Editing Embryo transfer

{{Short description|Method of assisted reproduction}}
{{Use dmy dates|date=September 2016}}
{{Infobox interventions |
  Name        = Embryo transfer 123 |
  Image       = Embryo, 8 cells.jpg |
  Caption     = 8-cell embryo for transfer 3 days after fertilization |
  ICD10       = |
  ICD9unlinked = |
  MeshID      = D004624 |
  OPS301      = |
  OtherCodes  = |
}}
'''Embryo transfer''' refers to a step in the process of [[Assisted reproductive technology|assisted reproduction]] in which [[embryo]]s are placed into the [[uterus]] of a female with the intent to establish a [[Pregnancy (mammals)|pregnancy]]. This technique - which is often used in connection with [[in vitro fertilization]] (IVF) - may be used in humans or in other animals, in which situations and goals may vary.

Embryo transfer can be done at day two or day three, or later in the [[blastocyst]] stage, which was first performed in 1984.<ref>{{cite journal | vauthors = Cohen J, Simons RF, Fehilly CB, Fishel SB, Edwards RG, Hewitt J, Rowlant GF, Steptoe PC, Webster JM | title = Birth after replacement of hatching blastocyst cryopreserved at expanded blastocyst stage | journal = Lancet | volume = 1 | issue = 8429 | pages = 647 | date = March 1985 | pmid = 2857991 | doi = 10.1016/s0140-6736(85)92194-4 | s2cid = 32746730 }}</ref>

Factors that can affect the success of embryo transfer include the endometrial receptivity, embryo quality, and embryo transfer technique.

== Fresh versus frozen ==
Embryos can be either "fresh" from fertilized egg cells of the same [[menstrual cycle]], or "frozen", that is they have been generated in a preceding cycle and undergone [[embryo cryopreservation]], and are thawed just prior to the transfer, which is then termed "frozen embryo transfer" (FET). The outcome from using cryopreserved embryos has uniformly been positive with no increase in birth defects or development abnormalities,<ref>{{cite web|url=http://www.givf.com/fertility/embryofreezing.cfm |archive-url=https://archive.today/20121206043620/http://www.givf.com/fertility/embryofreezing.shtml |archive-date=6 December 2012 |title=Genetics & IVF Institute |publisher=Givf.com |url-status=dead |access-date=22 September 2016 |df=dmy }}</ref> also between fresh versus frozen eggs used for [[intracytoplasmic sperm injection]] (ICSI).<ref name=Wennerholm2009>{{cite journal | vauthors = Wennerholm UB, Söderström-Anttila V, Bergh C, Aittomäki K, Hazekamp J, Nygren KG, Selbing A, Loft A | title = Children born after cryopreservation of embryos or oocytes: a systematic review of outcome data | journal = Human Reproduction | volume = 24 | issue = 9 | pages = 2158–72 | date = September 2009 | pmid = 19458318 | doi = 10.1093/humrep/dep125 | doi-access = free }}</ref> In fact, [[pregnancy rate]]s are increased following FET, and perinatal outcomes are less affected, compared to embryo transfer in the same cycle as [[controlled ovarian hyperstimulation|ovarian hyperstimulation]] was performed.<ref name="EvansHannan2014">{{cite journal | vauthors = Evans J, Hannan NJ, Edgell TA, Vollenhoven BJ, Lutjen PJ, Osianlis T, Salamonsen LA, Rombauts LJ | title = Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence | journal = Human Reproduction Update | volume = 20 | issue = 6 | pages = 808–21 | date = 2014 | pmid = 24916455 | doi = 10.1093/humupd/dmu027 | doi-access = free }}</ref> The [[endometrium]] is believed to not be optimally prepared for [[Implantation (human embryo)|implantation]] following ovarian hyperstimulation, and therefore frozen embryo transfer avails for a separate cycle to focus on optimizing the chances of successful implantation.<ref name="EvansHannan2014" /> Children born from [[Vitrification in cryopreservation|vitrified]] [[blastocysts]] have significantly higher [[birthweight]] than those born from non-frozen blastocysts.<ref>{{cite journal | vauthors = Wikland M, Hardarson T, Hillensjö T, Westin C, Westlander G, Wood M, Wennerholm UB | title = Obstetric outcomes after transfer of vitrified blastocysts | journal = Human Reproduction | volume = 25 | issue = 7 | pages = 1699–707 | date = July 2010 | pmid = 20472913 | doi = 10.1093/humrep/deq117 | doi-access = free }}</ref> When transferring a frozen-thawed oocyte, the chance of pregnancy is essentially the same whether it is transferred in a natural cycle or one with [[ovulation induction]].<ref name=Farquhar2014 />

There is probably little or no difference between FET and fresh embryo transfers in terms of live birth rate and ongoing pregnancy rate and the risk of [[ovarian hyperstimulation syndrome]] may be less using the "freeze all" strategy.<ref name=":0">{{Cite journal|last1=Zaat|first1=Tjitske|last2=Zagers|first2=Miriam|last3=Mol|first3=Femke|last4=Goddijn|first4=Mariëtte|last5=van Wely|first5=Madelon|last6=Mastenbroek|first6=Sebastiaan|date=2021-02-04|title=Fresh versus frozen embryo transfers in assisted reproduction|journal=The Cochrane Database of Systematic Reviews|volume=2021|issue=2|pages=CD011184|doi=10.1002/14651858.CD011184.pub3|issn=1469-493X|pmid=33539543|pmc=8095009}}</ref> The risk of having a large-for-gestational-age baby and higher birth rate, in addition to [[maternal hypertensive disorders]] of pregnancy may be increased using a "freeze all" strategy.<ref name=":0" /> 

