Horses Helping Humans

Horse chromosomes and pregnancies share many similarities with humans, but could equine miscarriage indicate causes of early human pregnancy loss? A recent study published in PNAS reveals chromosomal abnormalities that could support both veterinarian and human pregnancy care (1).

We connected with the team behind this study to learn more about their findings, and what this could mean for human pregnancy and clinical care.

What inspired this study?
 

As veterinarians, we support conception and pregnancy health in breeding mares. From our clinical experience and published studies, we found that embryonic and fetal loss remain a major barrier to producing live foals. Failing to produce a live foal during a breeding season can be both financially and emotionally challenging. While past research has focused on the role of the mare’s uterus in supporting embryo development, there is limited understanding of other causes of pregnancy loss, which make up 60-80 percent of cases. In our large epidemiological study, we found that the greatest risk factor for pregnancy loss in the first two months of gestation was the mare's age. Given the connection between advanced maternal age and aneuploidy in human miscarriages, we wondered if this might also be a cause of equine miscarriage.

What were your main findings – did anything surprise you?
 

This study has provided evidence that up to 60 percent of horse pregnancies that fail by 110 days of gestation (first trimester) are due to chromosomal errors, similar to those in humans. Like in women, we observed a high rate of trisomies and monosomies in the second half of the first trimester, closely matching findings from human studies for the same period. We also examined conceptus material from failed pregnancies as early as two weeks, where we identified a different chromosomal issue called triploidy (an extra full set of chromosomes). These errors are most common in the first seven weeks of equine pregnancy. Triploidy, although noted in human pregnancies, is less studied due to limited conceptus material, so we were surprised to find it caused over 40 percent of miscarriages in the first eight weeks.

Did you face any challenges during your research – how did you overcome them?
 

The biggest challenge was collecting conceptus material from failed pregnancies into our biobank of tissues. We knew this would be difficult since there were very few reports of obtaining such material from any species other than humans, especially from natural pregnancy losses within the first six weeks. In fact, a reviewer of our first grant proposal said it would be impossible!

To overcome this, we built a network of collaborators, mainly in the UK and US, who helped us develop methods to collect the material, which we could then analyze in our lab. Since the samples come from elite horses, we had to create agreements with clinics and use secure data storage to protect the identity of the horses and owners, similar to human studies.

Did you find any unique signs of miscarriage in horses that differ from humans? How might these differences affect using horses as a model to study human miscarriage?
 

We suggested that horses could serve as a model for studying miscarriage in humans due to several similarities: both have a similar pregnancy loss rate (around 15 percent after confirmation by ultrasound), older maternal age increases miscarriage risk in both, and horses receive detailed gynecologic care. Additionally, conceptus material from both miscarried and normal pregnancies can be collected non-invasively. Other parallels include single pregnancies, similar gestation lengths (11 months for horses, 9 months for humans), similar early embryo development rates, and chromosomal defects as a major cause of miscarriage in both species.

A unique difference between these two species, however, is the type of placentation. In humans, the chorionic villi (fetal tissue) are in direct contact with maternal blood, while in horses, several layers of cells separate the maternal and fetal tissue, making prenatal screening for chromosomal errors in horses more difficult. Additionally, the equine embryo implants much later than the human embryo. Further studies are needed to understand the source of genetic errors and whether they are similar in both species.

Since you found many chromosomal issues early in pregnancy, what markers could we use to detect at-risk pregnancies early on in both horses and humans?
 

This is a big challenge. Non-invasive prenatal testing (NIPT), screens for chromosomal defects using fetal DNA from a mother's blood sample, but it isn’t sensitive enough to detect errors at the early stages of pregnancy in either species, and it's especially difficult in mares. Epidemiological studies are also used to identify high-risk pregnancies, with factors like older parental age and ethnicity helping to flag those who might need further testing for chromosomal defects. In horses, we are using similar research methods to identify factors, such as hormone use before conception, that could increase the risk of these defects. This research might also provide insights for human studies. For now, the data is most helpful for diagnosing the cause of miscarriage after it happens, giving couples and horse owners information that can guide the management of future pregnancies.

Based on your research, is there potential to develop better screening programs to catch chromosomal abnormalities early in pregnancy?
 

The chromosomal errors we identified before eight weeks of gestation are incompatible with life, making miscarriage inevitable in most cases, and there is no treatment for them. However, as molecular testing and ultrasound technology improve, better screening tests may become available. For example, we are currently using micro CT to screen equine fetuses with genetic errors and link them to specific developmental issues, which could eventually be detected by ultrasound and included in screening protocols.

In the meantime, our findings will change the methods veterinarians use to manage these cases. Currently, hormonal and antimicrobial treatments are often used when ultrasound shows signs of impending miscarriage, but this approach has several issues: (i) the treatments don't address the root cause and are ineffective, (ii) treating pregnancies with lethal genetic traits prolongs them unnecessarily, preventing the mare from being bred again that year, (iii) antimicrobials are overused, and (iv) breeders face unnecessary costs. Our findings will help improve the management of broodmares and ensure treatments are used more appropriately.

Any plans to continue with this research?
 

In addition to our population-based research aimed at identifying factors that may influence the risk of chromosomal abnormalities, the next step is to study these abnormalities in the lab to understand why they happen. We are growing cells from both normal and failed pregnancies in vitro and will use these cells to investigate the mechanisms behind these chromosomal errors, focusing on centromere biology and genome instability. We hope this research will benefit both humans and horses. A postdoctoral fellow and a PhD student will be joining our lab soon to move this research forward.