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      Reduced Ectopic Pregnancy Rate on Day 5 Embryo Transfer Compared with Day 3: A Meta-Analysis

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          Abstract

          Objective

          To compare the risk of ectopic pregnancy (EP) after embryo transfer on day 3(D3-ET) and day 5(D5-ET).

          Design

          Meta-analysis

          Patients

          Women with pregnancy resulting from in vitro undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)

          Result(s)

          Twenty-two studies were identified through research conducted using the PubMed, Embase, and Cochrane databases and ClinicalTrials.gov. All studies were conducted prior to October 2016. Adding the reproductive data from our center, a total of 143 643 pregnancies were reviewed(D3-ET: n = 62027,D5-ET:n = 81616). A lower EP rate was found in women undergoing D5-ET than in those undergoing D3-ET [relative risk (RR), 0.67;95% confidence interval (CI), 0.54–0.85;143643 pregnancies in 23 studies; I 2 = 67%]. These results were validated in subgroups of fresh embryo-transfer (Fre-ET) cycles [RR, 0.78; 95%CI, 0.69–0.88; 91 871 pregnancies in 21 studies; I 2 = 29%] and frozen-thawed embryo-transfer (Fro-ET) cycles [RR, 0.43; 95%CI, 0.36–0.51; 51 772 pregnancies in 10 studies; I 2 = 33%]. After separating out the randomized controlled trials (RCTs), a significant difference was found in the retrospective studies in both subgroups [both Fre-ET (RR,0.78;95% CI 0.69–0.88);91182 pregnancies in 14 studies; I 2 = 45%] and Fro-ET(RR,0.43;95% CI 0.36–0.51; 51751pregnancies in 9 studies;I 2 = 33%)], while the RCTs showed no statistical significance for Fre-ET cycles[RR,0.86;95% CI 0.32–2.26); 689 pregnancies in 7 studies; I 2 = 0%].

          Conclusion(s)

          The present study indicates that D5-ET reduces the risk for EP in cycles that use IVF or ICSI, compared with D3-ET. It suggests that D5-ET may be a better choice for decreasing the EP rate in assisted reproductive technology. Further high-quality randomized controlled trials are anticipated.

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          Most cited references32

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          In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos.

          Efstratios Kolibianakis, Michel Camus, Andre van Zundert … (2006)
          Single-embryo transfer has been recommended to reduce the incidence of multiple gestations when in vitro fertilization is performed in women under 36 years of age. We designed a prospective, randomized, controlled trial to determine whether there were any differences in the rates of pregnancy and delivery between women undergoing transfer of a single cleavage-stage (day 3) embryo and those undergoing transfer of a single blastocyst-stage (day 5) embryo. We studied 351 infertile women under 36 years of age who were randomly assigned to undergo transfer of either a single cleavage-stage embryo (176 patients) or a single blastocyst-stage embryo (175 patients). Multifollicular ovarian stimulation was performed with a gonadotropin-releasing hormone antagonist and recombinant follicle-stimulating hormone. The study was terminated early after a prespecified interim analysis (which included 50 percent of the planned number of patients) found a higher rate of pregnancy among women undergoing transfer of a single blastocyst-stage embryo (P=0.02). The rate of delivery was also significantly higher in this group than in the group undergoing transfer of a single cleavage-stage embryo (32.0 percent vs. 21.6 percent; relative risk, 1.48; 95 percent confidence interval, 1.04 to 2.11). Two multiple births occurred, both of monozygotic twins, both of which were in the group undergoing transfer of a single cleavage-stage embryo. These findings support the transfer of a single blastocyst-stage (day 5) embryo in infertile women under 36 years of age. Copyright 2006 Massachusetts Medical Society.
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            Pregnancy of unknown location: a consensus statement of nomenclature, definitions, and outcome.

            Cecilia Bottomley, Matthew Kirk, Dirk Timmerman … (2011)
            To improve the interpretation of future studies in women who are initially diagnosed with a pregnancy of unknown location (PUL), we propose a consensus statement with definitions of population, target disease, and final outcome. A review of literature and a series of collaborative international meetings were used to develop a consensus for definitions and final outcomes of women initially diagnosed with a PUL. Global differences were noted in populations studied and in the definitions of outcomes. We propose to define initial ultrasound classification of findings into five categories: definite ectopic pregnancy (EP), probable EP, PUL, probable intrauterine pregnancy (IUP), and definite IUP. Patients with a PUL should be followed and final outcomes should be categorized as visualized EP, visualized IUP, spontaneously resolved PUL, and persisting PUL. Those with the transient condition of a persisting PUL should ultimately be classified as nonvisualized EP, treated persistent PUL, resolved persistent PUL, or histologic IUP. These specific categories can be used to characterize the natural history or location (intrauterine vs. extrauterine) of any early gestation where the initial location is unknown. Careful definition of populations and classification of outcomes should optimize objective interpretation of research, allow objective assessment of future reproductive prognosis, and hopefully lead to improved clinical care of women initially identified to have a PUL. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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              Ectopic pregnancy risk with assisted reproductive technology procedures.