== Uterine preparation ==
In the human, the uterine lining ([[endometrium]]) needs to be appropriately prepared so that the embryo can implant. In a natural cycle the embryo transfer takes place in the [[luteal phase]] at a time where the lining is appropriately undeveloped in relation to the status of the present Luteinizing Hormone. In a stimulated or cycle where a "frozen" embryo is transferred, the recipient woman could be given first estrogen preparations (about 2 weeks), then a combination of [[estrogen]] and [[progesterone]] so that the lining becomes receptive for the embryo. The time of receptivity is the [[Implantation (human embryo)|implantation window]]. A [[scientific review]] in 2013 came to the conclusion that it is not possible to identify one method of endometrium preparation in frozen embryo transfer as being more effective than another.<ref>{{cite journal | vauthors = Groenewoud ER, Cantineau AE, Kollen BJ, Macklon NS, Cohlen BJ | title = What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis | journal = Human Reproduction Update | volume = 19 | issue = 5 | pages = 458–70 | year = 2013 | pmid = 23820515 | doi = 10.1093/humupd/dmt030 }}</ref>

Limited evidence also supports removal of [[cervical mucus]] before transfer.<ref name=mains>{{cite journal | vauthors = Mains L, Van Voorhis BJ | title = Optimizing the technique of embryo transfer | journal = Fertility and Sterility | volume = 94 | issue = 3 | pages = 785–90 | date = August 2010 | pmid = 20409543 | doi = 10.1016/j.fertnstert.2010.03.030 }}</ref>

== Timing ==
Embryo transfer can be performed after various durations of [[embryo culture]], conferring different stages in [[human embryogenesis|embryogenesis]]. The main stages at which embryo transfer is performed are [[human embryogenesis|cleavage stage]] (day 2 to 4 after [[co-incubation]]) or the [[blastocyst]] stage (day 5 or 6 after [[co-incubation]]).<ref name="DarLazer2014">{{cite journal | vauthors = Dar S, Lazer T, Shah PS, Librach CL | title = Neonatal outcomes among singleton births after blastocyst versus cleavage stage embryo transfer: a systematic review and meta-analysis | journal = Human Reproduction Update | volume = 20 | issue = 3 | pages = 439–48 | date = 2014 | pmid = 24480786 | doi = 10.1093/humupd/dmu001 | doi-access = free }}</ref>

Because in vivo, a cleavage stage embryo still resides in the fallopian tube and it is known that the nutritional environment of the uterus is different from that of the tube, it is postulated that this may cause stress on the embryo if transferred on day 3 resulting in reduced implantation potential. A blastocyst stage embryo does not have this problem as it is best suited for the uterine environment  [https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD002118.pub5/full]

Embryos who reach the day 3 cell stage can be tested for chromosomal or specific genetic defects prior to possible transfer by [[preimplantation genetic diagnosis]] (PGD). Transferring at the blastocyst stage confers a significant increase in [[live birth rate]] per transfer, but also confers a decreased number of embryos available for transfer and [[embryo cryopreservation]], so the cumulative clinical pregnancy rates are increased with cleavage stage transfer.<ref name="Farquhar2014">{{cite journal | vauthors = Farquhar C, Rishworth JR, Brown J, Nelen WL, Marjoribanks J | title = Assisted reproductive technology: an overview of Cochrane reviews | journal = The Cochrane Database of Systematic Reviews | issue = 12 | pages = CD010537 | date = December 2014 | pmid = 25532533 | doi = 10.1002/14651858.CD010537.pub3 | editor1-last = Brown | editor1-first = Julie | hdl = 2292/26680 | hdl-access = free }}</ref>{{Update inline|reason=Updated version https://www.ncbi.nlm.nih.gov/pubmed/26174592|date = November 2018}} It is uncertain whether there is any difference in [[live birth rate]] between transfer on day two or day three after fertilization.<ref name="auto">{{cite journal |last1=Farquhar |first1=C |last2=Marjoribanks |first2=J |title=Assisted reproductive technology: an overview of Cochrane Reviews. |journal=Cochrane Database of Systematic Reviews |date=17 August 2018 |volume=2018 |issue=8 |pages=CD010537 |doi=10.1002/14651858.CD010537.pub5 |pmid=30117155|pmc=6953328 }}</ref>

[[Monozygotic twinning]] is not increased after blastocyst transfer compared with [[cleavage-stage embryo]] transfer.<ref>{{cite journal | vauthors = Papanikolaou EG, Fatemi H, Venetis C, Donoso P, Kolibianakis E, Tournaye H, Tarlatzis B, Devroey P | title = Monozygotic twinning is not increased after single blastocyst transfer compared with single cleavage-stage embryo transfer | journal = Fertility and Sterility | volume = 93 | issue = 2 | pages = 592–7 | date = February 2010 | pmid = 19243755 | doi = 10.1016/j.fertnstert.2008.12.088 | doi-access = free }}</ref>

There is a significantly higher odds of [[preterm birth]] ([[odds ratio]] 1.3) and [[congenital anomalies]] ([[odds ratio]] 1.3) among births having reached the blastocyst stage compared with cleavage stage.<ref name="DarLazer2014" /> Because of increased female embryo mortality due to epigenetic modifications induced by extended culture,<ref>{{Cite journal | doi=10.1073/pnas.1523538113| pmid=26951653| pmc=4812732| title=Impaired imprinted X chromosome inactivation is responsible for the skewed sex ratio following in vitro fertilization| journal=Proceedings of the National Academy of Sciences| volume=113| issue=12| pages=3197–3202| year=2016| last1=Tan| first1=Kun| last2=An| first2=Lei| last3=Miao| first3=Kai| last4=Ren| first4=Likun| last5=Hou| first5=Zhuocheng| last6=Tao| first6=Li| last7=Zhang| first7=Zhenni| last8=Wang| first8=Xiaodong| last9=Xia| first9=Wei| last10=Liu| first10=Jinghao| last11=Wang| first11=Zhuqing| last12=Xi| first12=Guangyin| last13=Gao| first13=Shuai| last14=Sui| first14=Linlin| last15=Zhu| first15=De-Sheng| last16=Wang| first16=Shumin| last17=Wu| first17=Zhonghong| last18=Bach| first18=Ingolf| last19=Chen| first19=Dong-bao| last20=Tian| first20=Jianhui| bibcode=2016PNAS..113.3197T| doi-access=free}}</ref> blastocyst transfer leads to more male births (56.1% male) versus 2 or 3 day transfer (a normal sex ratio of 51.5% male).

