To the query, “If the number of embryos transferred is under governance in your country, is there a penalty for violation?” (Table 1), 49 responded. Seventeen of the 49 (35%) indicated there was a penalty; 26 of the 49 (53%) noted that no penalty existed; 4 (8%) responded “unknown”, and one country did not answer.
To the question, “What is the maximum number of embryos allowed to be transferred?” (Table 1), 70 countries had complete answers from respondents, as follows:
- Oocyte age <35: 7 countries=Limited to 1 embryo, 18 countries=2 embryos, 15 countries=3 embryos, 2 countries=4 embryos, 20 countries=not addressed, and 8 countries responded “unknown”;
- Oocyte age 35-39: 5 countries limited to 1 embryo, 13 countries=2 embryos, 21 countries=3 embryos, 2 countries=4 embryos, 21 countries=not addressed, and 6 countries responded “unknown”; and
- Oocytes age >40: 3 countries limited to 1 embryo, 10 countries=2 embryos, 20 countries=3 embryos, 4 countries=4 embryos, 1 country=5 embryos, 2 countries=not addressed, and 6 countries responded “unknown”.
To the question regarding existence of criteria for the number of embryos to be transferred for donor oocyte recipients, 75 countries responded, as follows: “yes”, 28 countries (38%); “no”, 19 countries (25%); “unknown”, 4 countries (5%); and “not addressed”, 24 (32%).
When considering the age of the donor, 76 countries provided responses: 27 countries (35.5%) answered “yes”, 18 answered (24%) “no”, 5 answered (6.5%) “unknown”, and 26 answered (34%) “not addressed”
Regarding the quality of the embryos as a determinant, 78 countries provided responses: 44 countries answered (56%) “yes”, 12 answered (15%) “no”, 3 answered (5%) “unknown”, and 19 answered (24%) “not addressed”.
Regarding the stage of the embryo (cleavage or blastocyst stage), 78 countries provided responses: 45 countries answered (58%) “yes”, 10 answered (13%) “no”, 4 answered (5%) “unknown”, and 19 answered (24%) “not addressed”.
Table 3 lists the countries’ individual policies regarding the number of embryos allowed for transfer.
In 2010, Turkey introduced legislation that mandates, regardless of embryo quality, SET for the first one or two cycles in women under the age of 35. Similarly, Belgium, Canada, and Sweden have comparable restrictions mandating SET in young women[8,9]. In 2013, in an effort to reduce the twin birth rate to 10%[10,11], guidelines were issued in the United Kingdom of Great Britain and Northern Ireland instructing clinicians to use SET for first cycles for women under 37 years of age, and also for second cycles, if a top-quality embryo is available. In Australia, Denmark, Finland, New Zealand, and Norway, the vast majority (85.2%) of embryo transfer cycles for women under 35 years of age are currently conducted as SET[12,13].
In The United States of America, the guidelines of the American Society for Reproductive Medicine (ASRM) state, for women at any age: transfer only one euploid embryo[14,15]. For good prognosis, patients under 35 years of age (first cycle of IVF, prior IVF success, or good morphology embryos), transfer should be limited to one embryo; patients between 35 to 37 years of age, SET should be strongly suggested. Despite the stricter ASRM guidelines, preliminary data from the 2016 Society for Assisted Reproductive Technologies Clinic Summary Report show that fewer than 40% of transfers performed in The United States of America were SET.
The evidence from the 2018 IFFS Surveillance Survey shows no meaningful increase in the proportion of countries with legislation or clinical guidelines restricting the number of embryos permissible for transfer to women undergoing IVF/ART cycles: 59%, vs. 56% in 2015. More countries (35%, vs 24% in 2015) now report the presence of penalties for non-compliance regarding the number of embryos transferred.
Compared to 2016 data, progress in the actual reduction of the number of embryos transferred has been more gradual, with 10% of countries reporting mandatory SET for patients <35 years of age, 7% of the countries reporting mandatory SET for patients aged 35-39 years, and 6.5% of countries reporting mandatory SET for patients > 40 years old.
Recent advances in embryo culture systems, embryo selection methods, preimplantation genetic testing, and cryopreservation technology are leading to improved embryo implantation rates, but this putative advantage has not yet led to wider adoption of SET.
 Office for National Statistics. Statistical bulletin: Childhood, Infant and Perinatal Mortality in England and Wales: 2013; March 2015.
 Kulkarni AD, Jamieson DJ, Jones HW, et al. Fertility treatments and multiple births in the United States. N Engl J Med 2013;369(23):2218–2225. doi:10.1056/nejmoa1301467.
 Gardner DK, Lane M. Culture and selection of viable blastocysts: a feasible proposition for human IVF? Hum Reprod Update 1997;3:367–382.
 Gardner DK, Lane M, Stevens J, et al. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril 2000;73:1155–1158.
 Maheshwari A, Griffiths S, Bhattacharya S. Global variations in the uptake of single embryo transfer. Hum Reprod Update 2011;17(1):107–120.
 Harton G, Munne S, Surrey M, et al. Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertil Steril 2013;100:1695–1703.
 Ercan CM, Kerimoglu OS, Sakinci M, et al. Pregnancy outcomes in a university hospital after legal requirement for single-embryo transfer. Eur J Obstet Gynecol Reprod Biol 2014;175:163–166.
 Bissonnette F, Phillips SJ, Gunby J, et al. Working to eliminate multiple pregnancies: a success story in Québec. Reprod BioMed Online 2011;23(4):500–504.
 Kupka MS, Ferraretti AP, de Mouzon J, et al. European IVF-Monitoring Consortium, for the European Society of Human Reproduction and Embryology. Assisted reproductive technology in Europe, 2010: results generated from European registers by ESHRE. Hum Reprod 2014;29(10):2099–2113.
 NICE, 2013. Available at: www.nice.org.uk/guidance/CG156/chapter/1-Recommendations#procedures-used-during-ivf-treatment. Accessed January 16, 2019.
 Harbottle S, Hughes C, Cutting R, et al. Association of Clinical Embryologists (ACE) & The British Fertility Society (BFS). Elective single embryo transfer: an update to UK Best Practice Guidelines. Hum Fertil 2015;18(3):165–183.
 Maheshwari A, Griffiths S, Bhattacharya S. Global variations in the uptake of single embryo transfer. Hum Reprod Update 2011;17(1):107–120.
 Macaldowie A, Wang Y, Chughtai A, et al. 2014. Assisted Reproductive Technology in Australia and New Zealand 2012. National Perinatal Epidemiology and Statistics Unit. The University of New South Wales, Sydney. Available at: https://npesu.unsw.edu.au/sites/default/files/npesu/data_collection/Assisted%20reproductive%20technology%20in%20Australia%20and%20New%20Zealand%202012.pdf. Accessed January 16, 2019.
 Penzias A, Bendikson K, Butts S, et al. Guidance on the limits to the number of embryos to transfer: a committee opinion. Fertil Steril 2017;107(4):901–903. doi:10.1016/j.fertnstert.2017.02.107.
 Practice Committee of the Society for Assisted Reproductive Technology, Practice Committee of the American Society for Reproductive Medicine. Elective single-embryo transfer. Fertil Steril 2017;97:835–842.
 Society for Assisted Reproductive Technology. CSR 2016. Available at: https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2016. Accessed January 16, 2019.
CHAPTER 6: CRYOPRESERVATION
Cryopreservation is one of the most significant recent advancements in assisted reproduction technology (ART). Although interest in human tissue cryopreservation has existed for more than 200 years, significant progress in reproductive applications has occurred only in the last two or three decades.
The development of slow-freezing techniques and vitrification technology, and expansion in various combinations of newer cryoprotectants, have considerably advanced the field of ART. Sperm, oocytes, and embryos can now be frozen at various stages of development, making treatment potentially safer and more effective.
The chief objectives of cryopreservation are to make gametes or embryos available for future use by individuals or couples undergoing infertility treatment, and to preserve future fertility options for individuals at risk of losing their reproductive potential. Cryopreservation also offers the opportunity to forestall pregnancy to a safer, more optimal time. This is important for patients who are at risk of ovarian hyperstimulation syndrome (OHSS), or who have poor endometrial receptivity.
Frozen embryo transfer (FET) is a procedure – a cycle – in which frozen embryos are thawed, then transferred to a uterus. The improved results of embryo cryopreservation have been an essential component of preimplantation genetic diagnosis and screening.
The improved results of embryo cryopreservation have been an essential component for preimplantation genetic diagnosis/screening, using trophectoderm biopsy and array comparative genomic hybridization (CGH microarray) or Next Gen Sequencing (NGS). Blastocysts can be frozen, and genetic testing performed before the blastocysts are transferred. Embryo cryopreservation offers a way to avoid repeated ovarian stimulation, optimizes achieving embryo-endometrial synchrony, and aids in single embryo transfer (SET).
Analysis of the survey
Cryopreservation for fertility treatment
None of the respondent countries cited explicit prohibition of cryopreservation of sperm, oocytes, or pre-implantation embryos for fertility treatment. Cryopreservation for fertility treatment (Table 1) is expressly allowed or permitted for sperm in 71 of 83 (86%) of countries responding; for oocytes, in 68 of 82 (83%); and in all stages of pre-implantation embryos, in 66 out of 82 (80%). There are no regulations for cryopreservation for fertility treatment for sperm, according to 35 of 82 responders (43%); for oocytes, in 33 of 82 (40%); and all stages of pre-implantation embryos, in 32 of 82 (39%).
For countries that regulated cryopreservation for fertility treatment, the following were used to govern:
- Federal/national laws/statutes/ordinances were used for sperm in 39 of 82 (47.5%); to govern oocytes, only 3 of 82 (4%); and all stages of pre-implantation embryos, 36 of 82 (44%);
- State/provincial/regional laws/statutes/ordinances: sperm, oocytes, and all stages of pre-implantation embryos: 7 of 82 (8.5%);
- Municipal laws/statutes/ordinances: sperm and all stages of pre-implantation embryos: only 2 of 82 respondents (2%) and oocytes: only 3 of 82 (4%);
- Agency regulations/oversight: sperm: 10 of 82 respondents (12%); all stages of pre-implantation embryos, and oocytes as well: 11 out of 82 (13%);
- Professional organization standards/guidelines: sperm, 24 of 82 respondents (29%); oocytes, 23 of 82 (28%); and all stages of pre-implantation embryos: 21 of 82 (26%);
- Cultural practices to govern sperm: only 1 of 82 (1%), and all stages of pre-implantation embryos and oocytes: 2 of 82 (2%); and
- Religious decree: oocytes: 1 out of 82 responders (1%).
Duration of storage for fertility treatment
Duration of storage for fertility treatment was not limited for sperm in 38 out of 79 (48%); for oocytes, 36 out of 75 (48%); and for all stages of pre-implantation embryos: 33 out of 76 (43%). The duration of storage was limited for sperm in 17 of 79 (22%); oocytes, 16 of 75 (21%); and all stages of pre-implantation embryos: 19 of 76 (25%). The duration of storage was not addressed for sperm in 16 of 79 (20%); for oocytes, in 17 of 75 (23%); and for all stages of pre-implantation embryos in 18 of 76 (24%). The duration of storage for sperm was unknown in 8 of 79 (10%); for oocytes, in 6 of 75 (8%); and in all stages of pre-implantation embryos, 6 of 76 responders (8%).
The following durations were reported:
- Sperm: 2 years (Serbia); 5 years (Bulgaria, Cameroon, Nicaragua, Portugal, Turkey, and United Arab Emirates); 10 years (Hong Kong [China, reporting separately for this report], Iceland, Ireland, New Zealand, Singapore, Switzerland, Taiwan [China, reporting separately for this report], and Uganda); 25 years (Greece); and 55 years (United Kingdom of Great Britain and Northern Ireland) (Table 2a).
- Oocytes: 2 years (Serbia); 5 years (Bulgaria, Mali, Portugal, Turkey, and United Arab Emirates); 10 years (Hong Kong [China, reporting separately for this report], Iceland, Ireland, New Zealand, Singapore, Switzerland, Taiwan [China, reporting separately for this report], Uganda, and United Kingdom of Great Britain and Northern Ireland); and 25 years (Greece) (Table 2b); and
- All stages of preimplantation embryos: 5 years (Bulgaria, Cameroon, Mali, Norway, and The Republic of Korea); 10 years (Australia, Austria, Hong Kong [China, reporting separately for this report], Hungary, Iceland, Ireland, New Zealand, Singapore, Slovenia, Switzerland, Taiwan [China, reporting separately for this report], Uganda, and the United Kingdom of Great Britain and Northern Ireland); and 25 years (Greece) (Table 2c).
Cryopreservation for fertility preservation, medical indications
None of the respondent countries cited explicit prohibition of cryopreservation of sperm, oocytes, or pre-implantation embryos for fertility preservation. Cryopreservation for fertility preservation for medical indications (Table 1) is expressly allowed/permitted for sperm in 68 of 81 (84%) of responding countries; for oocytes, in 60 of 83 (82%); for pre-implantation embryos (all stages), in 62 of 82 (76%); for ovarian tissue, in 52 of 83 (65%); and for testicular tissue, in 53 of 82 (65%).
Countries reporting that cryopreservation to maintain fertility for medical indications is commonly performed for sperm in 28 of 439 countries (72%); for oocytes, in 18 out of 40 (45%); for all stages of pre-implantation embryos, in 19 of 42 (45%); for ovarian tissue, in 7 of 48 (14.5%); and for testicular tissue, 9 of 47 (19%).
Cryopreservation for fertility preservation, non-medical indications
According to responders, cryopreservation in non-medical indications is specifically allowed/permitted for sperm in 60 of 82 (73%); for oocytes, in 56 out of 81 (69%); for pre-implantation embryos (all stages), 51 of 82 (62%); for ovarian tissue, 44 of 82 (54%); and for testicular tissue, 45 of 83 (54%). Cryopreservation for fertility preservation in non-medical indications is frequently performed as follows: for sperm, 16 of 42 (38%); oocytes, 18 of 42 (43%); all stages of pre-implantation embryos, 8 of 43 (19%); ovarian tissue, 3 of 48 (6%); and testicular tissue, 4 of 49 (8%).
In 80 countries surveyed, 33 (41%) have no regulations for cryopreservation performed to preserve fertility for sperm and oocytes in all stages of pre-implantation embryos; 31 (39%); 30 (37.5%) have none for ovarian tissue; and 31 (39%) have none for testicular tissue.
Countries that regulated cryopreservation for fertility treatment provided responses, summarized below, indicating how uses were governed. (In all cases there were 80 responders):
- Federal/national laws/statutes/ordinances governed sperm and oocyte cryopreservation in 28 (35%); pre-implantation embryos, all stages, in 27 (34%); ovarian tissue, in 18 (23%); and testicular tissue, in 17 (21%);
- State/provincial/regional laws/statutes/ordinances governed sperm cryopreservation in 2 (3%); oocytes, in 3 (4%); and all stages of pre-implantation embryos, ovarian tissue, and testicular tissue, in 1 (1%);
- Municipal laws/statutes/ordinances were used to govern testicular tissue in 1 (1%);
- Agency regulations/oversight governed sperm in 6 (8%); oocytes in 3 (4%); and pre-implantation embryos (all stages), ovarian tissue, and testicular tissue in 4 (5%);
- Professional organization standards/guidelines were used to govern sperm in 20 (25%); oocytes, 19 (24%); pre-implantation embryos, all stages, 18 (23%); ovarian tissue, 14 (18%); and testicular, 15 (19%);
- Cultural practices governed sperm and oocytes in 2 (3%), and in pre-implantation embryos (all stages), ovarian tissue, and testicular tissue (1%); and
- Religious decree was used to govern ovarian tissue in 1 instance (1%).
Duration of storage for fertility treatment for medical indications
Listed below is the duration of storage for fertility preservation for medical indications. Storage duration was not limited for sperm in 38 of 77 (49%) countries; for oocytes, in 38 of 74 (51%) countries; for pre-implantation embryos (all stages), in 31 of 74 (42%), in ovarian tissue, in 30 of 74 (40%); and in testicular tissue, in 35 of 74 (47%).
