First clinical report of 179 surrogacy cases in the UK: implications for policy and practice.

RESEARCH QUESTION: What implications for policy and practice can be derived from outcomes and trends observed across 8 years of a surrogacy programme in two UK-regulated IVF centres (London, Cardiff)? DESIGN: Retrospective cohort study analysing surrogacy treatments undertaken between 2014 and September 2021. RESULTS: Surrogacy continues to rise in popularity in the UK despite the inability of those supporting safe and professional practice to advertise to recruit surrogates. In two IVF centres regulated by the Human Fertilisation and Embryology Authority (HFEA), both the number of surrogacy treatments and the proportion of those undertaken on behalf of same-sex male intended parents increased year on year in the period studied. From a cohort of 108 surrogates, 71 babies were born to 61 surrogates (with five pregnancies ongoing) by February 2022. No statistically significant difference in live birth rates (LBR) was observed between the heterosexual couples and same-sex male couples. Sample sizes of single and transgender intended parents were too small (n < 5) to compare. The use of vitrified oocytes in surrogacy treatments has increased year on year, while fresh oocyte use has declined since peaking in 2019. There was no significant difference in LBR between fresh and vitrified oocyte usage across the cohort. CONCLUSIONS: The number of surrogacy treatments steadily increased, with clear evidence that the proportion of same-sex male couples accessing surrogacy is a major contributor to this growth. Vitrified/warmed oocyte use now outstrips the use of fresh oocytes in the surrogacy treatment cycles studied here. The results represent a strong basis for supporting the liberalization of regulatory reform expected to be introduced in the UK later in 2022.

Embryos are exposed to a significant drop in temperature during the embryo transfer procedure: a pilot study.

RESEARCH QUESTION: During the embryo transfer procedure, to what degree of temperature drop are embryos exposed to between loading the transfer catheter and placing it into the uterus? DESIGN: Twenty-nine simulated embryo transfer procedures were carried out across five clinics. A thermocouple probe was used for standardized measurements inside the embryo transfer catheter to investigate the change in temperature that occurred in the time period between loading and placing the catheter in the uterus. RESULTS: In all cases, the temperature at the loaded catheter tip fell rapidly to ambient temperature during transit from the embryo transfer workstation in the laboratory to the procedure room, even though embryo transfer procedures, ambient temperatures and embryo transfer catheter temperatures at loading varied between clinics. CONCLUSIONS: Given the sensitivity of the pre-implantation embryo to its immediate environment, the rapid and profound drop in temperature observed at the catheter tip that houses the embryo during transit from laboratory to the uterus may affect embryo viability and health. This issue should be addressed to ensure that the tight temperature control aimed for by IVF laboratories continues throughout the embryo transfer procedure, and could improve clinical outcomes.

Factors predicting clinical outcomes from 494 vitrified oocyte donation cycles at a UK-regulated egg bank.

RESEARCH QUESTION: Do donor age, AMH, AFC, BMI and reproductive history predict response to ovarian stimulation? Do donor and recipient clinical markers and embryology parameters predict recipient pregnancy and live birth? DESIGN: Retrospective cohort study of 494 altruistic oocyte donors aged 18-35 years; 340 were matched to 559 recipients. Predictors of donor total oocyte yield and total mature oocyte yield were identified. Total and mature oocyte number were compared according to stratified donor AMH and age. Donor, recipient and embryology parameters predictive of recipient primary outcomes (clinical pregnancy and live birth) were identified. RESULTS: Donor age and AMH predicted total oocyte yield (P = 0.030 and P < 0.001)) and total mature oocyte yield (P = 0.011 and P < 0.001). Donors aged 30-35 years with AMH 15-29.9 pmol/l had lower total oocyte yield (P = 0.004) and mature oocyte yield (P < 0.001) than donors aged 18-24 years. Up to an AMH threshold of 39.9 pmol/l, increasing AMH levels predicted higher total oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.001; 15-29.9 pmol/l versus 30-39.9 pmol/l, P < 0.001; 30-39.9pmol/l versus ≥ 40 pmol/l, P = 1.0) and mature oocyte yield (<15 pmol/l versus 15-29.9 pmol/l, P = 0.005; 15-29.9 pmol/l versus 30-39.9 pmol/l, P = 0.006; 30-39.9 pmol/l versus ≥40 pmol/l, P = 1.0). In recipients, the rate of transferrable embryos per oocytes received, fertilized and number of embryo transfers needed to achieve the primary outcome were predictors of cumulative clinical pregnancy (P = 0.011, P = 0.017 and P < 0.001) and live birth (P = 0.008, P = 0.012 and P < 0.001) rates. Recipient BMI (P = 0.024) and previous miscarriages (P = 0.045) were predictors of cumulative live birth rate. Donor age 18-22 years was associated with a lower incidence of recipient clinical pregnancy (P = 0.004) and live birth (P = 0.001) after the first embryo transfer versus donor age 23-29 years. CONCLUSIONS: Donor age and AMH are independent predictors of oocyte yield. Raised recipient BMI and history of miscarriages reduce cumulative live birth rates, which may be increased by selecting donors aged 23-29 years, instead of younger donors.

