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<body>
<div style="position:absolute;left:50%;margin-left:-306px;top:0px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background01.jpg" width=612 height=790></div>
<div style="position:absolute;left:48.19px;top:27.19px" class="cls_003"><span class="cls_003">Human Reproduction Update, Vol.23, No.2 pp. 139-155, 2017</span></div>
<div style="position:absolute;left:48.19px;top:39.15px" class="cls_003"><span class="cls_003">Advanced Access publication on November 4, 2016</span></div>
<div style="position:absolute;left:222.12px;top:39.15px" class="cls_003"><span class="cls_003">doi:10.1093/humupd/dmw038</span></div>
<div style="position:absolute;left:150.18px;top:95.87px" class="cls_004"><span class="cls_004">Oocyte, embryo and blastocyst</span></div>
<div style="position:absolute;left:150.18px;top:122.86px" class="cls_004"><span class="cls_004">cryopreservation in ART: systematic</span></div>
<div style="position:absolute;left:150.18px;top:149.84px" class="cls_004"><span class="cls_004">review and meta-analysis comparing</span></div>
<div style="position:absolute;left:150.18px;top:176.88px" class="cls_004"><span class="cls_004">slow-freezing versus vitrification to</span></div>
<div style="position:absolute;left:150.18px;top:203.87px" class="cls_004"><span class="cls_004">produce evidence for the development</span></div>
<div style="position:absolute;left:150.18px;top:230.86px" class="cls_004"><span class="cls_004">of global guidance</span></div>
<div style="position:absolute;left:150.18px;top:270.01px" class="cls_005"><span class="cls_005">Laura Rienzi</span><span class="cls_006"><sup>1,*</sup></span><span class="cls_005">, Clarisa Gracia</span><span class="cls_006"><sup>2</sup></span><span class="cls_005">, Roberta Maggiulli</span><span class="cls_006"><sup>1</sup></span><span class="cls_005">,</span></div>
<div style="position:absolute;left:150.18px;top:287.01px" class="cls_005"><span class="cls_005">Andrew R. LaBarbera</span><span class="cls_006"><sup>3</sup></span><span class="cls_005">, Daniel J. Kaser</span><span class="cls_006"><sup>4</sup></span><span class="cls_005">, Filippo M. Ubaldi</span><span class="cls_006"><sup>1</sup></span><span class="cls_005">,</span></div>
<div style="position:absolute;left:150.18px;top:303.96px" class="cls_005"><span class="cls_005">Sheryl Vanderpoel</span><span class="cls_006"><sup>5,6</sup></span><span class="cls_005">, and Catherine Racowsky</span><span class="cls_006"><sup>4</sup></span></div>
<div style="position:absolute;left:150.18px;top:326.22px" class="cls_007"><span class="cls_007"><sup>1</sup></span><span class="cls_008">GENERA Centre for Reproductive Medicine, Clinica Valle Giulia, via de Notaris 2b, Rome, Italy</span><span class="cls_007"><sup>2</sup></span><span class="cls_008">Division of Reproductive Endocrinology</span></div>
<div style="position:absolute;left:150.18px;top:335.24px" class="cls_008"><span class="cls_008">and Infertility, Department of Obstetrics and Gynecology, University of Pennsylvania, Philadelphia, PA, USA</span><span class="cls_007"><sup>3</sup></span><span class="cls_008">American Society for</span></div>
<div style="position:absolute;left:150.18px;top:344.25px" class="cls_008"><span class="cls_008">Reproductive Medicine, Birmingham, Alabama 35216, USA</span><span class="cls_007"><sup>4</sup></span><span class="cls_008">Department of Obstetrics and Gynecology, Brigham and Women’s Hospital,</span></div>
<div style="position:absolute;left:150.18px;top:353.21px" class="cls_008"><span class="cls_008">Harvard Medical School, Boston, MA 02115, USA</span><span class="cls_007"><sup>5</sup></span><span class="cls_008">HRP (the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of</span></div>
<div style="position:absolute;left:150.18px;top:362.22px" class="cls_008"><span class="cls_008">Research, Development and Research Training in Human Reproduction), Geneva, Switzerland (at the time of the study)</span><span class="cls_007"><sup>6</sup></span><span class="cls_008">Population</span></div>
<div style="position:absolute;left:150.18px;top:372.38px" class="cls_008"><span class="cls_008">Council, Reproductive Health Programme, New York, USA</span></div>
<div style="position:absolute;left:150.18px;top:390.36px" class="cls_008"><span class="cls_008">*Correspondence address. E-mail: [email protected]</span></div>
<div style="position:absolute;left:150.18px;top:404.88px" class="cls_003"><span class="cls_003">Submitted on June 2, 2016; resubmitted on September 15, 2016; editorial decision on October 10, 2016; accepted on October 14, 2016</span></div>
<div style="position:absolute;left:150.18px;top:434.57px" class="cls_009"><span class="cls_009">TABLE OF CONTENTS</span></div>
<div style="position:absolute;left:150.18px;top:452.86px" class="cls_010"><span class="cls_010">•</span><span class="cls_011"> Introduction</span></div>
<div style="position:absolute;left:150.18px;top:464.82px" class="cls_010"><span class="cls_010">•</span><span class="cls_011"> Methods</span></div>
<div style="position:absolute;left:168.21px;top:476.84px" class="cls_012"><span class="cls_012">Oocyte cryopreservation: study eligibility criteria</span></div>
<div style="position:absolute;left:168.21px;top:488.86px" class="cls_012"><span class="cls_012">Oocyte cryopreservation: study search methods</span></div>
<div style="position:absolute;left:168.21px;top:500.82px" class="cls_012"><span class="cls_012">Oocyte cryopreservation: study descriptions</span></div>
<div style="position:absolute;left:168.21px;top:512.84px" class="cls_012"><span class="cls_012">Embryo cryopreservation: study eligibility criteria</span></div>
<div style="position:absolute;left:168.21px;top:524.86px" class="cls_012"><span class="cls_012">Embryo cryopreservation: study search methods</span></div>
<div style="position:absolute;left:168.21px;top:536.82px" class="cls_012"><span class="cls_012">Embryo cryopreservation: study descriptions</span></div>
<div style="position:absolute;left:168.21px;top:548.84px" class="cls_012"><span class="cls_012">Assessing the quality of each study</span></div>
<div style="position:absolute;left:168.21px;top:560.86px" class="cls_012"><span class="cls_012">Data synthesis and meta-analysis</span></div>
<div style="position:absolute;left:168.21px;top:572.82px" class="cls_012"><span class="cls_012">Assessment of the quality of the literature as a whole</span></div>
<div style="position:absolute;left:150.18px;top:584.84px" class="cls_010"><span class="cls_010">•</span><span class="cls_011"> Results</span></div>
<div style="position:absolute;left:168.21px;top:596.86px" class="cls_012"><span class="cls_012">Oocyte slow-freezing versus vitrification: clinical outcomes and oocyte cryosurvival</span></div>
<div style="position:absolute;left:168.21px;top:608.82px" class="cls_012"><span class="cls_012">Oocyte slow-freezing versus fresh oocytes: clinical outcomes</span></div>
<div style="position:absolute;left:168.21px;top:620.84px" class="cls_012"><span class="cls_012">Oocyte vitrification versus fresh oocytes: clinical outcomes</span></div>
<div style="position:absolute;left:168.21px;top:632.86px" class="cls_012"><span class="cls_012">Embryo slow-freezing versus vitrification</span></div>
<div style="position:absolute;left:150.18px;top:644.82px" class="cls_010"><span class="cls_010">•</span><span class="cls_011"> Discussion</span></div>
<div style="position:absolute;left:168.21px;top:656.84px" class="cls_012"><span class="cls_012">Contribution of cryopreservation to the cumulative LBR</span></div>
<div style="position:absolute;left:168.21px;top:668.86px" class="cls_012"><span class="cls_012">Embryo transfer policy and cryopreservation</span></div>
<div style="position:absolute;left:48.19px;top:709.02px" class="cls_010"><span class="cls_010">© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.</span></div>
<div style="position:absolute;left:48.19px;top:717.97px" class="cls_010"><span class="cls_010">This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (</span><A HREF="http://creativecommons.org/">http://creativecommons.org/</A> </div>
<div style="position:absolute;left:48.19px;top:726.99px" class="cls_010"><span class="cls_010">licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.</span></div>
<div style="position:absolute;left:48.19px;top:736.00px" class="cls_010"><span class="cls_010">For commercial re-use, please contact [email protected]</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:800px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background02.jpg" width=612 height=790></div>
<div style="position:absolute;left:45.35px;top:25.13px" class="cls_013"><span class="cls_013">140</span></div>
<div style="position:absolute;left:525.71px;top:26.63px" class="cls_014"><span class="cls_014">Rienzi et al.</span></div>
<div style="position:absolute;left:165.37px;top:56.80px" class="cls_012"><span class="cls_012">IVF cycle segmentation</span></div>
<div style="position:absolute;left:165.37px;top:68.82px" class="cls_012"><span class="cls_012">Cryopreservation and enhanced embryo evaluation</span></div>
<div style="position:absolute;left:165.37px;top:80.79px" class="cls_012"><span class="cls_012">New possibilities related to oocyte cryopreservation</span></div>
<div style="position:absolute;left:165.37px;top:92.80px" class="cls_012"><span class="cls_012">Standardization of protocols and automation</span></div>
<div style="position:absolute;left:165.37px;top:104.82px" class="cls_012"><span class="cls_012">Obstetric and perinatal outcomes</span></div>
<div style="position:absolute;left:147.34px;top:116.79px" class="cls_010"><span class="cls_010">•</span><span class="cls_011"> Conclusions</span></div>
<div style="position:absolute;left:55.84px;top:158.26px" class="cls_009"><span class="cls_009">BACKGROUND</span><span class="cls_015">:</span><span class="cls_011"> Successful cryopreservation of oocytes and embryos is essential not only to maximize the safety and efficacy of ovarian</span></div>
<div style="position:absolute;left:55.84px;top:171.78px" class="cls_011"><span class="cls_011">stimulation cycles in an IVF treatment, but also to enable fertility preservation. Two cryopreservation methods are routinely used: slow-</span></div>
<div style="position:absolute;left:55.84px;top:183.74px" class="cls_011"><span class="cls_011">freezing or vitrification. Slow-freezing allows for freezing to occur at a sufficiently slow rate to permit adequate cellular dehydration while</span></div>
<div style="position:absolute;left:55.84px;top:195.76px" class="cls_011"><span class="cls_011">minimizing intracellular ice formation. Vitrification allows the solidification of the cell(s) and of the extracellular milieu into a glass-like state</span></div>
<div style="position:absolute;left:55.84px;top:207.78px" class="cls_011"><span class="cls_011">without the formation of ice.</span></div>
<div style="position:absolute;left:55.84px;top:221.24px" class="cls_009"><span class="cls_009">OBJECTIVE AND RATIONALE</span><span class="cls_015">:</span><span class="cls_011"> The objective of our study was to provide a systematic review and meta-analysis of clinical outcomes</span></div>
<div style="position:absolute;left:55.84px;top:234.76px" class="cls_011"><span class="cls_011">following slow-freezing/thawing versus vitrification/warming of oocytes and embryos and to inform the development of World Health</span></div>
<div style="position:absolute;left:55.84px;top:246.78px" class="cls_011"><span class="cls_011">Organization guidance on the most effective cryopreservation method.</span></div>
<div style="position:absolute;left:55.84px;top:260.25px" class="cls_009"><span class="cls_009">SEARCH METHODS</span><span class="cls_015">:</span><span class="cls_011"> A Medline search was performed from 1966 to 1 August 2016 using the following search terms: (Oocyte(s) [tiab]</span></div>
<div style="position:absolute;left:55.84px;top:273.77px" class="cls_011"><span class="cls_011">OR (Pronuclear[tiab] OR Embryo[tiab] OR Blastocyst[tiab]) AND (vitrification[tiab] OR freezing[tiab] OR freeze[tiab]) AND (pregnancy</span></div>
<div style="position:absolute;left:55.84px;top:285.73px" class="cls_011"><span class="cls_011">[tiab] OR birth[tiab] OR clinical[tiab]). Queries were limited to those involving humans. RCTs and cohort studies that were published in</span></div>
<div style="position:absolute;left:55.84px;top:297.75px" class="cls_011"><span class="cls_011">full-length were considered eligible. Each reference was reviewed for relevance and only primary evidence and relevant articles from the</span></div>
<div style="position:absolute;left:55.84px;top:309.77px" class="cls_011"><span class="cls_011">bibliographies of included articles were considered. References were included if they reported cryosurvival rate, clinical pregnancy rate</span></div>
<div style="position:absolute;left:55.84px;top:321.73px" class="cls_011"><span class="cls_011">(CPR), live-birth rate (LBR) or delivery rate for slow-frozen or vitrified human oocytes or embryos. A meta-analysis was performed using a</span></div>
<div style="position:absolute;left:55.84px;top:333.75px" class="cls_011"><span class="cls_011">random effects model to calculate relative risk ratios (RR) and 95% CI.</span></div>
<div style="position:absolute;left:55.84px;top:347.27px" class="cls_009"><span class="cls_009">OUTCOMES</span><span class="cls_015">:</span><span class="cls_011"> One RCT study comparing slow-freezing versus vitrification of oocytes was included. Vitrification was associated with</span></div>
<div style="position:absolute;left:55.84px;top:360.74px" class="cls_011"><span class="cls_011">increased ongoing CPR per cycle (RR = 2.81, 95% CI: 1.05-7.51; P = 0.039; 48 and 30 cycles, respectively, per transfer (RR = 1.81, 95%</span></div>
<div style="position:absolute;left:55.84px;top:372.75px" class="cls_011"><span class="cls_011">CI 0.71-4.67; P = 0.214; 47 and 19 transfers) and per warmed/thawed oocyte (RR = 1.14, 95% CI: 1.02-1.28; P = 0.018; 260 and 238</span></div>
<div style="position:absolute;left:55.84px;top:384.77px" class="cls_011"><span class="cls_011">oocytes). One RCT comparing vitrification versus fresh oocytes was analysed. In vitrification and fresh cycles, respectively, no evidence for</span></div>
<div style="position:absolute;left:55.84px;top:396.73px" class="cls_011"><span class="cls_011">a difference in ongoing CPR per randomized woman (RR = 1.03, 95% CI: 0.87-1.21; P = 0.744, 300 women in each group), per cycle</span></div>
<div style="position:absolute;left:55.84px;top:408.75px" class="cls_011"><span class="cls_011">(RR = 1.01, 95% CI: 0.86-1.18; P = 0.934; 267 versus 259 cycles) and per oocyte utilized (RR = 1.02, 95% CI: 0.82-1.26; P = 0.873;</span></div>
<div style="position:absolute;left:55.84px;top:420.77px" class="cls_011"><span class="cls_011">3286 versus 3185 oocytes) was reported. Findings were consistent with relevant cohort studies.</span></div>
<div style="position:absolute;left:64.85px;top:432.73px" class="cls_011"><span class="cls_011">Of the seven RCTs on embryo cryopreservation identified, three met the inclusion criteria (638 warming/thawing cycles at cleavage and</span></div>
<div style="position:absolute;left:55.84px;top:444.75px" class="cls_011"><span class="cls_011">blastocyst stage), none of which involved pronuclear-stage embryos. A higher CPR per cycle was noted with embryo vitrification compared</span></div>
<div style="position:absolute;left:55.84px;top:455.38px" class="cls_011"><span class="cls_011">with slow-freezing, though this was of borderline statistical significance (RR = 1.89, 95% CI: 1.00-3.59; P = 0.051; three RCTs; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> =</span></div>
<div style="position:absolute;left:55.84px;top:468.74px" class="cls_011"><span class="cls_011">71.9%). LBR per cycle was reported by one RCT performed with cleavage-stage embryos and was higher for vitrification (RR = 2.28; 95%</span></div>
<div style="position:absolute;left:55.84px;top:480.75px" class="cls_011"><span class="cls_011">CI: 1.17-4.44; P =</span></div>
<div style="position:absolute;left:128.80px;top:480.75px" class="cls_011"><span class="cls_011">0.016; 216 cycles; one RCT). A secondary analysis was performed focusing on embryo cryosurvival rate. Pooled data</span></div>
<div style="position:absolute;left:55.84px;top:492.77px" class="cls_011"><span class="cls_011">from seven RCTs (3615 embryos) revealed a significant improvement in embryo cryosurvival following vitrification as compared with slow-</span></div>
<div style="position:absolute;left:55.84px;top:503.40px" class="cls_011"><span class="cls_011">freezing (RR = 1.59, 95% CI: 1.30-1.93; P < 0.001; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 93%).</span></div>
<div style="position:absolute;left:55.84px;top:518.26px" class="cls_009"><span class="cls_009">WIDER IMPLICATIONS</span><span class="cls_015">:</span><span class="cls_011"> Data from available RCTs suggest that vitrification/warming is superior to slow-freezing/thawing with regard</span></div>
<div style="position:absolute;left:55.84px;top:531.78px" class="cls_011"><span class="cls_011">to clinical outcomes (low quality of the evidence) and cryosurvival rates (moderate quality of the evidence) for oocytes, cleavage-stage</span></div>
<div style="position:absolute;left:55.84px;top:543.74px" class="cls_011"><span class="cls_011">embryos and blastocysts. The results were confirmed by cohort studies. The improvements obtained with the introduction of vitrification</span></div>
<div style="position:absolute;left:55.84px;top:555.76px" class="cls_011"><span class="cls_011">have several important clinical implications in ART. Based on this evidence, in particular regarding cryosurvival rates, laboratories that con-</span></div>
<div style="position:absolute;left:55.84px;top:567.78px" class="cls_011"><span class="cls_011">tinue to use slow-freezing should consider transitioning to the use of vitrification for cryopreservation.</span></div>
<div style="position:absolute;left:55.84px;top:585.75px" class="cls_011"><span class="cls_011">Key words: cryopreservation / vitrification / slow freezing / oocyte / embryo / blastocyst / World Health Organization</span></div>
<div style="position:absolute;left:314.65px;top:632.18px" class="cls_011"><span class="cls_011">countries, such as Switzerland, Finland, Netherlands, Sweden and</span></div>
<div style="position:absolute;left:45.35px;top:631.23px" class="cls_017"><span class="cls_017">Introduction</span></div>
<div style="position:absolute;left:314.65px;top:644.20px" class="cls_011"><span class="cls_011">Iceland, the proportion of cryopreserved embryo transfers is higher</span></div>
<div style="position:absolute;left:45.35px;top:655.20px" class="cls_011"><span class="cls_011">Cryopreservation of gametes and embryos is an essential aspect of</span></div>
