Obstetric and Neonatal Outcomes Following Hormone Replacement Therapy Versus Natural Cycle Frozen Embryo Transfer: A Propensity Score Matched Cohort Study

Obstetric and Neonatal Outcomes Following Hormone Replacement Therapy Versus Natural Cycle Frozen Embryo Transfer: A Propensity Score Matched Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Obstetric and Neonatal Outcomes Following Hormone Replacement Therapy Versus Natural Cycle Frozen Embryo Transfer: A Propensity Score Matched Cohort Study Goksu Goc, Velsa Maloku, Tefta Isufaj Haliti This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8437063/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background : Frozen embryo transfer (FET) has become the predominant approach in assisted reproductive technology, with endometrial preparation protocols, natural cycle FET versus hormone replacement therapy (HRT) FET potentially influencing maternal and neonatal outcomes. Recent meta-analyses report 2-3 fold increased hypertensive disorder risk with HRT-FET, but methodological limitations and inconsistent neonatal findings warrant further investigation using rigorous causal inference methods. Methods : We conducted a retrospective cohort study of 3,000 FET cycles (1,735 natural cycle, 1,265 HRT) performed at American Hospital Kosovo between 2012-2024. Early pregnancy outcomes were analyzed per transfer cycle using overlap weighting. Obstetric and neonatal outcomes were examined among 328 singleton live births (164 matched pairs) using 1:1 propensity score matching with 29 pre-treatment covariates. Risk ratios were estimated using Poisson regression with robust standard errors clustered by matched pair. Multiple sensitivity analyses assessed robustness, including overlap weighting, pairwise comparisons of natural cycle subtypes, and restriction to term births. Results : RT-FET was associated with significantly lower rates of positive hCG (52.0\% vs 63.9\%; RR 0.68, 95\% CI: 0.53--0.88, p=0.003), clinical pregnancy (46.6\% vs 58.7\%; RR 0.67, 95\% CI: 0.52--0.86, p=0.001), and live birth (37.2\% vs 50.7\%; RR 0.59, 95\% CI: 0.46--0.76, p$<$0.001) compared to natural cycle FET in per-cycle analyses. Among singleton live births, HRT-FET was associated with a 3.5-fold increased risk of hypertensive disorders (17.7\% vs 5.5\%; RR 3.50, 95\% CI: 1.41--8.70, p=0.007; absolute risk difference 12.2\%, number needed to harm 8) and a 3.2-fold increased risk of pre-eclampsia (9.8\% vs 3.1\%; RR 3.20, 95\% CI: 1.17--8.76, p=0.024). No significant differences were observed for gestational diabetes, postpartum hemorrhage, cesarean delivery, or any neonatal growth or prematurity outcomes. Findings were robust across multiple sensitivity analyses and consistent across natural cycle subtypes. Conclusions : HRT-FET was associated with lower pregnancy success rates in per-cycle analyses and markedly increased hypertensive disorder risk compared to natural cycle FET, with a clinically meaningful number needed to harm of 8. Natural cycle FET should be the preferred approach when feasible for women with regular ovulatory cycles. These findings support the corpus luteum hypothesis and have important implications for protocol selection, patient counseling, and maternal cardiovascular health. Frozen embryo transfer Hormone replacement therapy Natural cycle Hypertensive disorders of pregnancy Pre-eclampsia Propensity score matching Assisted reproductive technology Corpus luteum Figures Figure 1 Figure 2 Figure 3 Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryMaterials.pdf GraphicalAbstract.png Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 15 Feb, 2026 Reviewers agreed at journal 02 Feb, 2026 Reviewers invited by journal 21 Jan, 2026 Editor invited by journal 28 Dec, 2025 Editor assigned by journal 23 Dec, 2025 Submission checks completed at journal 23 Dec, 2025 First submitted to journal 23 Dec, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8437063","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":591630933,"identity":"a7c54b9e-d70b-4926-8229-854b08aed098","order_by":0,"name":"Goksu Goc","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYFACNijN3gAkDCxI0cJzAKRFghQtEglgkrAGefe25M88DLVy/DOfX93wo0CCgb+9OwGvFsMzx45J8zAcN5a4nVN2swfoMIkzZzfg1zIjvY2Zh+FY4gbpnLQbPEAtBhK5BLU0fwZrkTyTdvMPMVrkJdIOAB1Wk7hBgv3YbaJsMeA5liY5x+CAscSZHLbbMgYSPAT9It/eZvzhTUWdHH/78Wc33/yxATJ6CdhyAEweBhI8BiAmD17lYFsawFQdELM/IKh6FIyCUTAKRiYAAIfdRBzt0csIAAAAAElFTkSuQmCC","orcid":"","institution":"American Hospital Kosovo","correspondingAuthor":true,"prefix":"","firstName":"Goksu","middleName":"","lastName":"Goc","suffix":""},{"id":591630934,"identity":"ce5a67af-28d7-4707-b9e2-a21c5a7d1f33","order_by":1,"name":"Velsa Maloku","email":"","orcid":"","institution":"University of Prishtina","correspondingAuthor":false,"prefix":"","firstName":"Velsa","middleName":"","lastName":"Maloku","suffix":""},{"id":591630935,"identity":"dc38f406-2a4f-4a19-9e87-d6d662848f75","order_by":2,"name":"Tefta