Characterization of endometrial growth in proliferative and early luteal phase in IVF cycles.

Human endometrium has a definite role in implantation, although knowledge about its modifications in the course of IVF cycles is still limited. This study was performed to characterize endometrial growth throughout stimulation treatment in women undergoing IVF cycles, regardless of clinical outcomes. Endometrial growth was longitudinally evaluated by ultrasonography in the first induced ovarian stimulation cycle (717 patients). Acceleration and length of significant growth were used to assess the slope of the growth curve mathematically. Endometrial growth showed a parabolic trend and final thickness was significantly affected by age (P < 0.01). Endometria that tended to overgrowth had a more rapid and longer growth during the whole phase. A similar stimulation treatment was repeated within 6 months of the first one and a second evaluation was carried out to verify whether similar growth occurred. Similar growth was observed in 76% of the patients, with an absolute difference between the two cycles of <4 mm in 84% of cases. The endometrium seems to have an individual intrinsic potential that can be expressed regardless of the stimulation protocol. This supports the hypothesis that individual factors (intrinsic properties of the endometrium) significantly affect endometrial growth.

Intrauterine insemination with recombinant or urinary human chorionic gonadotropin: A prospective randomized trial.

AIM: Our aim was to compare the efficacy and safety of recombinant and urinary human chorionic gonadotropin (rhCG and uhCG, respectively) for the induction of follicle maturation in women undergoing intrauterine insemination (IUI). METHODS: Patients were randomized to receive rhCG or uhCG. IUI was carried out 24 h (day 1) and 48 h (day 2) after hCG administration, except for all cases in which ovulation occurred after 24 h. RESULTS: The two treatments were comparable in terms of progesterone levels on day 7 and day 12. Pregnancy rates were comparable between the treatment groups. Of the 64 women who received rhCG, 29.7% became pregnant; there were 16.7% clinical pregnancies and 3.1% biochemical pregnancies per started cycle, and an ongoing pregnancy rate of 93.7% was reported. Of the 61 patients who received uhCG, 24.6% became pregnant; there were 15.9% clinical pregnancies and 1.1% biochemical pregnancies per started cycle, and ongoing pregnancy rate was 92.9%. No adverse effects were noted in either group. CONCLUSION: The recombinant products can be effectively used instead of urinary products; moreover, apart from the equivalent efficacy in ovulation induction and safety described in this study, it is necessary to consider the advantages provided by the recombinant form.

Office hysteroscopy in an in vitro fertilization program.

OBJECTIVE: In the present paper we evaluate the incidence of intrauterine pathologies in a population undergoing in vitro fertilization (IVF) treatment. Moreover, we compare the IVF outcome between patients with normal and abnormal uterine findings to determine if office hysteroscopy (OH) is of any clinical significance. METHODS: The hysteroscopic findings in 866 consecutive patients were analyzed. The study group included 555 patients at the first IVF attempt and 311 patients with two or more failed IVF cycles. RESULTS: All hysteroscopic parameters were considered normal in 514 cases (59.4%); in 352 cases (40.6%) various pathological conditions were found. Patients were divided into two groups according to the hysteroscopic findings. The implantation and pregnancy rates were similar between the groups. Comparing the clinical outcomes in patients with repeated IVF failure who had hysteroscopy with no pathology and with pathology, we did not find any statistical differences. CONCLUSIONS: This study suggests that hysteroscopy as a routine infertility examination should be performed in all patients, owing to the elevated incidence of hysteroscopic pathological findings (59.4%); hysteroscopy also seems to be the best way to repair the uterine cavity when pathological conditions are present. However, performing OH before IVF-embryo transfer is of no significant value in improving pregnancy outcomes.

