RA Anderson, MC Davies, SA Lavery, on behalf of the Royal College of Obstetricians and Gynaecologists

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 Scientific Impact Paper No. XX Peer Review Draft January 2019 Elective Egg Freezing for Non-Medical Reasons RA Anderson, MC Davies, SA Lavery, on behalf of the Royal College of Obstetricians and Gynaecologists Correspondence: Royal College of Obstetricians and Gynaecologists, 27 Sussex Place, Regent s Park, London NW1 4RG. Email: clinicaleffectiveness@rcog.org.uk Plain language summary Although a woman s fertility declines markedly in her late-30s and early-40s, gradually more and more women are wishing to start a family at this stage of their lives, with the average age of childbirth progressively increasing. More women are storing their eggs to give them the potential opportunity to achieve pregnancy in the future. The technology for freezing eggs changed dramatically about a decade ago with the development of a technique called vitrification, which gives success rates almost as good as using fresh eggs. The growing use of this technique, and the publicity surrounding how this technique may have been promoted, has led to this guidance. It is essential that women are very clearly informed about the likely success rates of egg freezing, particularly as it is entirely provided by the private sector, with the associated concerns of costs and inappropriate or inaccurate marketing. Its success is strongly dependent on the age of the woman at the time of freezing her eggs, with much higher success rates in those aged 35 years and under. Current legislation only allows women to store eggs for 10 years, which conflicts with the better success rates when women do so at a younger age. The reasons behind the increase in egg freezing are complex, but the most common reason given by women storing eggs is that they are single and are concerned that by the time they do find themselves in a relationship within which they wish to start a family, they may be too old. We conclude that elective egg freezing provides women with an opportunity to take action about the decline in their fertility, but at present most women who are doing this are already in their later 30s when the success rates are limited. We strongly support the need for improved education of both women and men regarding the decline in female fertility with age. 1. Background The age at which women have their children has been increasing steadily for many years in developed countries. For example, the number of births to women over 35 in the UK has tripled since 1980 (Appendix I). 1 Societal changes reflect increasing educational and employment opportunities for women, with substantial social and economic benefits. However, age is the key determinant of female fertility, as the population of primordial follicles in the ovaries is established during fetal life and declines progressively until the menopause. In addition, the inability to maintain chromosomal integrity results in a decline in oocyte quality. This double jeopardy results in a fall in the likelihood of conceiving with age, along with an increase in the risk of such a pregnancy resulting in miscarriage. Men have similar parenthood aspirations as women, but may have limited knowledge of the impact of age on female fertility. 2 The dichotomy between women s reproductive ambitions and oocyte biology has led to increasing numbers of women utilising reproductive technology to undergo ovarian stimulation followed by the recovery and cryopreservation of oocytes (egg freezing) to allow deferment of their reproductive RCOG Scientific Impact Paper No. XX 1 of 8 Royal College of Obstetricians and Gynaecologists