<div style="position:absolute;left:314.65px;top:656.22px" class="cls_011"><span class="cls_011">than</span></div>
<div style="position:absolute;left:335.11px;top:656.22px" class="cls_011"><span class="cls_011">50% (</span><span class="cls_018">Kupka et al., 2016</span><span class="cls_011">). The observed differences among</span></div>
<div style="position:absolute;left:45.35px;top:667.22px" class="cls_011"><span class="cls_011">ART. Its widespread application has allowed increased safety and effi-</span></div>
<div style="position:absolute;left:314.65px;top:668.18px" class="cls_011"><span class="cls_011">European countries are mainly due to policies requiring lower trans-</span></div>
<div style="position:absolute;left:45.35px;top:679.24px" class="cls_011"><span class="cls_011">cacy of IVF treatments. The proportion of cryopreserved embryo</span></div>
<div style="position:absolute;left:314.65px;top:680.20px" class="cls_011"><span class="cls_011">fer order which, in turn, have led to more supernumerary embryos</span></div>
<div style="position:absolute;left:45.35px;top:691.20px" class="cls_011"><span class="cls_011">transfer cycles compared with fresh cycles is growing in Europe.</span></div>
<div style="position:absolute;left:314.65px;top:692.22px" class="cls_011"><span class="cls_011">available for cryopreservation</span></div>
<div style="position:absolute;left:432.17px;top:692.22px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Coetsier and Dhont,</span></div>
<div style="position:absolute;left:521.29px;top:692.22px" class="cls_018"><span class="cls_018">1998</span><span class="cls_011">). The</span></div>
<div style="position:absolute;left:45.35px;top:703.22px" class="cls_011"><span class="cls_011">Overall it has been estimated that cryopreserved cycles contributed</span></div>
<div style="position:absolute;left:314.65px;top:704.18px" class="cls_011"><span class="cls_011">recent systematic application of cryopreservation for new indications</span></div>
<div style="position:absolute;left:45.35px;top:715.23px" class="cls_011"><span class="cls_011">to 32% of the transfers in 2011 compared to 28% in 2010. In some</span></div>
<div style="position:absolute;left:314.65px;top:716.20px" class="cls_011"><span class="cls_011">such as cycle segmentation (i.e. planned freeze all) (</span><span class="cls_018">Devroey et al., 2011</span><span class="cls_011">),</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:1600px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background03.jpg" width=612 height=790></div>
<div style="position:absolute;left:48.19px;top:26.63px" class="cls_014"><span class="cls_014">Slow-freezing versus vitrification in ART</span></div>
<div style="position:absolute;left:550.66px;top:25.13px" class="cls_013"><span class="cls_013">141</span></div>
<div style="position:absolute;left:48.19px;top:56.80px" class="cls_011"><span class="cls_011">oocyte banking (</span><span class="cls_018">Cobo et al.,</span></div>
<div style="position:absolute;left:166.22px;top:56.80px" class="cls_018"><span class="cls_018">2011a</span><span class="cls_011">,</span><span class="cls_018">2012</span><span class="cls_011">) and pre-implantation</span></div>
<div style="position:absolute;left:317.48px;top:56.80px" class="cls_011"><span class="cls_011">of other cryoprotectants such as glycerol have been investigated for</span></div>
<div style="position:absolute;left:48.19px;top:68.82px" class="cls_011"><span class="cls_011">genetic testing at the blastocyst stage (</span><span class="cls_018">Schoolcraft et al., 2011</span><span class="cls_011">) likely</span></div>
<div style="position:absolute;left:317.48px;top:68.82px" class="cls_011"><span class="cls_011">cryopreservation of oocytes, biopsied embryos and blastocysts (</span><span class="cls_018">Cohen</span></div>
<div style="position:absolute;left:48.19px;top:80.79px" class="cls_011"><span class="cls_011">will contribute, in our opinion, to a further increase in the proportion</span></div>
<div style="position:absolute;left:317.48px;top:80.79px" class="cls_018"><span class="cls_018">et al., 1985</span><span class="cls_011">;</span><span class="cls_018"> Fabbri et al., 2001</span><span class="cls_011">;</span><span class="cls_018"> Jericho et al., 2003</span><span class="cls_011">;</span><span class="cls_018"> Veeck et al., 2004</span><span class="cls_011">).</span></div>
<div style="position:absolute;left:48.19px;top:92.80px" class="cls_011"><span class="cls_011">of cryopreserved cycles in the near future.</span></div>
<div style="position:absolute;left:317.48px;top:92.80px" class="cls_011"><span class="cls_011">Detailed analysis of biological principles and development of various</span></div>
<div style="position:absolute;left:57.20px;top:104.82px" class="cls_011"><span class="cls_011">Embryo cryopreservation has, however, generated ethical, moral</span></div>
<div style="position:absolute;left:317.48px;top:104.82px" class="cls_011"><span class="cls_011">slow-freezing procedures have been described previously (</span><span class="cls_018">Leibo and</span></div>
<div style="position:absolute;left:48.19px;top:116.78px" class="cls_011"><span class="cls_011">and legal issues. Some countries have enacted specific laws that</span></div>
<div style="position:absolute;left:317.48px;top:116.79px" class="cls_018"><span class="cls_018">Songstaken, 2002</span><span class="cls_011">).</span></div>
<div style="position:absolute;left:48.19px;top:128.80px" class="cls_011"><span class="cls_011">restrict (e.g. Germany, Switzerland, Austria) or even forbid (Italy with</span></div>
<div style="position:absolute;left:326.49px;top:128.80px" class="cls_011"><span class="cls_011">In contrast to slow-freezing, vitrification is a cryopreservation</span></div>
<div style="position:absolute;left:48.19px;top:140.82px" class="cls_011"><span class="cls_011">Law 40 in 2004) embryo cryopreservation. As an alternative and in</span></div>
<div style="position:absolute;left:317.48px;top:140.82px" class="cls_011"><span class="cls_011">method that allows solidification of the cell(s) and the extracellular</span></div>
<div style="position:absolute;left:48.19px;top:152.78px" class="cls_011"><span class="cls_011">accordance with the legal prohibition of embryo cryopreservation,</span></div>
<div style="position:absolute;left:317.48px;top:152.79px" class="cls_011"><span class="cls_011">milieu into a glass-like state without the formation of ice. The most</span></div>
<div style="position:absolute;left:48.19px;top:164.80px" class="cls_011"><span class="cls_011">oocyte cryopreservation had been introduced into routine practice in</span></div>
<div style="position:absolute;left:317.48px;top:164.80px" class="cls_011"><span class="cls_011">widely used vitrification method for mammalian embryos requires the</span></div>
<div style="position:absolute;left:48.19px;top:176.82px" class="cls_011"><span class="cls_011">Italy</span></div>
<div style="position:absolute;left:67.07px;top:176.82px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">La Sala et al.,</span></div>
<div style="position:absolute;left:126.14px;top:176.82px" class="cls_018"><span class="cls_018">2006</span><span class="cls_011">;</span><span class="cls_018"> Borini et al.,</span></div>
<div style="position:absolute;left:201.37px;top:176.82px" class="cls_018"><span class="cls_018">2006a</span><span class="cls_011">,</span><span class="cls_018">b</span><span class="cls_011">,</span><span class="cls_018"> 2007</span><span class="cls_011">;</span><span class="cls_018"> Levi Setti,</span></div>
<div style="position:absolute;left:317.48px;top:176.82px" class="cls_011"><span class="cls_011">use of high initial concentrations of cryoprotectants, low volumes and</span></div>
<div style="position:absolute;left:48.19px;top:188.79px" class="cls_018"><span class="cls_018">2006</span><span class="cls_011">;</span><span class="cls_018"> De Santis et al., 2007</span><span class="cls_011">;</span><span class="cls_018"> Ubaldi et al., 2010</span><span class="cls_011">). Not until 2009 did</span></div>
<div style="position:absolute;left:317.48px;top:188.78px" class="cls_011"><span class="cls_011">ultra-rapid cooling-warming rates. This approach was first introduced</span></div>
<div style="position:absolute;left:48.19px;top:200.80px" class="cls_011"><span class="cls_011">the Italian Constitutional Court (151/2009) declare the constitution-</span></div>
<div style="position:absolute;left:317.48px;top:200.80px" class="cls_011"><span class="cls_011">in human embryology for cleavage-stage embryos (</span><span class="cls_018">Mukaida et al.,</span></div>
<div style="position:absolute;left:48.19px;top:212.82px" class="cls_011"><span class="cls_011">ality of embryo cryopreservation. Nevertheless, some couples are</span></div>
<div style="position:absolute;left:317.48px;top:212.82px" class="cls_018"><span class="cls_018">1998</span><span class="cls_011">) and then for oocytes (</span><span class="cls_018">Kuleshova et al., 1999</span><span class="cls_011">) and pronuclear-</span></div>
<div style="position:absolute;left:48.19px;top:224.79px" class="cls_011"><span class="cls_011">concerned about the disposition of cryopreserved embryos</span></div>
<div style="position:absolute;left:317.48px;top:224.79px" class="cls_011"><span class="cls_011">stage embryos</span></div>
<div style="position:absolute;left:377.58px;top:224.79px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Jelinkova et al.,</span></div>
<div style="position:absolute;left:444.47px;top:224.79px" class="cls_018"><span class="cls_018">2002</span><span class="cls_011">;</span><span class="cls_018"> Selman and El-Danasouri,</span></div>
<div style="position:absolute;left:48.19px;top:236.80px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Nachtigall et al., 2010</span><span class="cls_011">) and therefore prefer to limit the number of</span></div>
<div style="position:absolute;left:317.48px;top:236.80px" class="cls_018"><span class="cls_018">2002</span><span class="cls_011">). In the last 15 years several vitrification protocols have been</span></div>
<div style="position:absolute;left:48.19px;top:248.82px" class="cls_011"><span class="cls_011">oocytes inseminated, with cryopreservation of the remainder (</span><span class="cls_018">Heng,</span></div>
<div style="position:absolute;left:317.48px;top:248.82px" class="cls_011"><span class="cls_011">described, which differ from one another in the type of cryoprotec-</span></div>
<div style="position:absolute;left:48.19px;top:260.79px" class="cls_018"><span class="cls_018">2007</span><span class="cls_011">). Oocyte cryopreservation also has emerged as an important</span></div>
<div style="position:absolute;left:317.48px;top:260.79px" class="cls_011"><span class="cls_011">tants (Ethylene glycol [EG] and/or DMSO and/or PROH and sucrose</span></div>
<div style="position:absolute;left:48.19px;top:272.80px" class="cls_011"><span class="cls_011">method for female fertility preservation for both medical and non-</span></div>
<div style="position:absolute;left:317.48px;top:272.80px" class="cls_011"><span class="cls_011">and/or Ficoll and/or Trehalose), equilibration and dilution para-</span></div>
<div style="position:absolute;left:48.19px;top:284.82px" class="cls_011"><span class="cls_011">medical indications (reviewed in</span><span class="cls_018"> De Vos et al., 2014</span><span class="cls_011"> and</span><span class="cls_018"> Stoop et al.,</span></div>
<div style="position:absolute;left:317.48px;top:284.82px" class="cls_011"><span class="cls_011">meters, the carrier tools and the cooling, storage and warming meth-</span></div>
<div style="position:absolute;left:48.19px;top:296.79px" class="cls_018"><span class="cls_018">2014</span><span class="cls_011">).</span></div>
<div style="position:absolute;left:317.48px;top:296.78px" class="cls_011"><span class="cls_011">ods</span></div>
<div style="position:absolute;left:336.81px;top:296.78px" class="cls_011"><span class="cls_011">(reviewed in</span><span class="cls_018"> Vajta and Nagy,</span></div>
<div style="position:absolute;left:462.50px;top:296.79px" class="cls_018"><span class="cls_018">2006</span><span class="cls_011">). To date the most</span></div>
<div style="position:absolute;left:57.20px;top:308.80px" class="cls_011"><span class="cls_011">Since the first pregnancy and delivery with cryopreserved embryos</span></div>
<div style="position:absolute;left:317.48px;top:308.80px" class="cls_011"><span class="cls_011">commonly used protocol for both oocyte and embryo vitrification</span></div>
<div style="position:absolute;left:48.19px;top:320.82px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Trounson and Mohr, 1983</span><span class="cls_011">;</span><span class="cls_018"> Zeilmaker et al., 1984</span><span class="cls_011">), various protocols</span></div>
<div style="position:absolute;left:317.48px;top:320.82px" class="cls_011"><span class="cls_011">involves the combination of 15% DMSO, 15% EG and 0.5 M sucrose</span></div>
<div style="position:absolute;left:48.19px;top:332.79px" class="cls_011"><span class="cls_011">have been introduced that differ from each other regarding the type</span></div>
<div style="position:absolute;left:317.48px;top:332.79px" class="cls_011"><span class="cls_011">in a minimum volume (≤1 µl) (</span><span class="cls_018">Kuwayama et al., 2005a</span><span class="cls_011">,</span><span class="cls_018">b</span><span class="cls_011">). Other fun-</span></div>
<div style="position:absolute;left:48.19px;top:344.80px" class="cls_011"><span class="cls_011">and concentration of cryoprotectants, equilibration timing, cooling</span></div>
<div style="position:absolute;left:317.48px;top:344.80px" class="cls_011"><span class="cls_011">damental aspects of the technique are related to the cooling and</span></div>
<div style="position:absolute;left:48.19px;top:356.82px" class="cls_011"><span class="cls_011">rates and cryopreservation devices used. Two principal approaches for</span></div>
<div style="position:absolute;left:317.48px;top:356.82px" class="cls_011"><span class="cls_011">storing method. At present most embryos and oocytes are vitrified</span></div>
<div style="position:absolute;left:48.19px;top:368.78px" class="cls_011"><span class="cls_011">cryopreservation have been adopted: slow-freezing and vitrification</span></div>
<div style="position:absolute;left:317.48px;top:368.79px" class="cls_011"><span class="cls_011">by exposing the sample to direct contact with liquid nitrogen (open</span></div>
<div style="position:absolute;left:48.19px;top:380.80px" class="cls_011"><span class="cls_011">(reviewed by</span><span class="cls_018"> Edgar and Gook, 2012</span><span class="cls_011">).</span></div>
<div style="position:absolute;left:317.48px;top:380.80px" class="cls_011"><span class="cls_011">system) to increase the cooling/warming rates and thus the efficiency</span></div>
<div style="position:absolute;left:57.20px;top:392.82px" class="cls_011"><span class="cls_011">Slow-freezing allows for cryopreservation to occur at a sufficiently</span></div>
<div style="position:absolute;left:317.48px;top:392.82px" class="cls_011"><span class="cls_011">of the procedure (</span><span class="cls_018">Vajta et al., 2015</span><span class="cls_011">). The ability to survive vitrification</span></div>
<div style="position:absolute;left:48.19px;top:404.79px" class="cls_011"><span class="cls_011">slow rate to permit adequate cellular dehydration while minimizing</span></div>
<div style="position:absolute;left:317.48px;top:404.79px" class="cls_011"><span class="cls_011">is in fact strictly dependent on the degree of cellular dehydration and</span></div>
<div style="position:absolute;left:48.19px;top:416.80px" class="cls_011"><span class="cls_011">intracellular ice formation. The first successful protocol applied in</span></div>
<div style="position:absolute;left:317.48px;top:416.80px" class="cls_011"><span class="cls_011">on the rate of warming, rather than on the type and concentration of</span></div>
<div style="position:absolute;left:48.19px;top:428.82px" class="cls_011"><span class="cls_011">1972 for mammalian embryo cryopreservation required a cooling</span></div>
<div style="position:absolute;left:317.48px;top:428.82px" class="cls_011"><span class="cls_011">cryoprotectants used (</span><span class="cls_018">Jin and Mazur, 2015</span><span class="cls_011">). High cryosurvival rates</span></div>
<div style="position:absolute;left:48.19px;top:440.78px" class="cls_011"><span class="cls_011">rate of</span></div>
<div style="position:absolute;left:78.52px;top:440.78px" class="cls_011"><span class="cls_011">~1°C/min to −70°C (</span><span class="cls_018">Whittingham et al., 1972</span><span class="cls_011">). Embryo</span></div>
<div style="position:absolute;left:317.48px;top:440.79px" class="cls_011"><span class="cls_011">of mouse oocytes and embryos have been recently obtained with the</span></div>
<div style="position:absolute;left:48.19px;top:452.80px" class="cls_011"><span class="cls_011">cooling performed this way is referred to as equilibrium freezing</span></div>
<div style="position:absolute;left:317.48px;top:452.80px" class="cls_011"><span class="cls_011">use of only non-permeating cryoprotectant and a relatively slow cool-</span></div>
<div style="position:absolute;left:48.19px;top:464.82px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Mazur, 1990</span><span class="cls_011">). Subsequently, slow-rate cooling was only applied to</span></div>
<div style="position:absolute;left:317.48px;top:464.82px" class="cls_011"><span class="cls_011">ing rate, but combined with an ultra-rapid warming (</span><span class="cls_018">Jin and Mazur,</span></div>
<div style="position:absolute;left:48.19px;top:476.79px" class="cls_011"><span class="cls_011">around −30°C (</span><span class="cls_018">Willadsen, 1977</span><span class="cls_011">). With this approach, intracellular</span></div>
<div style="position:absolute;left:317.48px;top:476.79px" class="cls_018"><span class="cls_018">2015</span><span class="cls_011">). This study also demonstrates that the osmotic withdrawal of a</span></div>
<div style="position:absolute;left:48.19px;top:488.80px" class="cls_011"><span class="cls_011">water content was converted into small intracellular ice crystals or</span></div>
<div style="position:absolute;left:317.48px;top:488.80px" class="cls_011"><span class="cls_011">very large proportion of intracellular water prior to cooling, and not</span></div>
<div style="position:absolute;left:48.19px;top:500.82px" class="cls_011"><span class="cls_011">into a glass. To avoid extensive crystallization, a very rapid warming</span></div>
<div style="position:absolute;left:317.48px;top:500.82px" class="cls_011"><span class="cls_011">the permeation of cryoprotectant in the cell, is the key for a success-</span></div>