The duration of storage was limited for sperm in 13 of 77 (17%) countries; for oocytes, in 13 of 74 (18%); all stages of pre-implantation embryos, in 18% of 74; for ovarian tissue, in 9% of 74, and for testicular tissue, in 11%. The duration of storage was not addressed for sperm in 19 of 77 (25%); for oocytes, in 18 of 74 (24%); all stages of pre-implantation embryos, 21 of 74 (28%); ovarian tissue, 28 of 74 (38%); and testicular tissue, 21 of 74 (28%). The duration of storage was unknown for sperm in 7 of 77 countries (9%); for oocytes, in 5 of 74 (7%); for all stages of pre-implantation embryos, in 9 of 74 (12%); for ovarian tissue, in 9 of 74 (12%); and for testicular tissue, in 10 in 74 (14%).
The following durations were reported:
- Sperm: 5 years (Bulgaria, Nicaragua, Portugal, Turkey, and United Arab Emirates); 10 years (Hong Kong [China, reporting separately for this report], Iceland, Ireland, New Zealand, Singapore, Taiwan [China, reporting separately for this report], and Uganda); and 55 years (United Kingdom of Great Britain and Northern Ireland);
- Oocytes: 5 years (Bulgaria, Nicaragua, Portugal, Turkey, and United Arab Emirates); 10 years (Hong Kong [China, reporting separately for this report], Iceland, Ireland, New Zealand, Singapore, Taiwan [China, reporting separately for this report], and Uganda); 55 years (United Kingdom of Great Britain and Northern Ireland);
- All Stages of preimplantation embryos: 5 years (Bulgaria, Norway, and The Republic of Korea); 10 years (Austria, Hong Kong [China, reporting separately for this report], Iceland, Ireland, New Zealand, Singapore, Switzerland, Taiwan [China, reporting separately for this report], and the United Kingdom of Great Britain and Northern Ireland);
- Ovarian Tissue: 5 years (Nicaragua, Portugal, and Turkey); 10 years (Hong Kong [China, reporting separately for this report], Iceland, New Zealand, and Singapore); and
- Testicular tissue: 5 years (Bulgaria, Nicaragua, Portugal, and Turkey); 10 years (Hong Kong [China, reporting separately for this report], Iceland, New Zealand, and Singapore).
Duration of storage for fertility treatment for non-medical indications
The duration of storage for fertility preservation for non-medical indications was not limited, as follows: for sperm, in 29 of 70 (41%); for oocytes, in 30 of 70 (43%); in all stages of pre-implantation embryos, in 26 of 68 (38%); in ovarian tissue, 28 of 69 (40%); and testicular tissue, in 28 of 69 (41%).
The duration of storage was limited, however, as follows: for sperm, in 13 of 70 (19%); for oocytes, in 10 of 70 (14%); in all stages of pre-implantation embryos, in 8 of 68 (12%); in ovarian tissue, in 5 of 69 (7%); and in testicular tissue, in 7 out of 69 (10%).
The duration of storage was not addressed, as follows: for sperm, in 22 of 70 (31%); for oocytes, in 25 of 70 (36%); all stages of pre-implantation embryos, in 27 of 68 (40%); ovarian tissue, 28 of 69 (40%); and testicular tissue in 27 of 69 (39%).
In some cases, the duration of storage was unknown. These include: for sperm, 6 of 70 (8%); for oocytes, 5 of 70 (7%); for all stages of pre-implantation embryos, 7 of 68 (10%); for ovarian tissue, 8 of 69 (12%); and for testicular tissue, 7 of 69 (10%).
The following durations for storage were reported:
- Sperm: 2 years (Serbia); 5 years (Bulgaria, Nicaragua, Portugal, and United Arab Emirates); 10 years (Iceland, Ireland, New Zealand, Switzerland, Taiwan [China, reporting separately for this report], Uganda, and United Kingdom of Great Britain and Northern Ireland); and 25 years (Greece);
- Oocytes: 2 years (Serbia); 5 years (Bulgaria, Nicaragua, and Portugal); 10 years (Iceland, Ireland, New Zealand, Switzerland, Taiwan [China, reporting separately for this report], Uganda, and United Kingdom of Great Britain and Northern Ireland);
- All Stages of preimplantation embryos: 5 years (Bulgaria and The Republic of Korea); 10 years (Iceland, Ireland, New Zealand, Switzerland, Taiwan [China, reporting separately for this report], Uganda, and the United Kingdom of Great Britain and Northern Ireland);
- Ovarian Tissue: 5 years (Nicaragua and Portugal); 10 years (Iceland, New Zealand, and Switzerland); and
- Testicular tissue: 1 year (Serbia), 5 years (Bulgaria, Nicaragua, and Portugal); 10 years (Iceland, New Zealand, and Switzerland).
Sperm cryopreservation is an established procedure, a standard technique for donor insemination and for preservation of male fertility in men who have a malignancy. Attempts are being made to cryopreserve small numbers of sperm from men who are infertile, and men with reduced fertility. Cryopreservation may reduce the need for future surgical procedures or the use of donor sperm.
Sperm can now be frozen using the freeze-drying technique, lyophilization. This procedure can preserve sperm for longer periods and more economically than current methods, without affecting the integrity of sperm DNA. Sperm banking is indicated for cancer patients facing gonadotoxic therapy. Testicular tissue has been obtained and preserved from prepubertal boys undergoing gonadotoxic treatment and those with cryptorchidism, but the procedure is experimental.
Some reviews have shown two procedures performed on oocytes – slow freezing and vitrification – have comparable rates when the oocytes are assessed for fertilization, pregnancy, and implantation, but vitrification is preferred because of its simplicity. The limited available studies suggest that the technique of vitrification of oocytes yields higher pregnancy rates when compared to slow-freezing.
Preliminary data on the safety of oocyte cryopreservation are reassuring, and the procedure is no longer considered experimental. Good evidence indicates that fertilization and pregnancy rates are similar with fresh oocytes or frozen-thawed oocytes. No increases in chromosomal abnormalities, birth defects, or developmental deficits have been noted in the children born from cryopreserved oocytes. Oocyte freezing has developed substantially, finding wider applications and use. There are not yet sufficient data to recommend oocyte cryopreservation as a mainstream option to mitigate reproductive aging in healthy women.
Also, oocyte freezing has simplified the oocyte donation process. The advent of donor egg cryobanks with cryopreserved oocytes facilitates creation of greater numbers of potential donor oocytes and uncouples the donor stimulation process from the recipient endometrial preparation cycle, which eliminates the need for cycle synchronization. Oocyte cryopreservation also allows for the quarantining of human immunodeficiency virus (HIV)-exposed oocytes[8,9]. Furthermore, it is a model for conserving potential fertility in women with malignancy or those who seek elective postponement of childbirth, potentially extending their reproductive lifespan in optimal circumstances.
Use of cryopreserved embryos appears to be increasing, and many centres are now switching to a “freeze all” protocol, in which all or almost all of the freshly created embryos are not transferred, but cryopreserved for subsequent transfer in a programmed cycle. A recent meta-analysis suggests that pregnancies after FET are associated with better clinical outcomes, including lower risks of placenta previa, placental abruption, low birth weight, very-low-birth-weight-very-pre-term birth, short-for-gestation age, and perinatal mortality, compared with fresh embryo transfer. Conversely, pregnancies following FET were associated with increased risks of pregnancy-induced hypertension, postpartum hemorrhage, and large-for-gestational-age fetuses compared to those produced with fresh embryo transfer.
Among the established methods for preserving fertility in women diagnosed with cancer, cryopreservation is the preferred option for the post-pubertal age group oocyte, and ovarian tissue cryopreservation is generally the only available option for pre-pubertal girls. Ovarian tissue cryopreservation before treatment for malignancy has been performed, and has led to a small number of live births following transplantation. The procedure of ovarian tissue cryopreservation has been found to be safe, relatively simple, and promising. Cited advantages are that it may eliminate certain ethical, moral, and potentially legal obstacles to oocyte or embryo freezing in minors.
Ovarian tissue cryopreservation is still considered an experimental procedure. It is an option for patients requiring immediate gonadotoxic treatment who must forego oocyte or embryo freezing, and it is the only option available for prepubertal girls. Vitrification of ovarian tissue was found to be similar to slow freezing, and both preserved the morphologic integrity of the ovarian tissue. Orthotopic transplantation of the cortical strips from the tissue has been successful, and live births have been reported. In vitro-activated ovarian tissue cryopreservation and transplantation is a new method requiring more clinical research. This procedure involves stimulation of dormant follicles within the cryopreserved tissue graft prior to transplantation, in order to generate mature oocytes shortly after transplantation.
Advances in cryopreservation, most notably vitrification, have led to wide adoption and successful application of cryopreservation of sperm, oocytes, and embryos. The 2018 Surveillance questionnaire did not uncover any countries that expressly prohibit cryopreservation of gametes or pre-implantation embryos for fertility treatment or for fertility preservation performed for medical or other indications. Approximately 65% to 80% of respondent countries noted the existence of laws, regulations, agency oversight, or professional guidelines that provided governance. However, there is extensive variation among the country respondents in terms of which practices are regulated, and how they are regulated.
 Griveau JF, Lopes M, Jouve G, et al. Vitrification: principles and results. J Gynecol Obstet Biol Reprod (Paris) 2015;44(6):485–495. French.
 Adler HL, Lee E, Ampeloquio M, et al. Blastocyst culture selects for euploid embryos: comparison of blastomere biopsy (EB) and trophectoderm biopsy (TE) for aneuploidy rates using array comparative genomic hybridization (a-CGH). Fertil Steril 2011;96:108–109.
 Konc J, Kanyo K, Kriston R, et al. Cryopreservation of embryos and oocytes in human assisted reproduction. Biomed Res Int 2014;2014:307268.
 Meirow D, Roness H, Kristensen SG, et al. Optimizing outcomes from ovarian tissue cryopreservation and transplantation; activation versus preservation. Hum Reprod 2015;30(11):2453–2456.
 The Practice Committees of the American Society for Reproductive Medicine; Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril 2013;99(1):37–43.
 Glujovsky D, Riestra B, Sueldo C, et al. Vitrification versus slow freezing for women undergoing oocyte cryopreservation. Cochrane Database Syst Rev 2014;9:CD010047.
 Gianaroli L, Racowsky C, Geraedts J, et al. Best practices of ASRM and ESHRE: a journey through reproductive medicine. Fertil Steril 2012;98(6):1380–1394.
 Cobo A, Remohi J, Chang CC, et al. Oocyte cryopreservation for donor egg banking. Reprod Biomed Online 2011;23(3):341–346.
 Vajta G, Rienzi L, Ubaldi FM. Open versus closed systems for vitrification of human oocytes and embryos. Reprod Biomed Online 2015;30(4):325–333.
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 Sha T, Yin X, Cheng W, et al. Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis Fertil Steril 2018;109(2):330–342.
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 Sanfilippo S, Canis M, Smitz J, et al. Vitrification of human ovarian tissue: a practical and relevant alternative to slow freezing. Reprod Biol Endocrinol 2015;13:67.
 Anderson RA, Wallace WHB, Telfer EE. Ovarian tissue cryopreservation for fertility preservation: clinical and research perspectives. Human Reproduction Open, 2017:Issue 1. Available at: https://academic.oup.com/hropen/article/2017/1/hox001/3092402. Accessed January 25, 2019.
CHAPTER 7: POSTHUMOUS REPRODUCTION
Posthumous reproduction broaches a diverse scope of emotional, medical, legal, and ethical concerns that represent one of the more challenging and sensitive areas in reproductive medicine. There is still substantial debate over the ethics and legality of several aspects of posthumous reproduction, and the rights of the deceased person’s parents, surviving partner, and any resulting offspring.
Posthumous reproduction utilizes cryopreserved gametes, or embryos created when the person was alive, but inseminated or transferred after the person’s death. Posthumous reproduction can occur in two distinctly separate modes, referred to as (1) immediate posthumous reproduction and (2) posthumous reproduction. Immediate posthumous reproduction involves either the immediate harvesting of gametes from a person declared to be in a brain-dead state, on life support; or the extraction of gametes from a person declared dead within the previous 24 hours. Reports of sperm retrieval post 24 hours have been described. Posthumous conception by artificial insemination using cryopreserved sperm has been practiced since the 1950s.
The acceptance, legality, and utilization of posthumous reproduction varies from country to country (Table 1). With the advent of more successful cryopreservation techniques, patients are cryopreserving gametes and embryos for a wider number of reasons, including onco-banking, elective fertility preservation, and delayed embryo transfer in in vitro fertilization (IVF), with or without pre-implantation genetic testing. The actual use of cryopreserved reproductive tissue after death depends on existing legislation, prior written legal agreements, and/or consent documentation. Most ART programmes now use consents that cover the deposition of gametes and embryos after death. When immediate posthumous reproduction is being considered, family input often is the only form of intent available to interpret the wishes of the deceased person. In some locales, gametes are considered an individual’s property, and the gamete’s subsequent ownership must be documented in a will. Otherwise, the burden to determine whether the person may have truly wished to procreate after death devolves to the courts to decide. This often precipitates the need for governments to update relevant legislation.
The first data regarding posthumous reproduction were reported in 2003, in the cryopreservation chapter. Surveillance reports from 2007 through 2013 included data regarding only the permissibility and utilization of posthumous insemination. The 2015 Surveillance questionnaire for the 2016 Surveillance report was expanded to include questions about posthumous reproduction involving insemination of frozen sperm or frozen ova, and implantation of frozen embryos from deceased persons. Questions were added regarding legislation and the frequency of use of posthumous reproduction. In 2018, responses regarding posthumous reproduction were received from 82 countries – a 23% increase from the 2015 survey.
Analysis of the Survey
Of the 97 countries participating in the survey, respondents from 82 countries (85%) addressed questions regarding posthumous reproduction governance. Fewer countries than in the 2016 Surveillance report said they had regulations that governed immediate posthumous reproduction: 16 of 82 (20%). The report broke down the governance data as follows: posthumous sperm insemination: 19 of 82 (23%), posthumous insemination of frozen ova: 19 of 82 (23%); and posthumous implantation of frozen embryos: 23 of 28 (28%). An additional 7 of 82 (9%) (Belgium, Côte d’Ivoire, Germany, Jordan, Mongolia, Namibia, and Netherlands) reported it was “unknown” whether any type of regulations existed to govern posthumous reproduction.
When regulations existed, posthumous reproduction procedures were reportedly largely covered by federal law (immediate posthumous reproduction, 13 of 19 (68%); insemination with frozen sperm, 16 of 19 (84%); insemination of frozen ova, 14 of 19 (74%); and implantation of frozen embryos, 17 of 19 (89%). Regulations were addressed by state, regional, or provincial laws, 5 of 39 (13%), municipal laws, 1 of 19 (5%); agency oversight, 4 of 60 (7%); a professional organization’s standards and guidelines, 12 of 60 (20%); cultural practice, 1 of 17 (6%); and religious decree 5 of 60 (8%).
In addition, respondents were then asked questions about the permissibility and utilization of posthumous reproduction.
Immediate posthumous reproduction
Respondents from 41 countries reported data on immediate posthumous reproduction procedures in their country. In 28 (68%) of the respondent countries, it was “unknown” whether immediate posthumous reproduction was “allowed/permitted or practiced/performed”. In 11 of 41 (27%), posthumous reproduction procedures were allowed/permitted, with 5 of 11 (45%) of these countries practicing/performing immediate posthumous reproduction procedures, and another 1 of 5 (20%) reporting “unknown” if this procedure was actually being practiced/performed. Two countries did not report whether posthumous reproduction was allowed/permitted, but did note that the procedure was being practiced/performed in their country (Table 1).
