Ovulation patterns affect the offspring sex ratios and change with the women's age.

BACKGROUND: The aim of this study was to evaluate whether women's ages at conception and the ratio of male to female infants are associated with various ovulation patterns. METHODS: An observational clinical study was conducted in private OB/GYN clinics. Infertile women with regular menstrual cycles receiving intrauterine insemination (IUI) and/or in-vitro fertilization (IVF) had their ovulation patterns monitored in three consecutive spontaneous cycles receiving infertility treatment in the third cycle. Ovulation patterns were also observed in women with slight ovulation disorders during IUI and/or IVF in clomiphene citrate stimulated cycles. All the pregnant women's ages at conception and their respective offspring sex ratios were compared to various ovulation patterns. Statistical evaluation was performed using ANOVA, unpaired t test, χ2 test or Fisher's exact test, heterogeneity χ2 test, odds ratios at 95% confidence intervals and logistic regression. RESULTS: Contralateral ovulation (i.e. ovulation jumping from ovary to the other) was more often observed in relatively younger women, who showed a higher probability of having a boy than after ipsilateral ovulation. There was a significantly higher frequency of boys being conceived following three consecutive ovulations with a left-left-right (LLR) ovulation pattern, while three ovulations from the left ovary (LLL) were associated with a higher frequency of girls. We also found two consecutive menstrual cycles the left-right (LR) ovulation pattern showed a similar significant difference compared to the left-left (LL) ovulation. Both the infertile and infertile + fertile women groups showing right-sided ovulation, regardless of age, showed significantly higher offspring sex ratio compared to left-sided ovulation, which was not observed in the group of fertile women alone. CONCLUSIONS: LLR, LR and contralateral ovulation happens more often in younger women and favors male offspring in infertile women. Right-sided ovulation favors male offspring in infertile and infertile + fertile women, which was not observed in the group of fertile women.

It is of interest to evaluate whether ovulation patterns change with women's ages at conception and affect offspring sex ratios. An observational clinical study was conducted in private OB/GYN clinics. Infertile women with regular menstrual cycles receiving intrauterine insemination (IUI) and/or in-vitro fertilization (IVF) had their ovulation patterns monitored in three consecutive spontaneous cycles receiving infertility treatment in the third cycle. Ovulation patterns were also observed in women with slight ovulation disorder during IUI and/or IVF in clomiphene citrate stimulated cycles. Women's ages and offspring sex ratios were compared to various ovulation patterns. The contralateral ovulation was more often observed in relatively younger women, who showed a higher probability of having a boy than following a pregnancy after ipsilateral ovulation. There was a significantly higher frequency of boys being conceived following three consecutive ovulations with after a left-left-right (LLR) ovulation pattern, while three ovulations from the left ovary (LLL) were associated with a higher frequency of girls. Only considering two consecutive menstrual cycles the left-right (LR) ovulation pattern showed a similar significant difference compared to the left-left (LL) ovulation. Both infertile and infertile + fertile women showing right-sided ovulation, regardless of age, showed significantly higher offspring sex ratio compared to left-sided ovulation, which was not observed in the group of fertile women alone. LLR, LR and contralateral ovulation happens more often in younger women and favor male offspring in infertile women. Right-sided ovulation favors male offspring in infertile and infertile + fertile women, which was not observed in the group of fertile women.

Predicting live birth by combining cleavage and blastocyst-stage time-lapse variables using a hierarchical and a data mining-based statistical model.

Prolonged embryo culture is increasingly used as a way of improving pregnancy rates, especially in the context of single embryo transfer. So far, only a handful of studies examined the relation between implantation potential and time-lapse parameters extracted from later stages (morula and blastocyst) of embryo development. For this retrospective study all 285 single vitrified-thawed blastocyst transfers (SVBT) from all consecutive unselected patients whose fertilized oocytes were submitted to time-lapse monitoring (TLM) from a two-year cohort were analysed. Two different statistical models were created; a hierarchical one including the two strongest live birth (LB) predictors (t2 and texpB2) and a more complex model based on principal component analysis (PCA) and logistic regression methods. The first, four-category, hierarchical model effectively distinguished between blastocysts of increasing LB rates (8, 30, 40, 53%). For the second data-mining model quartiles of the created Sc parameter had increasing LB rates (12, 19, 40, 49%). AUC values were comparable for both models (0.723, 95CI%:0.66-0.79 versus 0.717, 95CI%:0.65-0.78). The combination of cleavage- and blastocyst-stage variables through hierarchical or data mining-based algorithms was used successfully to predict live birth. However, due to the lack of internal / external validation the predictive capacities of this model could differ largely in different datasets.