<div style="position:absolute;left:48.19px;top:512.78px" class="cls_011"><span class="cls_011">was required.</span></div>
<div style="position:absolute;left:317.48px;top:512.78px" class="cls_011"><span class="cls_011">ful vitrification (</span><span class="cls_018">Jin and Mazur, 2015</span><span class="cls_011">).</span></div>
<div style="position:absolute;left:57.20px;top:524.80px" class="cls_011"><span class="cls_011">Although the first pregnancies with human cleavage-stage embryos</span></div>
<div style="position:absolute;left:326.49px;top:524.80px" class="cls_011"><span class="cls_011">To avoid potential contamination during open system vitrification,</span></div>
<div style="position:absolute;left:48.19px;top:536.82px" class="cls_011"><span class="cls_011">were obtained with the use of dimethylsulphoxide (DMSO) as the</span></div>
<div style="position:absolute;left:317.48px;top:536.82px" class="cls_011"><span class="cls_011">sterile liquid nitrogen can be used (</span><span class="cls_018">Vajta et al., 1998</span><span class="cls_011">;</span><span class="cls_018"> Parmegiani et al.,</span></div>
<div style="position:absolute;left:48.19px;top:548.78px" class="cls_011"><span class="cls_011">cryoprotectant</span></div>
<div style="position:absolute;left:106.47px;top:548.78px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Trounson and Mohr, 1983</span><span class="cls_011"> and</span><span class="cls_018"> Zeilmaker et al.,</span></div>
<div style="position:absolute;left:317.48px;top:548.79px" class="cls_018"><span class="cls_018">2009</span><span class="cls_011">). Alternatively, specific devices have been designed to avoid dir-</span></div>
<div style="position:absolute;left:48.19px;top:560.80px" class="cls_018"><span class="cls_018">1984</span><span class="cls_011">) this approach was rapidly replaced.</span></div>
<div style="position:absolute;left:317.48px;top:560.80px" class="cls_011"><span class="cls_011">ect contact of the samples with the nitrogen either during vitrification</span></div>
<div style="position:absolute;left:57.20px;top:572.82px" class="cls_011"><span class="cls_011">For nearly 20 years the protocol combining 1.5 M propylene glycol</span></div>
<div style="position:absolute;left:317.48px;top:572.82px" class="cls_011"><span class="cls_011">(closed system) and/or during storage (</span><span class="cls_018">Vajta et al., 1998</span><span class="cls_011">;</span><span class="cls_018"> Kuleshova</span></div>
<div style="position:absolute;left:48.19px;top:584.79px" class="cls_011"><span class="cls_011">(PROH) plus 0.1 M sucrose, as the permeable and non-permeable</span></div>
<div style="position:absolute;left:317.48px;top:584.79px" class="cls_018"><span class="cls_018">and Shaw 2000</span><span class="cls_011">;</span><span class="cls_018"> Isachenko et al., 2006</span><span class="cls_011">;</span><span class="cls_018"> Vanderzwalmen et al., 2009</span><span class="cls_011">;</span></div>
<div style="position:absolute;left:48.19px;top:596.80px" class="cls_011"><span class="cls_011">cryoprotectants, respectively, has been the most widely used (</span><span class="cls_018">Lassalle</span></div>
<div style="position:absolute;left:317.48px;top:596.80px" class="cls_018"><span class="cls_018">Abdelhafez et al., 2011</span><span class="cls_011">;</span><span class="cls_018"> Parmegiani, 2011</span><span class="cls_011">). Of note, not all closed sys-</span></div>
<div style="position:absolute;left:48.19px;top:608.82px" class="cls_018"><span class="cls_018">et al., 1985</span><span class="cls_011">;</span><span class="cls_018"> Testart et al., 1986</span><span class="cls_011">). The freezing curve adopted requires</span></div>
<div style="position:absolute;left:317.48px;top:608.82px" class="cls_011"><span class="cls_011">tems available on the market are completely free of any possible</span></div>
<div style="position:absolute;left:48.19px;top:620.79px" class="cls_011"><span class="cls_011">the use of a programmable freezing machine designed to provide</span></div>
<div style="position:absolute;left:317.48px;top:620.79px" class="cls_011"><span class="cls_011">sources of contamination (</span><span class="cls_018">Vajta et al., 2015</span><span class="cls_011">). On the other hand, a</span></div>
<div style="position:absolute;left:48.19px;top:632.80px" class="cls_011"><span class="cls_011">accurate and consistent cooling parameters. Briefly, the sample is</span></div>
<div style="position:absolute;left:317.48px;top:632.80px" class="cls_011"><span class="cls_011">lower degree of cooling/warming rate is generally associated with the</span></div>
<div style="position:absolute;left:48.19px;top:644.82px" class="cls_011"><span class="cls_011">exposed to a relatively rapid cooling rate of 2°C/min to around −7°C</span></div>
<div style="position:absolute;left:317.48px;top:644.82px" class="cls_011"><span class="cls_011">use of these systems. To date, neither open nor closed systems have</span></div>
<div style="position:absolute;left:48.19px;top:656.78px" class="cls_011"><span class="cls_011">followed by a manual seeding to induce ice crystal formation in the</span></div>
<div style="position:absolute;left:317.48px;top:656.78px" class="cls_011"><span class="cls_011">resulted in disease transmission during vitrification. However, to ensure</span></div>
<div style="position:absolute;left:48.19px;top:668.80px" class="cls_011"><span class="cls_011">solution. Then, a consistent slow cooling rate of 0.3-1.0°C/min is</span></div>
<div style="position:absolute;left:317.48px;top:668.80px" class="cls_011"><span class="cls_011">biosafety during cryopreservation, the use of sterile approaches is</span></div>
<div style="position:absolute;left:48.19px;top:680.82px" class="cls_011"><span class="cls_011">applied before the freezing device is plunged into liquid nitrogen after</span></div>
<div style="position:absolute;left:317.48px;top:680.82px" class="cls_011"><span class="cls_011">recommended (</span><span class="cls_018">Argyle et al., 2016</span><span class="cls_011">), providing that adequate cooling</span></div>
<div style="position:absolute;left:48.19px;top:692.78px" class="cls_011"><span class="cls_011">having reached temperatures around</span></div>
<div style="position:absolute;left:196.16px;top:692.78px" class="cls_011"><span class="cls_011">−40</span></div>
<div style="position:absolute;left:217.47px;top:692.78px" class="cls_011"><span class="cls_011">to</span></div>
<div style="position:absolute;left:231.48px;top:692.78px" class="cls_011"><span class="cls_011">−70°C using the</span></div>
<div style="position:absolute;left:317.48px;top:692.79px" class="cls_011"><span class="cls_011">and, particularly, warming rates are still guaranteed.</span></div>
<div style="position:absolute;left:48.19px;top:704.80px" class="cls_011"><span class="cls_011">approach of</span><span class="cls_018"> Trounson and Mohr (1983)</span><span class="cls_011"> or</span><span class="cls_018"> Lassale et al., (1985)</span><span class="cls_011">,</span></div>
<div style="position:absolute;left:326.49px;top:704.80px" class="cls_011"><span class="cls_011">The objective of the present study was to compare slow-freezing/</span></div>
<div style="position:absolute;left:48.19px;top:716.82px" class="cls_011"><span class="cls_011">respectively. Modifications to the concentration of sucrose and the use</span></div>
<div style="position:absolute;left:317.48px;top:716.82px" class="cls_011"><span class="cls_011">thawing versus vitrification/warming for cryopreservation of oocytes,</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:2400px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background04.jpg" width=612 height=790></div>
<div style="position:absolute;left:45.35px;top:25.13px" class="cls_013"><span class="cls_013">142</span></div>
<div style="position:absolute;left:525.71px;top:26.63px" class="cls_014"><span class="cls_014">Rienzi et al.</span></div>
<div style="position:absolute;left:45.35px;top:56.80px" class="cls_011"><span class="cls_011">embryos and blastocysts. RCTs and relevant observational cohort</span></div>
<div style="position:absolute;left:323.15px;top:56.96px" class="cls_014"><span class="cls_014">A secondary analysis was performed focusing on oocyte cryosurvival</span></div>
<div style="position:absolute;left:45.35px;top:68.82px" class="cls_011"><span class="cls_011">studies were included in this systematic review and meta-analysis.</span></div>
<div style="position:absolute;left:314.65px;top:67.96px" class="cls_014"><span class="cls_014">rate. One RCT (</span><span class="cls_019">Smith et al., 2010</span><span class="cls_014">), two RCTs where sibling oocytes</span></div>
<div style="position:absolute;left:54.37px;top:80.79px" class="cls_011"><span class="cls_011">This study was performed to support a prioritized clinical question</span></div>
<div style="position:absolute;left:314.64px;top:78.96px" class="cls_014"><span class="cls_014">were randomized, rather than patients, (</span><span class="cls_019">Paffoni et al., 2008</span><span class="cls_014">;</span><span class="cls_019"> Cao et al.,</span></div>
<div style="position:absolute;left:314.64px;top:89.96px" class="cls_019"><span class="cls_019">2009</span><span class="cls_014">) and three cohort studies (</span><span class="cls_019">Fadini et al., 2009</span><span class="cls_014">;</span><span class="cls_019"> Grifo and Noyes,</span></div>
<div style="position:absolute;left:45.35px;top:92.80px" class="cls_011"><span class="cls_011">and to provide a review of the evidence for debate and discussion</span></div>
<div style="position:absolute;left:314.64px;top:100.96px" class="cls_019"><span class="cls_019">2010</span><span class="cls_014">;</span><span class="cls_019"> Levi Setti et al., 2016</span><span class="cls_014">) were included.</span></div>
<div style="position:absolute;left:45.35px;top:104.82px" class="cls_011"><span class="cls_011">during the consultation for the development of the World Health</span></div>
<div style="position:absolute;left:45.35px;top:116.78px" class="cls_011"><span class="cls_011">Organization (WHO) global guidelines: ‘Addressing evidence-based</span></div>
<div style="position:absolute;left:314.65px;top:124.29px" class="cls_013"><span class="cls_013">Slow-frozen versus fresh oocytes: clinical outcomes</span></div>
<div style="position:absolute;left:45.35px;top:128.80px" class="cls_011"><span class="cls_011">guidance on infertility diagnosis, management and treatment.’</span></div>
<div style="position:absolute;left:314.65px;top:137.81px" class="cls_014"><span class="cls_014">No RCTs were identified comparing outcomes following transfer of</span></div>
<div style="position:absolute;left:314.65px;top:148.81px" class="cls_014"><span class="cls_014">embryos from oocytes that were either slow-frozen or fresh. Five cohort</span></div>
<div style="position:absolute;left:314.65px;top:159.81px" class="cls_014"><span class="cls_014">studies were identified comparing outcomes following transfer of</span></div>
<div style="position:absolute;left:45.35px;top:158.12px" class="cls_017"><span class="cls_017">Methods</span></div>
<div style="position:absolute;left:314.65px;top:170.80px" class="cls_014"><span class="cls_014">embryos derived from fresh or slow-frozen/thawed oocytes (</span><span class="cls_019">Chamayou</span></div>
<div style="position:absolute;left:314.64px;top:181.80px" class="cls_019"><span class="cls_019">et al., 2006</span><span class="cls_014">;</span><span class="cls_019"> Levi Setti et al., 2006</span><span class="cls_014">;</span><span class="cls_019"> Borini et al., 2007</span><span class="cls_014">;</span><span class="cls_019"> Borini et al., 2010</span><span class="cls_014">;</span></div>
<div style="position:absolute;left:45.35px;top:184.14px" class="cls_002"><span class="cls_002">Oocyte cryopreservation: study eligibility</span></div>
<div style="position:absolute;left:314.65px;top:192.80px" class="cls_019"><span class="cls_019">Virant-Klun et al., 2011</span><span class="cls_014">).</span></div>
<div style="position:absolute;left:45.35px;top:198.14px" class="cls_002"><span class="cls_002">criteria</span></div>
<div style="position:absolute;left:45.35px;top:215.65px" class="cls_014"><span class="cls_014">RCTs and well-designed cohort or case-control studies were included</span></div>
<div style="position:absolute;left:314.65px;top:216.13px" class="cls_013"><span class="cls_013">Vitrified versus fresh oocytes: clinical outcomes</span></div>
<div style="position:absolute;left:45.35px;top:226.65px" class="cls_014"><span class="cls_014">that compared outcomes following slow-freeze versus vitrification of</span></div>
<div style="position:absolute;left:314.65px;top:229.65px" class="cls_014"><span class="cls_014">One RCT was identified that randomized 600 donor recipients to trans-</span></div>
<div style="position:absolute;left:45.35px;top:237.64px" class="cls_014"><span class="cls_014">mature i.e. metaphase II (MII) oocytes from women undergoing ART.</span></div>
<div style="position:absolute;left:314.64px;top:240.65px" class="cls_014"><span class="cls_014">fer of embryos either from fresh or vitrified/warmed oocytes (</span><span class="cls_019">Cobo</span></div>
<div style="position:absolute;left:45.35px;top:248.64px" class="cls_014"><span class="cls_014">Given the paucity of studies making direct comparisons between the two</span></div>
<div style="position:absolute;left:314.64px;top:251.65px" class="cls_019"><span class="cls_019">et al.,</span></div>
<div style="position:absolute;left:340.16px;top:251.65px" class="cls_019"><span class="cls_019">2010</span><span class="cls_014">). Characteristics of this study are described in Table</span><span class="cls_019"> I</span><span class="cls_014">.</span></div>
<div style="position:absolute;left:45.35px;top:259.64px" class="cls_014"><span class="cls_014">cryopreservation methods, studies comparing slow-freeze or vitrification</span></div>
<div style="position:absolute;left:314.64px;top:262.65px" class="cls_014"><span class="cls_014">Ongoing clinical pregnancy at 10-11 weeks of gestation was reported;</span></div>
<div style="position:absolute;left:45.35px;top:270.64px" class="cls_014"><span class="cls_014">to fresh oocytes (control group) were also included. Only trials reported</span></div>
<div style="position:absolute;left:314.64px;top:273.64px" class="cls_014"><span class="cls_014">however, live-birth data were not reported.</span></div>
<div style="position:absolute;left:45.35px;top:281.64px" class="cls_014"><span class="cls_014">in peer-reviewed full publications involving MII oocyte cryopreservation</span></div>
<div style="position:absolute;left:323.15px;top:284.64px" class="cls_014"><span class="cls_014">Thirteen other studies were identified: five randomized sibling oocytes,</span></div>
<div style="position:absolute;left:45.35px;top:292.64px" class="cls_014"><span class="cls_014">were included; abstracts were excluded. Data from these studies were</span></div>
<div style="position:absolute;left:314.64px;top:295.64px" class="cls_014"><span class="cls_014">rather than patients, to vitrification versus fresh treatments (</span><span class="cls_019">Cobo et al.,</span></div>
<div style="position:absolute;left:45.35px;top:303.63px" class="cls_014"><span class="cls_014">used to assess the following outcomes: Clinical pregnancy rate (CPR),</span></div>
<div style="position:absolute;left:314.65px;top:306.64px" class="cls_019"><span class="cls_019">2008</span><span class="cls_014">;</span><span class="cls_019"> Rienzi et al.,</span></div>
<div style="position:absolute;left:386.59px;top:306.64px" class="cls_019"><span class="cls_019">2010</span><span class="cls_014">;</span><span class="cls_019"> Parmegiani et al.,</span></div>
<div style="position:absolute;left:475.09px;top:306.64px" class="cls_019"><span class="cls_019">2011</span><span class="cls_014">;</span><span class="cls_019"> Siano et al.,</span></div>
<div style="position:absolute;left:545.05px;top:306.64px" class="cls_019"><span class="cls_019">2013</span><span class="cls_014">;</span></div>
<div style="position:absolute;left:45.35px;top:314.63px" class="cls_014"><span class="cls_014">live-birth rate (LBR) and oocyte cryosurvival rate when reported.</span></div>
<div style="position:absolute;left:314.65px;top:317.64px" class="cls_019"><span class="cls_019">Forman et al., 2012</span><span class="cls_014">), and eight cohort studies (</span><span class="cls_019">Antinori et al., 2007</span><span class="cls_014">;</span><span class="cls_019"> Nagy</span></div>
<div style="position:absolute;left:314.64px;top:328.64px" class="cls_019"><span class="cls_019">et al., 2009</span><span class="cls_014">;</span><span class="cls_019"> Almodin et al., 2010</span><span class="cls_014">;</span><span class="cls_019"> Ubaldi et al., 2010</span><span class="cls_014">;</span><span class="cls_019"> Garcia et al., 2011</span><span class="cls_014">;</span></div>
<div style="position:absolute;left:314.65px;top:339.64px" class="cls_019"><span class="cls_019">Trokoudes et al., 2011</span><span class="cls_014">;</span><span class="cls_019"> Sole et al., 2013</span><span class="cls_014">;</span><span class="cls_019"> Doyle et al., 2016</span><span class="cls_014">). Three sibling</span></div>
<div style="position:absolute;left:45.35px;top:346.45px" class="cls_002"><span class="cls_002">Oocyte cryopreservation: study search</span></div>
<div style="position:absolute;left:314.64px;top:350.63px" class="cls_014"><span class="cls_014">oocyte RCTs (</span><span class="cls_019">Cobo et al., 2008</span><span class="cls_014">;</span><span class="cls_019"> Siano et al., 2013</span><span class="cls_014">;</span><span class="cls_019"> Forman et al., 2012</span><span class="cls_014">)</span></div>
<div style="position:absolute;left:45.35px;top:360.46px" class="cls_002"><span class="cls_002">methods</span></div>
<div style="position:absolute;left:314.64px;top:361.63px" class="cls_014"><span class="cls_014">and two cohort studies (</span><span class="cls_019">Nagy et al., 2009</span><span class="cls_014"> and</span><span class="cls_019"> Doyle et al., 2016</span><span class="cls_014">) were</span></div>
<div style="position:absolute;left:314.64px;top:372.63px" class="cls_014"><span class="cls_014">excluded from analysis due to study design (</span><span class="cls_019">Forman et al., 2012</span><span class="cls_014">) or data</span></div>
<div style="position:absolute;left:45.35px;top:377.96px" class="cls_014"><span class="cls_014">The searches for relevant studies were last performed and completed on 1</span></div>
<div style="position:absolute;left:314.64px;top:383.63px" class="cls_014"><span class="cls_014">reporting issues (</span><span class="cls_019">Cobo et al., 2008</span><span class="cls_014">;</span><span class="cls_019"> Nagy et al., 2009</span><span class="cls_014">;</span><span class="cls_019"> Siano et al., 2013</span><span class="cls_014">;</span></div>