Insemination with Frozen Sperm
Respondents from 44 countries reported data on insemination with frozen sperm in their country. In 24 of 44 (54.5%), it was “unknown” whether insemination with frozen sperm was allowed/permitted or practiced/performed. In 16 of 44 (36%), insemination with frozen sperm was allowed/permitted, with 4 of 16 (25%) of these countries practicing/performing insemination with frozen sperm and another 6%, 1 in 16, reporting “unknown” if this procedure was actually being practiced/performed. Four countries did not report if insemination with frozen sperm was allowed/permitted but reported that the procedure was being practiced/performed in their country.
Insemination of Frozen Ova
Respondents from 43 countries provided data on insemination of frozen ova in their country. In 24 of the 43 (56%), it was “unknown” whether insemination of frozen ova was allowed/permitted or practiced/performed. In 15 of the 43 (35%), insemination of frozen ova was allowed/permitted, with 3 of 15 (20%) practicing/performing insemination of frozen ova, and another 1 in 15 (7%) reporting “unknown” as to whether this procedure was actually being practiced/performed. Four countries did not report if insemination of frozen ova was allowed/permitted, but did report that the procedure was being practiced/performed in their country.
Implantation of Frozen Embryos
Respondents from 46 countries reported data on implantation of frozen embryos in their country. In 23 of the 46 (50%), it was “unknown” whether implantation of frozen embryos was allowed/permitted or practiced/performed. In 28 of the 46 (39%), implantation of frozen embryos was allowed/permitted, with 4 out of 18 (22%) of these countries practicing/performing implantation of frozen embryos, and another 1 out of 18 (6%) reporting “unknown” as to whether this procedure was actually being practiced/performed. Five countries did not report if frozen embryo implantation was allowed/permitted, but did report that the procedure was being practiced/performed in their country.
Compared to past Surveillance surveys, the use of any type of posthumous reproduction procedures has increased over the last 3 years. While scientific and medical advances allow the practitioner to retrieve and use gametes and embryos from deceased persons, complex issues remain unresolved, when it comes to clarifying who can decide when the retrieval and disposition of these reproductive tissues is appropriate, and under what circumstances.
In the 2016 Surveillance survey, more than a third of countries reported legislation in place to govern posthumous reproduction. In 2019, only about a quarter of the countries had governance. The 2019 Surveillance data illustrate the continued global need to address the controversial and complex issues of ethics and legalities associated with posthumous reproduction – especially now, when the procedure is being used more frequently, under what continues to be a limited extent of regulations and legislation.
 Gilbert S. Fatherhood from the grave: An analysis of postmortem insemination. Hofstra Law Rev 1993;22:521–565.
 Shefi S, Raviv G, Eisenberg ML, et al. Posthumous sperm retrieval: Analysis of time interval to harvest sperm. Hum Reprod 2006;21(11):2890–2893.
CHAPTER 8: DONATION AND ANONYMITY OF DONORS
Assisted reproductive technology (ART) programmes around the world increasingly rely on male and female gamete donation in ART cycles. From a cultural perspective, social trends leading to progressive legislation have improved global access to ART and widened the spectrum of potential users. In previous Surveillance reports, changes in legislation pertaining to gamete donation, marital status, and same-sex parenting policies, were observed in about 23% of countries over a three-year interval. Prospective parents seeking medical care now comprise not only infertility patients, carriers of genetic conditions, and HIV sero-discordant couples, but also single women, single men, same-sex couples, and transgender subjects. Enacting anti-discrimination policies favors access for these groups, and a current trend leans toward equal, inclusive, fair, safe, and efficient access to ART, most notably in Europe.
An additional driver, from a biological standpoint, has been the social phenomenon favoring delayed childhood in modern societies. This has shifted the “reproductive window” to an age in which ovarian follicular depletion impairs female fertility potential. As a result, use of donated oocytes has increased steadily over the last decades, a trend reflected in recently published global registry data (ICMART, 2017). Oocyte donation can also be performed with vitrified oocytes. Currently, more programmes are using egg banking for donation, as IVF results have been shown to be similar with the use of fresh and frozen oocytes.
Analysis of the survey
The vast majority of countries surveyed allowed gamete donation (Table 1, Charts 1 and 2). Sperm donation is allowed in 48 of 71 (68%), and is practiced in 41 of the 71 (58%). Oocyte donation is permitted in 43 of 69 (62%), but is performed in only 39 of 69 (56.5%). Donation of an embryo created by another couple in a previous IVF cycle is allowed in 31 of 53 (58%), but, surprisingly, is performed in 25 of 53 (47%).
Less commonly allowed is creating embryos purely for donation, “de novo” generation of embryos from donor gametes. Allowed in 21 of 50 countries (42%), it reportedly is practiced in 19 of 50 (38%). Overall, 49 of 71 (69%) reported “commonly using” sperm; oocyte, 44 of 71 (62%); embryo, 17 of 66 (26%). Less frequently allowed is cytoplasmic donation, 7 of 48 (14.5%), and gamete tissue donation—usage with either ovarian tissue 12 of 51 (23.5%) or testicular tissue, 11 of 50 (22%) permitted but only performed cytoplasmic donation 3 of 48 (6%), ovarian tissue donation, 3 of 51 (6%); or testicular tissue donation, 3 of 50 (6%); six countries reported “never having used” sperm, oocyte, or embryo donation. The same six countries indicated they had never used cytoplasmic and gamete tissue donation (Botswana, Egypt, Jordan, Lithuania, Mali, and Senegal).
More than half the countries surveyed have regulations addressing oocyte donation, 40 of 73 (55%), and sperm donation, 43 of 74 (58%) (Table 2). Many countries have regulations pertaining to embryo donation, 29 of 69 (42%), including previous IVF; or de novo embryos, 26 of 68 (38%). 17% of countries, 11 of 65, have regulations for cytoplasmic donation (Australia, Canada, Finland, Greece, Kazakhstan, New Zealand, Nicaragua, Singapore, Thailand, United Kingdom of Great Britain and Northern Ireland, and The United States of America), and 20% have regulations regarding ovarian (13 of 65) and testicular tissue donation, 13 of 66. Fourteen countries out of 65 (22%) reported allowing agencies to recruit and match third party donors; including donors, recipients, surrogates and/or gestational carriers. These countries are Australia, Canada, Finland, Greece, India, Kazakhstan, Mexico, Nicaragua, Portugal, Singapore, Thailand, United Arab Emirates, United Kingdom of Great Britain and Northern Ireland, and Uruguay.
The majority of countries allowed compensation for sperm and oocyte donors; 67 responders (67%) vs 64 responders (72%) and embryo donors 26% (n=54) of the countries surveyed permitting the practice (Chart 3). This includes reimbursement for donors’ time and expenses only, as follows: for sperm, 54%; oocyte, 55%; and for embryo, 2%. Compensation beyond reimbursement occurred in 12% of sperm donors, 17% of oocyte donors, and 7% of embryo donors. The eleven countries that allowed compensation of oocyte donors beyond simple reimbursement include Argentina, Brazil, Bolivia, Colombia, Ecuador, Georgia, Greece, India, Russian Federation, The United States of America, and Venezuela. Embryo donation with reimbursement/compensation practices is permitted in Armenia, Australia, Bolivia, Brazil, Georgia, Greece, Hong Kong [China, reporting separately for this report], India, New Zealand, Nigeria, Sri Lanka, The United States of America, Uruguay, and Zimbabwe. Reimbursement for gamete tissue, and for cytoplasmic and testicular tissues, was reported in 3 of 43 (7%); and for ovarian tissues, 4 out of 44 (9%). Such reimbursement is rare, and reportedly occurred only in Australia, Colombia, Finland, and Greece.
When addressing a specific value paid in terms of compensation to donors, only a few countries reported minimum and maximum amounts for gamete donors. For oocyte donors, amounts ranged from US $ 700 to $ 2,000 in some countries (e.g., Ecuador, Guatemala, Latvia, Hong Kong [China, reporting separately for this report], and Spain) to $ 5,000 to $ 99,000 in others (Brazil, Namibia, South Africa, Taiwan [China, reporting separately for this report], and The United States of America). Some countries reported no minimum or maximum values established, including Argentina, Bulgaria, Chile, Hungary, India, Côte d’Ivoire, Mexico, Panama, and Uganda. Twenty-one out of 41 countries (51%) responded to the item as “not addressed” or “unknown”).
When asked if subjects were required to meet medical, mental health, or lifestyle criteria to qualify as donors, 46 of 64 (72%) responded affirmatively for sperm donation, 47 of 63 (75%) for oocyte donation, and 28 out of 50 (56%) for embryo donation.
Ten of 78 countries (13%) reported having no regulations pertaining to the treatment of anonymity of donors; 37 of 65 (57%) of countries reported the existence of national or federal laws; 6 of 65 countries (9%) have municipal or regional laws; 10 of 65 (15%) countries reported the presence of governmental agency oversight, and 23 of 65 (35%) reported having professional organization oversight (Table 2). Seven countries, Cameroon, Colombia, Egypt, Germany, Greece, Jordan, and Switzerland, reported regulation of anonymity via “cultural practice or religious decree.”
Disclosure of information about gamete donors to the offspring varied widely. Some countries, 22 of 46 (48%), allowed non-identifying data to be provided by the donor to the offspring. Another 14 of 43 (30%) allow identifying data to be disclosed, including Australia, Austria, Cameroon, Canada, Finland, Greece, Iceland, Kazakhstan, New Zealand, Nicaragua, Norway, Russian Federation, Switzerland, and The United States of America. Nonetheless, when queried if these practices were “customary” only 8 of the former 22 countries (36%) and 6 of the latter group of 14 (43%) responded affirmatively.
Disclosure of information from the offspring to the donor is less frequently allowed. In 17 of 43 (40%) of countries surveyed, non-identifying data from the offspring could be obtained by the donors. Those countries include Australia, Barbados, Bolivia, Colombia, Finland, Greece, Hungary, Iceland, Kazakhstan, New Zealand, Russian Federation, Sri Lanka, Switzerland, Thailand, The United States of America, United Kingdom of Great Britain and Northern Ireland, and Uruguay. Identifying information from the offspring, in contrast, was allowed to be obtained by donors in only 6 out of 41 (15%) of other countries: Australia, Cameroon, Kazakhstan, New Zealand, Russian Federation, and The United States of America. Regarding how often these disclosure practices were observed, only 9 of 17 (53%) in the first group—offspring to donor—and 2 out of 6 (33%) in the second group—donor to offspring—responded positively.
Gamete and embryo donation are well established ART practices, employed, if not sanctioned, by a large majority of the responding countries. These donation trends are likely to continue due to evolving social and cultural norms in developed and developing countries. Most of the European countries, as well as Australia, New Zealand, and some Asian countries, are extensively regulated by national or regional laws and statutes. Overall, about 50% to 60% of countries surveyed report using gamete or embryo donation, although “de novo” embryo donation is somewhat less commonly accepted (about 25% to 35% of countries). Cytoplasmic donation is infrequent, as is ovarian tissue and testicular tissue donation, and used for the most part in experimental environments.
 Ory S, Miller K, Horton M, et al. IFFS Surveillance 2016. Global Reprod Health 2016;1–144.
 “Access and diversity of medically assisted reproduction in Europe”, organized by the European Society of Human Reproduction and Embryology, together with the Council of Europe Bioethics Committee, Strasbourg, France. Feb 22-23, 2018.
 Zegers-Hochschild F, Adamson GD, Dyer S, et al. The International Glossary on Infertility and Fertility Care, 2017. Hum Reprod 2017;32:(9):1786–1801.
 Laura Rienzi L, Romano S, Albricci L, et al. Embryo development of fresh “versus” vitrified metaphase II oocytes after ICSI: a prospective randomized sibling-oocyte study. Hum Reprod 2010;25:66–73.
CHAPTER 9. OOCYTE MATURATION
Utilization of in-vitro maturation (IVM) following the recovery of immature oocytes was first suggested as a potential useful application for women undergoing ART in the 1990s. This technology differs markedly from conventional in vitro fertilization (IVF) in that oocytes are retrieved without prior controlled ovarian hyperstimulation (COH), and the collected immature oocytes are then cultured in vitro in enhanced culture environments until maturation is completed, which occurs when metaphase II (MII) stage is achieved.
Several advantages of IVM over conventional IVF have been suggested. They include greater safety via elimination of COH, with less risk of ovarian hyperstimulation syndrome (OHSS), particularly with patients with polycystic ovarian syndrome (PCOS); and lower cost, by reducing the need for additional medications and monitoring. This advantage has an additional benefit for the patient: potentially less stress. But broad acceptance of IVM techniques has been slow in coming, due to perceived lower clinical success rates, and a relative dearth of data regarding safety issues. The safety issues of concern include the overall health of the resulting offspring, and the possibility of inducing permanent changes in the expression of imprinted genes.
Analysis of the survey
The 2018 survey included responses from 75 countries. IVM was permitted in 64 of the 75 (86%), and was disallowed in only 4 countries (Bangladesh, Germany, Mali, and Nigeria). Seven countries (9%) stated that the status of IVM application in their country was “unknown” (Chart 1). The procedure was infrequently used in 41 of 72 countries (57%), and was commonly employed in only 15 of the 72 (21%). Reportedly, it was never performed in 10 of the 72 countries (14%) (Chart 2).
IVM is regulated in 16 of 77 countries responding (21%), and is unknown in 7 (9%) of the countries that responded. IVM is regulated in 15 countries of the 75 (20%) by federal statute (Belgium, Bulgaria, Egypt, Germany, Montenegro, New Zealand, Norway, Portugal, Serbia, Spain, Taiwan [China, reporting separately for this report], Togo, Turkey, United Kingdom of Great Britain and Northern Ireland, and Viet Nam); 2 of 75 (3%) by state or provincial statute (Australia and Uruguay); and 9 of 75 (12%) by professional guidelines or agency oversight (Ecuador, Ghana, Guatemala, India, and Côte d’Ivoire). Agency regulations were followed in Côte d’Ivoire and Portugal. Oocyte maturation was being held as a “cultural practice” in Switzerland. The status of the regulatory body was reported as “unknown” for Cameroon, Jordan, Panama, and United Arab Emirates (Table 1).
Although there have been no significant discernible technical advances in IVM technology since the 2015 survey, there appears to be a continued trend favoring somewhat increased utilization of IVM since 2010. Despite having more countries participating in the 2018 survey, overall responses are similar to those received in 2015. Respondents appear to be more reticent to adopt IVM to the extent that other micromanipulation techniques have been applied in the absence of evidence suggesting comparable or superior results when compared to conventional IVF.
Oocyte maturation is a critical step for successful IVF, and it is essential that recovered oocytes be mature, competent, and viable, to achieve fertilization and ultimately produce a healthy offspring. It is a fundamental molecular and cellular process integral to IVF that largely occurs in vivo. Realizing the true clinical potential of IVM and opening new opportunities in ART awaits additional translational advances, likely to be accomplished with animal models for IVM [2,3]. Widespread clinical adoption will require considerable additional evidence regarding live birth rates, cumulative outcomes from frozen oocytes and embryos, and long-term follow up, to assess risk.
 Paulson RJ, Fauser BCJM, Vuong LTN, et al. Can we modify assisted reproductive technology practice to broaden reproductive care access? Fertil Steril 2016;105(5):1138–1143.
 Abbara A, Clarke SA, Dhillo WS. Novel concepts for inducing final oocyte maturation in In vitro fertilization treatment. Endocr Rev 2018;39(5):593–628.
 Richani D, Gilchrist RB. The epidermal growth factor network: role in oocyte growth, maturation and developmental competence. Hum Reprod Update 2018;24(1):1–14.
CHAPTER 10: MICROMANIPULATION
Micromanipulation embraces several unrelated technologies routinely used in the successful application of assisted reproduction technology (ART). Some technologies are essential to the selective practice of ART; they include intracytoplasmic sperm injection (ICSI), embryo biopsy (polar body, cleavage stage, or trophectoderm), and, possibly, assisted hatching. The introduction of ICSI, with the first successful pregnancy achieved in 1991, was a transformative event for ART, enabling many men who previously had no way to achieve biologic fatherhood, to produce offspring.
