The HERA (Hyper-response Risk Assessment) Delphi consensus definition of hyper-responders for in-vitro fertilization.

PURPOSE: To provide an agreed upon definition of hyper-response for women undergoing ovarian stimulation (OS)? METHODS: A literature search was performed regarding hyper-response to ovarian stimulation for assisted reproductive technology. A scientific committee consisting of 5 experts discussed, amended, and selected the final statements in the questionnaire for the first round of the Delphi consensus. The questionnaire was distributed to 31 experts, 22 of whom responded (with representation selected for global coverage), each anonymous to the others. A priori, it was decided that consensus would be reached when ≥ 66% of the participants agreed and ≤ 3 rounds would be used to obtain this consensus. RESULTS: 17/18 statements reached consensus. The most relevant are summarized here. (I) Definition of a hyper-response: Collection of ≥ 15 oocytes is characterized as a hyper-response (72.7% agreement). OHSS is not relevant for the definition of hyper-response if the number of collected oocytes is above a threshold (≥ 15) (77.3% agreement). The most important factor in defining a hyper-response during stimulation is the number of follicles ≥ 10 mm in mean diameter (86.4% agreement). (II) Risk factors for hyper-response: AMH values (95.5% agreement), AFC (95.5% agreement), patient's age (77.3% agreement) but not ovarian volume (72.7% agreement). In a patient without previous ovarian stimulation, the most important risk factor for a hyper-response is the antral follicular count (AFC) (68.2% agreement). In a patient without previous ovarian stimulation, when AMH and AFC are discordant, one suggesting a hyper-response and the other not, AFC is the more reliable marker (68.2% agreement). The lowest serum AMH value that would place one at risk for a hyper-response is ≥ 2 ng/ml (14.3 pmol/L) (72.7% agreement). The lowest AFC that would place one at risk for a hyper-response is ≥ 18 (81.8% agreement). Women with polycystic ovarian syndrome (PCOS) as per Rotterdam criteria are at a higher risk of hyper-response than women without PCOS with equivalent follicle counts and gonadotropin doses during ovarian stimulation for IVF (86.4% agreement). No consensus was reached regarding the number of growing follicles ≥ 10 mm that would define a hyper-response. CONCLUSION: The definition of hyper-response and its risk factors can be useful for harmonizing research, improving understanding of the subject, and tailoring patient care.

The HERA (Hyper-response Risk Assessment) Delphi consensus for the management of hyper-responders in in vitro fertilization.

PURPOSE: To provide agreed-upon guidelines on the management of a hyper-responsive patient undergoing ovarian stimulation (OS) METHODS: A literature search was performed regarding the management of hyper-response to OS for assisted reproductive technology. A scientific committee consisting of 4 experts discussed, amended, and selected the final statements. A priori, it was decided that consensus would be reached when ≥66% of the participants agreed, and ≤3 rounds would be used to obtain this consensus. A total of 28/31 experts responded (selected for global coverage), anonymous to each other. RESULTS: A total of 26/28 statements reached consensus. The most relevant are summarized here. The target number of oocytes to be collected in a stimulation cycle for IVF in an anticipated hyper-responder is 15-19 (89.3% consensus). For a potential hyper-responder, it is preferable to achieve a hyper-response and freeze all than aim for a fresh transfer (71.4% consensus). GnRH agonists should be avoided for pituitary suppression in anticipated hyper-responders performing IVF (96.4% consensus). The preferred starting dose in the first IVF stimulation cycle of an anticipated hyper-responder of average weight is 150 IU/day (82.1% consensus). ICoasting in order to decrease the risk of OHSS should not be used (89.7% consensus). Metformin should be added before/during ovarian stimulation to anticipated hyper-responders only if the patient has PCOS and is insulin resistant (82.1% consensus). In the case of a hyper-response, a dopaminergic agent should be used only if hCG will be used as a trigger (including dual/double trigger) with or without a fresh transfer (67.9% consensus). After using a GnRH agonist trigger due to a perceived risk of OHSS, luteal phase rescue with hCG and an attempt of a fresh transfer is discouraged regardless of the number of oocytes collected (72.4% consensus). The choice of the FET protocol is not influenced by the fact that the patient is a hyper-responder (82.8% consensus). In the cases of freeze all due to OHSS risk, a FET cycle can be performed in the immediate first menstrual cycle (92.9% consensus). CONCLUSION: These guidelines for the management of hyper-response can be useful for tailoring patient care and for harmonizing future research.

The impact of embryo vitrification on placental histopathology features and perinatal outcome in singleton live births.