Blastocyst collapse is not an independent predictor of reduced live birth: a time-lapse study.

OBJECTIVE: To ascertain the rate of blastocyst collapse observed by time-lapse monitoring in a retrospective cohort of unselected infertile patients undergoing single blastocyst transfer and to determine its association with live birth. DESIGN: Blastocyst collapse and morphokinetic variables were scored according to previously published criteria. The association between blastocyst collapse and live birth was evaluated by a multivariate logistic regression analysis including morphokinetic variables and other confounders. SETTING: Private infertility clinic. PATIENT(S): Patients who underwent 277 consecutive single blastocyst transfers (mean age, 38.4 ± 3.9 years; range, 28-47 years) after minimal ovarian stimulation. INTERVENTION(S): Minimal ovarian stimulation, prolonged embryo culture in time-lapse monitoring incubator, elective vitrification with subsequent vitrified-warmed single blastocyst transfer. MAIN OUTCOME MEASURE(S): Live birth rate per single blastocyst transfer in different blastocyst collapse groups (no, single, multiple collapses). RESULT(S): No, single, or multiple blastocyst collapses occurred in 54% (150/277), 22% (61/277), and 24% (66/277) of the cohort, respectively. In the multiple collapse group on average 2.9 contractions were seen (range, 2-9 contractions). Live birth rate decreased progressively between blastocyst collapse groups (36%, 31%, 14%); significantly lower if multiple collapses occurred. In a multivariate analysis, however, blastocyst collapse was not found to be a significant predictor and was confounded by stronger predictors such as morphokinetic variables t2, texpB2, and female age. CONCLUSION(S): Blastocyst collapse pattern should not be evaluated alone without taking into account morphokinetic variables that are stronger predictors of reproductive outcome.

Time-lapse variables and embryo gender: a retrospective analysis of 81 live births obtained following minimal stimulation and single embryo transfer.

PURPOSE: The purpose of this study was to determine which morphokinetic variables are related to embryo gender in a cohort of consecutive live births obtained through single blastocyst transfer following mild ovarian stimulation. METHODS: Eighty-one live births (49 % of them females) from successfully treated, consecutive infertile patients (maternal age 36.9 ± 3.8 years, range 28-46) who underwent minimal ovarian stimulation, prolonged embryo culture in a time-lapse monitoring (TLM) incubator and elective single blastocyst transfers during 2012-2014. Early (PNf, t2-t9, cc2a, b, s2, s3) and late (tM, tSB, tfullB, texpB1, and texpB2) morphokinetic variables were scored according to published consensus criteria and were normalized to the time of pronuclear fading. For each variable, the ranges with the highest proportion of female embryos (optimal range) were determined by detailed examination of histograms. RESULTS: Female embryo gender was associated both with late cleavage (t8), morula (tM), and blastocyst stage morphokinetic variables. The strongest associations (adjusted ORs, 7.0-7.8) were found for late, expanded stage blastocyst parameters; tfullB, texpB1, and texpB2. The proportion of female embryos was 69-71 and 25-26 % inside and outside of the optimal ranges, respectively. This allowed to predict 74-78 % of them, increasing their proportion by 57 % compared to the average. CONCLUSIONS: Although the sample size of our cohort was limited, our findings suggest that several expanded blastocyst stage morphokinetic parameters are associated with female embryo gender. If confirmed on a larger sample these could be potentially used to increase the proportion of female embryos among non-invasively selected blastocysts following single embryo transfer.

Influence of different oocyte insemination techniques on early and late morphokinetic parameters: retrospective analysis of 500 time-lapse monitored blastocysts.