Embryo biopsy has also been employed for an array of pre-implantation testing (PGT) applications, including selection of embryos without specific genetic diseases – a process known as preimplantation genetic testing for monogenic (single-gene) disorders (PGT-M). The first successful use of PGT-M was for selecting embryos unaffected by X-linked disease, reported in 1991. PGT has also been used to identify and exclude embryos with structural rearrangements (PGT-SR). Its most challenging, but potentially most impactful application, has been for detecting and excluding aneuploid embryos (PGT-A) for embryo transfer. The latter use has been hampered by the protracted development of a robust, reliable platform for performing a complete karyotype on a limited number of cells extracted from a developing embryo. Recent progress in this area may lead to much greater implantation rates, with potentially much higher live birth rates. It could also provide a chance to greatly reduce the primary risk of ART, multiple pregnancy, if a single euploid embryo could be transferred for all age groups.
Micromanipulation may also be used for several investigative, more controversial applications. These include cytoplasmic transfer, mitochondrial transfer, and the recently described “gene editing” technology, CRISPR-Cas9. No reports of human application of the latter existed when the survey was completed (March 2018).
Analysis of the survey
Of the respondents representing the 97 countries that participated in the 2018 Surveillance questionnaire, more than 70% provided specific responses regarding micromanipulation. Techniques of micromanipulation queried in the survey included the performance and legal status of ICSI with ejaculated or surgically obtained sperm; PGT with polar body, blastomere, or trophectoderm biopsy; assisted hatching; and cytoplasmic transfer, mitochondrial transfer, and CRISPR-Cas9 technology.
ICSI was permitted in almost all countries that responded to the survey – 79 of 80 (99%) – but it was performed in all. ICSI with sperm recovered following ejaculation is a common procedure in 77 countries, but it is infrequent in Sri Lanka, and is never performed in that country on surgically recovered sperm.
Most countries commonly perform ICSI with surgically retrieved sperm, but the procedure is infrequent in 21 of 78 (27%) (Table 1a). There were no regulations for ICSI in most countries; it was regulated in 27 out of 79 (34%). In 30 countries out of 79 (38%), ICSI was regulated by federal or national laws. Regional/state laws were followed in 7 countries out of 79 (9%). In 16 out of 79 (20%), countries, professional organization standards/guidelines were followed, and in two countries (Italy and Senegal) municipal laws were the regulation authority. ICSI was held as a cultural practice in Switzerland, and also in Italy, where the application of ICSI was interdicted by religious decree. In 6 countries of 79 (7.5%), agencies were used for regulation. The regulating authority was reported as “unknown” in 4 countries of 79 (5%).
Polar body biopsy was permitted in 54 of 75 countries (72%), but was commonly used in only 5 out of 70 (41%); infrequently used in 29 out of 70 (41%), and never performed in 26 out of 70 (15%). Polar body biopsy was not permitted in 10 out of 75 countries (13%). Blastomere 61 out of 77 (79%) and trophectoderm biopsy 61 out of 76 (80%) were allowed in most countries, but were not permitted in 14%: 11 of 77, and 10 of 76, respectively. Blastomere biopsy was used commonly in 30 of 72 (42%) countries, infrequently used in 20 of 72 (28%), and never performed in 15 of 72 (21%). Trophectoderm biopsy was used in 38 of 73 (52%) countries. It was infrequently used in 13 of 73 (18%) of countries, and never performed in 14 of 73 (19%) (Table 1b).
Seventy-six countries responded to questions regarding the regulation of these techniques; 15 countries (20%) regulated polar body biopsy, 6 countries (21%) regulated blastomere biopsy, and 19 countries (25%) regulated trophectoderm biopsy. Biopsy procedures were regulated by federal or national laws in 19 of 35 (54%) countries, and state or regional laws in 3 of 8 (37.5%) of the reporting countries. Polar body biopsy is regulated by municipal rules, agencies, and religious decree in Greece. Brazil also had regulation of polar body biopsy, by agency regulations or oversight. Professional organization recommendations were used in 10 of 17 (59%) of reporting countries. Biopsy procedures were addressed as a cultural practice in Switzerland. Respondents for 6 countries answered “unknown”.
In 71 of 79 (90%) of countries reporting, assisted hatching was said to be allowed. Assisted hatching was commonly used in 40 of 75 (53%) of countries, and was infrequently done in another 24 (32%). Five countries (7%) reported “unknown”, and said it was never performed in 6 countries (8%). Twenty-one countries - 78 - did report the existence of regulations for assisted hatching. The majority of countries – 21 (95%) – that cited regulation of assisted hatching noted the presence of federal or national law, and three (14%) were regulated by state/regional law. Only one country, Portugal, had agency regulation for assisted hatching. Professional organization standards or guidelines were used by 8 countries (38%). Assisted hatching was addressed as a cultural practice in Switzerland and Greece. The regulating body was reported as “unknown” by 4 countries.
Twenty five of 73 (34%) countries, but was allowed in 17 countries (23%). Cytoplasmic transfer was never performed in 33 of 71 (46%), and infrequently in 11 of 73 (15%). It was reported to be commonly used in three countries – Italy, Kazakhstan, and The Republic of Korea. Specific regulations for cytoplasmic transfer existed in 12 of 75 countries (16%). Cytoplasmic transfer was regulated by federal or national laws in 9 countries of 12 (75%). Portugal relied on agencies for regulation, and 6 countries followed professional organization standards or guidelines. The responsible regulatory body was reported as “unknown” for 6 countries (Table 1c).
Mitochondrial transfer was permitted in only 15 of 72 countries (21%). Mitochondrial transfer was never performed in 37 of 70 (53%), and infrequently in 6 countries (9%): Canada, Colombia, Japan, Mexico, Thailand, and United Kingdom of Great Britain and Northern Ireland. Mitochondrial transfer applications were regulated by federal or national legislation in Australia, Norway, Turkey, and United Kingdom of Great Britain and Northern Ireland. Professional organization standards or guidelines were observed in 4 countries. The regulation authority was “unknown” in seven countries (Table 1c).
CRISPR-Cas9 technology was permitted in 16 of 73 (22%). CRISPR-Cas9 technology was reported to be commonly used in Greece and Italy, according to 71 responders (3%), and infrequently used (4%) in Colombia, Finland, and The United States of America. Regulations existed in 8 of 74 countries (11%) for mitochondrial transfer, and in 6 of 75 (8%) countries for CRISPR-Cas9 technology. Federal or national laws regulated CRISPR-Cas9 technology in Australia, Norway, Singapore, Turkey, and United Kingdom of Great Britain and Northern Ireland. Professional organization standards or guidelines as existing recommendations were followed in Guatemala, Thailand, and The United States of America. Six countries replied “unknown” (Table 1c).
While all these technologies are micromanipulation techniques, they have a much different status in the successful deployment of ART. ICSI is an indispensable tool, widely embraced after validation and successful global application. It is almost universally accepted, performed successfully, and used with minimal regulatory oversight. This has been the case for many years, and the current survey has not revealed any significant changes.
PGT is a promising technology with successful, validated applications for PGT-M and PGT-SR. After an earlier problematic launch with a less successful technology, PGT-A may now be poised to be the next great breakthrough. However, after previous false starts, it is particularly critical that it be validated with successful widespread application before it can be universally recommended. Assisted hatching has been practiced for over 25 years, and has been shown to improve embryo implantation rates in certain circumstances by certain labs. The lack of clearly defined indications and the variable experience among ART labs has precluded its universal application, thus far. PGT is addressed in more detail in Chapter 13.
Cytoplasmic and mitochondrial transfer, and CRISPR-Cas9 are investigative technologies that hold great promise for addressing some of the most challenging clinical problems. But all are fraught with potential greater risks, and pose unique ethical dilemmas. None appears to be ready for broad clinical application at this time, as reflected by their limited use and acceptance. The 2018 questionnaire did not identify any emerging trends regarding these three technologies.
The ability to perform micromanipulation procedures on gametes and embryos has vastly expanded the scope of ART, but the various procedures are at different stages of development. ICSI is a universally available procedure, performed in all responding countries, but not officially sanctioned in one (Greece). Micromanipulation procedures, including ICSI and PGT-M, are now essential technologies; they are widely available in comprehensive ART centres. PGT-A and assisted hatching, shown to be useful adjuncts in certain circumstances, are still being defined in terms of their specific indications and overall value. The preliminary experiences with cytoplasmic transfer, mitochondrial transfer, and CRISPR-Cas9 technology have been promising, but these applications remain investigative; an accurate assessment of their true potential, limitations, and risks is awaited.
 Malter HE. Micromanipulation in assisted reproductive technology. Reprod Biomed Online 2016;32:339–347.
 Rosenwaks Z, Pereira N. The pioneering of intracytoplasmic sperm injection: historical perspectives. Reproduction 2017;154(6):71–77.
 Handyside AH, Kontogianni EH, Hardy K, et al. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990;344(6268):768–770.
CHAPTER 11: WELFARE OF THE CHILD AND IDENTITY RIGHTS
Safety, particularly for the offspring, has been of the utmost concern since the advent of ART. As early as 1985, publications have suggested that the risk of obstetrical and neonatal morbidity might be increased after ART. Reports were many; they included matched and non-matched studies of singletons and twins, and, more recently, reviews and meta-analyses comparing outcomes of spontaneous pregnancies after various procedures. The procedures include intracytoplasmic sperm injection (ICSI), elective single embryo transfer (eSET), frozen embryo transfer (FET), and blastocyst transfers. A marked increase in cases of antepartum hemorrhage, hypertensive disorders, prematurity, low birth weight, and perinatal mortality has occurred in the latter groups. Many current ART practices and techniques have the potential to harm the embryo; these include extended culture beyond the cleavage stage; invasive genetic testing; vitrification and warming procedures; and expanded applications for ICSI. These unresolved concerns make careful follow-up of newborns and children born from ART cycles, of paramount importance.
Much more recently, concern for the child’s welfare has been expanded to include an assessment of social factors pertaining to the prospective parents’ ability to provide a suitable home environment, before embarking on treatment. A model for best practice was enshrined in the Human Fertilisation and Embryology Authority’s (HFEA’s) code of practice of the United Kingdom of Great Britain and Northern Ireland. The model provides guidance parameters for assessing, obtaining further information, and refusing treatment. These measures have been adopted by many other countries, as well.
Analysis of the survey
Respondents representing 78 countries provided data for the 2018 questionnaire about measures in place to address the welfare of the child. Of this number, 41 of 55 (74.5%) noted the existence of federal laws or statutes dealing with the welfare of the child. This situation was prevalent in most of the European countries and in the United Kingdom of Great Britain and Northern Ireland; Australia, Botswana, Canada, Côte d’Ivoire, Ghana, Hong Kong [China, reporting separately for this report], New Zealand, Nigeria, Philippines, Russian Federation, Singapore, South Africa, Taiwan [China, reporting separately for this report], Thailand, Uganda, United Arab Emirates, and Zimbabwe; also, several countries in South America: Colombia, Nicaragua, Paraguay, Peru, and Uruguay. Some countries, 13 of 36 (36%), also had state or provincial laws in place. Twenty-seven of 56 (48%) did not have any regulation regarding this issue, and 17% (6/36) reported having only professional organization. These included Argentina, Ecuador, India, Japan, The United States of America, and Venezuela. Two countries, Belarus and Belgium, responded “unknown” (Table 1, Chart 1).
Formal assessment of the potential welfare of the child was either not an obligatory part of the fertility clinic evaluation of prospective parents, or the issue was “unknown” for the majority, 74%, of responding countries (53 of 72). Nineteen countries (26%) responded that a formal assessment of the welfare of the child was a requirement, including Austria, Bolivia, Botswana, Ecuador, El Salvador, Finland, Ghana, Greece, Hong Kong [China, reporting separately for this report], Hungary, Norway, Portugal, Serbia, Slovenia, Spain, Switzerland, Trinidad and Tobago , Turkey, and the United Kingdom of Great Britain and Northern Ireland (Chart 2).
Fertility care could be denied in 38 of 73 countries (52%) if concerns about the welfare of a potential future child existed. Eleven responders (15%) reported that they could not deny treatment for this reason, and the status was “unknown” for 24 (33%).
Additional questions surveyed prior background evaluations of prospective parents’ clinical, psychiatric, and derelictive histories (Table 2). Nine of 73 (12%) report asking about any previous convictions related to any of the following: harming a child, history of family violence, social services contacts regarding care of other children, alcohol or drug abuse, serious mental or physical illness that could impair child care, or counseling about the child’s risk of a serious medical condition. These countries include Australia, Hong Kong [China, reporting separately for this report], Italy, Serbia, Slovenia, Taiwan [China, reporting separately for this report], Trinidad and Tobago, United Kingdom of Great Britain and Northern Ireland, and Viet Nam. Another 12 of 73 (16%) declared prospective parents were not asked about any of these issues. Spain and Ecuador reported assessing the child’s risk of a serious medical condition, and the existence of a serious mental or physical condition in prospective parents that could impair child care. Botswana reported assessing the existence of a serious mental or physical condition, and asking social services for contacts regarding care of other children (Chart 3).
Although a sizeable majority of countries have no requirements for formally assessing the potential welfare of the child, some countries that do the assessment have considerably expanded their concerns. Increasingly, their assessment includes a rigorous pre-conception evaluation of social risk factors, along with a postnatal surveillance of neonatal and ongoing childhood development, something that has long been in place in many countries. While these pre-treatment measures now encompass more, and include sanctions to deny care in some countries, their impact has not been determined. In contrast, many of these countries have comprehensive registries evaluating the subsequent progress of ART children. And a clearer picture of the risks of ART is beginning to emerge.
Congenital anomalies have reportedly increased in newborns, after ART cycles. After adjusting for parental factors, a relative risk of 1.07 exists (95% CI, 0.90 to 1.26) for IVF and 1.57 (95% CI, 1.30 to 1.90) for ICSI. In newborns conceived with ICSI, but not with conventional IVF, an increase in de-novo sex chromosome anomalies and structural autonomic anomalies has been reported, probably inherited through the paternal pathway.
A variety of possible factors may have contributed to this putative increase in morbidity. These factors include parental background unrelated to the ART process, clinical interventions such as ovarian stimulation and endometrial preparation, and technical issues involving manipulation of the early developing embryo. While more recent reports have provided some reassurance regarding safety with a much higher proportion of singleton pregnancies than earlier reports, potential advantages of programmed over fresh cycle transfers and more reliable strategies to prevent ovarian hyperstimulation, a contemporary estimate of neonatal and maternal risk is still forthcoming.
The results of the survey reflect a very heterogeneous scenario in the importance given to the welfare of the child and the attention given to the welfare, although it shows a trend towards more attention paid to the correct assessment at time of prospective parent assessment and consultation. Welfare of the child is addressed mostly by federal or local laws/statutes, and, in countries without a law in place, professional organizations offer guidelines and standards to properly assess prospective parents. Sometimes these organizations also provide reporting mechanisms for monitoring newborn and child welfare.
 Lancaster PAL. High incidence of preterm births and early losses in pregnancy after in vitro fertilisation. Australian in vitro fertilisation collaborative group. Br Med J 1985;291(6503):1160–1163.
 Pandey S, Shetty S, Hamilton M, et al. Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis. Hum Reprod Update 2012;18(5):485–503.
 Davies MJ, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med 2012;366(19):1806–1813.
 Bonduelle M, Liebaers I, Deketelaere V, et al. Neonatal data on a cohort of 2889 infants born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999). Hum Reprod 2002;17(3):671–694.
 HFEA Code of Practice 9. Welfare of the Child. Available at: https://www.hfea.gov.uk/media/2609/june-2018-code-of-practice-9th-edition-draft.pdf. Accessed January 25, 2019.
CHAPTER 12: FETAL REDUCTION AND SEX SELECTION
Historically, ART has been associated with an unacceptably high multiple-pregnancy rate. This is a direct consequence of the practice of transferring more than one embryo. Many countries mandated the practice of single-embryo transfer more than fifteen years ago, and recent advances in embryo culture and embryo selection have further reduced the need for multiple transfer.
