Elective Egg Freezing for Non-Medical Reasons: Scientific Impact Paper No. 63.

Although a woman's fertility declines markedly in her late-30s and early-40s, gradually more and more women start a family at this stage of their lives, with the average age of childbirth progressively increasing. More women are storing their eggs (oocytes) to give them the potential opportunity to have a baby in the future. Nonetheless, the number of egg freezing cycles accounts for less than 2% of IVF cycles, and the number of cycles using stored eggs is even lower. The technology for freezing eggs changed dramatically about a decade ago with the development of a technique of rapid freezing 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 paper. 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 financial 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 do not have a partner and are concerned that by the time they do find themselves in a relationship within which they wish to start a family, they may not be able to. We conclude that elective egg freezing provides women with an opportunity to take action about the drop 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 and continuing education of both women and men regarding the decline in female fertility with age.

Clinical parameters of ovarian hyperstimulation syndrome following different hormonal triggers of oocyte maturation in IVF treatment.

OBJECTIVE: Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic condition, predominantly related to the hormone used to induce oocyte maturation during IVF treatment. Kisspeptin is a hypothalamic neuropeptide that has recently been demonstrated to safely trigger final oocyte maturation during IVF treatment even in women at high risk of OHSS. However, to date, the safety of kisspeptin has not been compared to current hormonal triggers of oocyte maturation. DESIGN: We conducted a retrospective single-centre cohort study investigating symptoms and clinical parameters of early OHSS in women at high risk of OHSS (antral follicle count or total number of follicles on day of trigger ≥23) triggered with human chorionic gonadotrophin (hCG) (n = 40), GnRH agonist (GnRHa; n = 99) or kisspeptin (n = 122) at Hammersmith Hospital IVF unit, London, UK (2013-2016). RESULTS: Clinical Parameters of OHSS: Median ovarian volume was larger following hCG (138 ml) than GnRHa (73 ml; P < .0001), and in turn kisspeptin (44 ml; P < .0001). Median ovarian volume remained enlarged 20-fold following hCG, 8-fold following GnRHa and 5-fold following kisspeptin compared to prestimulation ovarian volumes. Mean (±SD) ascitic volumes were lesser following GnRHa (9 ± 44 ml) and kisspeptin (5 ± 8 ml) than hCG (62 ± 84 ml; P < .0001). Symptoms of OHSS were most frequent following hCG and least frequent following kisspeptin. Diagnosis of OHSS: The odds ratio for OHSS diagnosis was 33.6 (CI 12.6-89.5) following hCG and 3.6 (CI 1.8-7.1) following GnRHa, when compared to kisspeptin. CONCLUSION: Triggering oocyte maturation by inducing endogenous gonadotrophin release is preferable to the use of exogenous hCG in women at high risk of OHSS.

The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function.