STUDY QUESTION: Does embryo vitrification affect placental histopathology pattern and perinatal outcome in singleton live births? SUMMARY ANSWER: Embryo vitrification has a significant effect on the placental histopathology pattern and is associated with a higher prevalence of dysfunctional labor. WHAT IS KNOWN ALREADY: Obstetrical and perinatal outcomes differ between live births resulting from fresh and frozen embryo transfers. The effect of embryo vitrification on the placental histopathology features associated with the development of perinatal complications remains unclear. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study evaluating data of all live births from one academic tertiary hospital resulting from IVF treatment with autologous oocytes during the period from 2009 to 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients had placentas sent for pathological evaluation irrelevant of maternal or fetal complications status. Placental, obstetric and perinatal outcomes of pregnancies resulting from hormone replacement vitrified embryo transfers were compared with those after fresh embryo transfers. A multivariate analysis was conducted to adjust the results for determinants potentially associated with the development of placental histopathology abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1014 singleton live births were included in the final analysis and were allocated to the group of pregnancies resulting from fresh (n = 660) and hormone replacement frozen (n = 354) embryo transfers. After the adjustment for confounding factors the frozen embryo transfers were found to be significantly associated with chorioamnionitis with maternal (odds ratio (OR) 2.0; 95% CI 1.2-3.3) and fetal response (OR 2.6; 95% CI 1.2-5.7), fetal vascular malperfusion (OR 3.9; 95% CI 1.4-9.2), furcate cord insertion (OR 2.3 95% CI 1.2-5.3), villitis of unknown etiology (OR 2.1; 95% CI 1.1-4.2), intervillous thrombi (OR 2.1; 95% CI 1.3-3.7), subchorionic thrombi (OR 3.4; 95% CI 1.6-7.0), as well as with failure of labor progress (OR 2.5; 95% CI 1.5-4.2). LIMITATIONS, REASONS FOR CAUTION: Since the live births resulted from frozen-thawed embryos included treatment cycles with previously failed embryo transfers, the factors over embryo vitrification may affect implantation and placental histopathology. WIDER IMPLICATIONS OF THE FINDINGS: The study results contribute to the understanding of the perinatal future of fresh and vitrified embryos. Our findings may have an implication for the clinical decision to perform fresh or frozen-thawed embryo transfer. STUDY FUNDING/COMPETING INTEREST(S): Authors have not received any funding to support this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Pregnancy outcomes in women with panhypopituitarism: a population-based study.

RESEARCH QUESTION: What are the consequences of panhypopituitarism on pregnancy outcomes? DESIGN: Retrospective population-based study using data from the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample (HCUP-NIS). A dataset was created of all deliveries between 2004 and 2014 inclusive. Within this group, all deliveries to women who had a diagnosis of panhypopituitarism during pregnancy were identified as part of the study group (n = 120), and the remaining deliveries comprised the reference group (n = 8,732,641). A multivariate logistic regression analysis, controlling for confounding effects, was conducted to explore associations between panhypopituitarism and pregnancy complications, delivery and neonatal outcomes. RESULTS: No significant differences were found in the risk of developing gestational hypertension, gestational diabetes mellitus, placental abruption, or preterm delivery delivering a small for gestational age neonate, or in the mode of delivery. There was a higher risk of developing maternal infection (odds ratio [OR] 3.14, 95% confidence interval [CI] 1.46-6.74) and congenital anomalies (OR 6.97, 95% CI 2.57-18.95); however, due to the small number of cases these results should be interpreted with caution. CONCLUSIONS: Pregnancy outcomes of women with panhypopituitarism are comparable to those of the general population. Further studies are needed to assess the risk of congenital anomalies and maternal infection in pregnant women with panhypopituitarism.

Relationship between surrogate estimates and direct measurement of insulin resistance in women with polycystic ovary syndrome.

PURPOSE: To evaluate the relationship between surrogate estimates of insulin resistance and a direct measurement of insulin-mediated glucose uptake women with and without PCOS. METHODS: Retrospective cohort study of 75 PCOS and 118 controls. Fasting plasma glucose and insulin concentrations, insulin resistance as determined by the insulin suppression test, calculation of multiple surrogate estimates of insulin resistance, total and free testosterone concentrations, and correlations between the direct measure and surrogate estimates of insulin resistance were evaluated. RESULT(S): Surrogate markers of insulin resistance were correlated to a variable, but statistically significant degree with the direct measure of insulin resistance in control population and the women with PCOS. There was no correlation between the surrogate estimates of insulin resistance and total or free plasma testosterone concentrations. CONCLUSION(S): The surrogate estimates of insulin resistance evaluated were significantly related to a direct measure of insulin resistance, and this was true of both the control population and women with PCOS. The magnitude of the relationship between the surrogate estimates and the direct measurement was comparable and not significantly altered by androgen levels. Fasting plasma insulin concentration seems to be at least as accurate as any other surrogate estimate, and is by far the simplest.

Management of recurrent implantation failure by gonadotropin-releasing hormone agonist and aromatase inhibitor suppression, in women without evidence of endometriosis.

