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How is gene study adding to the overall knowledge of preterm birth?

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OBG Management caught up with Dr. Muglia on how he feels the study of the human genome could lead to advancements in the prevention of preterm birth.


The 2018 meeting of the American Gynecological and Obstetrical Society, held in Philadelphia, Pennsylvania, September 6 to 8, featured a talk by Louis J. Muglia, MD, PhD, on “Evolution, Genetics, and Preterm Birth.” Dr. Muglia, who is Co-Director of the Perinatal Institute, Director of the Center for Prevention of Preterm Birth, and Director of the Division of Human Genetics at the Cincinnati Children’s Hospital Medical Center, discussed his recent research on genetic associations of gestational duration and spontaneous preterm birth and some of his key findings. OBG Management caught up with Dr. Muglia on how he feels the study of the human genome could lead to advancements in the prevention of preterm birth.

OBG Management: You discussed the “genetic architecture of human pregnancy.” Can you define what that is?

The genetic architecture tells us which pathways are activated that initiate birth to occur. By understanding that, we can begin to understand not only the genetic factors that the architecture describes, but also that the genetic architecture is going to be modified in response to environmental stimuli that will disrupt the outcomes. In the future, we will be able to develop biomarkers, predictive genetic algorithms, and other tools that will allow us to assess risk in a way that we can’t right now.

OBG Management: How is gene study adding to the overall knowledge of preterm birth?

Gene study is giving us new pathways to look at. It will give us biomarkers; it will give us targets for potential therapeutic interventions. I mentioned in my talk that one of the genes that we identified in our recent New England Journal of Medicine (NEJM) study pinpointed selenium as an important component and a whole process of determining risk for preterm birth that we never even thought of before. For instance, could there be preventive strategies for prematurity, like we have for neural tube defects and folic acid? The possibility of supplementation with selenium, or other micronutrients that some of the genetic studies will reveal to us in a nonbiased fashion, would not be discovered without the study of genes.

OBG Management : You mentioned your NEJM paper. Can you describe the large data sets that your team used in your gene research?

The discovery cohort, which refers to essentially the biggest compilation, was a wonderful collaboration that we had with the direct-to-consumer genotyping company 23andme. I had contacted them to determine if they had captured any pregnancy-related data, particularly birth-timing information related to individuals who had completed their research surveys. They indicated that they had asked the question, “What was the length of your first pregnancy?” With this information, we were able to get essentially 44,000 responses to that question. That really provided the foundation for the study in the NEJM.

Now, there are caveats with that information, since it was all recollection and self-reported data. We were unsure how accurate it would be. In addition, we did not always know why the delivery occurred—was it spontaneous or was it medically indicated? We were interested in the spontaneous, naturally-occurring preterm birth. Using that as a discovery cohort, with those reservations in mind, we identified 6 genes for birth length. We then asked in a carefully collected series of cohorts that we had amassed on our own, and with collaborators over the years from Finland, Norway, and Denmark, whether those same associations still existed. And every one of them did. Every one of them was validated in our carefully phenotyped cohort. In total, that was about 55,000 women that we had analyzed and studied between the discovery and the validation cohort. Since then, we have accessed another 3 or 4 cohorts, which has increased our sample size even more, so we have identified even more genes than we originally reported in our paper.

OBG Management: What do you identify as the next steps in your research after identifying several genes associated with the timing of birth?

The idea is not just to develop longer and longer lists of genes that are suggested or associated with birth timing phenotypes that we are interested in—either preterm birth or duration of gestation—but to actually understand what they are doing. That is a little bit trickier than saying we have identified genes. We have identified the precise region of mom’s genome that is involved in regulating birth timing, but in many cases I have indicated the closest gene that is involved in birth timing. For some of the regions, however, there are many genes involved, and so is it regulating one pathway, is it regulating many? Which tissue is involved in regulating? Is it in the uterus, in the cervix, or in the immune system? The next steps are to figure out how these things are acting so that we can design better strategies for prevention. The goal is to really bring down preterm birth rates by implementing strategies for prevention and treatment that we don’t currently have.

OBG Management: What is the significance of maternal selenium status and preterm birth risk?

Well, we really don’t know. We identified one of these gene regions, a variant near a factory involved in production of what are called selenoproteins—proteins that incorporate selenium into them. (There are about 25 of those in the human genome.) We identified a genetic risk factor in a region that is linked to the selenoprotein production chain. What we were brought to think about was this: In parts of the world where we know there is substantial selenium deficiency (parts of sub-Saharan Africa, parts of China, parts of Asia), could selenium deficiency itself be contributing to very high rates of preterm birth? Right now we are trying to figure out if there is an association by measuring maternal plasma selenium levels about halfway through pregnancy and then asking what was the outcome from the pregnancy. Are women with low levels of selenium at increased risk for preterm birth? There have been 2 studies published that do already suggest that women with lower selenium levels tend to give birth to premature babies often.

OBG Management : What is the HSPA1L pathway and why is it important for pregnancy outcomes?

In our study where we performed genome-wide association, we looked at what are called common variants in the human genome—common variants in general are carried by more people. They had to be carried by a couple percent of the population to be included in our study. But there is also the thought that individual, more severe variants (that do not necessarily get transmitted because of how severe their effects are), will also affect birth outcomes. So we did a study to sequence mom’s genome to look for these rarities, things that account for less than 1% of the whole population. We were able to identify this gene, HSPA1L, which again, as found in our genome-wide studies, seems to be involved in controlling the strength of the steroid hormone signal, which is very important for maintaining and ending pregnancy. Progesterone and estrogen are the yin and yang of maintaining and ending pregnancy, and we think HSPA1L, the variant we identified, decreases the steroid hormone signal function so that it is not able to regulate that progesterone/estrogen signal the same way anymore.

OBG Management: Why is this an exciting time to be studying genes in pregnancy?

To understand how gene study can optimize our knowledge of human pregnancy outcomes really requires a study of human pregnancy specifically, and one of the best opportunities we have is to gather these large data sets. And we can’t forget about collecting pregnancy outcomes on women as part of new National Institutes of Health initiatives that are developing personalized medicine strategies. We looked at 50,000 women in our research, but we have the capacity to look at 500,000 women. As we go from identifying 6 genes to 12 genes to 100 genes, we will be able to understand better how these things are talking to one another and better define the signatures of what tissues are being acted on. We will be able to get sequentially synergistic information that will allow us to solve this in a way we couldn’t before.

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