There has been a dramatic reduction in multiple-pregnancy rates in many countries, but the reduction has not been universal. Multiple pregnancies, especially those of high order, confer a considerable risk of inherent complications and sequelae. Fetal reduction is an established method to reduce the number of fetuses, improve the live-birth rate, and reduce risks to the surviving fetuses – risks of prematurity and other complications associated with multiple pregnancy.
In many ART centres, with preimplantation genetic screening for aneuploidy (PGT-A), has greatly improved the embryo selection process, routinely offering a greater than 50% chance of implanting a single euploid embryo. While these screening tools have great benefits in distinguishing normal from abnormal embryos, a potentially unanticipated or undesired result is the disclosure of the gender of the embryo. This application has become the most reliable method of selecting fetal gender, and has been extensively used for this purpose in some countries, with its attendant moral and ethical controversies.
Analysis of the survey
Regarding whether selective fetal reduction (SFR) was permitted, 47 of 77 countries (61%) responded positively, compared to 21 countries in the 2015 survey (Table 1, Chart 1). Of note, China and Czechia acknowledged that their status had changed from “allowed,” in the previous survey, to “allowed with conditions” in 2018.
The majority allowing SFR are in Europe. Another 17 (22%) of the countries do not allow SFR at all, and, as noted in 2016, most are in South America. Venezuela and the United Arab Emirates are new additions. The issue has not been addressed in 7 (9%) of the countries. The status of SFR in the remaining 6 out of 77 (8%) of countries is “unknown”. Seventeen of the 47 permitting countries (36%) allow SFR, with conditions applied.
SFR is performed in 52 of 78 countries (67%), but it is used infrequently in most – 48 of 68 (62%), Exceptions include Belgium, Bulgaria, Czechia, and Greece, where SFR is employed “frequently”. This trend toward SFR use has carried forward since the last survey. Italy responded in the last survey that SFR was not used, but in 2018 noted that it is used, but infrequently. Venezuela was the only country that responded in 2018 that SFR is not allowed – but is performed.
Fifty-five percent n=Twenty-six of 47 countries responding (55%) have federal or national regulations governing the practice of SFR. Of these 26, 2 also have state laws and ordinances; Bolivia has municipal laws, as well. One country (2%) has agency regulations, and 16 countries (34%) have professional organizational guidelines for SFR. Of these 16 with guidelines, 7 (44%) have no federal or state requirements, only professional organizational guidelines. Four countries have cultural and religious policies addressing SFR, in addition to other governances.
Only 19 of 66 surveyed (29%) consistently monitor or document SFR outcomes. That group includes several European countries, New Zealand, and Singapore. Nine countries of 66 (14%) conduct partial or inconsistent monitoring, while 25 countries (38%) do not monitor at all. Remarkably, several countries – including China, India, Russian Federation, and The United States of America – conducted regular monitoring and documentation in 2015, but reported “inconsistent” documenting and monitoring in 2018.
Twenty one of 48 (44%) permit sex selection with PGT-A. Another 6 countries (12.5%), Chile, Ecuador, Guatemala, Mexico, Panama, and Peru, perform PGT-A, although the survey did not address whether using it for sex selection is legally permissible. Twenty-one of 50 countries (42%) also allow sex selection via sperm sorting; 4 countries (8%) actually use it.
Thirteen countries out of 52 (25%) have regulations covering PGT-A use, 10 countries out of 55 (18%), for sperm sorting, and 15 countries out of 55 (59%) for SFR. Only 5 countries, Bulgaria, Hong Kong [China, reporting separately for this report], New Zealand, Singapore, and South Africa have regulations for all 3 categories (Table 2, Chart 2).
For PGT-A, 8 countries of 13 (61.5%) reported having governance regulated by federal or national statutes, ordinances or policies: 2 (15%) by state or provincial policies or legislation, 1 (8%) by municipal laws, statutes or ordinances, 2 (15%) by professional organizations standards or guidelines, one (8%) by existing cultural practices, and one (8%) by religious decrees. For sperm sorting, 8 countries (n=13) reported having governance regulated by federal or national statutes, ordinances or policies, and 1 (8%) by state or provincial policies or legislation. For SFR, 15 responders in 15 countries (100%) reported having governance regulated by federal or national statutes, ordinances or policies, 2 (21%), by state or provincial policies or legislation, 1 (7%) by municipal laws, statutes or ordinances, 2 (21%) by agency regulation or oversight, 2 (21%) by professional organizations standards or guidelines, and one (8%) by existing cultural practices.
Regarding centres where sex selection techniques were allowed, there was no significant difference in the type of clinic reporting. This applied to sole practitioners, small and large private clinics, public hospitals, and university hospitals. China was the only country that did not allow sex selection or fetal reduction procedures to be conducted in private clinics; a hospital or university setting was required.
Only two countries in the survey, Australia and Kazakhstan, reported that all three procedures are considered established medical practice. In Greece and The Republic of Korea, (2 of 58 or 3%) considered PGT-A an experimental method of sex selection; four countries of 52 (8%) considered sperm sorting to be experimental, and only Greece (1 of 56 or 2%) considered SFR to be experimental. Twenty-five of 58 countries (43%) thought of PGT-A as established medical practice, and 25 of 56 (44%) held that opinion of SFR. Only 9 of 52 (17%) considered sperm sorting to be established medical practice.
Regarding sex selection: 24 out of 64 (38%) conducted sex selection only during IVF/ICSI procedures; 8 out of 60 (13%) conducted it with IUI, and only 5 of 58 (9%) did it with SFR.
Sex selection has historically been used in many countries for non-medical reasons, such as “family balancing” and patient preference. Sex selection is a contentious issue, but it is culturally endorsed and offered in several countries. The practice of sex selection with ART has steadily increased with the reliability and availability of PGT-A.
A recent survey noted that 92% of 493 clinics in The United States of America offered PGT-A. Of these clinics, 94% offered sex selection for family balancing; 82% for elective reasons, such as patient preference; and 84% for patients without pre-existing infertility. Recent literature attests to greater acceptance and performance of sex selection for a variety of cultural and economic reasons. This is true in countries as diverse as The Republic of Korea, Ukraine, and Viet Nam. Essentially, a two-fold increase has occurred over the past decade, primarily favoring selection of males[2–4].
These trends may have profound demographic and cultural implications, yet to be addressed. Since 1990, the number of calculated “missing females” has risen by 43 percent (38 million) to 126 million in 2010. According to Bongaarts and Guilmoto, this trend is expected to peak in 2035, with a further increase of 24 million to 150 million, before declining slightly in 2050 to 142 million.
This study also outlines the 3 factors that are essential for prenatal sex selection to reach significant levels in any country:
- Strong preference for a son
- Easy access to prenatal diagnosis
- Low fertility
SFR has evolved over the past few years from a rarely used procedure, to avoid higher-order multiple births, to a more commonly performed practice in some countries for patients undergoing ART. In other countries, such as The United States of America, its availability has become more restricted as multiple pregnancy rates have fallen. In still others it is not permitted at all, although occasionally performed nevertheless by some practitioners.
PGT-A is performed primarily to identify euploid embryos, but gender is determined during the procedure, and this information injects gender selection into the decision options for many couples pursuing ART. Evans et al found that although in the late 80’s and early 90’s there was a definite son preference among individuals in The United States of America, the trend has now been declining steadily, with as many patients now preferring females to males.
Over the past 25 years, fetal reduction has been granted greater acceptance as a safe and preferred procedure in some societies. While reduction of pregnancies of triplets and higher order, to reduce fetal morbidity, has been widely accepted as an essential goal over the past two decades, now, even reduction of twins to singletons is gaining medical and social acceptance.
SFR remained a very contentious issue in 2018, with 39% of 77 responding countries permitting it outright. An additional 22% allowed SFR conditionally, and 22% banned it. The status of SFR was reported by 17% of responding countries as not addressed or “unknown”. While there has been some change in access in a few countries, no significant new trend over the past three years was discernible.
Recent literature suggests that sex selection, particularly with PGT-A, has become much more widely performed, and is almost universally available. Despite this trend, the minority of reporting countries (44%) expressly permit PGT-A for sex selection; even fewer (25%) have regulations restricting it. Sperm sorting and SFR, while available in a few countries, are infrequently practiced.
 Capelouto SM, Archer SR, Morris JR, et al. Sex selection for non-medical indications: a survey of current pre-implantation genetic screening practices among U.S. ART clinics. J Assist Reprod Genet 2018;35(3):409–416.
 King L, Michael M. No country for young girls: market reforms, gender roles and prenatal sex selection in post- Soviet Ukraine. J Polit Econ Res Inst. Working paper series no. 425. 2016:1–29.
 Den Boer A, Hudson V. Patrilineality, son preference, and sex selection in South Korea and Vietnam. Popul Dev Rev 2017;43(1):119–147.
 Bongaarts J, Guilmoto CZ. How many more missing women? Excess female mortality and prenatal sex selection, 1970–2050. Popul Dev Rev 2015;41(2):241–269.
 Evans MI, Andriole S, Britt DW. Fetal Reduction: 25 Years’ Experience. Fetal Diagn Ther 2014;35(2):69–82.
CHAPTER 13: PREIMPLANTATION GENETIC TESTING
Preimplantation genetic testing (PGT) was introduced as a method for embryonic diagnosis of molecular genetic defects linked to specific inherited diseases. Non-affected embryos were selected and transferred to the patient, with the expectation of producing a child free of that disease. Early in the history of PGT, other applications emerged. For example, PGT was used to produce a child selected by HLA haplotyping as a “savior sibling” for a family member afflicted with an incurable disease. Other non-traditional social and medical paradigms have been reported. Currently, PGT is used most commonly to identify a vast number of autosomal single-gene disorders (preimplantation genetic testing for monogenic/single gene disorders, PGT-M), for aneuploidy (preimplantation genetic testing for aneuploidy, PGT-A), and for structural rearrangements (PGT-SR).
PGT-A has been promoted as an adjunct to improve IVF implantation and birth rates, and to reduce risk of miscarriage[2–6]. It is used to identify structural or numerical chromosomal abnormalities[2–6], because euploid blastocysts are presumed to be optimal for transfer, by increasing implantation and live-birth rates per embryo transferred. As such, PGT-A could play an essential role in selecting embryos for single-embryo transfers (SET), and for avoiding multiple pregnancy.
Initially, PGT involved removal of one or two blastomeres from the embryo at the cleavage stage, typically on day three of in vitro development[2–6]. ART centres performing PGT today have for the most part abandoned day three biopsies, and now perform trophectoderm biopsy at the blastocyst stage. Removal of five to ten of the more than 150 cells normally available at this stage is far more than was possible with cleavage-stage embryos[2–6].
Other advantages of blastocyst biopsy include improved survival after biopsy; the need for fewer procedures, because day-five embryos have survived some of the natural selection process; and less mosaicism, because earlier mosaic embryos seem to have the potential to self-correct with advancing embryonic maturity. Biopsied blastocysts are usually cryopreserved with vitrification, with the intent of later replacement after the result of the molecular analysis is received. Molecular methods have evolved substantially over the past three years.
Molecular diagnosis is now performed on 24 chromosomes, using an array of advanced technologies. These include fluorescent in situ hybridization (FISH), polymerase chain reaction (PCR), array comparative genome hybridization (aCGH), single nucleotide polymorphism arrays (SNP arrays), next-generation sequencing technology (NGS), and preimplantation genetic haplotyping (PGH)[2–10]. Unaffected (normal) blastocysts are transferred after thaw. Because embryos with genetic abnormalities are disposed of, PGT allows couples to discard affected or abnormal embryos, rather than having to consider terminating an established pregnancy[2–10].
Earlier versions of PGT-A that relied solely on FISH limited analysis to smaller subsets of chromosomes – typically five to ten, rather than the 24 chromosomes analyzed with newer molecular technology. But clinical outcomes were disappointing. When 24-chromosome technology emerged, and three early randomized clinical trials using either qPCR-based CCS or rapid aCGH described higher birth rates, and single-pregnancy rates with single embryo transfer, the outcomes have not been reproducible in a larger clinical patient population. Although the 2018 Surveillance questionnaire reflects increasing global interest and application of PGT-A, evidence of improved outcomes is lacking, except in small series and selected cohorts, even with increasingly sophisticated molecular technology. Nevertheless, world-wide PGT-A utilization is again expanding, although it has not yet been confirmed to be an effective adjunct for IVF.
PGT is now typically performed for nine indications:
- Autosomal single gene disorders[8,14] (PGT-M)
- Some chromosomal rearrangements[2,4] (PGT-SR)
- X-linked diseases
- Human leukocyte antigen (HLA) typing
- Cancer predisposition genes
- Mitochondrial DNA disorders
- Preimplantation genetic testing for aneuploidy (PGT-A)
- Adult onset disorders[8,15]
- Non-medical sex selection
Analysis of the survey
Fifty-three of 70 responders (76%) indicated that PGT-M (Table 1) is expressly allowed, by statutes, laws, and guidelines. The status of PGT-M was not addressed in 17 of the 70 (24%); its status is indicated “unknown” in 16% – but PGT-M is not known to be specifically prohibited in any of the countries that responded.
When PGT-M is allowed, 24 of 53 countries responding (45%) have guidelines governing its use; use is not regulated in 26 countries responding (49%); and the procedure has a “not-known” status in three countries (6%). PGT-M for single gene disorders is commonly performed as a clinical service in 47 of 67 countries (70%), performed only experimentally in three countries (4%), and not addressed, or unknown, in 17 (25%) of the countries (Table 2, Charts 1 and 2).
PGT-M for single gene disorders is considered acceptable for preventing disease in offspring produced with ART – that is the opinion of 46 of 68 responders (68%). Twenty-one of 65 consider it acceptable to allow the disease in the offspring produced with ART. That was the response chosen in 18 of 64 (28%). Twenty-one of 65 (32%) say that it is permitted for helping to generate an embryo for any immunologically donor-matched diseased child, but it is prohibited in 17 (26%) of the countries. Twenty-three of 65 (35%) say it is considered acceptable in helping to generate a child for any immunologically donor-matched diseased child. It is also allowed for assisting in generating an embryo on behalf of a diseased sibling in 24 of 66 (36%) of the countries and for generating a child on behalf of a deceased sibling in 26 of 66 responders (39%). It is permitted to generate an embryo with a specific disease for research or experimentation, according to 5 in 65 responders (8%), but that is prohibited in 37 of 65 responding countries (57%).
PGT-A is expressly allowed by statutes, laws, and guidelines in 48 of 67 (72%) responding to that question; the status was not addressed or was marked “unknown” in 19 of the 67 (28%). When allowed, it is regulated by guidelines that govern its use in 20 of 48 countries responding (42%), not regulated in 24 of the 48 (50%); its status is not known in 1 of the 48 (2%).
PGT-A for single gene disorders is commonly performed as a clinical service in 42 of 65 countries (65%), performed only experimentally in 4 countries (6%), and is not addressed, or unknown, in 19 of the countries (29%). PGT-A is commonly performed in tandem with PGT-M in 38 of 62 countries (61%).
Regulatory bodies with oversight for PGT-M and PGT-A range from none to combinations of federal, provincial and municipal statutes; various government agencies; and guidelines from professional organizations (Chart 3).
For PGT-M, 100% of 24 responders reported having governance by federal or national statutes, ordinances or policies; in 4 (17%), this was accomplished by state or provincial policies or legislation; in 2 (8%), by municipal laws, statutes or ordinances; in another 2 (8%), by agency regulations or oversight; in 12, (50%) by professional organizations standards or guidelines; in 2 (8%), by existing cultural practices; and in another 2 (8%) by religious decrees.
For PGT-A, all of 20 responders (100%) reported having governance by federal or national statutes, ordinances or policies; 3 (15%) accomplished this by state, regional or provincial policies or legislation; 1 (5%) by municipal laws, statutes or ordinances; 1 (5%) by agency regulations or oversight, 11 (55%) by standards or guidelines professional organization; 1 (5%), by existing cultural practices; and 1 (5%) by religious decrees.