52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 potential. These can then be stored over long periods of time and used if more conventional ways of starting a family do not occur. This procedure is widely known as social egg freezing, but the term elective egg freezing does not have judgemental overtones and is preferred. Current UK legislation allows egg freezing for a maximum of only 10 years, in the absence of a medical indication. Oocyte freezing is also used for fertility preservation for purely medical reasons, e.g. for women with a new cancer diagnosis facing gonadotoxic therapy. It appears that many more women around the world are currently storing oocytes for elective rather than medical reasons, and many are already in their late 30s 3 when the efficacy of the procedure is declining. 2. Efficacy of cryopreservation Cryopreservation to preserve reproductive potential was first achieved with semen storage, and successful pregnancies have been reported using sperm frozen for more than 20 years. Embryo storage followed on the heels of in vitro fertilisation (IVF) and is in widespread use; the success rates achieved are now slightly above fresh embryo transfer. 4 Freezing of oocytes proved more technically challenging; despite the first report of a live birth in 1986, 5 pregnancy rates remained low until the development of vitrification 6 which has transformed success rates and replaced slow freezing in most, but not all, IVF laboratories. In the best hands, a vitrified oocyte has the same developmental potential as a fresh oocyte, thus preventing subsequent age-related decline. 7 The clinical pregnancy rates reported in randomised series using warmed oocytes fertilised in vitro are equivalent to fresh IVF treatment, 7 however, these are from egg donors, who are selected for optimum fertility and are usually much younger than the recipients. Nevertheless, the American Society for Reproductive Medicine (ASRM) changed the status of oocyte vitrification and warming from experimental to established in 2012. 8 The first UK data were reported by the Human Fertilisation and Embryology Authority in 2018 4 for the period 2014 16. In 2016, there were 1310 egg freezing cycles in the UK, and 519 cycles of treatment using frozen stored eggs (Appendix II) with a live birth rate of 18% per embryo transfer, compared to 26% for fresh IVF treatment in the same period 4. These data do not distinguish between egg donation cycles and women storing their own eggs for medical or elective reasons. Larger series are reported from the US, 9 with 8825 cycles for oocyte banking in 2016, although these data are based on voluntary reporting. The likelihood of future live birth is dependent on the woman s age at the time of oocyte storage, as well as the number of oocytes stored. Recent European data indicate high (more than 90%) cumulative live birth rates (CLBR) in women who had electively cryopreserved oocytes at 35 years and under, with storage of ten eggs giving a CLBR of 42.8% compared with 25.2% in women aged 36 years and over at the time of storage. 10 In the UK in 2016, 32% of women were under 35 years old, and 62% under 38, although how many were egg donors, who must be aged below 35, is not recorded by the HFEA. Modelling analyses indicating the effect of a range of ages and number of oocytes stored have also been published, 11 using data from fresh oocytes from couples undergoing intracytoplasmic sperm injection for male factor or tubal infertility. Such analyses may represent a best case scenario, which individual centres with less than perfect oocyte vitrification techniques may be unable to match. However, the current UK legal limit of 10 years for duration of elective oocyte freezing is against the interests of women wishing to freeze eggs at a younger, more effective age. Cryopreservation of ovarian tissue is also used for medical fertility preservation and could potentially be used for non-medical reasons; it would allow restoration of endocrine function as well as fertility, but the need for surgical intervention (both to remove tissue and later replace it) is an important RCOG Scientific Impact Paper No. XX 2 of 8 Royal College of Obstetricians and Gynaecologists

102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 consideration. In practice, elective ovarian tissue freezing is not routinely available, and would require licensing by the UK Human Tissue Authority. 3. The context of elective egg freezing Information from national databases confirm that the numbers of women banking eggs for nonmedical reasons is increasing 4 and we are beginning to understand what is motivating individuals to make this choice. The general demographic forces associated with delaying motherhood, including education and opportunity in the workplace, are well recognised, and this is also driven by the wish of men to defer parenthood. 2 The lack of a current partner is cited by women undergoing elective egg freezing as the most common reason for postponing childbearing. 12 Studies of these women show that the majority are university educated, in professional employment, between the ages of 36 and 40 years and not in a relationship at the time of egg banking. They express the desire to become a mother, ideally when in a committed relationship with a partner, but many would also consider the use of donor sperm if they were unable to find such a partner. 4. Ethical considerations The ethics of elective egg freezing has attracted much commentary, focussing on issues such as the medicalisation of reproduction, women s autonomy and idealisation about the right time to have a baby. It is likely that many women electively freezing eggs will never return to use them; concerns have therefore been expressed about the potential number of unnecessary medical interventions and the exploitation of reproductive anxiety. There is an additional concern that having eggs in storage might give women a false sense of security in the technology, encouraging them to delay parenthood even longer, with no guarantee of a future pregnancy. Elective egg freezing has been compared with autologous blood storage for elective surgery. 13 In both situations: there is storage of a tissue to treat possible future health issues the person is healthy at the point of intervention the procedures are established, with medical and psychological advantages for the patient the need for donor material is avoided there is no certainty the tissue will ever be used. All indications for oocyte freezing should be evaluated using standard ethical perspectives, such as focussing on the balance between benefit and risk/cost, whether women are concerned about the threat to their future fertility from, for example, chemotherapy, or solely increasing age. The Ethics Committee of the ASRM has found elective egg freezing to be ethically permissible, using as main arguments enhancing reproductive autonomy and promoting social equality, although the cost of egg banking may conversely be socially divisive. A key element of ethical practice involves the honest, accurate counselling of women about their individual expectation of success when contemplating this procedure. It is essential that this should include both the woman s age and centrespecific information. Marketing the technology as a form of reproductive insurance is inappropriate, given the limited success rates in the women most likely to store eggs. 5. Safety of cryopreservation While the greatest risks to offspring after fertility treatment using frozen oocytes are associated with multiple pregnancy and the sequelae of prematurity including cerebral palsy, 14 there are no known RCOG Scientific Impact Paper No. XX 3 of 8 Royal College of Obstetricians and Gynaecologists