Endogenous luteinizing hormone concentration and IVF outcome during ovarian stimulation in fixed versus flexible GnRH antagonist protocols: An RCT.

BACKGROUND: Luteinizing hormone (LH) is essential for normal follicular development and oocyte maturation. In particular, fluctuations of LH during the follicular phase have a significant impact on morphological and functional changes of the oocyte and determine its meiotic status and ability to be fertilized. OBJECTIVE: This prospective randomized controlled trial examined effects of endogenous follicular phase LH levels on oocyte maturity and IVF outcomes in fixed vs. flexible in vitro fertilization. MATERIALS AND METHODS: Normo-ovulatory women age <39 yr (n=213) were randomized to fixed or flexible gonadotrophin-releasing hormone (GnRH) antagonist protocols. Follicular phase LH, estradiol, and progesterone profiles were measured. Oocytes retrieved, implantation rate, and pregnancy rate were compared between the two groups. RESULTS: LH profiles were similar in both protocols. A lower trend of LH values at the end of ovarian stimulation correlated significantly with a higher pregnancy rate, regardless of protocol (p=0.02). Estradiol levels were statistically different with respect to time points within treatment groups (p<0.0001), but not between groups (p=0.43), or pregnancy outcomes (p=0.2595). Progesterone profiles were similar between groups. No differences were found in retrieved oocytes numbers, fertilization rate or embryos obtained. Significantly, younger age and a higher number of antral follicles were correlated with positive results. CONCLUSION: Fixed and flexible GnRH antagonist protocols did not produce an oscillation of endogenous LH values correlated to the outcome of ovarian stimulation.

Performance of different ovarian reserve markers for predicting the numbers of oocytes retrieved and mature oocytes.

OBJECTIVE: To assess the performance of different ovarian reserve tests for predicting the total numbers of oocytes retrieved and mature oocytes. METHODS: A retrospective study was performed on 71 women undergoing their first IVF/intracytoplasmic sperm injection treatment. Basal ovarian reserve screening was performed on days 2-3 of a spontaneous cycle. Patients were down-regulated with the GnRH agonist, whereas ovarian stimulation was carried out with recombinant FSH, starting from day 2 to 3 of the cycle. The main outcome measures were the numbers of oocytes retrieved and mature oocytes. RESULTS: The total number of oocytes was positively correlated with AFC (p<0.0001) and E(2) levels post-GnRH (p<0.004), whereas there was an inverse correlation with age (p<0.0001). The number of mature oocytes also correlated with AFC (p<0.008) and E(2) levels post-GnRH (p<0.009), and inversely with age (p<0.0004). Univariate linear regression of square root of number of oocytes (SQNO) shows that acceptable predictors of number oocytes, based on model significance and R(2) are AFC (R(2)=0.215), age (R(2)=0.24) and E(2) variation (R(2)=0.09). The following model is proposed to predict the number of mature oocytes: ln(MO)=ln(NO)-2.09+0.028 AGE+0.03 BMI. CONCLUSION(S): The number of antral follicles and patient age appear to be good markers of ovarian response in IVF treatments. Additional information is provided by stimulated E(2) levels.

Effects of insulin-like growth factor I and II on prostaglandin synthesis and plasminogen activator activity in human umbilical vein endothelial cells.

IGFs seem to contribute to the endothelial dysfunction observed in some vascular diseases. Because locally increased IGFs levels were detected in the preeclamptic fetoplacental unit, we hypothesized their involvement in the dysregulation of fibrinolysis and vascular tone typically observed in the fetoplacental compartment in this pregnancy disease. Therefore, in human umbilical vein endothelial cells (HUVECs), the potential effect of IGFs on the synthesis of plasminogen activators (PAs), PA inibitor-1 (PAI-1), and vasodilator and vasoconstrictor prostaglandins (PGs) was investigated. Moreover, in HUVECs treated with IGFs, the expression of cyclooxygenase (COX)-2, the rate-limiting enzyme in PG synthesis, was evaluated.HUVECs were treated for 24 h with IGFs (1-100 ng/ml) or IL-1beta (0.1 ng/ml). PA, PAI-1, and COX-2 mRNA was determined by RT-PCR and PG release and PA activity by RIA and colorimetric assay, respectively.We demonstrated an inhibition of urokinase-type PA activity and a 50% reduction of urokinase-type PA mRNA in HUVECs treated with IGFs. No effect was seen on PAI-1. Finally, both IGFs significantly decreased all PGs tested and COX-2 mRNA, whereas, as expected, IL-1beta had an opposite effect. In conclusion, our results suggest for IGFs a potential involvement in the endothelial dysfunction observed in preeclamptic fetoplacental unit.