OBJECTIVE: To determine how standard IVF vs. intracytoplasmic sperm injection (ICSI) fertilization influences early and late morphokinetic parameters during prolonged embryo culture. DESIGN: Five-hundred expanded blastocysts that were monitored in a time-lapse monitoring incubator were analysed retrospectively. Early (pronuclear fading [PNf], t2-t9) and late (start of blastulation, expanded blastocyst) morphokinetic variables were scored according to published consensus criteria. SETTING: Private infertility clinic. PATIENT(S): A total of 209 consecutive infertile patients (mean ± SD age, 38.4 ± 4 years; range, 28-47 years) undergoing 238 natural IVF/minimal ovarian stimulation cycles during 2012-2014. INTERVENTION(S): Minimal ovarian stimulation, oocyte retrieval, fertilization with standard IVF or ICSI, prolonged embryo culture in a time-lapse monitoring incubator. MAIN OUTCOME MEASURE(S): Differences in morphokinetic parameters according to insemination techniques. RESULT(S): In total, 29% and 71% of the whole cohort was fertilized with standard IVF and ICSI, respectively. During early cleavage stages (PNf to t4) there was a statistically significant delay (+1.5 to +1.1 hours) among IVF-fertilized embryos. By contrast, at the expanded blastocyst stage IVF-fertilized embryos showed faster development (-3.3 to -4.1 hours). After normalizing to the time point of PNf, differences in cleavage-stage parameters disappeared, but those at all blastocyst stages increased even further in favor of IVF-fertilized embryos (-3.2 to -5.7 hours). CONCLUSION(S): The observed 1.5-hour time difference between standard IVF- and ICSI-fertilized embryos is an artificial phenomenon. At the blastocyst stages, however, genuine timing differences arise between IVF- and ICSI-fertilized embryos, possibly related to their different quality. Normalization to a common time point permits the joint analysis of IVF- and ICSI-fertilized embryos, thus increasing the size of studied cohorts.

Time-lapse monitoring of zona pellucida-free embryos obtained through in vitro fertilization: a retrospective case series.

OBJECTIVE: To report time-lapse monitoring of human oocytes in which the damaged zona pellucida was removed, producing zona-free (ZF) oocytes that were cultured until the blastocyst stage in time-lapse incubators. DESIGN: Retrospective case series. SETTING: Private infertility clinic. PATIENT(S): Infertile patients (n = 32) undergoing minimal ovarian stimulation or natural cycle IVF treatment between October 2012 and June 2014. INTERVENTION(S): Intracytoplasmic sperm injection (ICSI) fertilization of ZF oocytes, prolonged embryo culture in time-lapse incubators, elective vitrification, and subsequent single vitrified-thawed blastocyst transfer (SVBT). MAIN OUTCOME MEASURE(S): Rate of fertilization, cleavage and blastocyst development, live-birth rate per SVBT cycle. RESULT(S): In spite of advanced maternal age (39 ± 4.2; range, 30-46 years), good fertilization (94%), cleavage (94%), and blastocyst development rates (38%) were reached after fertilization and culturing of ZF oocytes/embryos. All thawed ZF blastocysts survived, and up to this date seven SVBT transfers were performed, yielding three (43%) term live births with healthy newborns. CONCLUSION(S): Time-lapse imagery gives a unique insight into the dynamics of embryo development in ZF embryos. Moreover, our case series demonstrate that an oocyte with a damaged zona pellucida that has been removed could be successfully fertilized with ICSI, cultured until blastocyst stage in a time-lapse incubator and vitrified electively for subsequent use.

Cumulative success rates following mild IVF in unselected infertile patients: a 3-year, single-centre cohort study.

