Assisted reproductive technology use and outcomes in childhood cancer survivors.

BACKGROUND: Treatment exposures for childhood cancer reduce ovarian reserve. However, the success of assisted reproductive technology (ART) among female survivors is not well established. METHODS: Five-year survivors of childhood cancer in the Childhood Cancer Survivor Study were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, which captures national ART outcomes. The authors assessed the live birth rate, the relative risk (RR) with 95% confidence intervals (95% CIs), and associations with treatment exposure using generalized estimating equations to account for multiple ovarian stimulations per individual. Siblings from a random sample of survivors were recruited to serve as a comparison group. RESULTS: Among 9885 female survivors, 137 (1.4%; median age at diagnosis, 10 years [range, 0-20 years]; median years of follow-up after age 18 years, 11 years [range, 2-11 years]) underwent 224 ovarian stimulations using autologous or donor eggs and/or gestational carriers (157 autologous ovarian stimulation cycles, 67 donor ovarian stimulation cycles). In siblings, 33 (1.4%) underwent 51 autologous or donor ovarian stimulations. Of those who used embryos from autologous eggs without using gestational carriers, 97 survivors underwent 155 stimulations, resulting in 49 live births, for a 31.6% chance of live birth per ovarian stimulation (vs. 38.3% for siblings; p = .39) and a 43.9% chance of live birth per transfer (vs. 50.0%; p = .33). Prior treatment with cranial radiation therapy (RR, 0.44; 95% CI, 0.20-0.97) and pelvic radiation therapy (RR, 0.33; 95% CI, 0.15-0.73) resulted in a reduced chance of live birth compared with siblings. The likelihood of live birth after ART treatment in survivors was not affected by alkylator exposure (cyclophosphamide-equivalent dose, ≥8000 mg/m2 vs. none; RR, 1.04; 95% CI, 0.52-2.05). CONCLUSIONS: Childhood cancer survivors are as likely to undergo treatment using ART as sibling controls. The success of ART treatment was not reduced after alkylator exposure. The results from the current study provide needed guidance on the use of ART in this population.

Multiple embryo manipulations in PGT-A cycles may result in inferior clinical outcomes.

RESEARCH QUESTION: Do embryos that undergo a thaw, biopsy and re-vitrification (TBR) for pre-implantation genetic testing for aneuploidy (PGT-A) have different ploidy and transfer outcomes compared with fresh biopsied embryos? DESIGN: Retrospective cohort study of all embryos that underwent the following procedures: fresh biopsy for PGT-A (fresh biopsy); embryos that were warmed, biopsied for PGT-A and re-vitrified (single biopsy TBR); embryos with a no signal result after initial biopsy that were subsequently warmed, biopsied and re-vitrified (double biopsy TBR). The patients who underwent transfers of those embryos at a single academic institution between March 2013 and December 2021 were also studied. RESULTS: About 30% of embryos planned for TBR underwent attrition. Euploidy rates were similar after biopsy: fresh biopsy (42.7%); single biopsy TBR (47.5%) (adjusted RR: 0.99, 0.88 to 1.12); and double biopsy TBR 50.3% (adjusted RR: 0.99, 0.80 to 1.21). Ongoing pregnancy over 8 weeks was not statistically significant (double biopsy TBR: 6/19 [31.6%] versus fresh biopsy: 650/1062 [61.2%]) (adjusted RR 0.52, 95% CI 0.26 to 1.03). The miscarriage rate increased (double biopsy TBR: 4/19 [21.1%] versus fresh biopsy: 66/1062 [6.2%])(RR 3.39, 95% CI 1.38 to 8.31). Live birth rate was also lower per transfer for the double biopsy TBR group (double biopsy TBR [18.75%] versus fresh biopsy [53.75%]) (RR 0.35, 95% CI 0.12 to 0.98), though not after adjustment (adjusted RR 0.37, 95% CI 0.13 to 1.09). These differences were not seen when single biopsy TBR embryos were transferred. CONCLUSIONS: Embryos that undergo TBR have an equivalent euploidy rate to fresh biopsied embryos. Despite that, double biopsy TBR embryos may have impaired transfer outcomes.

The effects of male anxiety and depression on IVF outcomes.