<div style="position:absolute;left:45.35px;top:388.96px" class="cls_014"><span class="cls_014">August 2016 by two review authors (AL, RM) using the following search</span></div>
<div style="position:absolute;left:314.65px;top:394.63px" class="cls_019"><span class="cls_019">Doyle et al., 2016</span><span class="cls_014">).</span></div>
<div style="position:absolute;left:45.35px;top:399.96px" class="cls_014"><span class="cls_014">terms:</span></div>
<div style="position:absolute;left:71.21px;top:399.96px" class="cls_014"><span class="cls_014">(oocyte(s)</span></div>
<div style="position:absolute;left:109.81px;top:399.96px" class="cls_014"><span class="cls_014">[tiab]) AND (vitrification[tiab] OR freezing[tiab] OR</span></div>
<div style="position:absolute;left:323.15px;top:405.63px" class="cls_014"><span class="cls_014">The remaining eight studies were grouped together for comparison of</span></div>
<div style="position:absolute;left:45.35px;top:410.95px" class="cls_014"><span class="cls_014">freeze[tiab]) AND (embryo quality[tiab] OR survival[tiab] OR pregnancy</span></div>
<div style="position:absolute;left:314.64px;top:416.62px" class="cls_014"><span class="cls_014">clinical outcomes following transfer of embryos arising from oocytes that</span></div>
<div style="position:absolute;left:45.35px;top:421.95px" class="cls_014"><span class="cls_014">[tiab] OR birth[tiab]). The search was limited to human studies. Articles</span></div>
<div style="position:absolute;left:314.64px;top:427.62px" class="cls_014"><span class="cls_014">were exclusively either vitrified or fresh. Five meta-analyses (</span><span class="cls_019">Oktay et al.,</span></div>
<div style="position:absolute;left:45.35px;top:432.95px" class="cls_014"><span class="cls_014">were also identified via snowball sampling by hand-searching references</span></div>
<div style="position:absolute;left:314.65px;top:438.62px" class="cls_019"><span class="cls_019">2006</span><span class="cls_014">;</span><span class="cls_019"> Cobo et al., 2011b</span><span class="cls_014">;</span><span class="cls_019"> Cil et al., 2013</span><span class="cls_014">;</span><span class="cls_019"> Glujovsky et al., 2014</span><span class="cls_014">;</span><span class="cls_019"> Potdar</span></div>
<div style="position:absolute;left:45.36px;top:443.95px" class="cls_014"><span class="cls_014">from systematic reviews. The search returned 806 records, of which 88</span></div>
<div style="position:absolute;left:314.64px;top:449.62px" class="cls_019"><span class="cls_019">et al., 2014</span><span class="cls_014">) focusing on oocyte cryopreservation were reviewed.</span></div>
<div style="position:absolute;left:45.36px;top:454.95px" class="cls_014"><span class="cls_014">were screened manually for relevance. The information about potentially</span></div>
<div style="position:absolute;left:45.36px;top:465.95px" class="cls_014"><span class="cls_014">eligible studies was reported in a table describing the characteristics of the</span></div>
<div style="position:absolute;left:45.36px;top:477.00px" class="cls_014"><span class="cls_014">studies for assessing the reliability of the results. Full texts of potentially eli-</span></div>
<div style="position:absolute;left:314.65px;top:480.99px" class="cls_002"><span class="cls_002">Embryo cryopreservation: study eligibility</span></div>
<div style="position:absolute;left:45.36px;top:488.00px" class="cls_014"><span class="cls_014">gible studies were obtained and examined independently by the two differ-</span></div>
<div style="position:absolute;left:45.36px;top:499.00px" class="cls_014"><span class="cls_014">ent authors; disagreements as to study eligibility were resolved by</span></div>
<div style="position:absolute;left:314.65px;top:494.99px" class="cls_002"><span class="cls_002">criteria</span></div>
<div style="position:absolute;left:45.36px;top:509.99px" class="cls_014"><span class="cls_014">discussion (all authors). A total of 20 references were included (Fig.</span><span class="cls_019"> 1</span><span class="cls_014">a).</span></div>
<div style="position:absolute;left:314.65px;top:512.49px" class="cls_014"><span class="cls_014">RCTs and observational cohort studies were included that compared</span></div>
<div style="position:absolute;left:314.65px;top:523.49px" class="cls_014"><span class="cls_014">slow-freeze to vitrification of pronuclear embryos, cleavage-stage</span></div>
<div style="position:absolute;left:314.65px;top:534.49px" class="cls_014"><span class="cls_014">embryos or blastocysts from women undergoing ART. Only trials</span></div>
<div style="position:absolute;left:45.35px;top:541.82px" class="cls_002"><span class="cls_002">Oocyte cryopreservation: study descriptions</span></div>
<div style="position:absolute;left:314.65px;top:545.49px" class="cls_014"><span class="cls_014">reported in peer-reviewed full publications were included; abstracts were</span></div>
<div style="position:absolute;left:314.65px;top:556.48px" class="cls_014"><span class="cls_014">excluded. The following outcomes were assessed: CPR, LBR and embryo</span></div>
<div style="position:absolute;left:45.35px;top:560.83px" class="cls_013"><span class="cls_013">Slow-frozen versus vitrified oocytes: clinical outcomes and</span></div>
<div style="position:absolute;left:314.65px;top:567.48px" class="cls_014"><span class="cls_014">cryosurvival rate, when reported.</span></div>
<div style="position:absolute;left:45.35px;top:572.79px" class="cls_013"><span class="cls_013">cryosurvival</span></div>
<div style="position:absolute;left:45.35px;top:586.31px" class="cls_014"><span class="cls_014">One RCT was identified that randomized women to have an embryo</span></div>
<div style="position:absolute;left:45.35px;top:597.30px" class="cls_014"><span class="cls_014">transfer from MII oocytes that were either slow-frozen or vitrified (</span><span class="cls_019">Smith</span></div>
<div style="position:absolute;left:314.65px;top:598.79px" class="cls_002"><span class="cls_002">Embryo cryopreservation: study search</span></div>
<div style="position:absolute;left:45.35px;top:608.30px" class="cls_019"><span class="cls_019">et al., 2010</span><span class="cls_014">). Characteristics of this study are described in Table</span><span class="cls_019"> I</span><span class="cls_014">. A total</span></div>
<div style="position:absolute;left:314.65px;top:612.80px" class="cls_002"><span class="cls_002">methods</span></div>
<div style="position:absolute;left:45.35px;top:619.30px" class="cls_014"><span class="cls_014">of 230 patients with more than nine MII oocytes retrieved were allocated</span></div>
<div style="position:absolute;left:45.35px;top:630.30px" class="cls_014"><span class="cls_014">by random number generator to either slow-freezing or vitrification. This</span></div>
<div style="position:absolute;left:314.65px;top:630.30px" class="cls_014"><span class="cls_014">The searches for relevant studies were last performed and completed on</span></div>
<div style="position:absolute;left:45.35px;top:641.30px" class="cls_014"><span class="cls_014">results in 30 cases of oocyte thawing and 48 cases of warming (average</span></div>
<div style="position:absolute;left:314.65px;top:641.30px" class="cls_014"><span class="cls_014">August first 2016 using the following search terms: (Pronuclear[tiab] OR</span></div>
<div style="position:absolute;left:45.35px;top:652.30px" class="cls_014"><span class="cls_014">ages at oocyte retrieval: 32 ± 1 and 31 ± 1 years (mean + SD), respect-</span></div>
<div style="position:absolute;left:314.65px;top:652.30px" class="cls_014"><span class="cls_014">Embryo[tiab] OR Blastocyst[tiab]) AND (vitrification[tiab] OR freezing</span></div>
<div style="position:absolute;left:45.35px;top:663.29px" class="cls_014"><span class="cls_014">ively). LBRs were not reported. Ongoing CPRs were reported but not</span></div>
<div style="position:absolute;left:314.65px;top:663.29px" class="cls_014"><span class="cls_014">[tiab] OR freeze[tiab]) AND (pregnancy[tiab] OR birth[tiab] OR clinical</span></div>
<div style="position:absolute;left:45.35px;top:674.29px" class="cls_014"><span class="cls_014">defined by minimum gestational age.</span></div>
<div style="position:absolute;left:314.65px;top:674.29px" class="cls_014"><span class="cls_014">[tiab]). The search was limited to human studies. Articles were also iden-</span></div>
<div style="position:absolute;left:53.86px;top:685.29px" class="cls_014"><span class="cls_014">Two cohort studies were identified that compared CPRs from slow-</span></div>
<div style="position:absolute;left:314.65px;top:685.29px" class="cls_014"><span class="cls_014">tified by hand searching references from systematic reviews. The search</span></div>
<div style="position:absolute;left:45.35px;top:696.29px" class="cls_014"><span class="cls_014">frozen versus vitrified autologous oocytes (</span><span class="cls_019">Fadini et al., 2009</span><span class="cls_014">;</span><span class="cls_019"> Levi Setti</span></div>
<div style="position:absolute;left:314.65px;top:696.29px" class="cls_014"><span class="cls_014">returned 917 records, of which 587 were screened manually for rele-</span></div>
<div style="position:absolute;left:45.35px;top:707.29px" class="cls_019"><span class="cls_019">et al., 2014</span><span class="cls_014">). Oocyte cryopreservation was performed in these studies in</span></div>
<div style="position:absolute;left:314.65px;top:707.29px" class="cls_014"><span class="cls_014">vance. Full texts of potentially eligible studies were obtained and exam-</span></div>
<div style="position:absolute;left:45.35px;top:718.29px" class="cls_014"><span class="cls_014">an unselected population of infertile patients due to law restrictions (Law</span></div>
<div style="position:absolute;left:314.65px;top:718.29px" class="cls_014"><span class="cls_014">ined independently by two different authors (RM, DK); disagreements as</span></div>
<div style="position:absolute;left:45.35px;top:729.29px" class="cls_014"><span class="cls_014">40, 2004, Italy).</span></div>
<div style="position:absolute;left:314.65px;top:729.28px" class="cls_014"><span class="cls_014">to study eligibility were resolved by discussion (all Authors). A total of 20</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:3200px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background05.jpg" width=612 height=790></div>
<div style="position:absolute;left:48.19px;top:26.63px" class="cls_014"><span class="cls_014">Slow-freezing versus vitrification in ART</span></div>
<div style="position:absolute;left:550.66px;top:25.13px" class="cls_013"><span class="cls_013">143</span></div>
<div style="position:absolute;left:56.18px;top:526.68px" class="cls_020"><span class="cls_020">Figure 1</span><span class="cls_014"> Flow charts for a systematic review and meta-analysis comparing slow-freezing versus vitrification of oocytes, embryos and blastocysts in</span></div>
<div style="position:absolute;left:56.18px;top:538.17px" class="cls_014"><span class="cls_014">ART. (a) search for relevant studies for oocytes slow-freezing and vitrification (b) search for relevant studies for pronuclear, cleavage-stage embryo</span></div>
<div style="position:absolute;left:56.18px;top:549.17px" class="cls_014"><span class="cls_014">and blastocyst slow-freezing and vitrification.</span></div>
<div style="position:absolute;left:48.19px;top:596.96px" class="cls_014"><span class="cls_014">studies were included for this analysis, comparing outcomes following</span></div>
<div style="position:absolute;left:317.48px;top:596.96px" class="cls_014"><span class="cls_014">clinical outcomes were incomplete. Moreover, a meta-analysis (</span><span class="cls_019">AbdelHafez</span></div>
<div style="position:absolute;left:48.19px;top:607.96px" class="cls_014"><span class="cls_014">transfer of vitrified versus slow-frozen embryos (Fig.</span><span class="cls_019"> 1</span><span class="cls_014">b).</span></div>
<div style="position:absolute;left:317.48px;top:607.96px" class="cls_019"><span class="cls_019">et al.,</span></div>
<div style="position:absolute;left:341.18px;top:607.96px" class="cls_019"><span class="cls_019">2010</span><span class="cls_014">) focusing on clinical outcomes was reviewed. None of the</span></div>
<div style="position:absolute;left:317.48px;top:618.96px" class="cls_014"><span class="cls_014">included studies compared cryopreservation techniques at the pronuclear-</span></div>
<div style="position:absolute;left:317.48px;top:629.96px" class="cls_014"><span class="cls_014">stage. Two of the included RCTs were performed at the cleavage-stage</span></div>
<div style="position:absolute;left:317.48px;top:640.96px" class="cls_014"><span class="cls_014">(</span><span class="cls_019">Rama Raju et al., 2005</span><span class="cls_014">;</span><span class="cls_019"> Debrock et al., 2015</span><span class="cls_014">) and one at blastocyst stage</span></div>
<div style="position:absolute;left:48.19px;top:641.82px" class="cls_002"><span class="cls_002">Embryo cryopreservation: study descriptions</span></div>
<div style="position:absolute;left:317.48px;top:651.96px" class="cls_014"><span class="cls_014">(</span><span class="cls_019">Kim et al., 2000</span><span class="cls_014">). The primary outcome measures chosen were CPR</span></div>
<div style="position:absolute;left:48.19px;top:660.83px" class="cls_013"><span class="cls_013">Vitrified versus slow-frozen embryos: clinical outcomes</span></div>
<div style="position:absolute;left:317.48px;top:662.95px" class="cls_014"><span class="cls_014">and LBRs.</span></div>
<div style="position:absolute;left:48.19px;top:674.29px" class="cls_014"><span class="cls_014">Only one well-designed RCT comparing clinical outcomes following vitrifica-</span></div>
<div style="position:absolute;left:325.98px;top:673.95px" class="cls_014"><span class="cls_014">Eleven observational studies reporting clinical pregnancy per cycle</span></div>
<div style="position:absolute;left:48.19px;top:685.29px" class="cls_014"><span class="cls_014">tion versus slow-freezing between randomized women rather than embryos</span></div>
<div style="position:absolute;left:317.48px;top:684.95px" class="cls_014"><span class="cls_014">and/or per transfer of embryos at different stages of development were</span></div>
<div style="position:absolute;left:48.19px;top:696.29px" class="cls_014"><span class="cls_014">was identified (</span><span class="cls_019">Debrock et al., 2015</span><span class="cls_014">). Two RCTs (</span><span class="cls_019">Rama Raju et al., 2005</span></div>
<div style="position:absolute;left:317.48px;top:695.95px" class="cls_014"><span class="cls_014">pooled and analyzed (</span><span class="cls_019">Kuwayama et al., 2005a</span><span class="cls_014">,</span><span class="cls_019">b</span><span class="cls_014">;</span><span class="cls_019"> Stehilk et al., 2005</span><span class="cls_014">;</span></div>
<div style="position:absolute;left:48.19px;top:707.29px" class="cls_014"><span class="cls_014">and</span><span class="cls_019"> Kim et al., 2000</span><span class="cls_014">) comparing clinical outcomes between randomized</span></div>
<div style="position:absolute;left:317.48px;top:706.95px" class="cls_019"><span class="cls_019">Liebermann and Tucker, 2006</span><span class="cls_014">;</span><span class="cls_019"> Rezazadeh Valojerdi et al., 2009</span><span class="cls_014">;</span><span class="cls_019"> Wilding</span></div>
<div style="position:absolute;left:48.19px;top:718.29px" class="cls_014"><span class="cls_014">embryos were also included. Characteristics of these studies are described</span></div>
<div style="position:absolute;left:317.48px;top:717.95px" class="cls_019"><span class="cls_019">et al., 2010</span><span class="cls_014">;</span><span class="cls_019"> Sifer et al., 2012</span><span class="cls_014">;</span><span class="cls_019"> Wang et al., 2012</span><span class="cls_014">;</span><span class="cls_019"> Van Landuyt et al., 2013</span></div>
<div style="position:absolute;left:48.19px;top:729.29px" class="cls_014"><span class="cls_014">in Table</span><span class="cls_019"> I</span><span class="cls_014">. One additional RCT (</span><span class="cls_019">Bernal et al., 2008</span><span class="cls_014">) was excluded because</span></div>
<div style="position:absolute;left:317.48px;top:729.00px" class="cls_014"><span class="cls_014">and</span><span class="cls_019"> Liu et al.,</span></div>
<div style="position:absolute;left:375.14px;top:729.00px" class="cls_019"><span class="cls_019">2013</span><span class="cls_014">;</span><span class="cls_019"> Zhu et al.,</span></div>
<div style="position:absolute;left:443.57px;top:729.00px" class="cls_019"><span class="cls_019">2015</span><span class="cls_014">;</span><span class="cls_019"> Kaartinen et al.,</span></div>
<div style="position:absolute;left:530.36px;top:729.00px" class="cls_019"><span class="cls_019">2016</span><span class="cls_014">). An</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-395px;top:4000px;width:790px;height:612px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background06.jpg" width=790 height=612></div>
<div style="position:absolute;left:62.65px;top:50.75px" class="cls_020"><span class="cls_020">Table I</span><span class="cls_011"> Characteristics of the included RCTs comparing reproductive outcomes of slow-freezing versus vitrification.</span></div>
<div style="position:absolute;left:59.64px;top:72.22px" class="cls_003"><span class="cls_003">Authors</span></div>
<div style="position:absolute;left:106.36px;top:72.22px" class="cls_003"><span class="cls_003">Location Study design Cryopreservation protocols</span></div>
<div style="position:absolute;left:316.52px;top:72.22px" class="cls_003"><span class="cls_003">Study</span></div>
<div style="position:absolute;left:357.22px;top:72.22px" class="cls_003"><span class="cls_003">N°</span></div>
<div style="position:absolute;left:390.84px;top:72.22px" class="cls_003"><span class="cls_003">Control N°</span></div>
<div style="position:absolute;left:465.84px;top:72.22px" class="cls_003"><span class="cls_003">Outcomes Risk of bias</span></div>
<div style="position:absolute;left:655.06px;top:72.22px" class="cls_003"><span class="cls_003">Journal: Impact</span></div>
<div style="position:absolute;left:59.64px;top:82.25px" class="cls_003"><span class="cls_003">(year)</span></div>
<div style="position:absolute;left:316.52px;top:82.25px" class="cls_003"><span class="cls_003">group</span></div>
<div style="position:absolute;left:390.84px;top:82.25px" class="cls_003"><span class="cls_003">group</span></div>
<div style="position:absolute;left:655.08px;top:82.25px" class="cls_003"><span class="cls_003">factor</span></div>
<div style="position:absolute;left:63.89px;top:98.81px" class="cls_022"><span class="cls_022">Balaban</span></div>