== Embryo selection ==
{{Further|Embryo quality}}
Laboratories have developed grading methods to judge oocyte and [[embryo]] quality. In order to optimise [[pregnancy rate]]s, there is significant evidence that a morphological scoring system is the best strategy for the selection of embryos.<ref name=Rebmann>{{cite journal | vauthors = Rebmann V, Switala M, Eue I, Grosse-Wilde H | title = Soluble HLA-G is an independent factor for the prediction of pregnancy outcome after ART: a German multi-centre study | journal = Human Reproduction | volume = 25 | issue = 7 | pages = 1691–8 | date = July 2010 | pmid = 20488801 | doi = 10.1093/humrep/deq120 | doi-access = free }}</ref> Since 2009 where the first [[time-lapse microscopy]] system for IVF was approved for clinical use, morphokinetic scoring systems has shown to improve to [[pregnancy rate]]s further.<ref name="Meseguer">{{cite journal | vauthors = Meseguer M, Rubio I, Cruz M, Basile N, Marcos J, Requena A | title = Embryo incubation and selection in a time-lapse monitoring system improves pregnancy outcome compared with a standard incubator: a retrospective cohort study | journal = Fertility and Sterility | volume = 98 | issue = 6 | pages = 1481–9.e10 | date = December 2012 | pmid = 22975113 | doi = 10.1016/j.fertnstert.2012.08.016 | doi-access = free }}</ref> However, when all different types of [[time-lapse embryo imaging]] devices, with or without morphokinetic scoring systems, are compared against conventional embryo assessment for IVF, there is insufficient evidence of a difference in live-birth, pregnancy, stillbirth or miscarriage to choose between them.<ref>{{cite journal |last1=Armstrong |first1=S |last2=Bhide |first2=P |last3=Jordan |first3=V |last4=Pacey |first4=A |last5=Marjoribanks |first5=J |last6=Farquhar |first6=C |title=Time-lapse systems for embryo incubation and assessment in assisted reproduction. |journal=The Cochrane Database of Systematic Reviews |date=29 May 2019 |volume=5 |issue=5 |pages=CD011320 |doi=10.1002/14651858.CD011320.pub4 |pmid=31140578|pmc=6539473 }}</ref> A small prospectively randomized study in 2016 reported poorer embryo quality and more staff time in an automated [[time-lapse embryo imaging]] device compared to conventional embryology.<ref>{{cite journal | vauthors = Wu YG, Lazzaroni-Tealdi E, Wang Q, Zhang L, Barad DH, Kushnir VA, Darmon SK, Albertini DF, Gleicher N|author-link9=Norbert Gleicher | title = Different effectiveness of closed embryo culture system with time-lapse imaging (EmbryoScope(TM)) in comparison to standard manual embryology in good and poor prognosis patients: a prospectively randomized pilot study | journal = Reproductive Biology and Endocrinology | volume = 14 | issue = 1 | pages = 49 | date = August 2016 | pmid = 27553622 | pmc = 4995783 | doi = 10.1186/s12958-016-0181-x |doi-access=free }}</ref> Active efforts to develop a more accurate embryo selection analysis based on Artificial Intelligence and Deep Learning are underway. [[Embryo Ranking Intelligent Classification Algorithm]] (ERICA),<ref>{{Cite web | url=https://embryoranking.com/ |title = ERICA Embryo Ranking &#124; Artificial Intelligence for Assisted Reproduction}}</ref> is a clear example.  This Deep Learning software substitutes manual classifications with a ranking system based on an individual embryo's predicted genetic status in a non-invasive fashion.<ref>{{Cite journal | doi=10.1016/j.fertnstert.2019.07.715| title=Artificial vision and machine learning designed to predict PGT-A results| journal=Fertility and Sterility| volume=112| issue=3| pages=e231| year=2019| last1=Chavez-Badiola| first1=Alejandro| last2=Flores-Saiffe Farias| first2=Adolfo| last3=Mendizabal-Ruiz| first3=Gerardo| last4=Drakeley| first4=Andrew J.| last5=Garcia-Sánchez| first5=Rodolfo| last6=Zhang| first6=John J.| doi-access=free}}</ref> Studies on this area are still pending and current feasibility studies support its potential.<ref>{{cite journal |last1=Chavez-Badiola |first1=Alejandro |last2=Flores-Saiffe Farias |first2=Adolfo |last3=Mendizabal-Ruiz |first3=Gerardo |last4=Garcia-Sanchez |first4=Rodolfo |last5=Drakeley |first5=Andrew J. |last6=Garcia-Sandoval |first6=Juan Paulo |title=Predicting pregnancy test results after embryo transfer by image feature extraction and analysis using machine learning |journal=Scientific Reports |date=10 March 2020 |volume=10 |issue=1 |pages=4394 |doi=10.1038/s41598-020-61357-9 |pmid=32157183 |pmc=7064494 |bibcode=2020NatSR..10.4394C }}</ref>

