Decoding health and disease
The purpose of this blog is to present, discuss and share knowledge on topics related to population health and medical research. Blog posts are written mainly by researchers from the Faculty of Medicine.
Investigating the biological basis of preterm birth and pregnancy duration
Premature birth poses significant risks to newborn health, increasing the risk of death, disability, and illness. The regulation of the duration of pregnancy and the onset of labor are complex biological processes that involve both maternal and fetal genes, as well as the interaction between environmental and genetic factors. Recent research has improved the knowledge of the biological mechanisms underlying preterm birth and the regulation of pregnancy duration. In this blog post, guest authors Anu Pasanen and Heli Tiensuu, Postdoctoral researchers at the University of Oulu, share insights into their research on preterm birth and pregnancy duration. They discuss recent projects in which they have identified genetic variants affecting the duration of pregnancy and explored the molecular biological mechanisms related to premature birth.
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Preterm birth and factors affecting prematurity
Preterm birth is defined as birth before the 37th week of pregnancy, or gestation. Globally, about 15 million babies are born prematurely each year. In Finland, 5–6% of births are preterm (THL Birth Register). Due to their immature organ systems, including the incompletely developed brain and lungs, preterm infants face immediate risks of death or disability. Advances in neonatal care have drastically improved survival rates, even for infants born extremely preterm (<28 weeks). However, preterm infants are at risk of many long-term or later-onset health issues, including respiratory issues, cerebral palsy, impaired vision, and hearing problems.
The regulation of gestational duration and the onset of labor are complex biological processes influenced by multiple genetic, environmental, and congenital risk factors, as well as their interactions. Smoking, infections, and multiple pregnancy are some of the risk factors predisposing to prematurity. Genetic factors also play a role, with genes from both the mother and fetus contributing to the duration of pregnancy and, thus, exposing to or protecting from preterm birth.
Why is it important to study preterm birth, and how can the mechanisms of pregnancy duration be investigated?
The mechanisms that initiate preterm birth are incompletely understood, in part because the triggers of full-term labor in humans are still largely unknown. No effective method exists to predict or prevent most preterm births. Research focused on preterm birth can lead to the development of new prediction methods and interventions that may prolong pregnancy duration in at-risk cases. Effective prediction methods would facilitate the initiation of properly timed follow-up and treatment. On the other hand, new methods to extend gestational duration would help protect newborns from the immediate and long-term health problems associated with prematurity.
The biological factors regulating pregnancy duration likely function in a complex interplay among the fetus, placenta, and mother. By studying these factors and their interactions, we can identify pathways that initiate preterm labor. We mainly use hypothesis-free or data-oriented genetic and molecular biological methods, including genome-wide association studies (GWAS), which aim to find connections between genetic factors and prematurity by analyzing the entire genome. Samples used in these studies may consist of data from mothers with preterm and full-term births. Additionally, we investigate placental proteomes and differences in gene expression in placentas from premature versus full-term births.
The influence of the mother's genes on the risk of preterm birth
Genetic factors account for up to 40% of the variation in the timing of birth, with the maternal genome having a greater influence on the variation of pregnancy duration than the fetal genome. Our recent GWAS utilized samples from the FinnGen research project, focusing on mothers with preterm and full-term births. The study identified approximately 15 genomic regions, or loci, associated with pregnancy duration and/or premature birth, with about half of these loci previously unreported in this context. Overall, genome-wide association studies have identified around 50 regions associated with pregnancy duration by studying the mothers' genes.
In the current study, several identified genes were expressed in tissues associated with reproduction or in blood cells related to inflammation. For example, we found that higher expression of ZBTB38 gene in the inflammatory cells of the immune system is associated with a longer duration of pregnancy. Based on previous studies, this gene is also linked to the number of immune cells in the blood. While communication between inflammatory cells is essential to normal full-term birth, it can also influence the risk of premature birth. The insights from studying the ZBTB38 gene and other associated loci can help us understand the biological processes behind preterm birth and pregnancy duration.
The role of the placenta in the research of preterm birth
The placenta plays a critical role in mediating the transfer of nutrients and gas exchange between the mother and fetus, as well as protecting the fetus from infections. Placental functions are thought to significantly influence the duration of pregnancy and participate in processes that initiate labor. Thus, the placenta is one of the most important target organs in preterm birth research. For example, studying the protein composition of the placenta can help identify biological pathways leading to prematurity. Our research has shown that factors related to inflammation and immune defense within the placenta and those affecting its growth and development may contribute to the risk of premature birth.
The future of preterm birth research
Research focusing on biological factors of pregnancy duration can enhance our knowledge of the events that lead to preterm birth. In the future, we aim to uncover the specific roles of these genes and proteins within the biochemical cascades that contribute to preterm birth. Detailed mechanisms of these molecules can be studied, for example, by using mouse models and cell experiments. Ultimately, our goal is to leverage our research findings to promote better health outcomes for children in the future.
Authors:
Postdoctoral research scientists Anu Pasanen and Heli Tiensuu
Research articles mentioned in the text:
Pasanen A, Karjalainen MK; FinnGen; Zhang G, Tiensuu H, Haapalainen AM, Ojaniemi M, Feenstra B, Jacobsson B, Palotie A, Laivuori H, Muglia LJ, Rämet M, Hallman M. Meta-analysis of genome-wide association studies of gestational duration and spontaneous preterm birth identifies new maternal risk loci. PLoS Genet. 2023 Oct 23;19(10):e1010982. doi: 10.1371/journal.pgen.1010982. PMID: 37871108; PMCID: PMC10621942.
Tiensuu H, Haapalainen AM, Tissarinen P, Pasanen A, Määttä TA, Huusko JM, Ohlmeier S, Bergmann U, Ojaniemi M, Muglia LJ, Hallman M, Rämet M. Human placental proteomics and exon variant studies link AAT/SERPINA1 with spontaneous preterm birth. BMC Med. 2022 Apr 28;20(1):141. doi: 10.1186/s12916-022-02339-8. PMID: 35477570; PMCID: PMC9047282.