<div style="position:absolute;left:106.36px;top:98.81px" class="cls_003"><span class="cls_003">Turkey</span></div>
<div style="position:absolute;left:144.57px;top:98.81px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:98.81px" class="cls_003"><span class="cls_003">Vitrification 16%PrOH + 16%</span></div>
<div style="position:absolute;left:316.52px;top:98.81px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:357.22px;top:98.81px" class="cls_003"><span class="cls_003">234</span></div>
<div style="position:absolute;left:390.84px;top:98.81px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:432.28px;top:98.81px" class="cls_003"><span class="cls_003">232</span></div>
<div style="position:absolute;left:465.84px;top:98.81px" class="cls_003"><span class="cls_003">cryosurvival</span></div>
<div style="position:absolute;left:517.21px;top:98.81px" class="cls_003"><span class="cls_003">Serious risk of bias due to randomization</span></div>
<div style="position:absolute;left:655.08px;top:98.81px" class="cls_003"><span class="cls_003">Human</span></div>
<div style="position:absolute;left:63.89px;top:108.79px" class="cls_022"><span class="cls_022">et al.</span></div>
<div style="position:absolute;left:144.57px;top:108.79px" class="cls_003"><span class="cls_003">of embryos</span></div>
<div style="position:absolute;left:199.96px;top:108.79px" class="cls_003"><span class="cls_003">EG + 0.65 M sucrose + 10 mg/ml</span></div>
<div style="position:absolute;left:316.52px;top:108.79px" class="cls_003"><span class="cls_003">stage</span></div>
<div style="position:absolute;left:357.22px;top:108.79px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:390.84px;top:108.79px" class="cls_003"><span class="cls_003">stage slow-</span></div>
<div style="position:absolute;left:432.28px;top:108.79px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:465.84px;top:108.79px" class="cls_003"><span class="cls_003">rate,</span></div>
<div style="position:absolute;left:517.21px;top:108.79px" class="cls_003"><span class="cls_003">method, concealment of allocation,</span></div>
<div style="position:absolute;left:655.08px;top:108.79px" class="cls_003"><span class="cls_003">Reproduction:</span></div>
<div style="position:absolute;left:63.89px;top:118.82px" class="cls_022"><span class="cls_022">(2008)</span></div>
<div style="position:absolute;left:199.96px;top:118.82px" class="cls_003"><span class="cls_003">Ficoll- open system</span></div>
<div style="position:absolute;left:316.52px;top:118.82px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:390.84px;top:118.82px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:465.84px;top:118.82px" class="cls_003"><span class="cls_003">blastocyct</span></div>
<div style="position:absolute;left:517.21px;top:118.82px" class="cls_003"><span class="cls_003">blinding</span></div>
<div style="position:absolute;left:655.08px;top:118.82px" class="cls_003"><span class="cls_003">4.621</span></div>
<div style="position:absolute;left:199.96px;top:128.80px" class="cls_003"><span class="cls_003">Slow-freezing: 1.5 M PROH-0.1 M</span></div>
<div style="position:absolute;left:465.84px;top:128.80px" class="cls_003"><span class="cls_003">formation</span></div>
<div style="position:absolute;left:199.96px;top:138.84px" class="cls_003"><span class="cls_003">Sucrose</span></div>
<div style="position:absolute;left:63.89px;top:151.82px" class="cls_022"><span class="cls_022">Cao et al.</span></div>
<div style="position:absolute;left:106.36px;top:151.82px" class="cls_003"><span class="cls_003">China</span></div>
<div style="position:absolute;left:144.57px;top:151.82px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:151.82px" class="cls_003"><span class="cls_003">Vitrification 15% EG + 15%</span></div>
<div style="position:absolute;left:316.52px;top:151.82px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:357.22px;top:151.82px" class="cls_003"><span class="cls_003">292</span></div>
<div style="position:absolute;left:390.84px;top:151.82px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:432.28px;top:151.82px" class="cls_003"><span class="cls_003">123</span></div>
<div style="position:absolute;left:465.84px;top:151.82px" class="cls_003"><span class="cls_003">cryosurvival</span></div>
<div style="position:absolute;left:517.21px;top:151.82px" class="cls_003"><span class="cls_003">Serious risk of bias due to randomization</span></div>
<div style="position:absolute;left:655.08px;top:151.82px" class="cls_003"><span class="cls_003">Seminars in</span></div>
<div style="position:absolute;left:63.89px;top:161.80px" class="cls_022"><span class="cls_022">(2009)</span></div>
<div style="position:absolute;left:144.57px;top:161.80px" class="cls_003"><span class="cls_003">of sibling</span></div>
<div style="position:absolute;left:199.96px;top:161.80px" class="cls_003"><span class="cls_003">PROH + 0.5 M sucrose - open</span></div>
<div style="position:absolute;left:316.52px;top:161.80px" class="cls_003"><span class="cls_003">vitrificaiton</span></div>
<div style="position:absolute;left:357.22px;top:161.80px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:390.84px;top:161.80px" class="cls_003"><span class="cls_003">slow-</span></div>
<div style="position:absolute;left:432.28px;top:161.80px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:465.84px;top:161.80px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:517.21px;top:161.80px" class="cls_003"><span class="cls_003">method, concealment of allocation,</span></div>
<div style="position:absolute;left:655.08px;top:161.80px" class="cls_003"><span class="cls_003">Reproductive</span></div>
<div style="position:absolute;left:144.57px;top:171.77px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:199.96px;top:171.77px" class="cls_003"><span class="cls_003">system</span></div>
<div style="position:absolute;left:390.84px;top:171.78px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:517.21px;top:171.78px" class="cls_003"><span class="cls_003">blinding</span></div>
<div style="position:absolute;left:655.08px;top:171.78px" class="cls_003"><span class="cls_003">Medicine: 2.113</span></div>
<div style="position:absolute;left:199.96px;top:181.81px" class="cls_003"><span class="cls_003">Slow-freezing: 1.5 M</span></div>
<div style="position:absolute;left:199.96px;top:191.79px" class="cls_003"><span class="cls_003">PROH + 0.3 M sucrose</span></div>
<div style="position:absolute;left:63.89px;top:204.77px" class="cls_022"><span class="cls_022">Cobo et al.</span></div>
<div style="position:absolute;left:106.36px;top:204.77px" class="cls_003"><span class="cls_003">Spain</span></div>
<div style="position:absolute;left:144.57px;top:204.77px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:204.77px" class="cls_003"><span class="cls_003">Vitrification 15% EG + 15%</span></div>
<div style="position:absolute;left:316.52px;top:204.77px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:357.22px;top:204.77px" class="cls_003"><span class="cls_003">295</span></div>
<div style="position:absolute;left:390.84px;top:204.77px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:432.28px;top:204.77px" class="cls_003"><span class="cls_003">289</span></div>
<div style="position:absolute;left:465.84px;top:204.77px" class="cls_003"><span class="cls_003">CPR,</span></div>
<div style="position:absolute;left:517.21px;top:204.77px" class="cls_003"><span class="cls_003">No serious risk of bias</span></div>
<div style="position:absolute;left:655.08px;top:204.77px" class="cls_003"><span class="cls_003">Human</span></div>
<div style="position:absolute;left:63.89px;top:214.80px" class="cls_022"><span class="cls_022">(2010)</span></div>
<div style="position:absolute;left:144.57px;top:214.80px" class="cls_003"><span class="cls_003">of patients</span></div>
<div style="position:absolute;left:199.96px;top:214.80px" class="cls_003"><span class="cls_003">DMSO + 0.5 M sucrose - open</span></div>
<div style="position:absolute;left:316.52px;top:214.80px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:357.22px;top:214.80px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:390.84px;top:214.80px" class="cls_003"><span class="cls_003">fresh</span></div>
<div style="position:absolute;left:432.28px;top:214.80px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:465.84px;top:214.80px" class="cls_003"><span class="cls_003">cryosurvival</span></div>
<div style="position:absolute;left:655.08px;top:214.80px" class="cls_003"><span class="cls_003">Reproduction:</span></div>
<div style="position:absolute;left:199.96px;top:224.78px" class="cls_003"><span class="cls_003">system</span></div>
<div style="position:absolute;left:465.84px;top:224.78px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:655.08px;top:224.78px" class="cls_003"><span class="cls_003">4.621</span></div>
<div style="position:absolute;left:63.89px;top:237.76px" class="cls_022"><span class="cls_022">Debrock</span></div>
<div style="position:absolute;left:106.36px;top:237.76px" class="cls_003"><span class="cls_003">Belgium</span></div>
<div style="position:absolute;left:144.57px;top:237.76px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:237.76px" class="cls_003"><span class="cls_003">Vitrification 15% EG + 15%</span></div>
<div style="position:absolute;left:316.52px;top:237.76px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:357.22px;top:237.76px" class="cls_003"><span class="cls_003">121</span></div>
<div style="position:absolute;left:390.84px;top:237.76px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:432.28px;top:237.76px" class="cls_003"><span class="cls_003">85</span></div>
<div style="position:absolute;left:465.84px;top:237.76px" class="cls_003"><span class="cls_003">CPR, LBR,</span></div>
<div style="position:absolute;left:517.21px;top:237.76px" class="cls_003"><span class="cls_003">No serious risk of bias</span></div>
<div style="position:absolute;left:655.08px;top:237.76px" class="cls_003"><span class="cls_003">Human</span></div>
<div style="position:absolute;left:63.89px;top:247.80px" class="cls_022"><span class="cls_022">et al.</span></div>
<div style="position:absolute;left:144.57px;top:247.80px" class="cls_003"><span class="cls_003">of patients</span></div>
<div style="position:absolute;left:199.96px;top:247.80px" class="cls_003"><span class="cls_003">DMSO + 0.5 M sucrose - closed</span></div>
<div style="position:absolute;left:316.52px;top:247.80px" class="cls_003"><span class="cls_003">stage</span></div>
<div style="position:absolute;left:357.22px;top:247.80px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:390.84px;top:247.80px" class="cls_003"><span class="cls_003">stage slow-</span></div>
<div style="position:absolute;left:432.28px;top:247.80px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:465.84px;top:247.80px" class="cls_003"><span class="cls_003">cryosurvival</span></div>
<div style="position:absolute;left:655.08px;top:247.80px" class="cls_003"><span class="cls_003">Reproduction:</span></div>
<div style="position:absolute;left:63.89px;top:257.78px" class="cls_022"><span class="cls_022">(2015)</span></div>
<div style="position:absolute;left:199.96px;top:257.78px" class="cls_003"><span class="cls_003">system</span></div>
<div style="position:absolute;left:316.52px;top:257.78px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:390.84px;top:257.78px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:432.28px;top:257.78px" class="cls_003"><span class="cls_003">200</span></div>
<div style="position:absolute;left:465.84px;top:257.78px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:655.08px;top:257.78px" class="cls_003"><span class="cls_003">4.621</span></div>
<div style="position:absolute;left:199.96px;top:267.75px" class="cls_003"><span class="cls_003">Slow-freezing: 1.5 M PROH −</span></div>
<div style="position:absolute;left:357.22px;top:267.75px" class="cls_003"><span class="cls_003">217</span></div>
<div style="position:absolute;left:432.28px;top:267.75px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:199.96px;top:277.79px" class="cls_003"><span class="cls_003">0.1 M Sucrose</span></div>
<div style="position:absolute;left:357.22px;top:277.79px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:63.89px;top:290.77px" class="cls_022"><span class="cls_022">Fasano</span></div>
<div style="position:absolute;left:106.36px;top:290.77px" class="cls_003"><span class="cls_003">Belgium</span></div>
<div style="position:absolute;left:144.57px;top:290.77px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:290.77px" class="cls_003"><span class="cls_003">Vitrification 20% EG + 15%</span></div>
<div style="position:absolute;left:316.52px;top:290.77px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:357.22px;top:290.77px" class="cls_003"><span class="cls_003">516</span></div>
<div style="position:absolute;left:390.84px;top:290.77px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:432.28px;top:290.77px" class="cls_003"><span class="cls_003">260</span></div>
<div style="position:absolute;left:465.84px;top:290.77px" class="cls_003"><span class="cls_003">CPR, LBR,</span></div>
<div style="position:absolute;left:517.21px;top:290.77px" class="cls_003"><span class="cls_003">Serious risk of bias due to randomization</span></div>
<div style="position:absolute;left:655.08px;top:290.77px" class="cls_003"><span class="cls_003">Journal of Assisted</span></div>
<div style="position:absolute;left:63.89px;top:300.75px" class="cls_022"><span class="cls_022">et al.</span></div>
<div style="position:absolute;left:144.57px;top:300.75px" class="cls_003"><span class="cls_003">of embryos</span></div>
<div style="position:absolute;left:199.96px;top:300.75px" class="cls_003"><span class="cls_003">DMSO + 0.5 M sucrose - closed</span></div>
<div style="position:absolute;left:316.52px;top:300.75px" class="cls_003"><span class="cls_003">stage</span></div>
<div style="position:absolute;left:357.22px;top:300.75px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:390.84px;top:300.75px" class="cls_003"><span class="cls_003">stage slow-</span></div>
<div style="position:absolute;left:432.28px;top:300.75px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:465.84px;top:300.75px" class="cls_003"><span class="cls_003">cryosurvival</span></div>
<div style="position:absolute;left:517.21px;top:300.75px" class="cls_003"><span class="cls_003">method, concealment of allocation, and</span></div>
<div style="position:absolute;left:655.08px;top:300.75px" class="cls_003"><span class="cls_003">Reproduction and</span></div>
<div style="position:absolute;left:63.89px;top:310.78px" class="cls_022"><span class="cls_022">(2014)</span></div>
<div style="position:absolute;left:199.96px;top:310.78px" class="cls_003"><span class="cls_003">system</span></div>
<div style="position:absolute;left:316.52px;top:310.78px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:357.22px;top:310.78px" class="cls_003"><span class="cls_003">660</span></div>
<div style="position:absolute;left:390.84px;top:310.78px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:432.28px;top:310.78px" class="cls_003"><span class="cls_003">395</span></div>
<div style="position:absolute;left:465.84px;top:310.78px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:517.21px;top:310.78px" class="cls_003"><span class="cls_003">blinding</span></div>
<div style="position:absolute;left:655.08px;top:310.78px" class="cls_003"><span class="cls_003">Genetics: 1.772</span></div>
<div style="position:absolute;left:199.95px;top:320.76px" class="cls_003"><span class="cls_003">Slow-freezing: 1.5 M PROH −</span></div>
<div style="position:absolute;left:357.22px;top:320.76px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:432.28px;top:320.76px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:199.95px;top:330.74px" class="cls_003"><span class="cls_003">0.1 M Sucrose</span></div>
<div style="position:absolute;left:63.89px;top:343.78px" class="cls_022"><span class="cls_022">Huang</span></div>
<div style="position:absolute;left:106.36px;top:343.78px" class="cls_003"><span class="cls_003">Taiwan</span></div>
<div style="position:absolute;left:144.60px;top:343.78px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:343.78px" class="cls_003"><span class="cls_003">Vitrification 20% EG + 20%</span></div>
<div style="position:absolute;left:316.52px;top:343.78px" class="cls_003"><span class="cls_003">Blastocyst</span></div>
<div style="position:absolute;left:357.22px;top:343.78px" class="cls_003"><span class="cls_003">81</span></div>
<div style="position:absolute;left:390.84px;top:343.78px" class="cls_003"><span class="cls_003">Blastocyst</span></div>
<div style="position:absolute;left:432.28px;top:343.78px" class="cls_003"><span class="cls_003">72</span></div>
<div style="position:absolute;left:465.85px;top:343.78px" class="cls_003"><span class="cls_003">cryosurvial</span></div>
<div style="position:absolute;left:517.21px;top:343.78px" class="cls_003"><span class="cls_003">Serious risk of bias due to randomization</span></div>
<div style="position:absolute;left:655.09px;top:343.78px" class="cls_003"><span class="cls_003">Human</span></div>
<div style="position:absolute;left:63.89px;top:353.76px" class="cls_022"><span class="cls_022">et al.</span></div>
<div style="position:absolute;left:144.57px;top:353.76px" class="cls_003"><span class="cls_003">of embryos</span></div>
<div style="position:absolute;left:199.96px;top:353.76px" class="cls_003"><span class="cls_003">DMSO and 0.5 M sucrose - open</span></div>
<div style="position:absolute;left:316.52px;top:353.76px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:357.22px;top:353.76px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:390.84px;top:353.76px" class="cls_003"><span class="cls_003">slow-</span></div>
<div style="position:absolute;left:432.28px;top:353.76px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:465.85px;top:353.76px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:517.21px;top:353.76px" class="cls_003"><span class="cls_003">method, concealment of allocation,</span></div>
<div style="position:absolute;left:655.09px;top:353.76px" class="cls_003"><span class="cls_003">Reproduction:</span></div>
<div style="position:absolute;left:63.89px;top:363.74px" class="cls_022"><span class="cls_022">(2005)</span></div>
<div style="position:absolute;left:199.96px;top:363.74px" class="cls_003"><span class="cls_003">system</span></div>
<div style="position:absolute;left:390.84px;top:363.74px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:517.21px;top:363.74px" class="cls_003"><span class="cls_003">blinding</span></div>
<div style="position:absolute;left:655.09px;top:363.74px" class="cls_003"><span class="cls_003">4.621</span></div>
<div style="position:absolute;left:199.96px;top:373.77px" class="cls_003"><span class="cls_003">Slow-freezing: 5% glycerol + 9%</span></div>
<div style="position:absolute;left:199.96px;top:383.75px" class="cls_003"><span class="cls_003">glycerol 0.2 M sucrose</span></div>