== Procedure ==
The embryo transfer procedure starts by placing a speculum in the vagina to visualize the cervix, which is cleansed with saline solution or culture media.  A transfer catheter is loaded with the embryos and handed to the clinician after confirmation of the patient's identity. The catheter is inserted through the cervical canal and advanced into the uterine cavity.<ref>{{Cite web |url=https://www.youtube.com/watch?v=kvQZA7EWwmk  |archive-url=https://ghostarchive.org/varchive/youtube/20211213/kvQZA7EWwmk |archive-date=2021-12-13 |url-status=live|title=Embryo Transfer |date=25 March 2015 |publisher=Dr. John Jain on Youtube |last=Jain |first=John |access-date=17 December 2015}}{{cbignore}}</ref> Several types of catheters are used for this process, however, there is good evidence that using a soft vs a hard transfer catheter can increase the chances of clinical pregnancy.<ref>{{cite journal |last=Tayler |first=Bede |title=Interventions to optimize embryo transfer in women undergoing assisted conception: a comprehensive systematic review and meta-analyses |journal=Human Reproduction Update |year=2022 |volume=28 |issue=4 |pages=480–500 |doi=10.1093/humupd/dmac009|pmid=35325124 |pmc=9631462 }}</ref>

There is good and consistent evidence of benefit in ''ultrasound guidance'',<ref name=mains /> that is, making an abdominal ultrasound to ensure correct placement, which is 1–2&nbsp;cm from the uterine fundus.<ref>{{Cite journal |journal=Human Reproduction Update |year = 2022|doi=10.1093/humupd/dmac009|pmid = 35325124|last1 = Tyler|first1 = B.|last2 = Walford|first2 = H.|last3 = Tamblyn|first3 = J.|last4 = Keay|first4 = S. D.|last5 = Mavrelos|first5 = D.|last6 = Yasmin|first6 = E.|last7 = Al Wattar|first7 = B. H.|title=Interventions to optimize embryo transfer in women undergoing assisted conception: A comprehensive systematic review and meta-analyses | volume=28 | issue=4 | pages=480–500 | pmc=9631462 }}</ref> There is evidence of a significant increase in clinical pregnancy using ultrasound guidance compared with only "clinical touch", as well as performing the transfer with hyaluronic acid enriched transfer media.<ref name="OUP accepted manuscript">{{Cite journal |date=2022 |title=OUP accepted manuscript |url=https://doi.org/10.1093/humupd/dmac009 |journal=Human Reproduction Update |doi=10.1093/humupd/dmac009 |pmid=35325124 |issn=1355-4786|last1=Tyler |first1=B. |last2=Walford |first2=H. |last3=Tamblyn |first3=J. |last4=Keay |first4=S. D. |last5=Mavrelos |first5=D. |last6=Yasmin |first6=E. |last7=Al Wattar |first7=B. H. |volume=28 |issue=4 |pages=480–500 |pmc=9631462 }}</ref> Anesthesia is generally not required. Single embryo transfers in particular require accuracy and precision in placement within the uterine cavity. The optimal target for embryo placement, known as the maximal implantation potential (MIP) point, is identified using 3D/4D ultrasound.<ref>{{cite journal | vauthors = Gergely RZ, DeUgarte CM, Danzer H, Surrey M, Hill D, DeCherney AH | title = Three dimensional/four dimensional ultrasound-guided embryo transfer using the maximal implantation potential point | journal = Fertility and Sterility | volume = 84 | issue = 2 | pages = 500–3 | date = August 2005 | pmid = 16084896 | doi = 10.1016/j.fertnstert.2005.01.141 | doi-access = free }}.</ref> However, there is limited evidence that supports deposition of embryos in the midportion of the uterus.<ref name=mains /><ref name="OUP accepted manuscript"/>

After insertion of the catheter, the contents are expelled and the embryos are deposited. Limited evidence supports making trial transfers before performing the procedure with embryos.<ref name=mains /> After expulsion, the duration that the catheter remains inside the uterus has no effect on pregnancy rates.<ref>{{cite journal | vauthors = Sroga JM, Montville CP, Aubuchon M, Williams DB, Thomas MA | title = Effect of delayed versus immediate embryo transfer catheter removal on pregnancy outcomes during fresh cycles | journal = Fertility and Sterility | volume = 93 | issue = 6 | pages = 2088–90 | date = April 2010 | pmid = 20116786 | doi = 10.1016/j.fertnstert.2009.07.1664 | doi-access = free }}</ref> Limited evidence suggests avoiding negative pressure from the catheter after expulsion.<ref name=mains /> After withdrawal, the catheter is handed to the embryologist, who inspects it for retained embryos.

In the process of [[zygote intrafallopian transfer]] (ZIFT), eggs are removed from the woman, fertilised, and then placed in the woman's fallopian tubes rather than the uterus.
{{anchor|e-SET}}

== Embryo number ==
A major issue is how many embryos should be transferred, since placement of multiple embryos carries a risk of multiple pregnancy. While the past physicians placed multiple embryos to increase the chance of pregnancy, this approach has fallen out of favor. Professional societies, and legislatures in many countries, have issued guidelines or laws to curtail the practice.<ref>{{cite web|url=http://www.newlife-ivf.co.uk/blog/ivf-laws-in-greece-2014.php |title=New Law regarding the number of embryos transferred in Greece |publisher=newlife-ivf.co.uk |date=22 December 2014}}</ref> There is low to moderate evidence that making a double embryo transfer during one cycle achieves a higher live birth rate than a single embryo transfer; but making two single embryo transfers in two cycles has the same live birth rate and would avoid multiple pregnancies.<ref>{{Cite journal|title=Number of embryos for transfer following in vitro fertilisation or intra-cytoplasmic sperm injection|vauthors=Kamath MS, Mascarenhas M, Kirubakaran R, Bhattacharya S|journal=Cochrane Database of Systematic Reviews|year=2020|volume=2020|issue=8 |pages=CD003416|publisher=Cochrane Database Syst Rev.|publication-date=21 August 2020|doi=10.1002/14651858.CD003416.pub5|pmid=32827168|pmc=8094586}}</ref>