Centres providing PGT-M and PGT-A services, respectively, include sole practitioners in private clinics, 19 responders (95% and 100%); 26 responders, (92% and 88%), small private physician clinics; large multiple practitioner clinics, 27 responders (96% and 93%); hospital based clinics, 22 responders (86% and 100%); university clinics, 28 (93% and 82%); and public hospitals, 19, (95% for both responding countries.
Compared to the 2015 Surveillance questionnaire, PGT-M now comprises an increasing percentage of ART services throughout the world. Its application is often regulated or restricted by statute or local clinical tradition. It is allowed in all countries surveyed. PGT-M was commonly performed in 43% of the 90 responding countries in 2018, compared to 34% of 67 countries in 2015. It is now a well-established and reliable procedure with a low error rate. Drawbacks remain the high cost and inefficiency of IVF as a requisite platform, requirements for extended culture to the blastocyst stage, and relatively reduced birth rates even among fertile women because of the more limited number of embryos available for transfer.
In the United States of America, PGT is frequently deemed experimental by insurance carriers and is usually not covered except for single gene disorders and selected chromosomal defects. Demand for PGT-M in The United States of America, European Union, and Middle East, however, is expanding to include couples that are not infertile but are carriers at risk for transmission of genetic disorders to their progeny. Many of these couples have previously had affected offspring and were reluctant to consider additional pregnancies without PGT-M and others were unwilling to attempt pregnancy at all without some assurance of reduced risk. PGT-M also offers the opportunity to identify embryos carrying relatively common genetic conditions including oncogenes with high penetrance, such as BRCA, that pose risk for devastating diseases later in life. The availability of new molecular genetic tests, public initiatives surrounding specific genetic diseases, and increasing internet marketing of tests and identification of carriers are expected to increased demand for PGT-M worldwide[4,6].
PGT-A appears to be universally available in all 90 countries participating in the questionnaire but is commonly performed in only 50% (Table 1). In 2015, it was commonly performed in 38% of countries. If the newer technologies are proven to truly improve implantation rates, application is likely to be vastly expanded, as was the case with ICSI. However, available current data, while offering preliminary encouragement, are too inadequate and inconclusive to justify broader use.
Surveillance 2019 confirms an ongoing trend of increased accessibility and use of PGT-M and PGT-A worldwide. PGT, and especially PGT-M, provide proven benefits. Both are generally considered safe, and are associated with a low frequency of errors. PGT-M largely prevents women from delivering offspring with serious genetic disorders, avoids the potential need for pregnancy termination, and provides critical reassurance to fearful couples who otherwise would not choose to have children.
Since Surveillance 2016 was published, advances have occurred in the discovery of genetic linkages to common diseases. Examples include many cancers, diabetes, cardiovascular disease, degenerative disorders of old age, some mental illnesses, and even autism spectrum disorders. It seems likely that there will be expanded indications and greater use of PGT-M for some of these common disorders.
PGT-A, more widely used in embryo selection now than in 2016, remains controversial. Although it is claimed to be a valuable tool for embryo selection, and many ART centres have attributed improved clinical success to its use, results have not been widely replicated in appropriately designed clinical trials.
The potential value and role of PGT-A will likely become clearer during the next triennial.
 Simpson JL. Preimplantation genetic diagnosis at 20 years. Prenat Diagn 2010;30(7):682–695.
 Penzias A, Bendikson K, Butts S, et al. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion Fertil Steril 2018;109(3):429–436.
 Sermon KD, Spits C, Mertzanidou A, et al. Detecting mosaicism in trophectoderm biopsies Hum Reprod 2017;32(3):712–713.
 Sermon K. Novel technologies emerging for preimplantation genetic diagnosis and preimplantation genetic testing for aneuploidy. Expert Rev Mol Diagn 2017;17(1):71–82.
 Sermon K, Capalbo A, Cohen J, et al. The why, the how and the when of PGS 2.0: current practices and expert opinions of fertility specialists, molecular biologists, and embryologists. Mol Hum Reprod 2016;22(8):845–857.
 Geraedts J, Sermon K. Preimplantation genetic screening 2.0: the theory. Mol Hum Reprod 2016;22(8):839–844.
 Zamani Esteki M, Dimitriadou E, Mateiu L, et al. Concurrent whole-genome haplotyping and copy-number profiling of single cells. Am J Hum Genet 2015;96(6):894–912.
 Roos RA. Huntington’s disease: a clinical review. Orphanet J Rare Dis 2010;5:40.
 Forman EJ, Hong KH, Ferry KM, et al. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril 2013;100(1):100–107.
 Scott RT, Upham KM, Forman EJ, et al. Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. Fertil Steril 2013(3);100:697–703.
 Yang Z, Liu J, Collins GS, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet 2012;5(1):24–31.
 Calpalbo A, Treff N, Cimadomo D, et al. Comparison of array comparative genomic hybridization and quantitative real-time PCR-based aneuploidy screening of blastocyst biopsies. Eur J Hum Genet 2015;23(7):901–906.
 Simpson JL, Rechitsky S, Kuliev A. Next generation sequencing for preimplantation genetic diagnosis. Fertil Steril 2013;99(5):1203–1204.
 Treff NR, Fedick A, Tao X, et al. Evaluation of targeted next-generation sequencing-based preimplantation genetic diagnosis of monogenic disease Fertil Steril 2013;99(5):1377–1384.
 SenGupta SB, Vadaparampil ST, Menon. Preimplantation genetic diagnosis for hereditary cancers. Adv Exp Med Biol 2012;732:103–113.
CHAPTER 14: SURROGACY
Surrogacy is an arrangement in which a woman (the surrogate) becomes pregnant, then carries and gives birth to a child or children, with the intention of giving the child to another person or couple (the intended parent or parents), who will rear the child. The 2018 IFFS Surveillance questionnaire considered “gestational” and “traditional” surrogacy.
Gestational surrogacy, sometimes referred to as full surrogacy, or “IVF surrogacy”, the gametes of both intended parents, or of one intended parent and a donor egg and/or sperm, are used to create the embryo. Alternatively, a donated embryo created from unrelated gametes is used. The surrogate is genetically unrelated to the offspring intended to be produced by this arrangement.
Traditional surrogacy, sometimes termed natural surrogacy, or partial surrogacy, the surrogate is inseminated with the semen of an intended parent, and the surrogate’s own oocyte is fertilized in vivo. This may involve reproductive assistance, most often in the form of artificial or intrauterine insemination performed at a fertility clinic. Usually, however, the procedure is performed at home. The resulting child or children are genetically related to the surrogate, as her oocytes are used.
The laws that govern IVF surrogacy are complex, and vary among jurisdictions. Determining the local legal status is the usual first step. Full and informed legal advice from someone familiar with the laws of the country where the treatment will occur, or, if different, the country of domicile of the couple, is mandatory. Also essential is careful medical assessment and thorough counseling of all parties involved in an IVF surrogacy arrangement.
The principal reasons people enter into surrogacy arrangements are:
 Medical reasons in which the female intended parent:
- (a) Is without a uterus but has one or both ovaries functioning. This may include women with congenital absence of the uterus, and women who have had a hysterectomy for carcinoma or other reasons;
- (b) has had repeated miscarriages, and the potential for carrying a baby to term is remote. This may include women who have repeatedly failed to become pregnant after IVF treatment;
- (c) has a medical condition that may make pregnancy life threatening, but whose long-term health prospects are good.
 Non-medical or social reasons, such as same-sex coupling, or ongoing single status. This is permitted in only some jurisdictions.
Analysis of the survey
In the 2018 IFFS surveillance of the 89 participating countries, 73 countries (82%) sent responses to at least one question pertaining to surrogacy. This is in comparison to 65 countries in 2016, and 62 countries in 2013.
Differential responding to questions may have reflected the respondents’ knowledge of surrogacy regulation and/or practices in their countries. For example, some respondents knew whether or not there were laws, but did not know whether surrogacy was practiced in their country.
Of the countries that responded to the question “are there regulations that govern IVF surrogacy in your country”, in relation to gestational surrogacy, answers were: yes, 31 out of 72 (43%); no, 35 (49%) and “Unknown”, 6 (8%). In relation to traditional surrogacy: yes, 22 of 68 (32%) no, 40 (59%), and “Unknown,” 6 (9%) (Table 1).1
Twenty-seven countries specified the type or types of regulation used for gestational surrogacy, as follows: 13 respondents (48%), only federal laws; 2 (7%), only state laws; and 5 (19%), only professional standards/guidelines. Seven (26%) of these countries reported a combination of these regulatory instruments (Table 2).
Seventeen countries specified the type or types of regulation used for traditional surrogacy: six (35%) reported having only federal laws; 3 (18%) reported having only state laws, and another 3 (18%) said they had only professional standards/guidelines. Five (29%) of these countries reported a combination of these regulatory instruments.
Regarding the question “is surrogacy permitted or practiced in your country”, 53 countries responded regarding gestational surrogacy, and 45 countries responded regarding traditional surrogacy (Table 3).
To the topic of gestational surrogacy, 24 countries (45%) reported that it was allowed/permitted; 22 (41.5%) reported it was practiced/performed, and 16 (30%) reported “unknown”. For traditional surrogacy, sixteen countries (36%) reported that it was allowed/permitted; 12 (27%) said, practiced/performed; and 22 (49%) reported “unknown”.
Sixty-eight countries participated in the survey regarding the frequency of usage of gestational and traditional surrogacy, 14 (20%) reported that gestational surrogacy was commonly used, 17 (25%) said it was infrequently used; 27 (40%) indicated it was never performed, and 10 (15%) reported “unknown”. As for traditional surrogacy, 3 (4%) said that it was commonly used, 18 (26%) it was infrequently used, 35 (51%) that it was never performed, and 12 (19%) reported “unknown” (Table 4, Chart 1).
In response to the question, “if surrogacy is allowed in your country, are surrogates compensated”, was asked in two ways: for gestational surrogacy and for traditional surrogacy (Table 5).
For gestational surrogacy compensation, 48 responses were received (as opposed to 61 in 2016). Of these responses, 9 countries (19%) reported that compensation beyond reimbursement was permitted; 14 countries (29%) reported that no compensation was allowed; 14 countries (29%) reported reimbursement was allowed for time and expenses only; and 11 countries (23%) responded “unknown”.
As for “traditional surrogacy”, 44 responses were received; 4 countries (9%) reported that compensation beyond reimbursement was permitted; 15 countries (34%) indicated no compensation was allowed; 12 countries (27%) said reimbursement for time and expense was permitted; and 13 countries (30%) responded “unknown”.
In relation to limits on compensation existed, and if so, the range; respondents replied with only limited data. Regarding gestational surrogacy, 33 countries responded. Three countries (9%) replied yes, 4 countries (12%) responded that there was no minimum or maximum amount for compensation, 17 countries (52%) responded that compensation was not addressed, and 9 countries (27%) responded “unknown”.
With regards to traditional surrogacy, 30 countries responded. One country (3%) replied yes, 2 countries (7%) indicated there was no minimum or maximum amount for compensation, 19 countries (63%) responded that compensation was not addressed, and 8 countries (27%) responded “unknown”.
Regarding the topic, “if third party reproduction is permitted in your country, are the qualifications to be a surrogate, based upon medical and/or any lifestyle criteria”, 26 countries (51%) replied yes for gestational surrogacy, and 17 of 45 countries (38%) for traditional surrogacy.
Surrogacy remains a contentious issue worldwide. Respondents from the countries that replied to the current survey reported that neither gestational nor traditional surrogacy were commonly used. When surrogacy was used, gestational surrogacy was used slightly more frequently than traditional surrogacy. Approximately one-third of respondents noted that gestational surrogacy was commonly or infrequently performed in their countries. In many countries, neither gestational nor traditional surrogacy are used at all. As discussed in Chapter 15 (Cross Border Reproduction), some countries will treat intended parent(s) from other countries that prohibit or do not offer surrogacy, or that provide surrogacy, but at high costs.
Both gestational and traditional surrogacy are fraught with multiple potential conflicts when the interests of the various stakeholders clash. These issues are further exacerbated when conducted in an international arena, as several highly publicized cases have demonstrated.
Payment of surrogates continues to be an issue that provokes much debate. Many countries prohibit any form of compensation as a way to prevent the commodification or exploitation of children or reproductive capabilities. In countries where payment is not allowed, surrogates are usually relatives or personal friends of the intended parent(s), and may be permitted to receive reimbursement for “reasonable expenses”. Where there are no laws, practices may occur that are of particular concern, particularly in less developed countries with greater potential for exploitation.
Some limited studies have offered reassurance regarding the psychological and physical well-being of children produced with gestational surrogacy, the surrogate mothers, and the intended parents[1,2]. In most countries, the “birth mother” has always been the legal mother of a child. This issue has been resolved in many countries or states by legislation enabling the genetic parents to become legal parents at the birth of the child. Most surrogacy cases reportedly proceeded without problems, and provided a positive and successful treatment option for a small group of women who otherwise would be unable to have their own genetic children.
Both the European Society of Human Reproduction and Embryology (ESHRE) and the American Society of Reproductive Medicine (ASRM) have published ethical and clinical guidelines pertaining to surrogacy[4,5], advocating thorough evaluation and provisions for managing the small group of women who need this specialized treatment.
IVF or gestational surrogacy is a useful and effective treatment option for women who have no uterus or are otherwise unable to bear children. It allows the commissioning (genetic) couple to have their own children. Gestational surrogacy is practiced in 42% of responding countries; fewer perform traditional surrogacy, a procedure that remains controversial and is permitted in relatively few countries, usually with significant limitations, particularly regarding compensation. The topic engenders considerable international debate about indications for its application, and the potential for exploiting its participants.
 Golombok S, MacCallum F, Murray C, et al. Surrogacy families: parental functioning, parent-child relationships and children’s psychological development at age 2. J Child Psychol Psychiatry 2006;47(2):213–222.
 MacCallum F, Lycett E, Murray C, et al. Surrogacy: the experience of commissioning couples. Hum Reprod 2003;18(6):1334–1342.
 Shenfield F, Pennings G, Cohen J, et al. ESHRE Task Force on Ethics and Law 10: Surrogacy. Hum Reprod 2005;20(10):2705–2707.
 Pfeifer S, Butts S, Fossum G, et al. Recommendations for practices utilizing gestational carriers: a committee opinion. Practice Committee of the American Society for Reproductive Medicine and Practice Committee of the Society for Assisted Reproductive Technology. Fertil Steril 2017;107(2):e3–e10.
 Amato P, Brzyski R, Braverman A, et al. The Ethics Committee of the American Society of Reproductive Medicine. Using family members as gamete donors or surrogates. Fertil Steril 2012;98(4):797–803.
CHAPTER 15: CROSS BORDER REPRODUCTIVE CARE
The term cross-border reproduction (CBR) pertains to ART or related services sought by citizens of one country from within another country. When this situation arises, it usually means that ART procedures are unavailable or encumbered by legal or economic barriers in one country, but not in the other.
CBR is a contentious, largely unregulated area, making data collection particularly challenging. Some topics pertaining to CBR were covered in the 2018 Surveillance questionnaire; the purpose was to find out if people traveled to or from the respondent’s country to engage in ART, and, if they did so, the motive was to seek lower cost services, higher quality services, or services not available in their home country. Some queries sought information about egg, embryo, and sperm donation, and gestational and traditional surrogacy. Some of the information gathered explored whether any regulations applied to inbound and outbound travelers wishing to engage in CBR; other information regarded the importation and exportation of gametes and embryos.
Analysis of the survey
Seventy-five respondents replied to some or all the questions about CBR. The following analysis includes data from the country respondents who provided at least one relevant answer to the issues mentioned.