<div style="position:absolute;left:63.89px;top:396.73px" class="cls_022"><span class="cls_022">Kim et al.</span></div>
<div style="position:absolute;left:106.36px;top:396.73px" class="cls_003"><span class="cls_003">USA</span></div>
<div style="position:absolute;left:144.57px;top:396.73px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:396.73px" class="cls_003"><span class="cls_003">Vitrification 5.5 M EG + 1 M</span></div>
<div style="position:absolute;left:316.52px;top:396.73px" class="cls_003"><span class="cls_003">Blastocyst</span></div>
<div style="position:absolute;left:357.22px;top:396.73px" class="cls_003"><span class="cls_003">42</span></div>
<div style="position:absolute;left:390.84px;top:396.73px" class="cls_003"><span class="cls_003">Blastocyst</span></div>
<div style="position:absolute;left:432.28px;top:396.73px" class="cls_003"><span class="cls_003">216</span></div>
<div style="position:absolute;left:465.85px;top:396.73px" class="cls_003"><span class="cls_003">CPR,</span></div>
<div style="position:absolute;left:517.21px;top:396.73px" class="cls_003"><span class="cls_003">Unclear risk of bias related to random</span></div>
<div style="position:absolute;left:655.09px;top:396.73px" class="cls_003"><span class="cls_003">Fertility and</span></div>
<div style="position:absolute;left:63.89px;top:406.76px" class="cls_022"><span class="cls_022">(2000)</span></div>
<div style="position:absolute;left:144.57px;top:406.76px" class="cls_003"><span class="cls_003">of embryos</span></div>
<div style="position:absolute;left:199.96px;top:406.76px" class="cls_003"><span class="cls_003">sucrose</span></div>
<div style="position:absolute;left:316.52px;top:406.76px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:357.22px;top:406.76px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:390.84px;top:406.76px" class="cls_003"><span class="cls_003">slow-</span></div>
<div style="position:absolute;left:432.28px;top:406.76px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:465.85px;top:406.76px" class="cls_003"><span class="cls_003">cryosurvival</span></div>
<div style="position:absolute;left:517.21px;top:406.76px" class="cls_003"><span class="cls_003">sequence generation, allocation of</span></div>
<div style="position:absolute;left:655.09px;top:406.76px" class="cls_003"><span class="cls_003">Sterility: 4.426</span></div>
<div style="position:absolute;left:199.96px;top:416.74px" class="cls_003"><span class="cls_003">Slow freezing: 5% glycerol and 9%</span></div>
<div style="position:absolute;left:357.22px;top:416.74px" class="cls_003"><span class="cls_003">141</span></div>
<div style="position:absolute;left:390.84px;top:416.74px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:432.28px;top:416.74px" class="cls_003"><span class="cls_003">790</span></div>
<div style="position:absolute;left:465.85px;top:416.74px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:517.21px;top:416.74px" class="cls_003"><span class="cls_003">concealment acceptable, and blinding</span></div>
<div style="position:absolute;left:199.96px;top:426.72px" class="cls_003"><span class="cls_003">glycerol + 0.2 M sucrose</span></div>
<div style="position:absolute;left:357.22px;top:426.72px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:432.28px;top:426.72px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:63.89px;top:439.76px" class="cls_022"><span class="cls_022">Paffoni</span></div>
<div style="position:absolute;left:106.36px;top:439.76px" class="cls_003"><span class="cls_003">Italy</span></div>
<div style="position:absolute;left:144.57px;top:439.76px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:439.76px" class="cls_003"><span class="cls_003">Vitrification 15% DMSO, 15% EG,</span></div>
<div style="position:absolute;left:316.52px;top:439.76px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:357.22px;top:439.76px" class="cls_003"><span class="cls_003">90</span></div>
<div style="position:absolute;left:390.84px;top:439.76px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:432.28px;top:439.76px" class="cls_003"><span class="cls_003">90</span></div>
<div style="position:absolute;left:465.85px;top:439.76px" class="cls_003"><span class="cls_003">Cryosurvival</span></div>
<div style="position:absolute;left:517.21px;top:439.76px" class="cls_003"><span class="cls_003">Serious risk of bias due to randomization</span></div>
<div style="position:absolute;left:655.09px;top:439.76px" class="cls_003"><span class="cls_003">Reproductive</span></div>
<div style="position:absolute;left:63.89px;top:449.74px" class="cls_022"><span class="cls_022">et al.</span></div>
<div style="position:absolute;left:144.57px;top:449.74px" class="cls_003"><span class="cls_003">of sibling</span></div>
<div style="position:absolute;left:199.96px;top:449.74px" class="cls_003"><span class="cls_003">and 0.5 M sucrose - closed</span></div>
<div style="position:absolute;left:316.52px;top:449.74px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:357.22px;top:449.74px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:390.84px;top:449.74px" class="cls_003"><span class="cls_003">slow-</span></div>
<div style="position:absolute;left:432.28px;top:449.74px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:465.85px;top:449.74px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:517.21px;top:449.74px" class="cls_003"><span class="cls_003">method, concealment of allocation,</span></div>
<div style="position:absolute;left:655.09px;top:449.74px" class="cls_003"><span class="cls_003">Sciences: 2.429</span></div>
<div style="position:absolute;left:63.89px;top:459.72px" class="cls_022"><span class="cls_022">(2008)</span></div>
<div style="position:absolute;left:144.57px;top:459.72px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:199.96px;top:459.72px" class="cls_003"><span class="cls_003">system</span></div>
<div style="position:absolute;left:390.84px;top:459.72px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:517.21px;top:459.72px" class="cls_003"><span class="cls_003">blinding</span></div>
<div style="position:absolute;left:199.96px;top:469.75px" class="cls_003"><span class="cls_003">Slow freezing: 1.5 mol/L PROH</span></div>
<div style="position:absolute;left:199.96px;top:479.73px" class="cls_003"><span class="cls_003">and 0.3 mol/L sucrose</span></div>
<div style="position:absolute;left:63.89px;top:492.71px" class="cls_022"><span class="cls_022">Parmegiani</span></div>
<div style="position:absolute;left:106.36px;top:492.71px" class="cls_003"><span class="cls_003">Italy</span></div>
<div style="position:absolute;left:144.57px;top:492.71px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:492.71px" class="cls_003"><span class="cls_003">Vitrification 15% EG + 15%</span></div>
<div style="position:absolute;left:316.52px;top:492.71px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:357.22px;top:492.71px" class="cls_003"><span class="cls_003">168</span></div>
<div style="position:absolute;left:390.84px;top:492.71px" class="cls_003"><span class="cls_003">Oocyte</span></div>
<div style="position:absolute;left:432.28px;top:492.71px" class="cls_003"><span class="cls_003">120</span></div>
<div style="position:absolute;left:465.84px;top:492.71px" class="cls_003"><span class="cls_003">Cryosurvival</span></div>
<div style="position:absolute;left:517.21px;top:492.71px" class="cls_003"><span class="cls_003">Serious risk of bias due to randomization</span></div>
<div style="position:absolute;left:655.08px;top:492.71px" class="cls_003"><span class="cls_003">RBM online:2.796</span></div>
<div style="position:absolute;left:63.89px;top:502.75px" class="cls_022"><span class="cls_022">et al.</span></div>
<div style="position:absolute;left:144.57px;top:502.75px" class="cls_003"><span class="cls_003">of sibling</span></div>
<div style="position:absolute;left:199.96px;top:502.75px" class="cls_003"><span class="cls_003">DMSO + 0.5 M sucrose - open</span></div>
<div style="position:absolute;left:316.52px;top:502.74px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:357.22px;top:502.74px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:390.84px;top:502.74px" class="cls_003"><span class="cls_003">Fresh</span></div>
<div style="position:absolute;left:432.28px;top:502.74px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:465.84px;top:502.74px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:517.21px;top:502.74px" class="cls_003"><span class="cls_003">method, concealment of allocation, and</span></div>
<div style="position:absolute;left:63.89px;top:512.72px" class="cls_022"><span class="cls_022">(2011)</span></div>
<div style="position:absolute;left:144.57px;top:512.72px" class="cls_003"><span class="cls_003">oocytes</span></div>
<div style="position:absolute;left:199.96px;top:512.72px" class="cls_003"><span class="cls_003">system</span></div>
<div style="position:absolute;left:517.21px;top:512.72px" class="cls_003"><span class="cls_003">blinding</span></div>
<div style="position:absolute;left:63.89px;top:525.71px" class="cls_022"><span class="cls_022">Rama Raju</span></div>
<div style="position:absolute;left:106.36px;top:525.71px" class="cls_003"><span class="cls_003">India</span></div>
<div style="position:absolute;left:144.57px;top:525.71px" class="cls_003"><span class="cls_003">Randomization</span></div>
<div style="position:absolute;left:199.96px;top:525.71px" class="cls_003"><span class="cls_003">Vitrification 40% EG + 0.6 M</span></div>
<div style="position:absolute;left:316.52px;top:525.71px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:357.22px;top:525.71px" class="cls_003"><span class="cls_003">84</span></div>
<div style="position:absolute;left:390.84px;top:525.71px" class="cls_003"><span class="cls_003">Cleavage</span></div>
<div style="position:absolute;left:432.28px;top:525.71px" class="cls_003"><span class="cls_003">80</span></div>
<div style="position:absolute;left:465.85px;top:525.71px" class="cls_003"><span class="cls_003">CPR,</span></div>
<div style="position:absolute;left:517.21px;top:525.71px" class="cls_003"><span class="cls_003">Unclear risk of bias related to random</span></div>
<div style="position:absolute;left:655.09px;top:525.71px" class="cls_003"><span class="cls_003">RBM online:2.796</span></div>
<div style="position:absolute;left:63.89px;top:535.69px" class="cls_022"><span class="cls_022">et al.</span></div>
<div style="position:absolute;left:144.57px;top:535.69px" class="cls_003"><span class="cls_003">of embryos</span></div>
<div style="position:absolute;left:199.96px;top:535.69px" class="cls_003"><span class="cls_003">sucrose - open system</span></div>
<div style="position:absolute;left:316.52px;top:535.69px" class="cls_003"><span class="cls_003">stage</span></div>
<div style="position:absolute;left:357.22px;top:535.69px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:390.84px;top:535.69px" class="cls_003"><span class="cls_003">stage slow-</span></div>
<div style="position:absolute;left:432.28px;top:535.69px" class="cls_003"><span class="cls_003">cycles</span></div>
<div style="position:absolute;left:465.85px;top:535.69px" class="cls_003"><span class="cls_003">cryosurvival</span></div>
<div style="position:absolute;left:517.21px;top:535.69px" class="cls_003"><span class="cls_003">sequence generation, allocation of</span></div>
<div style="position:absolute;left:63.89px;top:545.72px" class="cls_022"><span class="cls_022">(2005)</span></div>
<div style="position:absolute;left:199.96px;top:545.72px" class="cls_003"><span class="cls_003">Slow-freezing: 1.5 M PROH- 0.1 M</span></div>
<div style="position:absolute;left:316.52px;top:545.72px" class="cls_003"><span class="cls_003">vitrification</span></div>
<div style="position:absolute;left:357.22px;top:545.72px" class="cls_003"><span class="cls_003">127</span></div>
<div style="position:absolute;left:390.84px;top:545.72px" class="cls_003"><span class="cls_003">freezing</span></div>
<div style="position:absolute;left:432.28px;top:545.72px" class="cls_003"><span class="cls_003">120</span></div>
<div style="position:absolute;left:465.85px;top:545.72px" class="cls_003"><span class="cls_003">rate</span></div>
<div style="position:absolute;left:517.21px;top:545.72px" class="cls_003"><span class="cls_003">concealment acceptable, and blinding</span></div>
<div style="position:absolute;left:199.96px;top:555.70px" class="cls_003"><span class="cls_003">Sucrose</span></div>
<div style="position:absolute;left:357.22px;top:555.70px" class="cls_003"><span class="cls_003">embryos</span></div>
<div style="position:absolute;left:432.28px;top:555.70px" class="cls_003"><span class="cls_003">embryos</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:4622px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background07.jpg" width=612 height=790></div>
<div style="position:absolute;left:48.19px;top:26.63px" class="cls_014"><span class="cls_014">Slow-freezing versus vitrification in ART</span></div>
<div style="position:absolute;left:550.66px;top:25.13px" class="cls_013"><span class="cls_013">145</span></div>
<div style="position:absolute;left:317.48px;top:56.96px" class="cls_014"><span class="cls_014">additional two studies described by the authors as RCT’s were not truly</span></div>
<div style="position:absolute;left:317.48px;top:67.96px" class="cls_014"><span class="cls_014">randomized studies and were therefore included in the analysis with</span></div>
<div style="position:absolute;left:317.48px;top:78.96px" class="cls_014"><span class="cls_014">observational studies (</span><span class="cls_019">Li et al., 2007</span><span class="cls_014"> and</span><span class="cls_019"> Summers et al., 2016</span><span class="cls_014">).</span></div>
<div style="position:absolute;left:325.98px;top:89.96px" class="cls_014"><span class="cls_014">LBR per cycle and/or per transfer was reported in six studies</span></div>
<div style="position:absolute;left:317.48px;top:100.96px" class="cls_014"><span class="cls_014">(</span><span class="cls_019">Kuwayama et al., 2005a</span><span class="cls_014">,</span><span class="cls_019">b</span><span class="cls_014">;</span><span class="cls_019"> Wilding et al., 2010</span><span class="cls_014">;</span><span class="cls_019"> Wang et al., 2012</span><span class="cls_014">;</span><span class="cls_019"> Liu</span></div>
<div style="position:absolute;left:317.48px;top:111.96px" class="cls_019"><span class="cls_019">et al., 2013</span><span class="cls_014">;</span><span class="cls_019"> Van Landuyt et al., 2013</span><span class="cls_014">;</span><span class="cls_019"> Kaartinen et al., 2016</span><span class="cls_014">).</span></div>
<div style="position:absolute;left:317.48px;top:138.58px" class="cls_013"><span class="cls_013">Slow-frozen versus vitrified embryos: survival</span></div>
<div style="position:absolute;left:317.48px;top:152.04px" class="cls_014"><span class="cls_014">A secondary analysis was performed focusing on embryo cryosurvival</span></div>
<div style="position:absolute;left:317.48px;top:163.04px" class="cls_014"><span class="cls_014">rate. Seven RCTs (</span><span class="cls_019">Kim et al., 2000</span><span class="cls_014">;</span><span class="cls_019"> Huang et al., 2005</span><span class="cls_014">;</span><span class="cls_019"> Rama Raju et al.,</span></div>
<div style="position:absolute;left:317.48px;top:174.04px" class="cls_019"><span class="cls_019">2005</span><span class="cls_014">;</span><span class="cls_019"> Zheng et al.,</span></div>
<div style="position:absolute;left:392.20px;top:174.04px" class="cls_019"><span class="cls_019">2005</span><span class="cls_014">;</span><span class="cls_019"> Balaban et al.,</span></div>
<div style="position:absolute;left:471.40px;top:174.04px" class="cls_019"><span class="cls_019">2008</span><span class="cls_014">;</span><span class="cls_019"> Fasano et al.,</span></div>
<div style="position:absolute;left:547.88px;top:174.04px" class="cls_019"><span class="cls_019">2014</span><span class="cls_014">;</span></div>
<div style="position:absolute;left:317.48px;top:185.03px" class="cls_019"><span class="cls_019">Debrock et al.,2015</span><span class="cls_014">) were included. Characteristics of these studies are</span></div>
<div style="position:absolute;left:317.48px;top:196.03px" class="cls_014"><span class="cls_014">described in Table</span><span class="cls_019"> I</span><span class="cls_014">. Moreover,</span></div>
<div style="position:absolute;left:437.22px;top:196.03px" class="cls_014"><span class="cls_014">12 observational studies</span></div>
<div style="position:absolute;left:527.64px;top:196.03px" class="cls_014"><span class="cls_014">(</span><span class="cls_019">Kuwayama</span></div>
<div style="position:absolute;left:317.48px;top:207.03px" class="cls_019"><span class="cls_019">et al.,</span></div>
<div style="position:absolute;left:341.46px;top:207.03px" class="cls_019"><span class="cls_019">2005a</span><span class="cls_014">,</span><span class="cls_019">b</span><span class="cls_014">;</span><span class="cls_019"> Stehilk et al.,</span></div>
<div style="position:absolute;left:424.69px;top:207.03px" class="cls_019"><span class="cls_019">2005</span><span class="cls_014">;</span><span class="cls_019"> Liebermann and Tucker, 2006</span><span class="cls_014">;</span><span class="cls_019"> Li</span></div>
<div style="position:absolute;left:317.48px;top:218.03px" class="cls_019"><span class="cls_019">et al., 2007</span><span class="cls_014">;</span><span class="cls_019"> Rezazadeh Valojerdi et al., 2009</span><span class="cls_014">;</span><span class="cls_019"> Wilding et al., 2010</span><span class="cls_014">;</span><span class="cls_019"> Sifer</span></div>
<div style="position:absolute;left:317.48px;top:229.03px" class="cls_019"><span class="cls_019">et al., 2012</span><span class="cls_014">;</span><span class="cls_019"> Wang et al., 2012</span><span class="cls_014">;</span><span class="cls_019"> Van Landuyt et al., 2013</span><span class="cls_014"> and</span><span class="cls_019"> Liu et al.,</span></div>
<div style="position:absolute;left:317.48px;top:240.03px" class="cls_019"><span class="cls_019">2013</span><span class="cls_014">;</span><span class="cls_019"> Zhu et al., 2015</span><span class="cls_014">;</span><span class="cls_019"> Summers et al., 2016</span><span class="cls_014">) and two meta-analyses</span></div>
<div style="position:absolute;left:317.48px;top:251.02px" class="cls_014"><span class="cls_014">comparing results obtained with vitrification/warming and slow-freezing/</span></div>
<div style="position:absolute;left:317.48px;top:262.02px" class="cls_014"><span class="cls_014">thawing (</span><span class="cls_019">Loutradi et al., 2008</span><span class="cls_014">;</span><span class="cls_019"> Kolibianakis et al., 2009</span><span class="cls_014">) were identified.</span></div>
<div style="position:absolute;left:317.48px;top:296.62px" class="cls_002"><span class="cls_002">Assessing the quality of each study</span></div>