STUDY QUESTION: What are the in vivo and in vitro actions of kisspeptin-54 on the expression of genes involved in ovarian reproductive function, steroidogenesis and ovarian hyperstimulation syndrome (OHSS) in granulosa lutein (GL) cells when compared with traditional triggers of oocyte maturation? SUMMARY ANSWER: The use of kisspeptin-54 as an oocyte maturation trigger augmented expression of genes involved in ovarian steroidogenesis in human GL cells including, FSH receptor (FSHR), LH/hCG receptor (LHCGR), steroid acute regulatory protein (STAR), aromatase, estrogen receptors alpha and beta (ESR1, ESR2), 3-beta-hydroxysteroid dehydrogenase type 2 (3BHSD2) and inhibin A (INHBA), when compared to traditional maturation triggers, but did not alter markers of OHSS. WHAT IS KNOWN ALREADY: hCG is the most widely used trigger of oocyte maturation, but is associated with an increased risk of OHSS. The use of GnRH agonists to trigger oocyte maturation is a safer alternative to hCG. More recently, kisspeptin-54 has emerged as a novel therapeutic option that safely triggers oocyte maturation even in women at high risk of OHSS. Kisspeptin indirectly stimulates gonadotropin secretion by acting on hypothalamic GnRH neurons. Kisspeptin and its receptor are also expressed in the human ovary, but there is limited data on the direct action of kisspeptin on the ovary. STUDY DESIGN SIZE, DURATION: Forty-eight women undergoing IVF treatment for infertility consented to kisspeptin-54 triggering and/or granulosa cell collection and were included in the study. Twelve women received hCG, 12 received GnRH agonist and 24 received kisspeptin-54 to trigger oocyte maturation. In the kisspeptin-54 group, 12 received one injection of kisseptin-54 (9.6 nmol/kg) and 12 received two injections of kisspeptin-54 at a 10 h interval (9.6 nmol/kg × 2). PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid was aspirated and pooled from follicles during the retrieval of oocytes for IVF/ICSI. GL cells were isolated and either RNA extracted immediately or cultured in vitro ± kisspeptin or hCG. MAIN RESULTS AND THE ROLE OF CHANCE: GL cells from women who had received kisspeptin-54 had a 14-fold and 8-fold higher gene expression of FSHR and a 2-fold (ns) and 2.5-fold (P < 0.05) higher expression of LHCGR than GL cells from women who had received hCG or GnRH agonist, respectively. CYP19A1 expression was 3.6-fold (P < 0.05) and 4.5-fold (P < 0.05) higher, STAR expression was 3.4-fold (P < 0.01) and 1.8-fold (P < 0.05) higher, HSD3B2 expression was 7.5- (P < 0.01) and 2.5-fold higher (P < 0.05), INHBA was 2.5-fold (P < 0.01) and 2.5-fold (P < 0.01) higher in GL cells from women who had received kisspeptin-54 than hCG or GnRHa, respectively. ESR1 (P < 0.05) and ESR2 (P < 0.05) both showed 3-fold higher expression in cells from kisspeptin treated than GnRHa treated women. Markers of vascular permeability and oocyte growth factors were unchanged (VEGFA, SERPINF1, CDH5, amphiregulin, epiregulin). Gene expression of kisspeptin receptor was unchanged. Whereas treating GL cells in vitro with hCG induced steroidogenic gene expression, kisspeptin-54 had no significant direct effects on either OHSS genes or steroidogenic genes. LIMITATIONS REASONS FOR CAUTION: Most women in the study had PCOS, which may limit applicability to other patient groups. For the analysis of the in vitro effects of kisspeptin-54, it is important to note that GL cells had already been exposed in vivo to an alternate maturation trigger. WIDER IMPLICATIONS OF THE FINDINGS: The profile of serum gonadotropins seen with kisspeptin administration compared to other triggers more closely resemble that of the natural cycle as compared with hCG. Thus, kisspeptin could potentially permit an ovarian environment augmented for steroidogenesis, in particular progesterone synthesis, which is required for embryo implantation. STUDY FUNDING/COMPETING INTEREST(S): Dr Owens is supported by an Imperial College London PhD Scholarship. Dr Abbara is supported by an National Institute of Health Research Academic Clinical Lectureship. The authors do not have any conflict of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01667406.

Management of carriers and babies with haemophilia.

Although up to 30% of babies born with haemophilia do not have a family history of the disorder, the remaining 70% are born in families where haemophilia has been diagnosed. It has been estimated that for each male with haemophilia, there are five potential female carriers. Such women will benefit from knowledge of both their genetic (mutation present or not) and phenotype (level of plasma factor activity) status. Genetic counselling services to provide information and testing, together with plasma factor measurement, should be offered where available to all women at risk of being carriers. It is critical that women know their plasma factor measurement as they may have mild haemophilia (factor 5-30%, reference range 50-150%) which requires management at times of medical and surgical procedures and following trauma. Close liaison between adult and paediatric haemophilia centres and obstetric-gynaecology units is important to ensure that clinical carers identify and address carriers' needs. Genetic testing should be performed only after a potential carrier has been counselled and supported to receive such information. There is no coercion to accept such testing. An advantage of genetic testing is to then discuss pre-implantation genetic diagnosis which is an ex-vitro form of prenatal diagnosis. This can assist couples at risk of having a child with haemophilia who wish to reduce their anxieties about reproduction. Approximately 4% of boys with haemophilia, born in countries with good maternal care, will have intracranial haemorrhage in the neonatal period. There are no high-level evidence-based guidelines for the management of delivery or of the newborn with haemophilia. Obstetricians or other birth attendants need to be advised of the possibility of delivery of a boy with haemophilia and seek support from a haemophilia specialist during the pregnancy. The mother can then be monitored and plans for delivery be developed between her medical consultants and discussed with her. It is always preferable for a carrier to know of her genetic and phenotypic status before becoming pregnant so that she is informed as to her options and requirements for safe delivery.