The appropriate number of embryos to be transferred depends on the age of the woman, whether it is the first, second or third full IVF cycle attempt and whether there are top-quality embryos available. According to a guideline from The [[National Institute for Health and Care Excellence]] (NICE) in 2013, the number of embryos transferred in a cycle should be chosen as in following table:<ref name="nice2013">[http://guidance.nice.org.uk/CG156 Fertility: assessment and treatment for people with fertility problems]. [[NICE guidelines|NICE clinical guideline]] CG156 – Issued: February 2013</ref>

{|class="wikitable"
! Age !! Attempt No. !! Embryos transferred
|-
|rowspan=3| <37 years || 1st || 1
|-
| 2nd || 1 if top-quality
|-
| 3rd || No more than 2
|-
|rowspan=3| 37–39 years ||rowspan=2| 1st & 2nd || 1 if top-quality
|-
| 2 if no top-quality
|-
| 3rd || No more than 2
|-
| 40–42 years ||  || 2
|}

=== e-SET<!--'Elective-single embryo transfer', 'Elective-Single Embryo Transfer', 'E-SET' redirect here--> ===
{{Redirect|e-SET|the mathematical concept|E-set}}
The technique of selecting only one embryo to transfer to the woman is called '''elective-single embryo transfer'''<!--boldface per WP:R#PLA--> ('''e-SET'''<!--boldface per WP:R#PLA-->) or, when embryos are at the blastocyst stage, it can also be called ''elective single blastocyst transfer (eSBT)''.<ref name=mullin>{{cite journal | vauthors = Mullin CM, Fino ME, Talebian S, Krey LC, Licciardi F, Grifo JA | title = Comparison of pregnancy outcomes in elective single blastocyst transfer versus double blastocyst transfer stratified by age | journal = Fertility and Sterility | volume = 93 | issue = 6 | pages = 1837–43 | date = April 2010 | pmid = 19249756 | doi = 10.1016/j.fertnstert.2008.12.137 | doi-access = free }}</ref> It significantly lowers the risk of multiple pregnancies, compared with e.g. Double Embryo Transfer (DET) or ''double blastocyst transfer'' (2BT), with a twinning rate of approximately 3.5% in sET compared with approximately 38% in DET,<ref name=Fauque>{{cite journal | vauthors = Fauque P, Jouannet P, Davy C, Guibert J, Viallon V, Epelboin S, Kunstmann JM, Patrat C | title = Cumulative results including obstetrical and neonatal outcome of fresh and frozen-thawed cycles in elective single versus double fresh embryo transfers | journal = Fertility and Sterility | volume = 94 | issue = 3 | pages = 927–35 | date = August 2010 | pmid = 19446806 | doi = 10.1016/j.fertnstert.2009.03.105 }}</ref> or 2% in eSBT compared with approximately 25% in 2BT.<ref name=mullin /> At the same time, [[pregnancy rate]]s is not significantly less with eSBT than with 2BT.<ref name=mullin /> That is, the cumulative live birth rate associated with single fresh embryo transfer followed by a single frozen and thawed embryo transfer is comparable with that after one cycle of double fresh embryo transfer.<ref name="auto" /> Furthermore, SET has better outcomes in terms of mean gestational age at delivery, mode of delivery, birthweight, and risk of [[neonatal intensive care unit]] necessity than DET.<ref name=Fauque /> e-SET of embryos at the cleavage stage reduces the likelihood of live birth by 38% and multiple birth by 94%.<ref name=gelbaya>{{cite journal | vauthors = Gelbaya TA, Tsoumpou I, Nardo LG | title = The likelihood of live birth and multiple birth after single versus double embryo transfer at the cleavage stage: a systematic review and meta-analysis | journal = Fertility and Sterility | volume = 94 | issue = 3 | pages = 936–45 | date = August 2010 | pmid = 19446809 | doi = 10.1016/j.fertnstert.2009.04.003 }}</ref> Evidence from randomized, controlled trials suggests that increasing the number of e-SET attempts (fresh and/or frozen) results in a cumulative live birth rate similar to that of DET.<ref name=gelbaya />

The usage of single embryo transfer is highest in Sweden (69.4%), but as low as 2.8% in the USA. Access to public funding for ART, availability of good [[cryopreservation]] facilities, effective education about the risks of multiple pregnancy, and legislation appear to be the most important factors for regional usage of single embryo transfer.<ref name=Maheshwari2011>{{cite journal | vauthors = Maheshwari A, Griffiths S, Bhattacharya S | title = Global variations in the uptake of single embryo transfer | journal = Human Reproduction Update | volume = 17 | issue = 1 | pages = 107–20 | year = 2010 | pmid = 20634207 | doi = 10.1093/humupd/dmq028 | doi-access = free }}</ref> Also, personal choice plays a significant role as many subfertile couples have a strong preference for twins.<ref name=Maheshwari2011 />

== Adjunctive procedures ==
It is uncertain whether the use of mechanical closure of the cervical canal following embryo transfer has any effect.<ref name="Farquhar_2018">{{cite journal |last1=Farquhar |first1=C |last2=Marjoribanks |first2=J |title=Assisted reproductive technology: an overview of Cochrane Reviews. |journal=The Cochrane Database of Systematic Reviews |date=17 August 2018 |volume=2018 |issue=8 |pages=CD010537 |doi=10.1002/14651858.CD010537.pub5 |pmid=30117155|pmc=6953328 }}</ref>

There is considerable evidence that prolonges bed rest (more than 20 minutes) after embryo transfer is associated with reduced chances of clinical pregnancy.<ref>{{cite journal |last=Tyler |first=Bede |title=Interventions to optimize embryo transfer in women undergoing assisted conception: a comprehensive systematic review and meta-analyses |journal=Human Reproduction Update |year=2022 |volume=28 |issue=4 |pages=480–500 |doi=10.1093/humupd/dmac009|pmid=35325124 |pmc=9631462 }}</ref>

