Why Some Pregnancies End Before They Begin

Leon Wirz
1 day ago
5 min read

Published in Nature, February 2026 | Johns Hopkins University (USA)

Introduction

It is estimated that between 30% and 50% of all human conceptions do not result in birth, with many losses occurring before a pregnancy is even clinically recognized. The most common reason is aneuploidy (a condition in which an embryo has too many or too few chromosomes). Humans normally have 46 chromosomes. If an embryo carries 45 or 47, development often stops very early, frequently before a pregnancy is even clinically recognized.

For decades, maternal age has been known as the strongest risk factor for these chromosomal errors. However, age alone does not explain why some women experience repeated miscarriages while others of the same age do not. A large 2026 study published in Nature now provides new insight. By analyzing more than 139,000 in vitro fertilization (IVF) embryos, researchers identified common genetic variants in key meiosis genes that subtly influence chromosome stability and pregnancy viability.

The Core Discovery

The study connects three biological processes that were previously studied mostly separately: meiotic recombination, chromosome segregation, and pregnancy loss.

Meiotic recombination involves so-called crossovers (points where paired chromosomes exchange DNA segments during egg formation). These crossovers are not random accidents, they are essential. They physically link homologous chromosomes (matching chromosome pairs) so they can separate properly when the egg matures.

The researchers found that embryos affected by aneuploidy tend to originate from eggs with fewer crossovers. In other words, when fewer of these stabilizing DNA exchanges occur, chromosomes are more likely to mis-segregate.

They further identified a common genetic variant near the gene SMC1B, which encodes part of the cohesin complex (a protein ring structure that holds sister chromatids (identical chromosome copies) together). This variant reduces expression of SMC1B and increases the risk of maternal meiotic aneuploidy. Importantly, the variant does not change the protein sequence itself; it alters how strongly the gene is expressed.

How the Study Was Conducted

The researchers analyzed data from 139,416 embryos generated through IVF and preimplantation genetic testing (PGT). PGT involves taking a small biopsy from a five-day-old embryo and testing its chromosomes before transfer to the uterus.

Using SNP microarray data from embryos and both biological parents, the team reconstructed parental haplotypes (blocks of inherited genetic variants) and developed a computational model to detect both crossover events and chromosomal abnormalities.

In total, they mapped more than 3.8 million meiotic crossovers and identified over 92,000 aneuploid chromosomes. Approximately 30% of embryos carried at least one chromosomal abnormality. As expected, most aneuploidies were maternal in origin and strongly increased with maternal age.

The large dataset enabled genome-wide association studies (GWAS), allowing researchers to test whether common genetic variants in mothers influence aneuploidy risk.

Key Findings

The analysis confirmed that embryos derived from eggs with fewer crossovers are significantly more likely to be aneuploid. Crossovers help maintain chromosome alignment during the prolonged arrest phase of female meiosis, which begins before birth and resumes decades later during ovulation. Insufficient crossover formation increases the probability of chromosome mis-segregation when meiosis restarts.

A specific genetic variant (rs6006737) on chromosome 22 was significantly associated with maternal meiotic aneuploidy. Each copy of the risk allele increased the probability of producing an aneuploid embryo by approximately 1.65% at age 40. The effect intensified with increasing maternal age, suggesting that genetic susceptibility interacts with age-related biological decline.

Functional experiments demonstrated that the associated haplotype reduces expression of SMC1B through a regulatory mechanism. The variant affects a promoter region (a DNA segment controlling gene activity) and alters binding of the transcription factor ATF1. Reduced SMC1B expression plausibly weakens cohesin integrity, compromising chromosome stability.

The study also implicated additional meiosis genes, including C14orf39, a component of the synaptonemal complex (a protein structure that aligns chromosomes during recombination), and the ubiquitin ligases CCNB1IP1 and RNF212, which regulate crossover formation. These findings suggest a shared genetic architecture linking recombination rates and aneuploidy risk.

Interestingly, the risk allele was also associated with later menarche, earlier menopause, and a shorter reproductive lifespan, pointing toward a broader biological connection between chromosome maintenance and ovarian aging.

Limitations of the Study

Although the dataset is unprecedented in scale, it has important limitations. The cohort consists of individuals undergoing IVF, which may not perfectly represent the general population. IVF patients are often older or experience subfertility for various reasons.

Moreover, common genetic variants explained only a small fraction of total risk (SNP heritability around 2%). This indicates that environmental influences, rare mutations, or stochastic biological factors likely play major roles.

Because the study is observational, it identifies strong associations but cannot directly prove that the genetic variant causes chromosome errors inside human egg cells.

Relevance for Switzerland

Switzerland has one of the highest maternal ages at first birth in Europe, averaging around 31–32 years. With increasing maternal age, aneuploidy rates rise steeply. IVF cycles in Switzerland typically cost between CHF 8,000 and CHF 12,000, and multiple cycles are often required.

Understanding that common genetic variation contributes modestly but measurably to chromosomal error risk could refine reproductive counseling. While this is not yet a screening tool, it reinforces why age remains biologically decisive and highlights the molecular mechanisms behind age-related fertility decline.

From a health-economic perspective, repeated IVF cycles and miscarriages carry emotional and financial burdens. Better biological understanding may eventually reduce inefficient cycles through improved risk modeling.

Potential Impacts of a Successful Translation

If future research integrates genetic risk profiles with ovarian reserve markers and age, clinicians could offer more individualized fertility predictions. This might improve IVF success rates, optimize treatment timing, and reduce repeated unsuccessful attempts.

In the long term, deeper knowledge of cohesin biology and recombination control could even inform therapeutic strategies aimed at stabilizing meiotic chromosome segregation, though such applications remain speculative.

Risks

Genetic findings in fertility research carry ethical implications. There is potential for overinterpretation of small risk effects, genetic determinism, or pressure toward expanded embryo screening. Because common variants explain only a small portion of total risk, clinical translation must proceed cautiously.

Equity considerations are also important. Access to advanced reproductive genomics may widen disparities if not integrated thoughtfully into healthcare systems.

Overall Assessment

This study represents a landmark in reproductive genetics. It provides the largest direct mapping of human meiotic crossovers to date and establishes a clear connection between common regulatory variation in meiosis genes and pregnancy loss risk.

The findings reinforce a central biological principle: crossovers are not only generators of genetic diversity but also guardians of chromosomal stability. When their number or regulation is altered, the risk of aneuploidy increases.

At the same time, most risk remains unexplained, underscoring the complexity of human reproduction.

What Comes Next

Future work will likely focus on rare genetic variants, long-read sequencing of centromeres (chromosome regions critical for segregation), and integration of environmental exposures. Functional validation in human oocyte models will be essential.

Ultimately, this research deepens our understanding of why pregnancy loss is common and how subtle genetic variation shapes the earliest stages of human life.