              Laurence B. Peterson, Teri Reynolds, Catherine Clayton … (2006)
              To assess the ectopic pregnancy risk among women who conceived with assisted reproductive technology (ART) procedures. The ectopic rate for ART pregnancies was calculated from population-based data of pregnancies conceived with ART in U.S. clinics in 1999-2001. Variation in ectopic risk by patient and ART treatment factors was assessed by using bivariate analyses and multivariable logistic regression. Of 94,118 ART pregnancies, 2,009 (2.1%) were ectopic. Variation was observed by procedure type. In comparison with the ectopic rate (2.2%) among pregnancies conceived with in vitro fertilization and transcervical transfer of freshly fertilized embryos from the patient's oocytes (fresh, nondonor IVF-ET), the ectopic rate was significantly increased when zygote intrafallopian transfer (ZIFT) was used (3.6%) and significantly decreased when donor oocytes were used (1.4%) or when a gestational surrogate carried the pregnancy (0.9%). Among fresh nondonor IVF-ET procedures, the risk for ectopic pregnancy was increased among women with tubal factor infertility (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.7-2.4; referent group = ART for male factor), endometriosis (OR 1.3, 95% CI 1.0-1.6), and other nontubal female factors of infertility (OR 1.4, 95% CI 1.2-1.6) and decreased among women with a previous live birth (OR 0.6, 95% CI 0.5-0.7). Transfer of embryos with an indication of high implantation potential was associated with a decreased ectopic risk when 2 or fewer embryos were transferred (OR 0.7, 95% CI 0.5-0.9), but not when 3 or more embryos were transferred. Ectopic risk among ART pregnancies varied according to ART procedure type, reproductive health characteristics of the woman carrying the pregnancy, and estimated embryo implantation potential. II-2.
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                Author and article information

                Contributors
                Qing-Yuan Sun: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 25 January 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 1
                Electronic Location Identifier: e0169837
                Affiliations
                [1 ]Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
                [2 ]National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan, China
                [3 ]The Key laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
                [4 ]Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
                [5 ]Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
                Institute of Zoology Chinese Academy of Sciences, CHINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: LC.

                • Data curation: LC BZ.

                • Formal analysis: BZ LC.

                • Funding acquisition: ZC LC LY.

                • Methodology: LC BZ.

                • Project administration: ZC.

                • Resources: ZC LY.

                • Software: BZ.

                • Supervision: ZC LY.

                • Validation: ZC.

                • Visualization: LC RT LD LY.

                • Writing – original draft: BZ.

                • Writing – review & editing: LC.

                Article
                Publisher ID: PONE-D-16-44244
                DOI: 10.1371/journal.pone.0169837
                PMC ID: 5266274
                PubMed ID: 28121989
                SO-VID: c1dfed99-c5c7-4f19-82ab-f7b1a6e1e083
                Copyright © © 2017 Zhang et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 7 November 2016
                Date accepted : 22 December 2016
                Page count
                Figures: 4, Tables: 0, Pages: 14
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81501223
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81571414
                Award Recipient :
                Funded by: National Research and Development Plan
                Award ID: 2016YFC1000600
                Award Recipient :
                Funded by: the State Key Program of National Natural Science Foundation of China
                Award ID: 81430029
                Award Recipient :
                Funded by: Research fund of National Health and Family Planning Commission of China
                Award ID: 201402004
                Award Recipient :
                1 Author: ZC, Grant numbers: 2016YFC1000600, Funding name: National Research and Development Plan, The URL: http://program.most.gov.cn, Role: conceived and designed the experiments; 2 Author: ZC, Grant numbers: 81430029, Funding name: the State Key Program of National Natural Science Foundation of China, The URL: http://www.nsfc.gov.cn, Role: conceived and designed the experiments; 3 Author: ZC, Grant numbers: 201402004, Funding name: Research fund of National Health and Family Planning Commission of China, Role: conceived and designed the experiments; 4 Author: LC, Grant numbers: 81501223, Funding name: National Natural Science Foundation of China, The URL: http://www.nsfc.gov.cn, Role: preparation of the manuscript; 5 Author: LY, Grant numbers: 81571414, Funding name: National Natural Science Foundation of China, The URL: http://www.nsfc.gov.cn, Role: preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Maternal Health
                Subject: Pregnancy
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Obstetrics and Gynecology
                Subject: Pregnancy
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Maternal Health
                Subject: Pregnancy
                Subject: Embryo Transfer
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Obstetrics and Gynecology
                Subject: Pregnancy
                Subject: Embryo Transfer
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Embryology
                Subject: Embryos
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Embryology
                Subject: Blastocysts
                Subject: Medicine and Health Sciences
                Subject: Clinical Medicine
                Subject: Clinical Trials
                Subject: Randomized Controlled Trials
                Subject: Medicine and Health Sciences
                Subject: Pharmacology
                Subject: Drug Research and Development
                Subject: Clinical Trials
                Subject: Randomized Controlled Trials
                Subject: Research and Analysis Methods
                Subject: Clinical Trials
                Subject: Randomized Controlled Trials
                Subject: Research and Analysis Methods
                Subject: Research Design
                Subject: Retrospective Studies
                Subject: Research and Analysis Methods
                Subject: Database and Informatics Methods
                Subject: Database Searching
                Custom metadata
                Data Availability All relevant data are within the paper.

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