Do people visit your country to seek cross-border reproduction? (Table 1, Charts 1–3)
Incoming for lower cost ART services
Fifty-six of the 75 countries (75%) responding to this question reported that people traveled to their country to seek lower cost ART services. Austria, Botswana, Ireland, Japan, New Zealand, Norway, Serbia, Singapore, the United Arab Emirates, and The United States of America (13%) reported that people do not travel to their country for lower cost services. In Australia, Chile, Mali, Nigeria, Poland, Switzerland, and Venezuela, the respondents answered “unknown” (9%). Two countries, Finland and Portugal (3%), provided responses to other questions on cross-border reproduction, but said this issue was “not addressed” in their country.
Incoming for higher quality ART services
Fifty-six of the 71 respondent countries (79%) reported that people travel to their country for higher quality services. Nigeria, Botswana, Ireland, Norway, Serbia, El Salvador, Greece, Mexico, Trinidad and Tobago (13%) responded that people do not travel to their country for higher quality services. In Australia, Poland, Lithuania, Venezuela, and the Philippines, the response was “unknown” (7%). One country, Portugal, reported that this was “not addressed” (1%).
Incoming for ART services unavailable in their home country
Forty-eight of the 72 respondents (66%) that answered questions about CBR reported that people travel to their country to access services that are not available in their home country. Fifteen countries (21%) reported that people do not engage in CBR and come to their country for these purposes. One country, Mongolia, answered that this was “not addressed” (1%); and eight countries (11%) replied “unknown”.
Incoming for egg donation
Thirty-four respondents out of 72 (47%) reported that people travel to their country to access egg donation. Twenty-three respondents (32%) reported that potential recipients from other countries do not travel to their country for egg donation. Eleven countries (15%) reported “unknown”. Four countries (5.5%) selected “not addressed”.
Incoming for embryo donation
Twenty-six of 70 respondents (37%) that answered questions concerning CBR reported that people travel to their country to access embryo donation; 27 (39%) reported that people from other countries do not travel to their country to seek embryo donation; 6 (9%) selected that this was “not addressed” in their country; and 11 (16%) reported that the status of this practice was “unknown”.
Incoming for sperm donation
Thirty-six of 71 who responded to this question (51%) reported that people travel to their country to access sperm donation; 21 (29%) said that people from other countries do not travel to their country to receive sperm donation; 12 (17%) reported this as “unknown”, and 2 (3%) selected the answer “not addressed”.
Incoming for gestational surrogacy
Respondents were asked if people travelled to their country to engage in gestational surrogacy. Twenty of the 71 respondents answering questions on cross-border surrogacy (28%) answered in the affirmative; thirty-six countries (51%) answered “no”; eleven respondents (15%) said that the status was “unknown”; and four (6%) selected the answer “not addressed”.
Incoming for traditional surrogacy
Respondents were asked if people travelled to their countries to engage in traditional surrogacy. Of the 68 who answered, 13 (19%) replied in the affirmative; 39 countries (57%) answered “no”; 12 respondents (18%) answered “unknown”; and 4 (6%) selected the answer “not addressed”.
Do people travel from your country to another country to seek cross-border reproduction? (Table 2, Charts 4–6)
Outgoing for lower cost ART services
Of the 29 countries that responded, (43%) reported that people traveled from their country to seek lower cost ART services; twenty-one (31%) indicated that people do not travel from their country for lower cost services; and 14 (21%) chose the answer “unknown”. Three countries (5%) responded “not addressed”.
Outgoing for higher quality ART services
of 72 respondents (60%) affirmed that people travel from their country for higher quality services; 12 (17%) responded that people do not travel from their country for higher quality services;14 respondents (19%) chose “unknown”, and three (4%), “not addressed”.
Outgoing for ART services unavailable in their home country
Forty-two of the 69 respondents (61%) that answered questions pertaining to CBR reported that people travel from their country to access services that are not available in their home country; 16 country respondents (23%) said that people do not travel from their country to engage in CBR elsewhere; 4 (6%) answered that this was “not addressed”; and 7 respondents (10%) replied “unknown”.
Outgoing for egg donation
Forty-six of 71 responding countries, 46 (65%) reported that people travel from their country to another country to access egg donation; 12 (16%) indicated that people from their countries do not travel to other countries to seek egg donation; 11 (16%) said that this was “unknown”; and 2 countries (3%) responding to questions on CBR selected “not addressed”.
Outgoing for embryo donation
Thirty-six of 69 responding (52%) reported that people travel from their country to another country to access embryo donation; 12 respondents (17%) said that people from their country do not travel to other countries for embryo donation; 19 (27%) said that the status was “unknown”; and 2 respondents (3%) selected “not addressed”.
Outgoing for sperm donation
Thirty-six of 70 country respondents (51%) reported that people travel from their country to another country to access sperm donation; 14 respondents (20%) said that people from other countries do not travel to their country to engage with sperm donation; 18 respondents (26%) reported status “unknown”; and 2 (3%) selected “not addressed”.
Outgoing for gestational surrogacy
Of 70 countries, forty respondent countries (57%) answered “yes”; 12 (17%), “no”; 14 (20%), “unknown”; 4 (6%), “not addressed”.
Outgoing for traditional surrogacy
Of 69 countries, 32 (46%) responded in the affirmative (“yes”); 13 (19%), “no”; 20 (29%) said status was “unknown”; and 4 respondents (6%) selected “not addressed”.
Regulation of cross-border reproduction (Table 3)
Respondents were asked if their country had regulations that governed cross-border surrogacy. Specifically, they were asked about regulations governing citizens that visit other countries seeking treatment, and people visiting their home country seeking treatment (Table 3).
Four respondents (6%) (Austria, Italy, Spain, and the United Kingdom of Great Britain and Northern Ireland) answered that they did not have regulations governing people who travel to other countries to access assisted reproduction. Four respondents (6%) (Bulgaria, Romania, Slovenia, and Zimbabwe) said that they do not have regulations governing people coming to their countries for ART. Forty-two respondents (60%) reported that they had neither.
Five respondents (6%) reported having laws that govern only inbound people, not outbound people seeking ART; 1 country, Italy, said it had laws governing only outbound people; 9 respondents (13%) reported having laws that governed both inbound and outbound people seeking treatment. Of these countries there was a mixture between federal laws, state/municipal laws, or both. In general, people travelling to a country to access ART are governed by the laws and regulations of that country.
Columbia and Senegal reported that cultural practices were relevant, and Greece and Italy reported that cultural practices and/or religious decrees were relevant for CBR.
Regulation of the import and export of tissue (Table 4 and 5)
Ova: Thirty-four out of 73 respondents (47%) said that regulations covered the importing of oocytes into their countries, while 20 (27%) reported no regulations; 12 (16%) claimed an “unknown” status, and 7 (10%) selected “not addressed”.
Thirty five out of 73 (48%) said that regulations applied to the importing of spermatozoa into their countries; 19 respondent countries (26%) reported no regulations; 12 (16%) claimed “unknown” status, and 7 respondents (10%) selected “not addressed”.
Zygotes: 32 respondents of 71 (45%) said there were regulations for importing zygotes into their countries; 19 countries (27%) reported no regulations; 12 (17%) reported the status as “unknown”; and eight respondents (11%) selected “not addressed”.
Ova: Of 74 respondents, 33 (44%) said there were regulations addressing the exportation of ova from their countries; and 22 (30%) countries reported the absence of regulations. Eleven respondents (15%) answered “unknown”; and eight (11%) selected the response “not addressed”.
Spermatozoa: 33 of 74 respondents (44%) said there were regulations for the exportation of spermatozoa from their countries; 22 (30%) reported no regulations; 11 respondents (15%) answered “unknown”; and 8 (11%) selected the response “not addressed”.
Zygotes: 31 of 74 respondents (42%) affirmed the existence of regulations pertaining to export of ova from their countries; 22 (30%) reported no regulations; 13 respondents (17%) answered “unknown”; 8 (11%) selected the response “not addressed”.
Overall, a rather large proportion of respondents reported that individuals and couples were travelling to the respondents’ home country to seek treatments that were lower cost (75%), or of higher quality (79%) than those in their own home country, or not available there (66%). Fewer respondents reported people travelling to their country to donate tissue (egg, 47%; embryo, 37%, or sperm, 51%); and even fewer for gestational surrogacy (28%) or traditional surrogacy (19%). These data confirm the existence of these practices, but provide no data about the extent or volume of such services.
A smaller proportion of respondents reported people travelling from their home country to seek treatment that was lower cost (65%), of higher quality (51%), or services not available at home (51%). Figures for seeking egg, embryo and sperm donation were higher for outbound for egg and embryos than inbound, (47% vs, 65%, 37% vs, 52% respectively) and equal for spermatozoa (51%). Rates for outbound people seeking surrogacy were higher than inbound figures, with 57% vs. 28%of respondents reporting people travelling out of the country for gestational surrogacy, and 46% vs. 19% reporting people travelling out of the country for traditional surrogacy. This reflects the desire of individuals to seek services that are otherwise unavailable to them in their own countries.
In regard to regulation, despite a perception of significantly higher levels of movement across borders, the responses indicated that there was little regulation of people travelling to or from other countries to seek ART treatment. Regulation of the import and export of tissue appeared more prevalent; however, several respondents reported no regulation or did not know if regulation existed.
The lack of regulation and lack of knowledge about regulation, may be relevant to egg, embryo and sperm donation, and surrogacy stakeholders. This would likely come about when children born as a result may seek information about their donors or surrogate mothers in the future. This is occurring more frequently all over the world. Tracking and reporting of treatments and treatment outcomes may also become difficult. Patient follow up across borders is considerably more challenging.
CBR appears to be increasingly prevalent; most country respondents noted that individuals traveled to their country seeking ART services that were less expensive, perceived to be of higher quality, or unavailable in their home country. A much smaller group noted patients seeking CBR for sperm, egg, or embryo donation, and even fewer for any type of surrogacy. A relatively smaller proportion reported patients traveling from their country for any of these services. Almost two-thirds (64%) of responding countries reported the absence of regulations for patients either coming to or leaving a country to seek CBR services. These data suggest that a substantial amount of CBR care is being provided, but no data are available regarding the actual volume, and oversight is limited.
CHAPTER 16: HUMAN PRE-IMPLANTATION EMBRYO RESEARCH
In the United States of America, pre-implantation embryos that are not intended for pregnancy are protected by federal mandates of the “Common Rule” at a level surpassing that of surgically removed organs and tissues. Adaptations and interpretations from “Common Rule” governance appear to have been adapted by local and national regulatory bodies as templates for regulation of embryo research internationally, and are reflected in the responses included in the 2018 Surveillance survey.
“Common Rule” regulations emerged after the introduction of IVF. The two major US bodies charged with oversight are the Office of Human Research Protections (OHRP) and the Food and Drug Administration (FDA). Additionally, the National Institutes of Health (NIH), a primary source of funding for research, has regulations and policies that are followed to the extent that a research project (or institution) is funded by the NIH. Subpart A of the regulations, known as the “Common Rule,” has been adopted and separately codified by fourteen agencies other than Health and Human Services (HHS). Its tenants are well known to researchers working in western Europe and in The United States of America, and are likely followed by most of the survey respondents, some of whom trained in these regions.
The questions posed by the Surveillance 2018 questionnaire to the respondents of the 90 countries are based on Common Rule standards. The questions were expected to highlight embryo research as practiced internationally and influenced by federal and regional customs, and interpreted by governments, municipalities, and scholarly committees.
Analysis of the survey
Is experimentation/research on the pre-implantation embryo allowed/permitted in your country?
Research involving donated, unused pre-implantation embryos is allowed in 29 countries out of 74 (39%), and not allowed in 30 countries (41%); its status was marked “unknown” in 15 countries (20%). Research on donated, unused pre-implantation embryos for stem cell research is allowed in 25 of 72 countries (35%), and not allowed in 32 countries (44%); its status was “unknown” in 15 countries (21%). Reproductive cloning generating a human clone is allowed in 2 of 72 countries (3%), and not allowed in 59 (82%); its status was “unknown” in 11 countries (15%). Therapeutic cloning is allowed in in 8 of 72 countries (11%), and not allowed in 51 countries (71%); its status was “unknown” in 13 countries (18%). Embryonic stem cell research is allowed in 13 of 72 countries (18%), and not allowed in 45 (63%); its status was “unknown” in 14 countries (19%) (Table 1, Chart 1).
Is there a requirement for specific approval of experimentation/research proposals? If the answer is yes, is the following allowed or not allowed?
Research involving donated, unused pre-implantation embryos is allowed with specific approval in 26 of 36 countries (72%) not allowed in 5 countries (14%); the status was marked “unknown” in 5 countries (14%). Research on donated, unused pre-implantation embryos for stem cell research is allowed, with specific approval, in 28 countries out of 37 (76%); not allowed in 5 countries (13%); and the status was “unknown” in 4 countries (11%). Reproductive cloning generating a human clone is allowed, with specific approval, in 6 of 18 countries (33%), not allowed in 7, (39%); the status was marked “unknown” in 5 countries (28%) (Chart 2).
In 2015, a single country, Uruguay, responded that human cloning was permitted. Therapeutic cloning is allowed with specific approval in 8 of 21 countries (38%), not allowed in 7 (33%), and the status was “unknown” in 6 countries (29%). Embryonic stem cell research is allowed, with specific approval, in 11 of 24 countries (46%), not allowed in 4 (17%); and the status was “unknown” in 9 countries (37%), compared to five countries responding affirmatively in the 2015 survey.
What body or agency approves experimentation/research?
Research involving donated, unused pre-implantation embryos was reviewed for specific approval by a local or national institutional review board in 14 of 48 countries (29%), by a national ethics or oversight panel in 24 countries (50%), and by an ethics panel in 12 countries (25%); the status was marked “unknown” in 11 countries (23%). Research on donated, unused pre-implantation embryos for stem cell research is reviewed for specific approval by a local or national institutional review board in 14 countries out of 46 (30%), by national ethics or oversight panels in 25 countries (54%); by ethics panels in 12 countries (26%); and the status was marked “unknown” in 10 countries (22%). Reproductive cloning intended to generate a human clone was reviewed for specific approval by a local or national institutional review board in 1 country of 25 (4%); by national ethics or oversight panels in 12 countries (48%); and by ethics panels in 2 countries (8%). The status was “unknown” in 12 countries (48%), and 1 country reported “other” without additional description. Therapeutic cloning is reviewed for specific approval by a local or national institutional review board in 3 countries out of 27 (11%), by national ethics or oversight panels in 10 countries (37%), and by ethics panels in 5 countries (18.5%). The status was marked “unknown” in 12 countries (44%), and 1 country reported “other” as federal regulations. Embryonic stem cell research is reviewed for specific approval by local or national oversight panels in 6 of 33 countries (18%), by national ethics or oversight panels in 14 countries (42%), and by ethics panel in 6 countries (18%). The status was marked “unknown” in 11 countries (33%), and 2 countries responded “other”.
In your country up to what age development in days can experimentation be performed on a developing non-implanted embryo?
There were 20 responses to this question. The full range of responses was 0 to 45 days, with a median of 23 days.
Is experimentation/research on the pre-implantation embryo performed in your country?
Research involving donated unused pre-implantation embryos is underway in 24 countries out of 65 responders (37%). In comparison, 6 countries cited ongoing stem cell research from donated pre-embryos in 2015. Research on donated, unused pre-implantation embryos for stem cell research was performed in 21 of 63 countries (33%). Reproductive cloning generating a human clone was reportedly performed in 2 countries out of 60 (3%). Therapeutic cloning was performed in 7 of 61 countries (11%). Embryonic stem cell research was performed in 12 of 60 countries (20%).
Are there regulations that address experimentation on the pre-implantation embryo in your country?
Research involving donated, unused pre-implantation embryos was regulated in 34 of 66 countries (52%). Reproductive cloning generating a human clone was regulated in 41 of 68 countries (60%). Therapeutic cloning was regulated 40 of 61 countries (61%). Embryonic stem cell research was regulated in 33 of 63 countries (52%).