A 3-year, retrospective, single-centre cohort study was conducted in a private infertility centre to determine cumulative live birth rates (LBR) per scheduled oocyte retrieval following minimal ovarian stimulation/natural-cycle IVF in unselected infertile patients. A total of 727 consecutive infertile patients were analysed who underwent 2876 (median 4) cycles with scheduled oocyte retrieval from November 2008 to December 2011. Natural-cycle IVF or clomiphene-based minimal ovarian stimulation was coupled with single-embryo transfer and increased use of delayed vitrified-warmed blastocyst transfer. Main outcome measures were crude and expected age-specific cumulative LBR per scheduled oocyte retrieval. Crude cumulative LBR were 65%, 60%, 39%, 15% and 5% in patients aged 26-34, 35-37, 38-40, 41-42 and 43-44 years, respectively. No live births occurred in patients aged ⩾ 45 years. Dropout rates per cycle were 13-25%. Success rates gradually reached a plateau, with few additional live births after six cycles. Most of the expected success rate was reached within 6 months with almost maximal rates within 15 months of the first oocyte retrieval. Acceptable cumulative LBR are reached with an exclusive minimal ovarian stimulation/single-embryo transfer policy especially in patients aged <38 years but also in intermediate aged patients (38-40 years).

Oocyte retrieval timing based on spontaneous luteinizing hormone surge during natural cycle in vitro fertilization treatment.

OBJECTIVE: To determine the efficiency of oocyte retrieval (OR) timing based on the occurrence of spontaneous LH surge during natural cycle IVF (ncIVF) treatment. DESIGN: Retrospective cohort study. The cohort was divided into five subgroups according to the presumed stage of spontaneous LH surge on scheduling day (1A: before onset; 1B: surge start; 2: ascending slope; 3: peak; and 4: descending slope). SETTING: Private infertility clinic. PATIENT(S): Three hundred sixty-five infertile patients who underwent 1,138 ncIVF treatment cycles during 2008-2011. INTERVENTION(S): Drug-free ncIVF treatment. MAIN OUTCOME MEASURE(S): Rate of successfully retrieved, fertilized oocytes, cleaved embryos, and live births per scheduled oocyte retrieval. RESULT(S): In 61% of the cycles OR was scheduled before or just at the start of the LH surge (groups 1A-1B), whereas in the remaining cases it was scheduled after the surge had already started (groups 2-4). The proportion of cycles with successfully recovered (range, 71%-86%), inseminated (range, 61%-78%), fertilized oocytes (range, 47%-68%), cleaved embryos (range, 45%-66%), and live births (range, 4.1%-9.2%) was not significantly different among subgroups. CONCLUSION(S): In ncIVF treatment OR timing based on the occurrence of spontaneous LH surge is feasible, yielding acceptable oocyte recovery, fertilization, and embryo cleavage rates. This strategy combined with a rapid and low-risk OR procedure permits the management of a large ncIVF program on a 7-days-per-week basis within working hours.

Short-term, low-dose, non-steroidal anti-inflammatory drug application diminishes premature ovulation in natural-cycle IVF.

A retrospective cohort study was conducted in a private infertility centre to evaluate the use of non-steroidal antiinflammatory drugs (NSAID) in natural-cycle IVF (nIVF) treatment. A total of 1865 first-rank nIVF cycles performed during 2009­2010 were evaluated. Low-dose, post-trigger NSAID was administered in a non-randomized way in cycles at higher ovulation risk where an imminent LH surge was detected on triggering day. Main outcome measures were premature ovulation rate, embryo transfer rate per scheduled cycle and clinical pregnancy and live birth rates per embryo transfer. NSAID use was associated with a significantly lower risk of premature ovulation (3.6% versus 6.8%, adjusted OR 0.24, 95% CI 0.15­0.39, P < 0.0001) and higher embryo transfer rate (46.8% versus 39.5%, adjusted OR 1.38, 95% CI 1.06­1.61, P = 0.012) per scheduled cycle. Clinical pregnancy (39.1% versus 35.9%) and live birth rates per embryo transfer (31.3% versus 31.4%) were comparable. In this retrospective series, short-term low-dose NSAID application positively influenced nIVF cycles by diminishing the rate of unwanted premature ovulations and increasing the proportion of cycles reaching embryo transfer.

Blue nevus of the endometrium.

A 36-year-old woman with a long history of amenorrhea underwent endometrial curettage. An aggregate of short spindle cells containing a finely granular, dark brown pigment with the histochemical characteristics of melanin was detected in the endometrial stroma. This finding is considered analogous to the occurrence of similar cells in the endocervical stroma and is most appropriately designated a "blue nevus" of the endometrium. The occurrence of nonneoplastic, melanin-laden cells in the endometrial stroma is an extremely rare phenomenon, which has been reported only once previously.