Endometrial evaluation in superovulation programs: relationship with successful outcome.

It is well known that an adequate endometrial receptivity is required for successful implantation in both natural and assisted reproductive cycles. In particular, a brief "implantation window", during which endometrium undergoes anatomical and molecular changes necessary for embryo implantation, has been observed. The hormonal treatment applied to induce ovulation seems to be able to modify the normal development of the prenidatory endometrium, with possible negative effect on the implantation rate. For this reason, several attempts have been made to identify specific markers of endometrial receptivity, useful for predicting implantation outcome in clinical practice. Even if different histological, immunohistochemical, and ultrasonographic parameters are studied, none unfortunately has been univocally shown to be predictive of pregnancy outcome. Therefore, the evaluation of endometrial receptivity remains a challenge in clinical practice.

Parabolic trend in endometrial thickness at embryo transfer in in vitro fertilization/intracytoplasmic sperm injection cases with clinical pregnancy evidence.

Sonographic measurement of endometrial thickness at embryo transfer is thought to be a good predictor of the success of in vitro fertilization/intracytoplasmic sperm injection cycles because the clinical pregnancy rate increases as the endometrium thickens. Nevertheless, a retrospective analysis of a study population of 606 patients showed a decrease of clinical pregnancy rates in the setting of extreme endometrial thicknesses.

Do uterine fibroids affect IVF outcomes?

The effect of myomectomy on implantation and pregnancy rates prior to assisted reproduction treatments is controversial. This study was designed to assess clinical outcomes of IVF cycles in women with uterine fibroids. A retrospective single-centre assessment of clinical outcomes of IVF/intracytoplasmic sperm injection (ICSI) treatments in infertile women in a 4-year span was carried out. All patients underwent detailed transvaginal ultrasound and hysteroscopy to precisely identify presence, location and intracavitary growth of uterine fibroids. Cumulative pregnancy, ongoing pregnancy and live birth rates were considered primary outcome measurements. Fifty-one women with fibroids (97 treatment cycles), 63 patients with previous myomectomy (127 cycles), and 106 infertile women who did not demonstrate fibroids anywhere in the uterus (215 cycles) were considered for the analysis. No significant difference was found for pregnancy and live birth rates between groups. Women with fibroids>4 cm required an increased number of cycles to obtain an ongoing pregnancy, compared with the other groups. The data do not support pre-IVF myomectomy in women with small-to-moderate uterine fibroids, regardless of their location. This represents valuable information in the counselling of women with fibroids before reproductive assisted cycles.

Effects of nicotine on human luteal cells in vitro: a possible role on reproductive outcome for smoking women.

We investigated the effect of nicotine and its methylated metabolite, N-methyl-nicotine (M-nicotine), on human luteal cells by measuring release of progesterone and prostaglandins (PGs) from cultured cells and by testing gene expression of vascular endothelial growth factor (VEGF), an angiogenic factor strictly involved in luteal pathophysiology. Primary cultures of human luteal cells were treated for 24 h with nicotine and M-nicotine (from 10(-6) to 10(-11) M) either alone or combined with hCG (25 ng/ml); progesterone and PGs were assayed in the culture medium. In another group of experiments, luteal cells were treated for 24 h with nicotine and M-nicotine (10(-7) M) to perform reverse transcriptase-polymerase chain reaction on VEGF mRNA. Nicotine and M-nicotine negatively affected basal luteal steroidogenesis at all tested concentrations, but neither was able to affect hCG-induced progesterone release. Both substances were able to significantly increase PGF2alpha release from luteal cells, with a dose-related efficacy for M-nicotine. On the contrary, PGE2 release was significantly inhibited by both nicotine and its metabolite. Finally, nicotine was able to increase VEGF mRNA expression significantly, whereas M-nicotine was not. In conclusion, nicotine and M-nicotine can induce a sort of luteal insufficiency by inhibiting progesterone release, probably through modulation of the PG system.