Using [[hyaluronic acid]] as an adherence medium for the embryo may increase live birth rates.<ref name="Farquhar_2018" /> There may be little or no benefit in having a full bladder, removal of cervical mucus, or flushing of the endometrial or endocervical cavity at the time of embryo transfer.<ref name="Farquhar_2018" /> Adjunctive antibiotics in the form of [[amoxicillin]] plus [[clavulanic acid]] probably does not increase the clinical pregnancy rate compared with no antibiotics.<ref name="Farquhar_2018" /> The use of Atosiban, G-CSF and hCG around the time of embryo transfer showed a trend towards increased clinical pregnancy rate.<ref>{{cite journal |last=Tyler |first=Bede |title=Interventions to optimize embryo transfer in women undergoing assisted conception: a comprehensive systematic review and meta-analyses |journal=Human Reproduction Update |year=2022 |volume=28 |issue=4 |pages=480–500 |doi=10.1093/humupd/dmac009 |pmid=35325124 |pmc=9631462 }}</ref>

For frozen-thawed embryo transfer or transfer of embryo from [[egg donation]], no previous [[Controlled ovarian hyperstimulation|ovarian hyperstimulation]] is required for the recipient before transfer, which can be performed in spontaneous ovulatory cycles. Still, various protocols exist for frozen-thawed embryo transfers as well, such as protocols with [[Controlled ovarian hyperstimulation|ovarian hyperstimulation]], protocols in which the endometrium is artificially prepared by [[estrogen]] and/or [[progesterone]]. There is some evidence that in cycles where the endometrium is artificially prepared by estrogen or progesterone, it may be beneficial to administer an additional drug that suppresses hormone production by the ovaries such as continuous administration of a [[gonadotropin releasing hormone agonist]] (GnRHa).<ref>{{cite journal |last1=Ghobara |first1=T |last2=Gelbaya |first2=TA |last3=Ayeleke |first3=RO |title=Cycle regimens for frozen-thawed embryo transfer. |journal=The Cochrane Database of Systematic Reviews |date=5 July 2017 |volume=2017 |issue=7 |pages=CD003414 |doi=10.1002/14651858.CD003414.pub3 |pmid=28675921|pmc=6483463 }}</ref> For [[egg donation]], there is evidence of a lower pregnancy rate and a higher cycle cancellation rate when the progesterone supplementation in the recipient is commenced ''prior'' to [[oocyte retrieval]] from the donor, as compared to commenced day of oocyte retrieval or the day after.<ref name=Farquhar2014 />

[[Semen|Seminal fluid]] contains several proteins that interact with epithelial cells of the [[cervix]] and [[uterus]], inducing active [[gestational immune tolerance]]. There are significantly improved outcomes when women are exposed to seminal plasma around the time of embryo transfer, with statistical significance for [[clinical pregnancy]], but not for ongoing pregnancy or [[live birth rate]]s with the limited data available.<ref name="CrawfordRay2014">{{cite journal | vauthors = Crawford G, Ray A, Gudi A, Shah A, Homburg R | title = The role of seminal plasma for improved outcomes during in vitro fertilization treatment: review of the literature and meta-analysis | journal = Human Reproduction Update | volume = 21 | issue = 2 | pages = 275–84 | date = 2014 | pmid = 25281684 | doi = 10.1093/humupd/dmu052 | doi-access = free }}</ref>

== Follow-up ==
Patients usually start progesterone medication after egg (also called oocyte) retrieval. While daily intramuscular injections of progesterone-in-oil (PIO) have been the standard route of administration, PIO injections are not FDA-approved for use in pregnancy.  A recent meta-analysis showed that the intravaginal route with an appropriate dose and dosing frequency is equivalent to daily intramuscular injections.<ref name="Zarutskiea_2007">{{cite journal | vauthors = Zarutskiea PW, Phillips JA | title = Re-analysis of vaginal progesterone as luteal phase support (LPS) in assisted reproduction (ART) cycles | journal = Fertility and Sterility | volume = 88 | issue = supplement 1 | pages = S113 | date = 2007| doi = 10.1016/j.fertnstert.2007.07.365 | doi-access = free }}</ref> In addition, a recent case-matched study comparing vaginal progesterone with PIO injections showed that live birth rates were nearly identical with both methods.<ref>Khan N, Richter KS, Blake EJ, et al. Case-matched comparison of intramuscular versus vaginal progesterone for luteal phase support after in vitro fertilization and embryo transfer. Presented at: 55th Annual Meeting of the Pacific Coast Reproductive Society; 18–22 April 2007; Rancho Mirage, CA.</ref> A duration of progesterone administration of 11 days results in almost the same [[birth rate]]s as longer durations.<ref>{{cite journal | vauthors = Goudge CS, Nagel TC, Damario MA | title = Duration of progesterone-in-oil support after in vitro fertilization and embryo transfer: a randomized, controlled trial | journal = Fertility and Sterility | volume = 94 | issue = 3 | pages = 946–51 | date = August 2010 | pmid = 19523613 | doi = 10.1016/j.fertnstert.2009.05.003 | doi-access = free }}</ref>

Patients are also given estrogen medication in some cases after the embryo transfer. Pregnancy testing is done typically two weeks after egg retrieval.

== History ==
{{more citations needed|section|date=February 2018}}<!--two paragraphs have no citations-->
The first transfer of an embryo from one human to another resulting in pregnancy was reported in July 1983 and subsequently led to the announcement of the first human birth 3 February 1984.<ref>{{cite news| url=https://query.nytimes.com/gst/fullpage.html?sec=health&res=9404EEDC143BF937A35751C0A962948260 | work=The New York Times |title=Infertile Woman Has Baby Through Embryo Transfer |first=Sandra |last=Blakeslee |date=4 February 1984 |access-date=1 May 2010}}</ref> This procedure was performed at the Harbor UCLA Medical Center <ref>{{cite web |url=http://www.humc.edu/calendar/careacc.html |title=HUMC – Celebrating 50 Years of Caring |work=humc.edu |access-date=18 January 2009 |archive-date=3 March 2016 |archive-url=https://web.archive.org/web/20160303200212/http://www.humc.edu/calendar/careacc.html |url-status=dead }}</ref> under the direction of Dr. [[John Buster]] and the University of California at Los Angeles School of Medicine.