<div style="position:absolute;left:317.48px;top:314.12px" class="cls_014"><span class="cls_014">According to the WHO Handbook for Guideline Development (</span><span class="cls_019">WHO,</span></div>
<div style="position:absolute;left:317.48px;top:325.12px" class="cls_019"><span class="cls_019">2012</span><span class="cls_014">) the quality of each study was assessed. In particular, each RCT was</span></div>
<div style="position:absolute;left:317.48px;top:336.12px" class="cls_014"><span class="cls_014">evaluated for the following factors: how randomization was performed,</span></div>
<div style="position:absolute;left:317.48px;top:347.12px" class="cls_014"><span class="cls_014">whether there was concealment of allocation, whether participants and</span></div>
<div style="position:absolute;left:317.48px;top:358.12px" class="cls_014"><span class="cls_014">personnel were blinded to the intervention and outcome, whether there</span></div>
<div style="position:absolute;left:317.48px;top:369.11px" class="cls_014"><span class="cls_014">was complete data reporting, whether an intention to treat analysis was</span></div>
<div style="position:absolute;left:317.48px;top:380.11px" class="cls_014"><span class="cls_014">performed and whether any other potential sources of bias existed</span></div>
<div style="position:absolute;left:317.48px;top:391.11px" class="cls_014"><span class="cls_014">(</span><span class="cls_019">WHO, 2012</span><span class="cls_014">). The overall risk of bias was classified as serious, not ser-</span></div>
<div style="position:absolute;left:317.48px;top:402.11px" class="cls_014"><span class="cls_014">ious, or unclear and is presented in Table</span><span class="cls_019"> I</span><span class="cls_014"> for each randomized trial</span></div>
<div style="position:absolute;left:317.48px;top:413.11px" class="cls_014"><span class="cls_014">included. The risk of bias is considered serious for all observational stud-</span></div>
<div style="position:absolute;left:317.48px;top:424.16px" class="cls_014"><span class="cls_014">ies given the high risk for selection bias and confounding inherent in these</span></div>
<div style="position:absolute;left:317.48px;top:435.16px" class="cls_014"><span class="cls_014">study designs.</span></div>
<div style="position:absolute;left:317.48px;top:469.70px" class="cls_002"><span class="cls_002">Data synthesis and meta-analysis</span></div>
<div style="position:absolute;left:317.48px;top:487.21px" class="cls_014"><span class="cls_014">Meta-analyses of studies were undertaken to estimate the pooled relative</span></div>
<div style="position:absolute;left:317.48px;top:498.21px" class="cls_014"><span class="cls_014">risk ratios (RR) of outcomes including CPR per cycle, CPR per transfer and</span></div>
<div style="position:absolute;left:317.48px;top:509.20px" class="cls_014"><span class="cls_014">cryosurvival of thawed/warmed oocytes or embryos. Statistical analyses</span></div>
<div style="position:absolute;left:317.48px;top:520.20px" class="cls_014"><span class="cls_014">and construction of forest and funnel plots were performed with Stata ver-</span></div>
<div style="position:absolute;left:317.48px;top:531.20px" class="cls_014"><span class="cls_014">sion 12.1 (StataCorp, TX, USA). RR and 95% CIs were calculated for each</span></div>
<div style="position:absolute;left:317.48px;top:542.20px" class="cls_014"><span class="cls_014">outcome. A random effects model was used for the meta-analysis.</span></div>
<div style="position:absolute;left:317.48px;top:551.95px" class="cls_014"><span class="cls_014">Heterogeneity was assessed with the use of the I</span><span class="cls_023"><sup>2</sup></span><span class="cls_014"> test. Publication bias</span></div>
<div style="position:absolute;left:317.48px;top:564.25px" class="cls_014"><span class="cls_014">was assessed by constructing funnel plots.</span></div>
<div style="position:absolute;left:317.48px;top:598.79px" class="cls_002"><span class="cls_002">Assessment of the quality of the literature as</span></div>
<div style="position:absolute;left:317.48px;top:612.80px" class="cls_002"><span class="cls_002">a whole</span></div>
<div style="position:absolute;left:317.48px;top:630.30px" class="cls_014"><span class="cls_014">According to the WHO Handbook for Guideline Development (</span><span class="cls_019">WHO,</span></div>
<div style="position:absolute;left:317.48px;top:641.30px" class="cls_019"><span class="cls_019">2012</span><span class="cls_014">) used to guide methodology in this systematic review, the quality of</span></div>
<div style="position:absolute;left:317.48px;top:652.30px" class="cls_014"><span class="cls_014">the literature for each analysis was classified as high, moderate, low or</span></div>
<div style="position:absolute;left:317.48px;top:663.29px" class="cls_014"><span class="cls_014">very low. A grade of high indicates that further research is very unlikely</span></div>
<div style="position:absolute;left:317.48px;top:674.29px" class="cls_014"><span class="cls_014">to change confidence in the estimate of effect; moderate indicates that</span></div>
<div style="position:absolute;left:317.48px;top:685.29px" class="cls_014"><span class="cls_014">further research is likely to have an important impact on confidence in</span></div>
<div style="position:absolute;left:317.48px;top:696.29px" class="cls_014"><span class="cls_014">the estimate of effect and may change the estimate; low indicates that</span></div>
<div style="position:absolute;left:317.48px;top:707.29px" class="cls_014"><span class="cls_014">further research is very likely to have an important impact on confidence</span></div>
<div style="position:absolute;left:317.48px;top:718.29px" class="cls_014"><span class="cls_014">in the estimate of effect and is likely to change the estimate; very low</span></div>
<div style="position:absolute;left:317.48px;top:729.28px" class="cls_014"><span class="cls_014">indicates that any estimate of effect is very uncertain (</span><span class="cls_019">WHO, 2012</span><span class="cls_014">).</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:5422px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background08.jpg" width=612 height=790></div>
<div style="position:absolute;left:45.35px;top:25.13px" class="cls_013"><span class="cls_013">146</span></div>
<div style="position:absolute;left:525.71px;top:26.63px" class="cls_014"><span class="cls_014">Rienzi et al.</span></div>
<div style="position:absolute;left:53.86px;top:56.96px" class="cls_014"><span class="cls_014">Factors used to determine the classification for any analysis took into</span></div>
<div style="position:absolute;left:314.65px;top:55.42px" class="cls_011"><span class="cls_011">2046 cycles; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 0.0%, very low quality evidence), and lower LBRs</span></div>
<div style="position:absolute;left:45.35px;top:67.96px" class="cls_014"><span class="cls_014">account the following factors: study design, consistency of the results</span></div>
<div style="position:absolute;left:314.65px;top:68.82px" class="cls_011"><span class="cls_011">per utilized oocyte (RR = 0.26, 95% CI: 0.21-0.32; P < 0.0001; three</span></div>
<div style="position:absolute;left:45.35px;top:78.96px" class="cls_014"><span class="cls_014">across the available studies, precision of the results (width of the CI), the</span></div>
<div style="position:absolute;left:314.65px;top:79.45px" class="cls_011"><span class="cls_011">studies; 5513 and 6670 cycles; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 0.0%, very low quality evidence)</span></div>
<div style="position:absolute;left:45.35px;top:89.96px" class="cls_014"><span class="cls_014">directness or generalizability of the results across populations, and the</span></div>
<div style="position:absolute;left:314.65px;top:92.80px" class="cls_011"><span class="cls_011">when slow-freeze was compared to fresh oocytes.</span></div>
<div style="position:absolute;left:45.35px;top:100.96px" class="cls_014"><span class="cls_014">likelihood of publications bias.</span></div>
<div style="position:absolute;left:323.66px;top:104.82px" class="cls_011"><span class="cls_011">The CPR per cycle (RR = 0.42, 95% CI: 0.31-0.58; P < 0.0001;</span></div>
<div style="position:absolute;left:314.65px;top:116.79px" class="cls_011"><span class="cls_011">five studies,</span></div>
<div style="position:absolute;left:366.07px;top:116.79px" class="cls_011"><span class="cls_011">1809</span></div>
<div style="position:absolute;left:390.28px;top:116.79px" class="cls_011"><span class="cls_011">and</span></div>
<div style="position:absolute;left:409.38px;top:116.79px" class="cls_011"><span class="cls_011">3323</span></div>
<div style="position:absolute;left:433.59px;top:116.79px" class="cls_011"><span class="cls_011">cycles, slow-freezing versus fresh,</span></div>
<div style="position:absolute;left:314.65px;top:127.42px" class="cls_011"><span class="cls_011">respectively; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 64.5%, very low quality evidence) (<A HREF="http://humupd.oxfordjournals.org/lookup/suppl/doi:10.1093/humupd/dmw038/-/DC1">Supplementary</A> </span></div>
<div style="position:absolute;left:45.35px;top:128.13px" class="cls_017"><span class="cls_017">Results</span></div>
<div style="position:absolute;left:314.65px;top:140.82px" class="cls_011"><span class="cls_011"> </span><A HREF="http://humupd.oxfordjournals.org/lookup/suppl/doi:10.1093/humupd/dmw038/-/DC1">Fig. S1b</A>), the CPR per transfer (RR = 0.45, 95% CI: 0.29-0.65, five</div>
<div style="position:absolute;left:314.65px;top:151.45px" class="cls_011"><span class="cls_011">studies; P < 0.0001; 1534 and 2989 transfers; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 78.5%, very low</span></div>
<div style="position:absolute;left:45.35px;top:154.15px" class="cls_002"><span class="cls_002">Oocyte slow-freezing versus vitrification:</span></div>
<div style="position:absolute;left:314.65px;top:164.80px" class="cls_011"><span class="cls_011">quality evidence) and the CPR per utilized oocytes (RR = 0.29, 95%</span></div>
<div style="position:absolute;left:45.35px;top:168.15px" class="cls_002"><span class="cls_002">clinical outcomes and oocyte cryosurvival</span></div>
<div style="position:absolute;left:314.65px;top:176.82px" class="cls_011"><span class="cls_011">CI: 0.25-0.35, four studies; 6600 and 9115 oocytes, slow-freezing</span></div>
<div style="position:absolute;left:45.35px;top:186.12px" class="cls_011"><span class="cls_011">A single RCT (</span><span class="cls_018">Smith et al., 2010</span><span class="cls_011">) revealed evidence of a difference in</span></div>
<div style="position:absolute;left:314.65px;top:187.45px" class="cls_011"><span class="cls_011">versus, fresh, respectively; P < 0.0001; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 4.8%, very low quality</span></div>
<div style="position:absolute;left:45.35px;top:198.14px" class="cls_011"><span class="cls_011">favor of vitrification regarding ongoing pregnancy rate per cycle</span></div>
<div style="position:absolute;left:314.65px;top:200.80px" class="cls_011"><span class="cls_011">evidence) were all in favor of fresh oocytes as compared to slow-</span></div>
<div style="position:absolute;left:45.35px;top:210.16px" class="cls_011"><span class="cls_011">(RR = 2.81, 95% CI: 1.05-7.51; P = 0.039; 48 and 30 cycles, vitrifica-</span></div>
<div style="position:absolute;left:314.65px;top:212.82px" class="cls_011"><span class="cls_011">frozen oocytes (</span><span class="cls_018">Chamayou et al., 2006</span><span class="cls_011">;</span><span class="cls_018"> Levi Setti et al., 2006</span><span class="cls_011">;</span><span class="cls_018"> Borini</span></div>
<div style="position:absolute;left:45.35px;top:222.12px" class="cls_011"><span class="cls_011">tion versus slow-freezing, respectively; low quality evidence) (Fig.</span><span class="cls_018"> 2</span><span class="cls_011">a)</span></div>
<div style="position:absolute;left:314.65px;top:224.79px" class="cls_018"><span class="cls_018">et al., 2007</span><span class="cls_011">,</span><span class="cls_018">2010</span><span class="cls_011">;</span><span class="cls_018"> Virant-Klun et al., 2011</span><span class="cls_011">). Each utilized slow-frozen</span></div>
<div style="position:absolute;left:45.35px;top:234.14px" class="cls_011"><span class="cls_011">and per warmed/thawed oocyte (RR = 1.14, 95% CI: 1.02-1.28;</span></div>
<div style="position:absolute;left:314.65px;top:236.80px" class="cls_011"><span class="cls_011">oocyte had a 2.27% (150/6600) likelihood of resulting in a pregnancy</span></div>
<div style="position:absolute;left:45.35px;top:246.16px" class="cls_011"><span class="cls_011">P = 0.018; 260 and 238 oocytes, vitrification versus slow-freezing,</span></div>
<div style="position:absolute;left:314.65px;top:248.82px" class="cls_011"><span class="cls_011">in the population of women studied.</span></div>
<div style="position:absolute;left:45.35px;top:258.12px" class="cls_011"><span class="cls_011">respectively; low quality evidence). Limited evidence demonstrated</span></div>
<div style="position:absolute;left:45.35px;top:270.14px" class="cls_011"><span class="cls_011">that clinical outcomes following vitrification versus slow-freezing were</span></div>
<div style="position:absolute;left:45.35px;top:282.16px" class="cls_011"><span class="cls_011">similar when ongoing pregnancy rate was expressed per embryo trans-</span></div>
<div style="position:absolute;left:314.65px;top:288.80px" class="cls_002"><span class="cls_002">Oocyte vitrification versus fresh oocytes:</span></div>
<div style="position:absolute;left:45.35px;top:294.12px" class="cls_011"><span class="cls_011">fer (RR = 1.81, 95% CI: 0.71-4.67; P = 0.214; 47 and 19 transfers, vit-</span></div>
<div style="position:absolute;left:45.35px;top:306.14px" class="cls_011"><span class="cls_011">rification versus slow-freezing, respectively; low quality evidence).</span></div>
<div style="position:absolute;left:314.65px;top:302.80px" class="cls_002"><span class="cls_002">clinical outcomes</span></div>
<div style="position:absolute;left:54.37px;top:318.16px" class="cls_011"><span class="cls_011">In two cohort studies (</span><span class="cls_018">Fadini et al., 2009</span><span class="cls_011">;</span><span class="cls_018"> Levi Setti et al., 2014</span><span class="cls_011">)</span></div>
<div style="position:absolute;left:314.65px;top:320.82px" class="cls_011"><span class="cls_011">Analysis of a single RCT (</span><span class="cls_018">Cobo et al., 2010</span><span class="cls_011">) revealed no evidence for</span></div>
<div style="position:absolute;left:45.35px;top:330.12px" class="cls_011"><span class="cls_011">the evidence also favored vitrification for CPR per cycle (RR = 1.72,</span></div>
<div style="position:absolute;left:314.65px;top:332.84px" class="cls_011"><span class="cls_011">a difference in ongoing CPR between the two groups when results</span></div>
<div style="position:absolute;left:45.35px;top:342.14px" class="cls_011"><span class="cls_011">95% CI: 0.74-3.95; P = 0.212; 5460 and 9212 cycles, vitrification ver-</span></div>
<div style="position:absolute;left:314.65px;top:344.80px" class="cls_011"><span class="cls_011">were expressed per woman randomized (RR = 1.03, 95% CI: 0.87-</span></div>
<div style="position:absolute;left:45.35px;top:352.77px" class="cls_011"><span class="cls_011">sus slow-freezing, respectively; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 81.5%, very low quality evidence)</span></div>
<div style="position:absolute;left:314.65px;top:356.82px" class="cls_011"><span class="cls_011">1.21; P = 0.744, 300 women in each group; moderate quality evi-</span></div>
<div style="position:absolute;left:45.35px;top:366.12px" class="cls_011"><span class="cls_011">(Fig.</span><span class="cls_018"> 2</span><span class="cls_011">b), per transfer (RR = 1.55, 95% CI: 0.82-2.92; P = 0.180, two</span></div>
<div style="position:absolute;left:314.65px;top:368.84px" class="cls_011"><span class="cls_011">dence), per cycle (RR = 1.01, 95% CI: 0.86-1.18; P = 0.934; 267 ver-</span></div>
<div style="position:absolute;left:45.35px;top:376.75px" class="cls_011"><span class="cls_011">studies; I</span><span class="cls_016"><sup>2</sup></span></div>
<div style="position:absolute;left:86.00px;top:378.14px" class="cls_011"><span class="cls_011">= 70.0%, very low quality evidence) and per warmed/</span></div>
<div style="position:absolute;left:314.65px;top:380.80px" class="cls_011"><span class="cls_011">sus 259 cycles vitrification versus fresh, respectively; moderate quality</span></div>
<div style="position:absolute;left:45.35px;top:390.16px" class="cls_011"><span class="cls_011">thawed oocyte (RR = 1.72, 95% CI: 0.84-3.52; P = 0.135; 26789</span></div>
<div style="position:absolute;left:314.65px;top:392.82px" class="cls_011"><span class="cls_011">evidence) or per utilized oocyte (RR = 1.02, 95% CI: 0.82-1.26;</span></div>
<div style="position:absolute;left:45.35px;top:402.12px" class="cls_011"><span class="cls_011">and 49264 oocytes, vitrification versus slow-freezing, respectively;</span></div>
<div style="position:absolute;left:314.65px;top:404.84px" class="cls_011"><span class="cls_011">P</span></div>
<div style="position:absolute;left:324.00px;top:404.84px" class="cls_011"><span class="cls_011">= 0.873; 3286 versus 3185 oocytes, vitrification versus fresh,</span></div>
<div style="position:absolute;left:45.35px;top:414.14px" class="cls_011"><span class="cls_011">very low quality evidence). However, the differences were not statis-</span></div>
<div style="position:absolute;left:314.65px;top:416.80px" class="cls_011"><span class="cls_011">respectively; moderate quality evidence).</span></div>
<div style="position:absolute;left:45.35px;top:426.16px" class="cls_011"><span class="cls_011">tically significant. Of note the CPR per cycle was relatively low in the</span></div>
<div style="position:absolute;left:323.66px;top:428.82px" class="cls_011"><span class="cls_011">The combined analysis of the cohort studies and the RCTs in</span></div>
<div style="position:absolute;left:45.35px;top:438.12px" class="cls_011"><span class="cls_011">unselected population of patients undergoing autologous oocyte</span></div>
<div style="position:absolute;left:314.65px;top:440.84px" class="cls_011"><span class="cls_011">which sibling oocytes were randomized to be vitrified or used fresh</span></div>
<div style="position:absolute;left:45.35px;top:450.14px" class="cls_011"><span class="cls_011">cryopreservation due to law restrictions for both approaches, 11.8%</span></div>
<div style="position:absolute;left:314.64px;top:452.80px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Sole et al., 2013</span><span class="cls_011">;</span><span class="cls_018"> Parmegiani et al., 2011</span><span class="cls_011">;</span><span class="cls_018"> Trokoudes et al., 2011</span><span class="cls_011">)</span></div>
