Labor-Associated Gene Expression in the Human Uterine Fundus, Lower Segment, and Cervix

Abstract

Background

Preterm labor, failure to progress, and postpartum hemorrhage are the common causes of maternal and neonatal mortality or morbidity. All result from defects in the complex mechanisms controlling labor, which coordinate changes in the uterine fundus, lower segment, and cervix. We aimed to assess labor-associated gene expression profiles in these functionally distinct areas of the human uterus by using microarrays.

Methods and Findings

Samples of uterine fundus, lower segment, and cervix were obtained from patients at term (mean ± SD = 39.1 ± 0.5 wk) prior to the onset of labor ( n = 6), or in active phase of labor with spontaneous onset ( n = 7). Expression of 12,626 genes was evaluated using microarrays (Human Genome U95A; Affymetrix) and compared between labor and non-labor samples. Genes with the largest labor-associated change and the lowest variability in expression are likely to be fundamental for parturition, so gene expression was ranked accordingly. From 500 genes with the highest rank we identified genes with similar expression profiles using two independent clustering techniques. Sets of genes with a probability of chance grouping by both techniques less than 0.01 represented 71.2%, 81.8%, and 79.8% of the 500 genes in the fundus, lower segment, and cervix, respectively. We identified 14, 14, and 12 those sets of genes in the fundus, lower segment, and cervix, respectively. This enabled networks of co-regulated and co-expressed genes to be discovered. Many genes within the same cluster shared similar functions or had functions pertinent to the process of labor.

Conclusions

Our results provide support for many of the established processes of parturition and also describe novel-to-labor genes not previously associated with this process. The elucidation of these mechanisms likely to be fundamental for controlling labor is an important prerequisite to the development of effective treatments for major obstetric problems—including prematurity, with its long-term consequences to the health of mother and offspring.

Editors' Summary

Background.

Childbirth, or labor, although a basic event in life, is actually a complex process that involves three parts of the uterus (womb) working together to expel the baby. One particularly important part of the process, which is poorly understood, is how labor begins. The actual changes that occur in the uterus once labor has begun are well known, and include contractions in the muscle of the uterus wall (the myometrium) and dilation of the cervix (the neck of the womb). Some of the triggers for these changes are also known: for example, in non-primate animals changes in the blood levels of the hormones estrogen and progesterone and changes in the membranes that surround the fetus. Previous studies have suggested that these effects are likely, in turn, to be triggered by changes in many genes, but exactly which ones is not clear.

Why Was This Study Done?

Learning more about which genes are important in the various stages of labor may help to design treatments for the various problems that occur in labor (such as failure of labor to begin, or, alternatively, preterm labor). Little is known about the genes that trigger, or are necessary for, labor to start and to continue in a coordinated fashion. A technology known as DNA microarrays allows researchers to take a sample from any part of the body and use it to look at how active many thousands of genes are, all at the same time. By analyzing these results, it is possible to suggest either single genes or groups of genes that may be important in a particular process.

What Did the Researchers Do and Find?

The authors took samples from the uterus top, lower part, and cervix of six women before their labor started, and seven from those whose labor had started. All women were having cesarean sections either for medically indicated reasons, or for choice. Then, in each of the samples in each woman, they looked at 12,626 known genes to see how active they were (scientists call these active genes “expressed”). They found that the changes in gene expression were not, generally, the same across the three parts of the uterus. Of the 500 genes with the largest change in expression, 28 were common to both the upper and lower parts of the uterus, and this small group of genes may be important in labor in both the upper and lower parts of the uterus. The authors also classified the 500 genes into related groups, and they believe that these relationships may be important in controlling how labor happens.

What Do These Findings Mean?

Identifying new genes or groups of genes involved in labor is important for understanding how labor occurs. One limitation of this study is the small number of women who were studied—which is understandable, given the difficulty of obtaining such samples—and the differences between the women studied. Another difficulty with such studies is that the methods used to analyze the expression patterns can affect the results. However, as is the custom with these types of studies, all the results were placed in a public database so anyone can look at them and, if they wish, do further analyses. In a related Perspective article that was commissioned to comment on this paper, Roberto Romero, one of the original reviewers of the paper, has done just that. He finds that there were differences in the results of his analyses and those of the authors'. He goes on to discuss the question of how hard it is to use these techniques to look at complex problems, such as how labor starts. Clearly, much more work needs to be done before it is clear what all these results really mean. Nonetheless, these studies have the potential to help to understand more about the basic science behind labor.

Additional Information.

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030169.

• Medline Plus has a page of links on childbirth

Abstract

Radek Bukowski and colleagues used microarrays to assess labor-associated gene expression profiles in the uterus and discover networks of co-regulated and co-expressed genes.