Endometriosis is common among those with infertility, although many cases go undiagnosed. This study was performed to determine whether empiric treatment with two months of depo-leuprolide 3.75 mg monthly (dep-GnRH-ag) and letrozole 5 mg daily improves pregnancy outcomes in patients with at least two unexplained failed embryo transfers (ETs) but without a previous diagnosis of endometriosis. A retrospective cohort study was performed with subjects who failed at least two good quality ET. The study excluded women with a known history of endometriosis or ovarian cysts (possible endometriomas). Subjects (N = 38) were treated with dep-GnRH-ag and letrozole pre-cycle. Matched women (N = 37) who did not receive either pretreatment served as a control group. Data were compared by non-paired T-tests and multivariate logistic regression to control for confounding effects. Demographic data, hormonal profiles, and ovarian reserve parameters were similar between the two groups. The treated group had failed more embryo transfers (3.5 ± 1.7 vs. 2.0 ± 1.3, p = .01) than the controls. When adjusting for the number of MII oocytes collected, number of blastocysts developed and number of blastocysts transferred, there were more pregnancies (24/38 vs. 11/37, p = .02) and ongoing pregnancies (18/38 vs. 9/37, p = .03) in the treated group. Patients with multiple unexplained failed ET may have undiagnosed endometriosis and may benefit from pretreatment with dep-GnRH-ag and letrozole. These results would benefit from being subjected to a randomized prospective study.

The relationship between fat and progesterone, estradiol, and chorionic gonadotropin levels in Quebec cow's milk.

PURPOSE: The majority of milk in industrialized countries is obtained from pregnant cows, which contains increased levels of estrogen and progesterone compared to non-pregnant cows. The aim of this study was to quantify the amount of hormones present in milk with different fat content because previous studies on humans have shown potential effects of increased milk consumption on serum and urine hormone levels as well as on sperm parameters. However, it is unclear whether consumption of milk at the currently recommended levels would lead to systemic effects. METHODS: Samples of cow's milk of varying fat concentrations (0, 1, 2, 3.25, 10, and 35%) were analyzed via competitive ELISA assays. RESULTS: Progesterone concentrations were significantly correlated to increasing fat content of milk (r = 0.8251, p = 0.04). CONCLUSIONS: Research on conditions in which additional progesterone may have an effect on human health should consider inclusion of limitation of milk intake and its effects. Further studies are needed to determine the concentration of progesterone in milk of different fat content in other regions and countries and to quantify the potential pathophysiologic role.

Pregnancy rates with intrauterine insemination: comparing 1999 and 2010 World Health Organization semen analysis norms.

Over the past 30 years, The World Health Organization has serially measured norms for human sperm. In this study, 1999 and 2010 semen analysis norms as predictors of pregnancy were compared during intrauterine insemination (IUI). A retrospective cohort study was conducted using data collected from the Stanford Fertility Center, between 2005 and 2007, with 981 couples undergoing 2231 IUI cycles. Collected semen was categorized according to total motile sperm counts (TMSC): 'normal (N.) 1999 TMSC', 'abnormal (AbN.) 1999/N. 2010 TMSC', or 'AbN. 2010 TMSC'. Sample comparison was also based on individual semen parameters: 'N. 1999 WHO', 'AbN. 1999/N. 2010 WHO', or 'AbN. 2010 WHO'. Pregnancy (defined by beta-HCG concentration) rates were calculated. Data were compared using correlation coefficients, t-tests and chi-squared tests, with and without adjusting for confounders. Pregnancy rate comparison based on TMSC ('N. 1999 TMSC', 'AbN. 1999/N. 2010 TMSC' and 'AbN. 2010 TMSC') showed a negative correlation (r = -0.41, P = 0.05). Pregnancy rate did not differ when comparisons were based on the presence of abnormal parameters, even when controlling for confounders. Therefore, TMSC based on the 1999 parameters shows best correlation with pregnancy rate for IUI; updating these norms in 2010 has little clinical implication in infertile populations.

Obstetric outcomes of IVF trichorionic triamniotic triplets which are spontaneously or electively reduced to twins.

PURPOSE: To assess the obstetric outcome of IVF triplets which are spontaneously or electively reduced to twins. METHODS: Retrospective study of trichorionic triplets (TT) and dichorionic twins (DT) conceived with IVF. RESULTS: Compared to TT without reduction, TT with spontaneous reduction (SR) (OR: 5.6, 95% CI: 1.6-19.9) or elective reduction (ER) (OR: 14.0, 95% CI: 3.92-50.02) to twins were significantly more likely to be delivered at ≥34 weeks. Compared to DT likelihood of delivery ≥34 weeks was similar for SR and ER. Compared to TT without reduction, the risk of pregnancy loss before 24 weeks was not increased with SR or ER. Compared to DT the risk of pregnancy loss before 24 weeks was not significantly increased for SR or ER. CONCLUSION: Obstetric outcome of IVF triplets with SR is better than ongoing triplets and is similar to that of ER of TT and DT.