ESHRE PGD Consortium 'Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)'.

Among the many educational materials produced by the European Society of Human Reproduction and Embryology (ESHRE) are guidelines. ESHRE guidelines may be developed for many reasons but their intent is always to promote best quality practices in reproductive medicine. In an era in which preimplantation genetic diagnosis (PGD) has become a reality, we must strive to maintain its efficacy and credibility by offering the safest and most effective treatment available. The dominant motivators for the development of current comprehensive guidelines for best PGD practice were (i) the absence of guidelines and/or regulation for PGD in many countries and (ii) the observation that no consensus exists on many of the clinical and technical aspects of PGD. As a consequence, the ESHRE PGD Consortium undertook to draw up guidelines aimed at giving information, support and guidance to potential, fledgling and established PGD centres. The success of a PGD treatment cycle is the result of great attention to detail. We have strived to provide a similar level of detail in this document and hope that it will assist staff in achieving the best clinical outcome for their patients.

Preimplantation genetic diagnosis: patients' experiences and attitudes.

BACKGROUND: This study aims to report the experiences and attitudes of patients who have undergone preimplantation genetic diagnosis (PGD). The extent to which this technique is acceptable to the individuals for whom it is intended is relatively unexplored, and remains a crucial issue that may ultimately determine the value of PGD as an alternative to prenatal diagnosis in high-risk couples. METHODS: An information sheet and questionnaire was distributed to 67 couples who had been treated at the Hammersmith Hospital, London and the Dexeus Institute, Barcelona. RESULTS: One-third of patients had an affected child, over half had previous experience of conventional prenatal diagnosis and over one-third had had terminations of pregnancy because of a genetic risk. Patients perceive the main advantage of PGD to be that only unaffected embryos are transferred to the uterus and thus therapeutic termination of pregnancy can be avoided; the main disadvantage is the low success rate. A total of 41% of patients found the treatment cycle extremely stressful, and, of the 20 patients who had experienced both prenatal diagnosis and PGD, 40% of patients found PGD less stressful, although 35% experienced more stress. Of those couples who contemplated a further pregnancy 76% would choose PGD, 16% would opt for prenatal diagnosis, and 8% no tests at all. CONCLUSIONS: The experience of prenatal diagnosis and termination of pregnancy can be an unwelcome memory and this leads to a demand for an alternative approach. Our data suggest that PGD is acceptable to patients and is a valuable alternative to prenatal diagnosis.

An analysis of the demand for and cost of preimplantation genetic diagnosis in the United Kingdom.

Research in the field of preimplantation genetic diagnosis (PGD) has concentrated on increasing the number of diseases diagnosed, different strategies for single cell analysis and improving efficiency and reliability. Of equal importance are clinical issues such as the demand for and cost of PGD. This study assesses patient awareness of PGD and its potential benefits; additionally the awareness, attitudes and referral patterns of Assisted Conception Units, Regional Genetics Centres and Health Authorities (funding bodies) have been analysed to establish the demand for PGD within the United Kingdom. The licensed units are able to perform 128 cycles of PGD annually, however 256 cases were referred within the last year. It is clear that the currently licensed units operating at their present capacity are unable to meet the demand for PGD in the U.K. Concerns raised by this study include the unequal geographical distribution of PGD services and the lack of a uniform funding policy by Health Authorities. The investment in personnel and technology to establish a PGD service is considered and a costing provided. We estimate an initial investment in the region of 139,000 Pounds with annual running costs of 55,000 Pounds. This information should contribute towards an appropriate allocation of resources at a national level in the U.K.