Countries that regulated research involving donated, unused preimplantation embryos reported having federal or national laws, statutes, ordinances, or policies in 19 out of 34 (56%); state, provincial, or regional laws, statutes, or ordinances in 2 (6%); agency regulations or oversight in 2 (6%); professional organization standards and guidelines in 5 (15%); cultural practices in 1 (3%); and religious decrees in 1 (3%). Countries that regulated embryonic stem cell research reported having federal or national laws, statutes, ordinances, or policies in 18 of 33 (55%); state, provincial, or regional laws, statutes or ordinances in 2 (6%); municipal laws, statutes, or ordinances in 1 (3%); agency regulations or oversight in 1 (3%); and professional organization standards and guidelines in 4 (12%). Countries that regulated therapeutic cloning reported having federal or national laws, statutes, ordinances, or policies in 16 out of 40 (40%); state, provincial, or regional laws, statutes, or ordinances in 2 (5%); and professional organization standards and guidelines in 2 (5%). Countries that regulated reproductive cloning reported having federal or national laws, statutes, ordinances, or policies in 15 out of 41 (37%); state, provincial or regional laws, statutes, or ordinances in 2 (5%); professional organization standards and guidelines in 2 (5%); cultural practice in 1 (2%); and religious decrees in 1 (2%).
Are clinical research programmes in your country performing experimentation on the pre-implantation embryo?
Research on donated, unused pre-implantation embryos for stem cell research is commonly performed in only 2 countries out of 66 reporting (3%), infrequently performed in 12 countries (18%), and never performed in 36 countries (55%); the status was marked “unknown” in 16 countries (24%) (Table 1).
Reproductive cloning generating a human clone is commonly performed in only 1 country out of 67 (2%), infrequently performed in 2 countries (3%), and never performed in 54 countries (81%); the status was marked “unknown” in 10 countries (15%). Therapeutic cloning is commonly performed in only 2 countries of 65 (3%), infrequently performed in 4 (6%), and never performed in 49 countries (75%); the status was marked “unknown” in 10 countries (16%). Embryonic stem cell research is commonly performed in only 7 of 67 countries (11%), infrequently performed in 9 countries (13%), and never performed in 36 countries (54%); the status was “unknown” in 15 countries (22%) (Chart 3).
The United Nations Declaration on Human Cloning, which prohibits all forms of human cloning, was passed in 2005 with 84-member nations voting in support, 34 in opposition, and 37 abstaining. No global consensus emerged because there were concerns expressed regarding its interpretation and potential application to various types of cloning. The 2018 Surveillance survey was intended to assess, in part, the extent of observance of the United Nations resolution 13 years later, and not to seek responses regarding specific research initiatives. As expected, nations that had prior experience with Common Rule tended to have the most strenuous infrastructures for managing research funds, legislation, publication, and enforcement standards. The majority of responding countries now have some form of oversight for research in place.
The 2018 survey reflects an increased amount of investigative activity with donated, unused embryos, usually with restrictions in place and a still small but growing number of countries actively involved in embryonic stem cell research. Most of the countries involved in this research have existing oversight that has evolved, in part, from the Common Rule. Surprisingly, one country, Greece, reported ongoing research pertaining to human reproductive cloning.
In November 2018, the U.S. National Academy of Sciences, including the U.S. National Academy of Medicine, the Royal Society of the United Kingdom of Great Britain and Northern Ireland, and the Academy of Sciences of Hong Kong, convened an international summit to address human genome editing and other aspects of embryo research. More than 500 researchers, ethicists, policymakers, patient group representatives, and others from around the world took part. The potential benefits and risks of human genome editing, ethical and cultural perspectives, regulatory and policy considerations, and public outreach and engagement efforts were considered, and their recommendations were recently published.
Human pre-implantation embryo research remains a contentious topic, with a small minority of countries actively involved in its investigation. With recent advances in clinical application of stem cell research, a small but growing number of countries are conducting studies using embryonic stem cells provided by donated, unused embryos, with restrictions. Human reproductive cloning remains almost universally prohibited.
 Available at: https://www.nap.edu/catalog/25343/second-international-summit-on-human-genome-editing-continuing-the-global-discussion. Accessed January 26, 2019.
CHAPTER 17: STATUS OF THE EMBRYO
One of the first issues to be addressed with the inception of life created outside of the mother’s body was the status to be accorded the embryo. Determining when life begins is a topic that has preoccupied theologians, biologists, and legal scholars for millennia, but no one had anticipated the advent of in vitro fertilization. Universal moral and ethical principles govern the treatment of individuals, and are embraced by governments and societies, but ART poses unique potential conflicts of interest for prospective mother and child when their mutual welfare does not overlap. These moral dilemmas are not easily resolved by classical ethical tenets. These issues revolve around the question of whether there is a point in embryonic or fetal development when personhood is conveyed, with its inherent legal rights, before which time a person is not considered to exist. The striking differences in how various countries reconcile these dilemmas highlight some of the most significant issues in the international governance of ART.
In the 2018 questionnaire, the following questions were posed:
- “Is there a recognized point in time during human development in which a human exists and thus provided human rights?”
- “Through which governing bodies or agencies is this time of human existence determined?”
- “Is there a recognized point in time during human development before which a human person is considered not to exist and thus not provided human rights?”
- “Through which governing bodies or agencies is this time of human non-existence determined?”
Analysis of the survey
Representatives of 74 countries responded to the first question. Thirty-one (42%) noted that such a point existed (Table 1). It was day “0” (pre-fertilization), stated five nations (7%): Australia, Greece, Ireland, Spain, and Uruguay. Day “1” (post-fertilization) was the choice of 13 countries (18%): Bolivia, Brazil, Ecuador, El Salvador, Guatemala, Mexico, Nigeria, Peru, Philippines, Poland, Portugal, Senegal, and Zimbabwe. A time between day 2 and 126, said 9 countries (12%). The Russian Federation, Thailand, and The United States of America (4%) chose 280 days, and United Kingdom of Great Britain and Northern Ireland (1%) specified 281 days as the point at which human rights are conveyed (Chart 1).
Of the 31 countries that have chosen a point at which a human is recognized to exist, the majority of countries – 28 of them – (90%) back up their decision with federal or national statutes, ordinances, or policies, and 7 (23%) do so by state or provincial policies or legislation. Only 3 (10%) rely on municipal laws, statutes, or ordinances. Eight (26%) use professional organizations’ standards or guidelines, 9 (29%), existing cultural practices; and thirteen (42%), religious decrees.
Regarding question 3, responses were received from 66 countries; responders from 14 countries (21%) acknowledged a specific point before which a person was not considered to exist. Thirty-five respondents (53%) did not recognize such a point or time, and 17 (26%) reported “unknown” (Table 2). Among countries that did recognize such a point, it was day 0 for Ecuador, Ireland, and Senegal; day 1 for Argentina; and 280 days for Canada, Finland, The United States of America, and the United Kingdom of Great Britain and Northern Ireland. For Egypt, Kazakhstan, Georgia, Norway, Austria, and Germany, the time ranged from 41 to 97 days (Chart 1). The point was determined in most countries (13 out of 14; 93%) by federal or national statutes, laws, or ordinances.
In the 2018 survey, 10 more countries responded to the first question than had done so 3 years earlier (74 versus 64 responses). Considerably more countries now recognize a point at which personhood is acknowledged (42% vs 28%). There was less difference in the response rate to question 2 (66 vs 64 responses) and this time only 21% acknowledged that there was a point before which a person was not considered to exist. In 2015, the figure was 33%. The response “unknown” was given for question 1 by 20 responders (27%) and for question 3 by 17 responders (26%); in 2015, the responses for the same questions were 30% and 17%, respectively. The results suggest a greater emphasis currently on determining a time personhood is reached, but they still show great variability in when that time is recognized.
Since the original ruling of the Inter-American Court of Human Rights (IACHR) in Costa Rica, granting the rights of 18 plaintiffs to access ART, was upheld in February 2016. Since that time, Costa Rica has established two ART centres and participated in this most recent survey. No countries are currently known to continue to pose statutory obstacles to access of ART.
IVF now appears to be universally available, but marked differences exist among countries regarding the status and protection given to the embryo. An increasing proportion of countries now recognize a point at which an embryo or fetus reaches personhood, with attendant legal rights; and fewer countries are defining a point before which a person is said to not exist. Considerable variation continues among nations as to when these points are defined, and there does not seem to be a trend towards consensus.
CHAPTER 18: CONCLUSIONS
The 2018 questionnaire used to produce the International Federation of Fertility Societies’ Surveillance (IFFS) 2019: Global Trends in Reproductive Policy and Practice, 8th Edition, succeeded in engaging respondents from 97 countries to complete all or a portion of the 94 questions in the survey. With 22 more countries responding than was the case with the 2015 project, the 8th edition offers a more complete depiction of the international status of the practice of ART. But the opportunity to make meaningful comparisons over the three years is limited, because the two editions include some different participating countries.
The data collected suggest that several countries, primarily in Africa, have recently started their inaugural ART programmes; that overall the number of new ART centres around the world has leveled off, with most countries recording modest increases in the number of centres; and that several nations now have fewer centres than in 2015. If the latter finding is validated, uncovering the contributing factors will be a query for the next triennial review.
The proportion of countries that have some regulatory oversight continues to increase. More than 86% of respondents now cite a regulatory oversight system, including national or federal legislation, provincial or municipal statutes, agency inspections, and professional guidelines. New regulatory efforts have addressed anonymous donation, cross-border reproduction, IVF surrogacy, pre-implantation genetic diagnosis, and experimentation on embryos, and cover issues such as marital status, micromanipulation, and same-sex parenting. Additional licensing and monitoring requirements have been imposed, and certification and examination processes expanded. What has not taken place is a marked increase in the proportion of countries with legislation or clinical guidelines that restrict the number of embryos permissible for transfer to women undergoing IVF/ART cycles (currently 59%, vs. 56% in 2015). More countries (35% vs. 24% in 2015) now report penalties for non-compliance regarding the number of embryos transferred.
Insurance coverage for ART is offered by a minority of countries, with only 47% providing support for any infertility therapy. There are significant regional variations for eligibility and the extent of coverage offered. Greater support does seem to be provided for genetic screening. No significant changes were identified in the proportion of countries that tie reimbursement to the number of embryos transferred.
The majority of countries (62%) do not require couples or individuals to be in a recognized or stable relationship to access ART services. Countries accepting single women (68%) and female same-sex couples (45%) for provision of ART services is more prevalent than those extending the same access to men (32%) or male same-sex couples (21%).
Technologic advances in ART have been broadly adopted. ICSI is widely accepted and universally available. PGT-M is expressly permitted in about 75% of respondent countries, not prohibited by any, and performed in about half. PGT-A and assisted hatching have been shown to be valuable adjuncts for some types of patients, but their indications and overall value are still being defined. PGT-A for aneuploidy was available in all responding countries, but is actively performed in 50% (45 of 90), compared to 42% in 2015.
Considerable ongoing interest remains for IVM, but there has been no recent significant clinical progress, and clinical adoption awaits translational investigations and clinical validation. The same is true for cytoplasmic transfer, mitochondrial transfer, and CRISPR-Cas9 technology – for which there is ongoing research; but all are considered investigative. Human preimplantation embryo research remains controversial; relatively few countries are participants. This number is likely to increase, however, with recent advances in stem cell research. A growing number of countries use embryonic stem cells provided by donated, unused embryos, with restrictions. Human reproductive cloning remains almost universally prohibited.
Gamete and embryo donation are well established ART practices, and are employed, if not sanctioned, by a large majority of the responding countries. Overall, about 50% to 60% of countries surveyed report using gamete or embryo donation, although “de novo” embryo donation is used less often, accepted in around 25% to 35% of countries. The vast majority of country respondents (71%) noted acceptance and successful application of cryopreservation of sperm, oocytes, and embryos. However, extensive variation continues among the country respondents in terms of which practices are regulated and how they are regulated. Gamete and embryo donation have been well established ART practices, and are used by a large majority of countries. Overall, 50% to 60% of countries offer gamete or embryo donation. In contrast, “de novo” embryo donation is less commonly accepted, and available only in 25% to 35% of countries.
The 2018 Surveillance questionnaire reaffirmed the controversial aspects of several ART practices, including gestational surrogacy, posthumous reproduction, cross-border reproduction (CBR), and selective fetal reduction (SFR). About one-third of countries practice gestational surrogacy; fewer, traditional surrogacy. Most have measures in place prohibiting or sharply curtailing the practice.
Surveillance 2019 notes an increased application of all types of posthumous reproduction, including insemination of cryopreserved sperm and oocytes, and transfer of cryopreserved embryos – despite the apparent decline in the number of countries that have legislation or other measures in place pertaining to posthumous reproduction.
CBR has become increasingly prevalent. Most country respondents noted that individuals have traveled to their country for ART services that were less costly, perceived to be of better quality, or unavailable at home. About two thirds (64%) of respondents cited the absence of regulations for patients seeking CBR services entering or leaving a country. Only a third of the 89 responding countries permit SFR outright; another 19% allow it conditionally, and 19% ban it completely. Sex selection, usually performed with PGT-A, is being applied more frequently, and is almost universally available. Despite this, relatively few countries (24%) expressly permit PGT-A for sex selection; even fewer have regulations restricting it. Sperm sorting and SFR, while available in a few countries, is infrequently practiced.
There has been ongoing interest and legislative activity have addressed several social, legal, and non-technical aspects of ART. While possibly less contentious, they have widely different applications. Some countries have enacted extensive measures to ensure the welfare of the child; a discernible trend has been directed towards more intensive assessment of the prospective parents before treatment begins. Yet 74% of countries require no formal assessment. At a later stage in the ART process, an increasing proportion of countries are recognizing a point in embryo development at which personhood is achieved and specific legal rights are assigned. These points vary widely among countries, and there does not appear to be an identifiable trend towards consensus.
The International Federation of Fertility Societies’ Surveillance (IFFS) 2019: Global Trends in Reproductive Policy and Practice, 8th Edition, provides a more complete rendering of the global status of ART. It captures more data from a greater number of respondents, and makes the first effort to define the extent of the ART frontier by listing countries not thought to be engaged in the practice of ART. The publication provides a vast amount of data for a variety of stakeholders – including clinicians, researchers, patients, policy makers, and health ministers. It depicts considerable progress in technical application, access to ART services, and consensus around issues pertaining to safety and social justice, but also highlights some inconsistencies between intent and actual application of some ART policy. It attests to the dynamic aspects of a still rapidly evolving transformative field.
Dr. Sonia Allan OAM CF
Associate Professor of Health Law, Deakin University, Australia
Dr. Basak Balaban
IVF Laboratory Director, American Hospital of Istanbul, Istanbul, Turkey
Dr. Manish Banker MD
Medical Director, Nova IVI Fertility, India
Consultant, Nova IVI Fertility Ahmedabad
Dr. John Buster
Emeritus Professor, Brown University, Providence, RI
Dr. Marcos Horton
ART Lab Director, Pregna Medicina Reproductiva, Buenos Aires, Argentina
Dr. Kathleen Miller
Scientific Director, IVF Florida Reproductive Associates, Margate, FL
Laboratory Director, RMA Connecticut, Norwalk, CT
Laboratory Director, RMA Michigan, Troy, MI
Laboratory Director, Billings Clinic, Billings, MT
Vice President, MedTech For Solutions
Managing Editor, Surveillance
Dr. Edgar Mocanu
Rotunda Hospital and the Royal College of Surgeons in Ireland, Parnell Square, Dublin 1, Ireland
Dr. Steven J Ory
IVF Florida Reproductive Associates, Margate, FL
Professor of Obstetrics and Gynecology, Florida International University, Miami, FL
Voluntary Associate Professor of Obstetrics and Gynecology, University of Miami, Miami, Florida
Dr. Hirshikesh Pai
Medical Director, Bloom IVF Centre, Mumbai, India
Dr. Sheryl van der Poel
Scientist/Medical Officer, Population Council, New York, New York
Dr Fernando Zegers-Hochschild
Professor, University Diego Portales, Santiago, ChileCopyright © 2019 The Authors. Published by Wolters Kluwer on behalf of the International Federation of Fertility Societies. All rights reserved.