In the procedure, an embryo that was just beginning to develop was transferred from one woman in whom it had been conceived by [[artificial insemination]] to another woman who gave birth to the infant 38 weeks later. The sperm used in the artificial insemination came from the husband of the woman who bore the baby.<ref name="Time">{{cite magazine |url=http://www.time.com/time/magazine/article/0,9171,952517,00.html |archive-url=https://web.archive.org/web/20090216154049/http://www.time.com/time/magazine/article/0,9171,952517,00.html |url-status=dead |archive-date=16 February 2009 |magazine=Time |title=Medicine: A Legal, Moral, Social Nightmare |date=10 September 1984 |first1=Otto |last1=Friedrich |first2=Anne |last2=Constable |first3=Raji |last3=Samghabadi |access-date=1 May 2010}}</ref><ref name="ReferenceA">{{cite magazine |url=http://www.time.com/time/magazine/article/0,9171,952514,00.html |archive-url=https://web.archive.org/web/20050114224526/http://www.time.com/time/magazine/article/0,9171,952514,00.html |url-status=dead |archive-date=14 January 2005 |magazine=Time |title=The New Origins of Life |date=10 September 1984 |access-date=1 May 2010}}</ref>

This scientific breakthrough established standards and became an agent of change for women with infertility and for women who did not want to pass on genetic disorders to their children. Donor embryo transfer has given women a mechanism to become pregnant and give birth to a child that will contain their husband's genetic makeup. Although donor embryo transfer as practiced today has evolved from the original non-surgical method, it now accounts for approximately 5% of in vitro fertilization recorded births.

Prior to this, thousands of women who were [[infertile]], had adoption as the only path to parenthood. This set the stage to allow open and candid discussion of embryo donation and transfer. This breakthrough has given way to the donation of human embryos as a common practice similar to other donations such as blood and major organ donations. At the time of this announcement the event was captured by major news carriers and fueled healthy debate and discussion on this practice which impacted the future of reproductive medicine by creating a platform for further advancements in woman's health.

This work established the technical foundation and legal-ethical framework surrounding the clinical use of human [[oocyte]] and [[embryo donation]], a mainstream clinical practice, which has evolved over the past 25 years.<ref name="Time" /><ref name="ReferenceA" />

== Effectiveness ==
Fresh blastocyst (day 5 to 6) stage transfer seems to be more effective than cleavage (day 2 or 3) stage transfer in [[assisted reproductive technologies]]. The Cochrane study showed a small improvement in live birth rate per couple for blastocyst transfers. This would mean that for a typical rate of 31% in clinics that use early cleavage stage cycles, the rate would increase to 32% to 41% live births if clinics used blastocyst transfer.<ref name="Cochrane">{{cite journal |vauthors=Glujovsky D, Quinteiro Retamar AM, Alvarez Sedo CR, Ciapponi A, Cornelisse S, Blake D |date=May 2022 |title=Cleavage-stage versus blastocyst-stage embryo transfer in assisted reproductive technology |url= |journal=Cochrane Database Syst Rev |volume= 2022|issue= 6|pages= CD002118|doi=10.1002/14651858.CD002118.pub6 |pmid=35588094|pmc=9119424 }}</ref> Recent systematic review showed that along with selection of embryo, the techniques followed during transfer procedure may result in successful pregnancy outcome. The following interventions are supported by the literature for improving pregnancy rates:

•
Abdominal ultrasound guidance for embryo transfer

•
Removal of cervical mucus

•
Use of soft embryo transfer catheters

•
Placement of embryo transfer tip in the upper or middle (central) area of the uterine cavity, greater than 1&nbsp;cm from the fundus, for embryo expulsion

•
Immediate ambulation once the embryo transfer procedure is completed<ref>{{Cite journal |last1=Penzias |first1=Alan |last2=Bendikson |first2=Kristin |last3=Butts |first3=Samantha |last4=Coutifaris |first4=Christos |last5=Falcone |first5=Tommaso |last6=Fossum |first6=Gregory |last7=Gitlin |first7=Susan |last8=Gracia |first8=Clarisa |last9=Hansen |first9=Karl |last10=La Barbera |first10=Andrew |last11=Mersereau |first11=Jennifer |last12=Odem |first12=Randall |last13=Paulson |first13=Richard |last14=Pfeifer |first14=Samantha |last15=Pisarska |first15=Margareta |year=2017 |title=Performing the embryo transfer: a guideline |journal=Fertility and Sterility |language=en |volume=107 |issue=4 |pages=882–896 |doi=10.1016/j.fertnstert.2017.01.025 |pmid=28366416 |doi-access=free}}</ref>

== Embryo transfer in animals ==

Embryo transfer techniques allow top quality female [[livestock]] to have a greater influence on the genetic advancement of a herd or flock in much the same way that [[artificial insemination]] has allowed greater use of superior sires.<ref>[http://jobfunctions.bnet.com/abstract.aspx?docid=118654 Embryo Transfer in Cattle] {{webarchive |url=https://web.archive.org/web/20080514154230/http://jobfunctions.bnet.com/abstract.aspx?docid=118654 |date=14 May 2008 }}. Retrieved 21 October 2008.</ref> ET also allows the continued use of animals such as competition mares to continue training and showing, while producing [[foal]]s. The general epidemiological aspects of embryo transfer indicates that the transfer of embryos provides the opportunity to introduce genetic material into populations of livestock while greatly reducing the risk for transmission of infectious diseases. Recent developments in the sexing of embryos before transfer and implanting has great potential in the dairy and other livestock industries.<ref>[http://www.agnet.org/library/tb/151b/ Embryo Sexing Technology] {{webarchive|url=https://web.archive.org/web/20090302071934/http://www.agnet.org/library/tb/151b/ |date=2 March 2009 }}. Retrieved 21 October 2008.</ref>

Embryo transfer is also used in [[laboratory mice]]. For example, embryos of genetically modified strains that are difficult to breed or expensive to maintain may be stored frozen, and only thawed and implanted into a [[False pregnancy#Mice|pseudopregnant]] dam when needed.