<div style="position:absolute;left:45.35px;top:462.16px" class="cls_011"><span class="cls_011">and 14.4% for slow freezing and vitrification, respectively.</span></div>
<div style="position:absolute;left:314.65px;top:464.82px" class="cls_011"><span class="cls_011">revealed no evidence of a difference between cycles using exclusively</span></div>
<div style="position:absolute;left:54.37px;top:474.12px" class="cls_011"><span class="cls_011">The superiority of vitrification over slow-freezing was also observed</span></div>
<div style="position:absolute;left:314.65px;top:476.84px" class="cls_011"><span class="cls_011">vitrified versus fresh oocytes for LBR per cycle (RR = 1.04, 95% CI:</span></div>
<div style="position:absolute;left:45.35px;top:486.14px" class="cls_011"><span class="cls_011">when cryosurvival rates of MII oocytes were compared. In three RCTs</span></div>
<div style="position:absolute;left:314.65px;top:488.80px" class="cls_011"><span class="cls_011">0.61-1.76, P = 0.892; three studies; 171 and 171 cycles, vitrification</span></div>
<div style="position:absolute;left:45.35px;top:498.16px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Paffoni et al., 2008</span><span class="cls_011">;</span><span class="cls_018"> Cao et al., 2009</span><span class="cls_011">;</span><span class="cls_018"> Smith et al., 2010</span><span class="cls_011">) MII cryosurvi-</span></div>
<div style="position:absolute;left:314.65px;top:499.43px" class="cls_011"><span class="cls_011">versus fresh, respectively; I</span><span class="cls_016"><sup>2</sup></span></div>
<div style="position:absolute;left:424.91px;top:500.82px" class="cls_011"><span class="cls_011">= 52.3%; very low quality evidence)</span></div>
<div style="position:absolute;left:45.35px;top:510.12px" class="cls_011"><span class="cls_011">val rate was</span></div>
<div style="position:absolute;left:98.48px;top:510.12px" class="cls_011"><span class="cls_011">82.3% (602/731) following vitrification/warming and</span></div>
<div style="position:absolute;left:314.65px;top:512.84px" class="cls_011"><span class="cls_011">(</span><A HREF="http://humupd.oxfordjournals.org/lookup/suppl/doi:10.1093/humupd/dmw038/-/DC1">Supplementary Fig. S2</A>), LBR per oocyte utilized (RR = 2.35, 95% CI:</div>
<div style="position:absolute;left:45.35px;top:522.14px" class="cls_011"><span class="cls_011">66.1% (298/451) following slow-freezing/thawing (RR = 1.23, 95% CI:</span></div>
<div style="position:absolute;left:314.65px;top:524.80px" class="cls_011"><span class="cls_011">0.29-19.3, P = 0.427; two studies; 378 and 367 oocytes, vitrification</span></div>
<div style="position:absolute;left:45.35px;top:532.77px" class="cls_011"><span class="cls_011">1.02-1.49; P = 0.031; three studies; 1182 oocytes thawed; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 82.9%,</span></div>
<div style="position:absolute;left:314.65px;top:535.44px" class="cls_011"><span class="cls_011">versus fresh, respectively; I</span><span class="cls_016"><sup>2</sup></span></div>
<div style="position:absolute;left:424.91px;top:536.82px" class="cls_011"><span class="cls_011">= 58.5%; very low quality evidence)</span></div>
<div style="position:absolute;left:45.35px;top:546.12px" class="cls_011"><span class="cls_011">low quality evidence) (Fig.</span><span class="cls_018"> 2</span><span class="cls_011">c). In the three cohort studies, cryosurvival</span></div>
<div style="position:absolute;left:314.65px;top:548.84px" class="cls_011"><span class="cls_011">(</span><span class="cls_018">Parmegiani et al., 2011</span><span class="cls_011">;</span><span class="cls_018"> Trokoudes et al., 2011</span><span class="cls_011">), or LBR per transfer</span></div>
<div style="position:absolute;left:45.35px;top:558.14px" class="cls_011"><span class="cls_011">rate after vitrification was also significantly higher than after slow-</span></div>
<div style="position:absolute;left:314.65px;top:560.80px" class="cls_011"><span class="cls_011">(RR = 1.10, 95% CI: 0.64-1.88, P = 0.730; three studies; 166 and</span></div>
<div style="position:absolute;left:45.35px;top:570.16px" class="cls_011"><span class="cls_011">freezing (RR = 1.23, 95% CI: 1.11-1.36, P < 0.001; three studies;</span></div>
<div style="position:absolute;left:314.65px;top:571.43px" class="cls_011"><span class="cls_011">170 transfers, vitrification versus fresh, respectively, I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 54.6%; very</span></div>
<div style="position:absolute;left:45.35px;top:580.79px" class="cls_011"><span class="cls_011">99679 oocytes thawed; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 91.6%, very low quality evidence) (</span><span class="cls_018">Fadini</span></div>
<div style="position:absolute;left:314.65px;top:584.84px" class="cls_011"><span class="cls_011">low quality evidence). The two groups were also similar for CPR per</span></div>
<div style="position:absolute;left:45.35px;top:594.14px" class="cls_018"><span class="cls_018">et al., 2009</span><span class="cls_011">;</span><span class="cls_018"> Levi-Setti et al., 2016</span><span class="cls_011">;</span><span class="cls_018"> Grifo and Noyes, 2010</span><span class="cls_011">).</span></div>
<div style="position:absolute;left:314.65px;top:596.80px" class="cls_011"><span class="cls_011">cycle (RR = 0.94, 95% CI: 0.81-1.10; P = 0.457; eight studies; 526</span></div>
<div style="position:absolute;left:314.65px;top:607.43px" class="cls_011"><span class="cls_011">and 892 cycles, vitrification versus fresh, respectively; I</span><span class="cls_016"><sup>2</sup></span></div>
<div style="position:absolute;left:529.57px;top:608.82px" class="cls_011"><span class="cls_011">= 22.9%,</span></div>
<div style="position:absolute;left:314.64px;top:620.84px" class="cls_011"><span class="cls_011">very low quality evidence) (</span><span class="cls_018">Sole et al., 2013</span><span class="cls_011">;</span><span class="cls_018"> Antinori et al., 2007</span><span class="cls_011">;</span></div>
<div style="position:absolute;left:45.35px;top:624.82px" class="cls_002"><span class="cls_002">Oocyte slow-freezing versus fresh oocytes:</span></div>
<div style="position:absolute;left:314.65px;top:632.80px" class="cls_018"><span class="cls_018">Almodin et al., 2010</span><span class="cls_011">;</span><span class="cls_018"> Rienzi et al., 2010</span><span class="cls_011">;</span><span class="cls_018"> Ubaldi et al., 2010</span><span class="cls_011">;</span><span class="cls_018"> Garcia</span></div>
<div style="position:absolute;left:45.35px;top:638.82px" class="cls_002"><span class="cls_002">clinical outcomes</span></div>
<div style="position:absolute;left:314.65px;top:644.82px" class="cls_018"><span class="cls_018">et al., 2011</span><span class="cls_011">;</span><span class="cls_018"> Parmegiani et al., 2011</span><span class="cls_011">;</span><span class="cls_018"> Trokoudes et al., 2011</span><span class="cls_011">); CPR</span></div>
<div style="position:absolute;left:45.35px;top:656.84px" class="cls_011"><span class="cls_011">Analyses of the cohort studies (</span><span class="cls_018">Chamayou et al., 2006</span><span class="cls_011">;</span><span class="cls_018"> Borini et al.,</span></div>
<div style="position:absolute;left:314.65px;top:656.84px" class="cls_011"><span class="cls_011">per transfer (RR = 0.97, 95% CI: 0.81-1.16; P = 0.714; seven st-</span></div>
<div style="position:absolute;left:45.35px;top:668.80px" class="cls_018"><span class="cls_018">2010</span><span class="cls_011">;</span><span class="cls_018"> Virant-Klun et al., 2011</span><span class="cls_011">) in which sibling oocytes were not ran-</span></div>
<div style="position:absolute;left:314.65px;top:668.80px" class="cls_011"><span class="cls_011">udies,</span></div>
<div style="position:absolute;left:339.44px;top:668.80px" class="cls_011"><span class="cls_011">477 and 754 transfers, vitrification versus fresh, respectively;</span></div>
<div style="position:absolute;left:45.35px;top:680.82px" class="cls_011"><span class="cls_011">domized to be slow-frozen or used fresh revealed lower LBRs per</span></div>
<div style="position:absolute;left:314.64px;top:680.82px" class="cls_011"><span class="cls_011">I</span><span class="cls_016">2</span><span class="cls_011"> = 38.1%, very low quality evidence) (</span><span class="cls_018">Sole et al., 2013</span><span class="cls_011">; </span><span class="cls_018">Antinori et al.,</span></div>
<div style="position:absolute;left:45.35px;top:692.79px" class="cls_011"><span class="cls_011">cycle with slow-freezing (RR = 0.49, 95% CI: 0.39-0.60; P < 0.0001;</span></div>
<div style="position:absolute;left:314.65px;top:692.84px" class="cls_018"><span class="cls_018">2007</span><span class="cls_011">;</span><span class="cls_018"> Almodin et al., 2010</span><span class="cls_011">;</span><span class="cls_018"> Ubaldi et al., 2010</span><span class="cls_011">;</span><span class="cls_018"> Garcia et al., 2011</span><span class="cls_011">;</span></div>
<div style="position:absolute;left:45.35px;top:703.47px" class="cls_011"><span class="cls_011">three studies; 990 and 2271 cycles; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 0.0%, very low quality evi-</span></div>
<div style="position:absolute;left:314.65px;top:704.80px" class="cls_018"><span class="cls_018">Parmegiani et al., 2011</span><span class="cls_011">;</span><span class="cls_018"> Trokoudes et al., 2011</span><span class="cls_011">); and CPR per oocyte</span></div>
<div style="position:absolute;left:45.35px;top:716.82px" class="cls_011"><span class="cls_011">dence)</span></div>
<div style="position:absolute;left:78.58px;top:716.82px" class="cls_011"><span class="cls_011">(</span><A HREF="http://humupd.oxfordjournals.org/lookup/suppl/doi:10.1093/humupd/dmw038/-/DC1">Supplementary Fig. S1a</A>), lower LBRs per transfer</div>
<div style="position:absolute;left:314.65px;top:716.82px" class="cls_011"><span class="cls_011">utilized (RR = 1.16, 95% CI: 0.57-2.69; P = 0.654; six studies; 1759</span></div>
<div style="position:absolute;left:45.35px;top:728.79px" class="cls_011"><span class="cls_011">(RR = 0.55, 95% CI: 0.44-0.68; P < 0.0001; three studies; 799 and</span></div>
<div style="position:absolute;left:314.65px;top:727.45px" class="cls_011"><span class="cls_011">and 3832 oocytes, vitrification versus fresh, respectively; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 89.5%,</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:6222px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background09.jpg" width=612 height=790></div>
<div style="position:absolute;left:48.19px;top:26.63px" class="cls_014"><span class="cls_014">Slow-freezing versus vitrification in ART</span></div>
<div style="position:absolute;left:550.66px;top:25.13px" class="cls_013"><span class="cls_013">147</span></div>
<div style="position:absolute;left:56.18px;top:627.36px" class="cls_020"><span class="cls_020">Figure 2</span><span class="cls_014"> Comparison of slow-freezing versus vitrification: oocytes. (a) Comparison based on CPR/cycle for oocytes: RCT; (b) Comparison based</span></div>
<div style="position:absolute;left:56.18px;top:638.86px" class="cls_014"><span class="cls_014">on CPR/cycle for oocytes: cohort studies; (c) Comparison based on oocyte cryosurvival rate: RCTs. CPR, clinical pregnancy rate.</span></div>
<div style="position:absolute;left:48.19px;top:680.82px" class="cls_011"><span class="cls_011">very low quality evidence) (</span><span class="cls_018">Antinori et al., 2007</span><span class="cls_011">;</span><span class="cls_018"> Almodin et al., 2010</span><span class="cls_011">;</span></div>
<div style="position:absolute;left:317.48px;top:679.86px" class="cls_002"><span class="cls_002">Embryo slow-freezing versus vitrification</span></div>
<div style="position:absolute;left:48.19px;top:692.79px" class="cls_018"><span class="cls_018">Ubaldi et al.,</span></div>
<div style="position:absolute;left:102.61px;top:692.79px" class="cls_018"><span class="cls_018">2010</span><span class="cls_011">;</span><span class="cls_018"> Garcia et al.,</span></div>
<div style="position:absolute;left:182.32px;top:692.79px" class="cls_018"><span class="cls_018">2011</span><span class="cls_011">;</span><span class="cls_018"> Parmegiani et al.,</span></div>
<div style="position:absolute;left:277.45px;top:692.79px" class="cls_018"><span class="cls_018">2011</span><span class="cls_011">;</span></div>
<div style="position:absolute;left:317.48px;top:698.87px" class="cls_013"><span class="cls_013">Slow-freezing versus vitrification: CPR</span></div>
<div style="position:absolute;left:48.19px;top:704.80px" class="cls_018"><span class="cls_018">Trokoudes et al., 2011</span><span class="cls_011">). Each utilized vitrified oocyte had an 8.36%</span></div>
<div style="position:absolute;left:317.48px;top:712.86px" class="cls_011"><span class="cls_011">Given the limited number of RCTs available, results obtained in three</span></div>
<div style="position:absolute;left:48.19px;top:716.82px" class="cls_011"><span class="cls_011">(147/1759) likelihood of resulting in a pregnancy in the population of</span></div>
<div style="position:absolute;left:317.48px;top:724.87px" class="cls_011"><span class="cls_011">RCTs with slow-freezing/thawing versus vitrification/warming for</span></div>
<div style="position:absolute;left:48.19px;top:728.79px" class="cls_011"><span class="cls_011">women studied.</span></div>
</div>
<div style="position:absolute;left:50%;margin-left:-306px;top:7022px;width:612px;height:790px;border-style:outset;overflow:hidden">
<div style="position:absolute;left:0px;top:0px">
<img src="fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_id_fb5b0bf6-a85c-11eb-8b25-0cc47a792c0a_files/background10.jpg" width=612 height=790></div>
<div style="position:absolute;left:45.35px;top:25.13px" class="cls_013"><span class="cls_013">148</span></div>
<div style="position:absolute;left:525.71px;top:26.63px" class="cls_014"><span class="cls_014">Rienzi et al.</span></div>
<div style="position:absolute;left:45.35px;top:56.80px" class="cls_011"><span class="cls_011">cleavage-stage embryos and blastocysts (</span><span class="cls_018">Kim et al., 2000</span><span class="cls_011">;</span><span class="cls_018"> Rama Raju</span></div>
<div style="position:absolute;left:314.65px;top:56.80px" class="cls_018"><span class="cls_018">Li et al.,</span></div>
<div style="position:absolute;left:351.55px;top:56.80px" class="cls_018"><span class="cls_018">2007</span><span class="cls_011">;</span><span class="cls_018"> Rezazadeh Valojerdi et al., 2009</span><span class="cls_011">;</span><span class="cls_018"> Wilding et al.,</span></div>
<div style="position:absolute;left:45.35px;top:68.82px" class="cls_018"><span class="cls_018">et al., 2005</span><span class="cls_011">;</span><span class="cls_018"> Debrock et al., 2015</span><span class="cls_011">) were pooled. Overall, 638 warming/</span></div>
<div style="position:absolute;left:314.64px;top:68.82px" class="cls_018"><span class="cls_018">2010</span><span class="cls_011">;</span><span class="cls_018"> Sifer et al., 2012</span><span class="cls_011">;</span><span class="cls_018"> Wang et al., 2012</span><span class="cls_011">;</span><span class="cls_018"> Liu et al., 2013</span><span class="cls_011">;</span><span class="cls_018"> Van</span></div>
<div style="position:absolute;left:45.35px;top:80.79px" class="cls_011"><span class="cls_011">thawing cycles (vitrification: n</span></div>
<div style="position:absolute;left:156.02px;top:80.79px" class="cls_011"><span class="cls_011">= 247; slow-freezing: n = 391) were</span></div>
<div style="position:absolute;left:314.65px;top:80.79px" class="cls_018"><span class="cls_018">Landuyt et al., 2013</span><span class="cls_011">;</span><span class="cls_018"> Zhu et al., 2015</span><span class="cls_011">;</span><span class="cls_018"> Kaartinen et al., 2016</span><span class="cls_011">), there</span></div>
<div style="position:absolute;left:45.35px;top:92.80px" class="cls_011"><span class="cls_011">included. Data from pronuclear-stage warming cycles were not available.</span></div>
<div style="position:absolute;left:314.65px;top:92.80px" class="cls_011"><span class="cls_011">was no statistically significant difference in CPR per cycle or CPR</span></div>
<div style="position:absolute;left:45.35px;top:104.82px" class="cls_011"><span class="cls_011">A higher CPR per cycle was obtained with embryo vitrification com-</span></div>
<div style="position:absolute;left:314.65px;top:104.82px" class="cls_011"><span class="cls_011">per transfer with vitrification compared with slow-freezing</span></div>
<div style="position:absolute;left:45.35px;top:116.78px" class="cls_011"><span class="cls_011">pared with slow-freezing though this was of borderline statistical signifi-</span></div>
<div style="position:absolute;left:314.65px;top:116.79px" class="cls_011"><span class="cls_011">(RR = 1.27, 95% CI: 1.00-1.55; P = 0.62; six observational stud-</span></div>
<div style="position:absolute;left:45.35px;top:128.80px" class="cls_011"><span class="cls_011">cance (RR = 1.89, 95% CI: 1.00-3.58; P = 0.051, 638 cycles, three</span></div>
<div style="position:absolute;left:314.65px;top:128.80px" class="cls_011"><span class="cls_011">ies;</span></div>
<div style="position:absolute;left:332.66px;top:128.80px" class="cls_011"><span class="cls_011">7789</span></div>
<div style="position:absolute;left:357.05px;top:127.42px" class="cls_011"><span class="cls_011">cycles; I</span><span class="cls_016"><sup>2</sup></span></div>
<div style="position:absolute;left:398.55px;top:128.80px" class="cls_011"><span class="cls_011">= 78.8%, very low quality evidence and</span></div>
<div style="position:absolute;left:45.35px;top:139.44px" class="cls_011"><span class="cls_011">RCTs; I</span><span class="cls_016"><sup>2</sup></span><span class="cls_011"> = 71.9%, low quality evidence, Fig.</span><span class="cls_018"> 3</span><span class="cls_011">a). However, a significant</span></div>
<div style="position:absolute;left:314.64px;top:140.82px" class="cls_011"><span class="cls_011">RR = 1.05, 95% CI: 0.95-1.16; P = 0.33; 10 observational studies;</span></div>
<div style="position:absolute;left:45.35px;top:152.79px" class="cls_011"><span class="cls_011">difference in favor of vitrification was observed when CPR per embryo</span></div>
<div style="position:absolute;left:314.64px;top:151.45px" class="cls_011"><span class="cls_011">17448 embryo transfers; I</span><span class="cls_016"><sup>2</sup></span></div>
<div style="position:absolute;left:427.58px;top:152.79px" class="cls_011"><span class="cls_011">= 67%; very low quality evidence,</span></div>
<div style="position:absolute;left:45.35px;top:164.80px" class="cls_011"><span class="cls_011">transfer was calculated (RR = 1.51, 95% CI: 1.03-2.23; P =</span></div>