Activation of peripheral leukocyte migration before spontaneous labor at term - 05/06/24
Abstract |
Background |
Leukocytes are induced to migrate into the uterus at parturition, releasing cytokines and chemokines that activate it for delivery. A specific chemotactic signal is required for these actions, and published evidence suggests that it comes from the human fetal membranes and has a time-dependent component (ie, cells obtained at term in labor migrate more than cells obtained at term not yet in labor). The hypothesis that the fetal membrane chemoattractants activate the leukocytes to become responsive for migration was tested.
Objective |
This study aimed to: (1) examine the changes in leukocyte migration-responsiveness longitudinally from the late third trimester, to in labor, to 3 days postpartum; (2) explore the specific week-to-week changes in migration before delivery; (3) define the timing of chemokine receptor expression patterns in leukocytes relative to migration and the changes in cytokine and chemokine concentrations in maternal serum; (4) examine the ability of term fetal membrane-conditioned medium and term maternal serum to increase cell responsiveness; and (5) test the potential of the leukocyte migration assay to predict delivery within 1 week.
Study Design |
Leukocyte migration in response to a chemoattractive extract of term human fetal membranes was studied using a modified Boyden chamber. Flow cytometry assessed migrated cell phenotypes. The relationship between the expression of chemokine receptors and migration was tested using quantitative polymerase chain reaction, the bioassay, and regression analyses. Cytokines and chemokines in maternal serum were quantified using multiplex analysis. Conditioned medium from fetal membrane explants and maternal serum were evaluated for their abilities to enhance leukocyte migration using the bioassay. The ability of the bioassay to predict term delivery was assessed using receiver-operating characteristic curve and cost-curve analysis.
Results |
The number of leukocytes that migrated at term delivery was increased relative to the late third trimester, followed by a significant fall in numbers that migrated at 3 days postpartum (P=.002). The largest increase in migrated cells occurred 1 to 2 weeks before delivery. The messenger RNA abundance of several chemokine receptors increased in peripheral leukocytes at term in labor relative to the third trimester, and this correlated with an increase in migrated cells in 5 of 6 cases (R=0.589 to 0.897; P<.03). The concentrations of several chemokines and cytokines in maternal serum increased with labor onset. Fetal membrane explant-conditioned medium and maternal serum obtained at term labor increased the responsiveness of leukocytes to fetal membrane chemoattractive extract. The bioassay was demonstrated to predict delivery within 7 days with excellent performance characteristics using a cohort prevalence of 71.7% (positive predictive value=96.1%; negative predictive value=58.5%; sensitivity=74.2%; specificity=92.3%; positive likelihood ratio=9.25; and negative likelihood ratio=0.28). A single determination was validated to have a high degree of confidence.
Conclusion |
Term human fetal membranes release chemoattractants near the end of pregnancy that increase in ability to activate and attract an increasing number of leukocytes as gestation advances.
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Key words : biomarker, chemoattractants, chemokines, common pathway of parturition, cytokines, delivery, fetal membranes, maternal serum, neutrophils, prediction, pregnancy
Plan
| H.L. and A.T. share first authorship. |
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| The authors report no conflict of interest. D.M.O. is a Scientific Officer of Maternica Therapeutics, Inc. and the CEO of Livmor Biosciences, Inc. |
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| The collection of samples and analyses performed in Japan was funded by a Health Labour Sciences Research Grant, Grant-in-Aid for Young Scientists (B) (Japan) (to J.T.). The Canadian Institutes of Health Research (Nos. 165980, 168858, and 173390 to D.M.O.) provided the funds for all the sample collection, laboratory work, and analyses performed in Edmonton, Canada, and costs associated with the writing and publication of this article. A Worldwide Universities Network Research Mobility grant provided funding for H.L.’s research exchange in China. The Chinese cohort’s sample collection and analyses were funded by the National Natural Science Foundation of China (No. 8180061745 to H.Q.) and the National Key Research and Development Program, namely the project “The research on birth defect prevention and control of reproductive health” (No. 2016YFC1000407 to H.Q.). |
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| The findings of this study were presented at the 68th Annual Meeting of the Society for Reproductive Investigation, Boston, MA, July 6–9, 2021. |
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| Cite this article as: Lee H, Takamizu A, Nishizaki Y, et al. Activation of peripheral leukocyte migration before spontaneous labor at term. Am J Obstet Gynecol 2024;XX:x.ex–x.ex. |
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