On February 19, 2020, the first pair of Cheetah cubs to be conceived through embryo transfer from a surrogate cheetah mother was born at Columbus Zoo in Ohio.<ref>{{Cite web|url=https://nationalzoo.si.edu/news/first-cheetah-cubs-born-result-embryo-transfer|title=First Cheetah Cubs Born as Result of Embryo Transfer|date=2020-02-24|website=Smithsonian's National Zoo|language=en|access-date=2020-02-25}}</ref>

=== Frozen embryo transfer in animals ===
[[File:Embriões Bovinos.jpg|thumb|Bovine embryos ''in vitro.'']]
The development of various methods of [[cryopreservation]] of [[bovine]] [[embryos]]<ref>{{cite journal |vauthors=Wilmut I, Rowson LE |year=1973 |title=Experiments on the low-temperature preservation of cow embryos |journal=Vet Rec |volume=92 |issue=26 |pages=686–690 |doi=10.1136/vr.92.26.686 |pmid=4730118 |title-link= embryos |doi-broken-date=1 November 2024 |s2cid=46005842 }}</ref><ref>Leibo SP, Mazur P. 1978. Methods for the preservation of mammalian embryos by [[freezing]]. In: Mapletoft. History and [[bovine]] [[embryo]] transfer. Anim. Reprod., v.10, n.3, p.168-173, Jul./Sept. 2013 173</ref> improved embryo transfer technique considerably efficient technology, no longer depending on the immediate readiness of suitable recipients. Pregnancy rates are just slightly less than those achieved with fresh embryos.<ref>Leibo SP, Mapletoft RJ. 1998. Direct transfer of cryopreserved [[cattle]] [[embryos]] in North America. In: Proceedings of the 17th Annual Convention of [[AETA]], 1998, San Antonio, TX. San Antonio, TX: AETA. pp. 91-98.</ref> Recently, the use of [[cryoprotectants]] such as [[ethylene glycol]] has permitted the direct transfer of bovine embryos.<ref>{{cite journal | vauthors = Voelkel SA, Hu YX | year = 1992 | title = Direct transfer of frozen-thawed bovine embryos | journal = Theriogenology | volume = 37 | issue = 3| pages = 23–37 | doi=10.1016/0093-691x(92)90245-m| pmid = 16727070 }}</ref><ref>{{cite journal | vauthors = Hasler JF, Hurtgen PG, Jin ZQ, Stokes JE | year = 1997 | title = Survival of IVF-derived bovine embryos frozen in glycerol or ethylene glycol | journal = Theriogenology | volume = 48 | issue = 4| pages = 563–579 | doi=10.1016/s0093-691x(97)00274-4| pmid = 16728153 }}</ref> The world's first live [[crossbred]] bovine calf produced under [[tropical]] conditions by Direct Transfer (DT) of embryo [[freezing|frozen]] in ethylene glycol freeze media was born on 23 June 1996. Dr. Binoy Sebastian Vettical of Kerala Livestock Development Board Ltd has produced the embryo stored frozen in Ethylene Glycol freeze media by [[slow programmable freezing]] (SPF) technique and transferred directly to recipient [[cattle]] immediately after thawing the frozen straw in water for the birth of this calf. In a study, in vivo produced crossbred bovine embryos stored frozen in ethylene glycol freeze media were transferred directly to recipients under tropical conditions and achieved a pregnancy rate of 50 percent.<ref>Binoy Sebastian Vettical, Kuruvilla Varghese and K.Muraleedharan. [[Cryopreservation]] of [[Embryos]] in [[Ethylene Glycol]] Freeze Media and Direct Transfer in [[Crossbred]] [[Cattle]] in the [[Tropics]], Compendium: 9th International Congress on [[Biotechnology]] in Animal Reproduction</ref> In a survey of the North American embryo transfer industry, embryo transfer success rates from direct transfer of embryos were as good as to those achieved with [[glycerol]].<ref>Leibo SP, Mapletoft RJ. 1998. Direct transfer of [[cryopreserved]] [[cattle]] [[embryos]] in North America. In: Proceedings of the 17th Annual Convention of [[AETA]], 1998, San Antonio, TX. San Antonio, TX: [[AETA]]. pp. 91-98.</ref> Moreover, in 2011, more than 95% of frozen-thawed embryos were transferred by Direct Transfer.<ref>{{cite journal | vauthors = Stroud B | year = 2012 | title = The year 2011 worldwide statistics of embryo transfer in domestic farm animals. | journal = IETS Newslet | volume = 50 | pages = 16–25 }}</ref>

== References ==
{{Reflist}}

== External links ==
*[https://web.archive.org/web/20090425210637/http://www.hfea.gov.uk/543.html How embryo transfer works as part of fertility treatment]
*[https://web.archive.org/web/20090515114718/http://www.hfea.gov.uk/544.html The blastocyst transfer process – a form of embryo transfer]
*{{usurped|1=[https://web.archive.org/web/20080408015939/http://www.oneatatime.org.uk/ One at a time website – benefits of Single Embryo Transfer]}}

{{Assisted reproductive technology}}

[[Category:Fertility medicine]]
[[Category:In vitro fertilisation]]
[[Category:Cryobiology]]
[[Category:Fertility]]
[[Category:Theriogenology]]