153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 additional risks specific to cryopreservation. These issues should be considered in women who intend to use their own stored eggs at a later age, especially the risk of multiple pregnancy which is related to age (as an index of oocyte quality) at storage, 13 and should be minimised by a single embryo transfer strategy. Women embarking on pregnancy at a later age also experience greater obstetric risks, particularly in a first pregnancy, notably pre-eclampsia, gestational diabetes, and the likelihood of delivery by caesarean section. Storing a sufficient number of eggs requires the use of gonadotrophins to stimulate the ovaries to produce multiple follicular development, and therefore carries the risk of ovarian hyperstimulation syndrome, although the refinement of stimulation protocols (for example, the use of an agonist trigger) greatly reduces this risk. 11 Possible complications from the egg harvest procedure include bleeding, pelvic infection, thrombosis, and the risks of anaesthesia. There are no long-term follow-up studies on children born from frozen oocytes. 6. Opinion Elective egg freezing provides women who are not in a position to start their family an opportunity to mitigate the inevitable decline in their fertility with increasing age. While often perceived (and promoted) as a form of insurance, it is essential that women undertaking egg freezing do so with a full understanding of the likelihood of success, as well as costs and risks. Success rates will be limited in women who are already in their mid late 30s, while younger women are disadvantaged by the current legislated limit of 10 years duration of storage, 14 which we feel strongly should be changed. An upper limit based on age (for both storage and use) might be more sensible for medical, biological and social reasons, but as it would be difficult to justify a single age that would be appropriate for all situations, a limit specified in primary legislation should be removed. The significant costs associated with the procedure and subsequent egg storage preclude many women from being able to consider it, raising issues of equality of access. Given that the NHS (or analogous state insurance systems in other countries) will not provide egg banking, this service is provided in the private sector with inevitable commercial implications and concerns over marketing strategies. It seems likely that the future will see increasing numbers of women storing eggs, mostly because they are not in a relationship, but there remains a need for societal changes that support women in the workplace to have their family at an appropriate age without compromising their career prospects. The increasing recognition of the need to improve public education about age-related changes in female fertility should highlight the importance of men s knowledge as well as that of women. References 1. Office for National Statistics. Births in England and Wales: 2015. http://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/livebirths/ bulletins/birthsummarytablesenglandandwales/2015. 2. Hammarberg K, Collins V, Holden C, Young K, McLachlan R. Men's knowledge, attitudes and behaviours relating to fertility. Hum Reprod Update 2017;23:458 80. 3. Cobo A, García-Velasco JA, Coello A, Domingo J, Pellicer A, Remohí J. Oocyte vitrification as an efficient option for elective fertility preservation. Fertil Steril 2016;105:755 64.e8. RCOG Scientific Impact Paper No. XX 4 of 8 Royal College of Obstetricians and Gynaecologists

