What is the most common genetic reason for early pregnancy loss (EPL) in the first trimester in a female patient of childbearing age?

Most Common Genetic Cause of First Trimester Early Pregnancy Loss

Chromosomal abnormalities, specifically aneuploidies (abnormal chromosome number), are the most common genetic cause of first trimester early pregnancy loss, accounting for approximately 50-60% of all cases, with trisomies being the predominant type. 1, 2, 3

Specific Chromosomal Abnormalities

Numerical chromosomal abnormalities (aneuploidies) represent the overwhelming majority of genetic causes:

• Aneuploidies account for 60.4% of all chromosomal variants detected in first trimester pregnancy loss, with trisomies being the most frequent type 4
• Autosomal trisomies (extra copies of chromosomes) are the most common specific abnormality, particularly trisomy 16, followed by trisomies 21,22, and 15 2, 3
• Polyploidies (complete extra chromosome sets like triploidy) account for approximately 6.9% of chromosomal variants 4
• Chromosomal mosaicism (multiple cell lines with different chromosomal compositions) represents about 5.5% of cases 4

Structural Chromosomal Abnormalities

Structural alterations are much less common than numerical changes:

• Pathogenic copy number variations (CNVs) involving deletions or duplications of chromosomal segments account for 8.2% of chromosomal variants 4
• Structural rearrangements including translocations, deletions, and insertions are rare but can result in partial trisomies and monosomies leading to pregnancy loss 2, 5

Maternal Origin and Age Factors

The majority of aneuploid pregnancy losses originate from maternal meiotic errors:

• Most trisomic miscarriages are of maternal origin, with errors occurring during meiotic division of oocytes 5
• Advanced maternal age (≥35 years) significantly increases the frequency of aneuploidy in both sporadic and recurrent pregnancy loss (71/121 vs 155/432 in younger women) 4
• Chromosome segregation errors may be sporadic events secondary to advancing maternal age, though maternal germline factors may also contribute 5

Clinical Detection and Testing

Next-generation sequencing (NGS) and conventional karyotyping can identify these abnormalities:

• NGS analysis detects chromosomal variants in approximately 62.8% of first trimester pregnancy loss specimens (634/1,010 cases) 4
• Conventional G-banding karyotyping remains a standard method, though molecular techniques provide additional detection capabilities 3
• Proper collection and preparation of chorionic villi samples is essential for reliable genetic testing, as maternal cell contamination and placental mosaicism can complicate interpretation 3

Important Clinical Caveats

Several factors can affect detection and interpretation:

• Some routine laboratory techniques will fail to detect chromosomal instability patterns such as jumping translocations and complex rearrangements 2
• Maternal cell contamination in samples can lead to false-negative results if not properly identified 3
• Placental mosaicism may not reflect the true fetal karyotype, requiring careful interpretation 3

Practical Implications

Understanding the genetic basis guides clinical management:

• Fetal chromosome analysis should be offered routinely for all pregnancy losses, regardless of whether they are sporadic or recurrent 4
• Genetic counseling should address the high likelihood of sporadic chromosomal errors, particularly in women of advanced maternal age 4, 5
• Recurrence risk for most aneuploid losses is low unless there is an underlying parental chromosomal rearrangement or maternal germline factor 5