychosocial Factors
- High perceived stress levels show association, though not independently significant in multivariate analysis 4
Clinical Implications
The multifactorial nature of missed miscarriage demands comprehensive preconception assessment focusing on metabolic optimization, particularly weight management, vitamin D supplementation, and thyroid function screening. Women with advanced age, obesity, or metabolic disorders require heightened surveillance. When chromosomal abnormalities are suspected or confirmed, genetic counseling becomes essential for future pregnancy planning.
The evidence demonstrates that approximately one-third of missed miscarriages remain unexplained even after thorough investigation 8, though comprehensive evaluation including placental pathology (64.6% diagnostic yield), post-mortem examination (42.4% yield), and genetic testing (11.9% yield) maximizes diagnostic accuracy 8.
Common pitfall: Failing to recognize that multiple sequential or concurrent factors often contribute rather than a single isolated cause. Clinicians should avoid premature diagnostic closure and pursue comprehensive investigation including placental pathology, genetic testing, and maternal metabolic screening to identify modifiable risk factors for future pregnancies.