Isufaj Haliti","email":"","orcid":"","institution":"University of Prishtina","correspondingAuthor":false,"prefix":"","firstName":"Tefta","middleName":"Isufaj","lastName":"Haliti","suffix":""}],"badges":[],"createdAt":"2025-12-23 20:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8437063/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8437063/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107482804,"identity":"9883ed27-499c-4d77-97bf-37f4c6c2f6e8","added_by":"auto","created_at":"2026-04-22 02:24:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":689955,"visible":true,"origin":"","legend":"\u003cp\u003eSTROBE Flow Diagram\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticipant flow through the study showing inclusion and exclusion criteria, propensity score matching process, and final analytical cohorts. Of 3,000 FET cycles meeting inclusion criteria, 2,853 had complete covariate data for propensity score estimation. Among 1,457 singleton live births, 1:1 propensity score matching with caliper of 0.2 SD yielded 164 matched pairs (328 total) for the primary analysis. Early pregnancy outcomes were analyzed in the full cohort (n=3,000) using overlap weighting.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8437063/v1/7c72e5c16f8d92dbbed7c0ca.png"},{"id":107482580,"identity":"a66e3bd3-1f2f-45b9-90cf-a88020493ab5","added_by":"auto","created_at":"2026-04-22 02:24:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":682489,"visible":true,"origin":"","legend":"\u003cp\u003ePropensity Score Diagnostics\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFour-panel figure showing propensity score model performance. Panel A: Propensity score dis813 tributions before matching, showing substantial but imperfect overlap between HRT-FET (n=607) and natural cycle (n=850) groups. Panel B: Propensity score distributions after 1:1 matching, show815 ing excellent overlap for both groups (n=164 each). Panel C: Covariate balance (Love plot) showing standardized mean differences before (red circles) and after (green squares) matching for 20 key covariates, with all post-matching SMDs \u0026lt;0.10 (below the balance threshold). Panel D: Sum818 mary table of propensity score model performance metrics including c-statistic (0.78), calibration (Hosmer-Lemeshow p=0.42), matched pairs (164), covariate balance (all 29 SMDs \u0026lt;0.10), com820 mon support (95% overlap), and effective sample size (ESS=287, 87.5% efficiency).\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8437063/v1/84972927cd2dbcbc014890dd.png"},{"id":107257779,"identity":"ade09f00-0788-4b10-9a88-0ce74da5ad6d","added_by":"auto","created_at":"2026-04-19 12:34:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":682685,"visible":true,"origin":"","legend":"\u003cp\u003eForest Plot of All Outcomes\u003c/p\u003e\n\u003cp\u003eTwo-panel forest plot showing risk ratios and 95% confidence intervals for all maternal and neonatal outcomes from propensity score matched analysis (n=328). Panel A: Maternal complica824 tions showing significantly increased risks of hypertensive disorders (RR 3.50, p=0.007) and pre825 eclampsia (RR 3.20, p=0.024) with HRT-FET (red diamonds), with no significant differences for gestational diabetes, postpartum hemorrhage, or cesarean delivery (blue circles). Panel B: Neonatal outcomes showing no significant differences for any growth or prematurity outcomes (all blue cir828 cles). Null line at RR=1.0 shown as black dashed line. Shaded regions indicate direction of effect (red: favors natural cycle; green: favors HRT-FET). All estimates include event counts, risk ratios with 95% CI, and p-values.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-8437063/v1/32de8b358d51897114aaedd6.png"},{"id":107487237,"identity":"b719a9e6-f51a-4cf8-8a32-496dba395975","added_by":"auto","created_at":"2026-04-22 02:40:09","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2336968,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptLaTeX.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8437063/v1_covered_f9bab02f-14db-446d-ae10-1f90883bce7c.pdf"},{"id":107257776,"identity":"1db5050a-9646-4df1-9122-8b8964eaff4c","added_by":"auto","created_at":"2026-04-19 12:34:52","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":543400,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterials.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8437063/v1/f1513763d7f3a8c6e30c572f.pdf"},{"id":107484950,"identity":"ee4822fd-d36c-4c0e-b260-063e02b18958","added_by":"auto","created_at":"2026-04-22 02:33:21","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":332710,"visible":true,"origin":"","legend":"","description":"","filename":"GraphicalAbstract.png","url":"https://assets-eu.researchsquare.com/files/rs-8437063/v1/4b11e536457657faf166820c.