202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 4. Human Fertilisation and Embryology Authority. Egg freezing in fertility treatment Trends and figures: 2010-2016. HFEA; 2018 [https://www.hfea.gov.uk/media/2656/egg-freezing-in-fertilitytreatment-trends-and-figures-2010-2016-final.pdf]. Accessed 2019 Jan 22. 5. Chen C. Pregnancy after human oocyte cryopreservation. Lancet 1986;1:884 6. 6. Argyle CE, Harper JC, Davies MC. Oocyte cryopreservation: where are we now? Hum Reprod Update 2016;22:440 9. 7. Cobo A, Kuwayama M, Pérez S, Ruiz A, Pellicer A, Remohí J. Comparison of concomitant outcome achieved with fresh and cryopreserved donor oocytes vitrified by the Cryotop method. Fertil Steril 2008;89:1657 64. 8. Practice Committees of American Society for Reproductive Medicine; Society for Assisted Reproductive Technology. Mature oocyte cryopreservation: a guideline. Fertil Steril 2013;99:37 43. 9. Society for Assisted Reproductive Technology National Summary Report [https://www.sartcorsonline.com/rptcsr_publicmultyear.aspx?reportingyear=2016]. Accessed 2018 Sep 20. 10. Cobo A, García-Velasco J, Domingo J, Pellicer A, Remohí J. Elective and onco-fertility preservation: factors related to IVF outcomes. Hum Reprod 2018;33:2222 31. 11. Youssef MA, Van der Veen F, Al-Inany HG, Griesinger G, Mochtar MH, Aboulfoutouh I, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev 2011;(1):CD008046. 12. Baldwin K, Culley L, Hudson N, Mitchell H, Lavery S. Oocyte cryopreservation for social reasons: demographic profile and disposal intentions of UK users. Reprod Biomed Online 2015;31:239 45. 13. Pennings G. Ethical aspects of social freezing. Gynecol Obstet Fertil 2013;41:521 3. 14. El-Toukly T, Bhattacharya S, Akande VA, on behalf of the Royal College of Obstetricians and Gynaecologists. Multiple pregnancies following assisted conception. BJOG; 2018. RCOG Scientific Impact Paper No. XX 5 of 8 Royal College of Obstetricians and Gynaecologists

229 230 Appendix I: Births in England and Wales 1981 2015 by woman s age. 1 140 Births per 1000 women, England and Wales 120 100 80 60 40 20 Under 20 20-24 25-29 30-34 35-39 40 and over 231 232 233 0 1980 1990 2000 2010 RCOG Scientific Impact Paper No. XX 6 of 8 Royal College of Obstetricians and Gynaecologists

234 235 Appendix II: Number of egg freezing and egg thawing cycles in UK, 2010 16. 4 236 237 238 RCOG Scientific Impact Paper No. XX 7 of 8 Royal College of Obstetricians and Gynaecologists

239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 This Scientific Impact Paper was produced on behalf of the Royal College of Obstetricians and Gynaecologists by: Professor RA Anderson FRCOG, Edinburgh; Miss MC Davies FRCOG, London; and Mr SA Lavery MRCOG, London and peer reviewed by: XXXX The Scientific Advisory Committee lead reviewer was: Dr K Jayaprakasan MRCOG, Nottingham. The chair of the Scientific Advisory Committee was: Professor MD Kilby FRCOG, Birmingham. All RCOG guidance developers are asked to declare any conflicts of interest. A statement summarising any conflicts of interest for this Scientific Impact Paper is available from: https://www.rcog.org.uk/en/guidelinesresearch-services/guidelines/sipxx/. The final version is the responsibility of the Scientific Advisory Committee of the RCOG. The paper will be considered for update 3 years after publication, with an intermediate assessment of the need to update 2 years after publication. DISCLAIMER The Royal College of Obstetricians and Gynaecologists produces guidelines as an educational aid to good clinical practice. They present recognised methods and techniques of clinical practice, based on published evidence, for consideration by obstetricians and gynaecologists and other relevant health professionals. The ultimate judgement regarding a particular clinical procedure or treatment plan must be made by the doctor or other attendant in the light of clinical data presented by the patient and the diagnostic and treatment options available. This means that RCOG Guidelines are unlike protocols or guidelines issued by employers, as they are not intended to be prescriptive directions defining a single course of management. Departure from the local prescriptive protocols or guidelines should be fully documented in the patient s case notes at the time the relevant decision is taken. RCOG Scientific Impact Paper No. XX 8 of 8 Royal College of Obstetricians and Gynaecologists