Study Question: Is there a genetic contribution to the change in cervical length during pregnancy and, if so, how is this related to the known genetic contribution to pregnancy duration? Summary Answer: Genomic analyses suggest that cervical length change across pregnancy is a polygenic trait with appreciable heritability. Bivariate genetic correlations estimated using genome-wide complex trait analysis (GCTA) indicated that a large proportion of the genes influencing cervical change across pregnancy also influenced gestational duration. What is Known Already: Sonographic cervical length is a powerful predictor of maternal risk for spontaneous preterm birth (sPTB). Twin and family studies have established a maternal genetic heritability for sPTB ranging from 13 - 20%. However, there is no corresponding estimate for the heritability of mid-trimester cervical length, or an understanding of how genetic factors contribute to cervical changes across pregnancy. Study Design, Size, Duration: This study was based on a prospective longitudinal cohort of (N = 5,160) Black/African American women who underwent serial sonographic examination of the uterine cervix during pregnancy and were followed until delivery. Maternal DNA extracted from whole-blood samples was genotyped via next-generation low-pass whole genome sequencing. Participants/Materials, Settings, Methods: Repeated measurements of sonographic cervical length were collected during singleton pregnancies in 5,160 unique women and longitudinal changes in cervical length were described using latent growth models. Individual-level low-pass whole genome sequencing data from a subset of 4,423 women were used to calculate the heritability of cervical length change during pregnancy and estimate its genetic correlation with gestational duration. Main Results and the Role of Chance: Changes in cervical length across pregnancy were found to be substantially influenced by genetic factors (h2 = 51%). Furthermore, the genetic factors influencing cervical change were significantly correlated with genetic influences on pregnancy duration, implying a shared genetic architecture. The strongest genetic correlation was observed for the overall linear change in cervical length (rg = 0.982 [95% CI 0.951, 0.993]), and less so for the genetic correlation with mid-trimester values (rg = 0.714 [95% CI 0.419, 0.873]) and aspects of non-linear change that are most pronounced at the end of pregnancy (rg = -0.490 [95% CI -0.766, -0.062]). SNP-level associations were observed near genes involved in the progesterone, estrogen, and insulin signaling pathways. Limitations, Reasons for Caution: While the study cohort was not designed to identify individual genetic variants associated with cervical length change or gestational duration, it was well powered to assess aggregate genome-wide summary statistics to estimate trait heritability, bivariate genetic correlations, and genetic enrichment of suggestive associations. To date, this study is the largest genome-wide study of preterm birth in a cohort of Black/African American women, a population that is disproportionately affected by health disparities in preterm birth and perinatal outcomes. Wider Implications of the Findings: The significant genetic correlation between cervical length and gestational duration suggests shared causal loci between these two traits. These results raise the question of whether a large proportion of genetic loci for gestational duration exert their influence through the process of cervical remodeling. Polygenic profiling of maternal genetic liability to cervical shortening could aid in the development of clinical risk assessment tools to identify high-risk women who may benefit from more frequent cervical length screening and earlier interventions to prevent preterm delivery.

The authors have declared no competing interest.

This research was supported, in part, by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, United States Department of Health and Human Services (NICHD/NIH/DHHS); and, in part, by federal funds from NICHD/NIH/DHHS (Contract No. HHSN275201300006C). RR has contributed to this work as part of his official duties as an employee of the United States Federal Government. ALT, NGL, and SSH were also supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health. Additional support was provided from the March of Dimes Prematurity Research Center at the University of Pennsylvania (22-FY18-812).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Participants were enrolled under the protocols for Biological Markers of Disease in the Prediction of Preterm Delivery and for Preeclampsia and Intra-Uterine Growth Restriction: A Longitudinal Study (WSU IRB#110605MP2F and NICHD/NIH# OH97-CH-N067) between 2005 to 2017 at the Center for Advanced Obstetrical Care and Research (CAOCR) at Hutzel Womens Hospital. The Institutional Review Boards of Wayne State University and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Institutes of Health (NIH)/U.S. Department of Health and Human Services (DHHS) (Detroit MI USA) approved the study. All participants provided written informed consent for the collection of cervical length data and blood samples for future genetic research studies.

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All data produced in the present study are available upon reasonable request to the authors