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"Obstetric and Neonatal Outcomes Following Hormone Replacement Therapy Versus Natural Cycle Frozen Embryo Transfer: A Propensity Score Matched Cohort Study","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":" Frozen embryo transfer, Hormone replacement therapy, Natural cycle, Hypertensive disorders of pregnancy, Pre-eclampsia, Propensity score matching, Assisted reproductive technology, Corpus luteum","lastPublishedDoi":"10.21203/rs.3.rs-8437063/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8437063/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Frozen embryo transfer (FET) has become the predominant approach in assisted reproductive technology, with endometrial preparation protocols, natural cycle FET versus hormone replacement therapy (HRT) FET potentially influencing maternal and neonatal outcomes. Recent meta-analyses report 2-3 fold increased hypertensive disorder risk with HRT-FET, but methodological limitations and inconsistent neonatal findings warrant further investigation using rigorous causal inference methods.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We conducted a retrospective cohort study of 3,000 FET cycles (1,735 natural cycle, 1,265 HRT) performed at American Hospital Kosovo between 2012-2024. Early pregnancy outcomes were analyzed per transfer cycle using overlap weighting. Obstetric and neonatal outcomes were examined among 328 singleton live births (164 matched pairs) using 1:1 propensity score matching with 29 pre-treatment covariates. Risk ratios were estimated using Poisson regression with robust standard errors clustered by matched pair. Multiple sensitivity analyses assessed robustness, including overlap weighting, pairwise comparisons of natural cycle subtypes, and restriction to term births.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: RT-FET was associated with significantly lower rates of positive hCG (52.0\\% vs 63.9\\%; RR 0.68, 95\\% CI: 0.53--0.88, p=0.003), clinical pregnancy (46.6\\% vs 58.7\\%; RR 0.67, 95\\% CI: 0.52--0.86, p=0.001), and live birth (37.2\\% vs 50.7\\%; RR 0.59, 95\\% CI: 0.46--0.76, p$\u0026lt;$0.001) compared to natural cycle FET in per-cycle analyses. Among singleton live births, HRT-FET was associated with a 3.5-fold increased risk of hypertensive disorders (17.7\\% vs 5.5\\%; RR 3.50, 95\\% CI: 1.41--8.70, p=0.007; absolute risk difference 12.2\\%, number needed to harm 8) and a 3.2-fold increased risk of pre-eclampsia (9.8\\% vs 3.1\\%; RR 3.20, 95\\% CI: 1.17--8.76, p=0.024). No significant differences were observed for gestational diabetes, postpartum hemorrhage, cesarean delivery, or any neonatal growth or prematurity outcomes. Findings were robust across multiple sensitivity analyses and consistent across natural cycle subtypes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: HRT-FET was associated with lower pregnancy success rates in per-cycle analyses and markedly increased hypertensive disorder risk compared to natural cycle FET, with a clinically meaningful number needed to harm of 8. Natural cycle FET should be the preferred approach when feasible for women with regular ovulatory cycles. These findings support the corpus luteum hypothesis and have important implications for protocol selection, patient counseling, and maternal cardiovascular health.\u003c/p\u003e","manuscriptTitle":"Obstetric and Neonatal Outcomes Following Hormone Replacement Therapy Versus Natural Cycle Frozen Embryo Transfer: A Propensity Score Matched Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:34:48","doi":"10.21203/rs.3.rs-8437063/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-02-15T12:54:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"172792283298660725977478596690401846748","date":"2026-02-02T07:49:18+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-21T10:19:26+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-28T13:59:52+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-24T01:22:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-24T01:22:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pregnancy and Childbirth","date":"2025-12-23T20:50:36+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pregnancy-and-childbirth","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"prch","sideBox":"Learn more about [BMC Pregnancy and Childbirth](http://bmcpregnancychildbirth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/prch/default.aspx","title":"BMC Pregnancy and Childbirth","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2d7799f2-9398-4592-b467-fb738f179092","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-19T12:34:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:34:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8437063","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8437063","identity":"rs-8437063","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}