Submit a comment
Abstract
BACKGROUND. In vitro fertilization (IVF) culminates in embryo transfer into a hormonally primed endometrium, often via a programmed cycle (PC) regimen postulated to influence hypertensive disorders of pregnancy (HDP) risk. We thus generated a single-cell atlas of PC endometrium to define cell type-specific differences relative to natural cycle (NC) endometrium, and evaluated whether PC-associated modulation of the window of implantation (WOI) endometrium influences angiogenic balance in pregnancy. METHODS. Single-nucleus RNA-seq of prospectively collected PC and NC WOI endometrium. An independent prospective cohort of 548 singleton pregnancies was separately analyzed for maternal serum angiogenic markers (soluble fms-like tyrosine kinase-1; placental growth factor) and HDP incidence in PC- versus NC-conceived pregnancies, adjusting for clinical confounders and IVF use. RESULTS. Prominent transcriptomic differences were observed between PC (n = 7; 48,843 nuclei) and NC (n = 9; 44,230 nuclei) WOI endometrium, particularly in glandular epithelium (682 up- and 979 down-regulated genes; adjusted P < 0.05) and stromal fibroblasts (108 up- and 168 down-regulated). PC endometrium showed reduced uterine natural killer cell abundance, potentially from CXCL14 downregulation. Functional enrichment revealed downregulation of embryo implantation, angiogenesis, and extracellular matrix remodeling pathways in PC. Altered cell-cell signaling in decidualization, angiogenesis, and inflammatory response was also observed. Despite these WOI perturbations, PC-conceived pregnancies were not associated with early gestational angiogenic imbalance or increased HDP risk. CONCLUSION. PC endometrial preparation induced distinct cellular and signaling alterations in the WOI, but was not associated with subsequent development of angiogenic imbalance or HDP, thereby underscoring the resilience and adaptability of the early maternal-fetal interface. TRIAL REGISTRATION. ClinicalTrials.gov NCT03799107. FUNDING. ABOG/AAOGF; NICHD-R01-HD084380; NCTRI-P50-HD055764; NIAMS-P30-AR070155.
Authors
David Huang, Emily Flynn, Brittany R. Davidson, Juan C. Irwin, Mohammad Naser, Ana Laura Almonte, Jennifer Qin, Yue Song, Fleurdeliza B. Rabara, Rebecca Wong, Lydia B. Zablotska, Mitchell P. Rosen, Torsten Wittmann, Gabriela K. Fragiadakis, Alexis J. Combes, Marina Sirota, Marcelle I. Cedars, Linda C. Giudice
Guidelines
The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.
- Comments appear on the Journal’s website and are linked from the original article’s web page.
- Authors are notified by email if their comments are posted.
- The Journal reserves the right to edit comments for length and clarity.
- No appeals will be considered.
- Comments are not indexed in PubMed.
Specific requirements
- Maximum length, 400 words
- Entered as plain text or HTML
- Author’s name and email address, to be posted with the comment
- Declaration of all potential conflicts of interest (even if these are not ultimately posted); see the Journal’s conflict-of-interest policy
- Comments may not include figures
