Genetic Factors Increasingly Linked to Miscarriage Risk
Pregnancy loss is a deeply personal and often isolating experience, affecting an estimated 15% of clinically confirmed pregnancies. However, many more conceptions are lost in the very early stages, before a woman even knows she is pregnant. Recent research is shedding light on the complex interplay of factors contributing to miscarriage, with a growing focus on genetic predispositions – both in the developing embryo and, increasingly, in the mother herself.
A large-scale study, analyzing data from over 139,000 embryos created through in vitro fertilization (IVF), has identified numerous genetic variants associated with an increased risk of pregnancy loss. These variants are frequently linked to meiosis, the crucial cell division process responsible for forming egg and sperm cells. The findings, published in Nature, underscore the significant role genetics play in reproductive success and offer potential avenues for future interventions.
Understanding the Genetic Landscape of Miscarriage
For a long time, chromosomal abnormalities – an incorrect number of chromosomes in the embryo – have been recognized as a primary cause of miscarriage, accounting for roughly half of first and second-trimester losses. Conditions like Down syndrome, caused by an extra copy of chromosome 21, are examples of chromosomal alterations that can sometimes be compatible with life, but many others are lethal. While maternal age is a well-established risk factor for these errors – the likelihood increases as a woman ages – the broader genetic context has remained less clear.
Researchers at Johns Hopkins University, leading a collaborative effort with Danish scientists, sought to address this gap in knowledge. By analyzing a vast dataset of genetic information from both embryos and their biological parents, they aimed to pinpoint specific genetic variations that might predispose a woman to produce eggs with an abnormal number of chromosomes. According to Rajiv McCoy, a computational biologist at Johns Hopkins University and senior author of the study, identifying these subtle genetic influences is challenging because they often have modest effects and are masked by other factors.
Key Genes Identified in the Study
The study identified 138 genes where heterozygous – meaning one copy of the gene is altered – lethal variants are present in the general population with a frequency of 0.5% or greater. Screening for these genes could identify between 4.6% (in the Finnish population) and 39.8% (in the East Asian population) of couples at risk of miscarriage, potentially explaining approximately 1.1-10% of cases caused by these specific genetic variants.
Among the most significant findings was the identification of genes involved in crucial processes during egg formation: pairing, recombination, and chromosome cohesion. The SMC1B gene, which encodes a protein that forms a ring-like structure holding chromosomes together, emerged as particularly important. This structure is essential for ensuring accurate chromosome separation during cell division, and its function tends to decline with age.
The researchers emphasize that these findings align with decades of research in animal models, such as mice and worms, where these same genes have been shown to be critical for proper chromosome behavior. This convergence of evidence strengthens the confidence in the study’s conclusions.
Implications for Future Screening and Treatment
The identification of these genetic variants has significant implications for the future of preconception genetic carrier screening (PGCS). Currently, PGCS panels primarily focus on identifying risks for newborn genetic disorders. However, this research highlights the need for more comprehensive, “pan-ethnic” PGCS panels that also include genes associated with miscarriage risk. The variation of these genes across different ethnic groups underscores the importance of tailored screening approaches.
While the study represents a major step forward, researchers caution that it does not yet allow for precise individual risk calculation. Maternal age and various environmental factors remain important determinants of pregnancy loss. However, the findings provide a crucial foundation for developing more accurate risk assessment tools and, potentially, interventions to reduce the incidence of miscarriage.
A separate study, published in January 2026, also revealed connections between specific variations in a mother’s DNA and her risk of miscarriage, further solidifying the link between genetics and reproductive health. This research reinforces the idea that understanding the molecular pathways involved in chromosomal errors is key to improving fertility care.
The KIF18A Gene and Reproductive Aging
Further research, published in November 2024, identified a mutation in the KIF18A gene as a factor contributing to accelerated reproductive aging and increased miscarriage risk, even in younger women. This mutation speeds up the aging process of eggs, diminishing their quality and increasing the likelihood of chromosomal abnormalities. This discovery could pave the way for a genetic test to assess female fertility and identify women at higher risk of pregnancy loss.
Pregnancy loss remains a complex issue with multiple contributing factors. However, the growing body of evidence clearly demonstrates that genetics plays a significant, and often underestimated, role. Continued research in this area promises to improve our understanding of human reproduction and ultimately help more individuals achieve a healthy pregnancy.