STUDY QUESTION: What are the effects of male anxiety and depression on IVF outcomes? SUMMARY ANSWER: Men with anxiety had lower final total motile sperm counts (fTMSC) during IVF compared to men without anxiety; however, there were no differences in live birth rates (LBRs). WHAT IS KNOWN ALREADY: Studies have shown that male anxiety causes low sperm motility, worse sperm morphology, and increased DNA fragmentation, which are known to be influential factors on fertilization rates and embryo quality during IVF. However, data are lacking on whether there is a direct association between male anxiety and/or depression and IVF outcomes. STUDY DESIGN, SIZE, DURATION: This was a survey-based, retrospective cohort study completed at a single, large hospital-affiliated fertility center with 222 respondents who underwent IVF with or without ICSI. The study was conducted between 6 September 2018 and 27 December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Male partners of couples who underwent IVF or IVF/ICSI completed a Hospital Anxiety and Depression Scale (HADS) questionnaire. They were separated into two groups for both anxiety (HADS-A ≥ 8 or HADS-A < 8) and depression (HADS-D ≥ 8 or HADS-D < 8). Men with an elevated HADS-A or HADS-D score ≥8 were considered to have anxiety or depression, respectively. The primary outcome was LBR. Secondary outcomes included semen parameters at the time of IVF, cycle outcomes, pregnancy outcomes, and prevalence of erectile dysfunction and low libido. MAIN RESULTS AND THE ROLE OF CHANCE: There were a total of 222 respondents, of whom 22.5% had a HADS-A ≥ 8 and 6.5% had a HADS-D ≥ 8. The average age of respondents was 37.38 ± 4.90 years old. Antidepressant use was higher in the respondents with a HADS-A or HADS-D ≥ 8 (P < 0.05). Smoking use was similar between groups for both HADS-A and HADS-D (P > 0.05). When adjusted for male BMI, antidepressant use and smoking, men with a HADS-A or HADS-D ≥ 8 had similar rates of erectile dysfunction (adjusted relative risk (aRR) = 1.12 (95% CI 0.60, 2.06)) and low libido (aRR = 1.70 (95% CI 0.91, 3.15)) compared to those with a HADS-A or HADS-D ≤ 8. Men with a HADS-A ≥ 8 were more likely to have a lower fTMSC on the day of oocyte retrieval (11.8 ≥ 8 vs 20.1 < 8, adjusted ß = -0.66 (95% CI -1.22, -0.10)). However, the LBR per embryo transfer (ET) was similar between the HADS-A groups (43.2% ≥8 vs 45.1% <8, adjusted relative risk = 0.90 (95% CI 0.65, 1.06)). Although depression was uncommon in the entire cohort, the HADS-D groups were clinically similar for fTMSC (18.7 ≥ 8 vs 16.0 < 8) and LBR per ET (46.7% ≥8 vs 45.4% <8). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study are the survey-based design, the lack of sperm morphology assessment at the time of IVF, our inability to fully assess the HADS-D ≥ 8 cohort due to the small sample size and the large Caucasian demographic. WIDER IMPLICATIONS OF THE FINDINGS: Couples undergoing IVF have an increased likelihood of suffering from anxiety and/or depression. There is currently a debate on whether or not men should be treated with antidepressants while attempting to conceive due to potential detrimental effects on sperm quality. Our study shows that, regardless of antidepressant use, couples with men who did or did not report anxiety and/or depression have similar LBRs when undergoing IVF. Therefore, it is important to assess both partners for mental health and to not withhold treatment due to a concern about a potential impact of antidepressants or anxiety/depression on sperm quality. STUDY FUNDING/COMPETING INTEREST(S): There was no funding to report for this study. Z.W. is a contributing author for UptoDate. S.S.S. is on the advisory board for Ferring Pharmaceuticals. E.G. was a medical consultant for Hall-Matson Esq, Teladoc, and CRICO and is a contributing author for UptoDate. The remaining authors have nothing to report. TRIAL REGISTRATION NUMBER: N/A.

Utility of Office Hysteroscopy in Diagnosing Retained Products of Conception Following Early Pregnancy Loss After In Vitro Fertilization.

OBJECTIVE: To evaluate the utility of office hysteroscopy in diagnosing and treating retained products of conception in patients with infertility who experience early pregnancy loss (EPL) after in vitro fertilization (IVF). METHODS: We evaluated a retrospective cohort of 597 pregnancies that ended in EPL in patients aged 18-45 years who conceived through fresh or frozen embryo transfer at an academic fertility practice between January 2016 and December 2021. All patients underwent office hysteroscopy after expectant, medical, or surgical management of the EPL. The primary outcome was presence of retained products of conception at the time of office hysteroscopy. Secondary outcomes included incidence of vaginal bleeding, presence of intrauterine adhesions, treatment for retained products of conception, and duration of time from EPL diagnosis to resolution. Log-binomial regression and Poisson regression were performed, adjusting for potential confounders including oocyte age, patient age, body mass index, prior EPL count, number of prior dilation and curettage procedures, leiomyomas, uterine anomalies, and vaginal bleeding. RESULTS: Of the 597 EPLs included, 129 patients (21.6%) had retained products of conception diagnosed at the time of office hysteroscopy. The majority of individuals with EPL were managed surgically (n=427, 71.5%), in lieu of expectant management (n=140, 23.5%) or medical management (n=30, 5.0%). The presence of retained products of conception was significantly associated with vaginal bleeding (relative risk [RR] 1.72, 95% CI 1.34-2.21). Of the 41 patients with normal pelvic ultrasonogram results before office hysteroscopy, 10 (24.4%) had retained products of conception detected at the time of office hysteroscopy. When stratified by EPL management method, retained products of conception were significantly more likely to be present in individuals with EPL who were managed medically (adjusted RR 2.66, 95% CI 1.90-3.73) when compared with those managed surgically. Intrauterine adhesions were significantly less likely to be detected in individuals with EPL who underwent expectant management when compared with those managed surgically (RR 0.14, 95% CI 0.04-0.44). Of the 127 individuals with EPL who were diagnosed with retained products of conception at the time of office hysteroscopy, 30 (23.6%) had retained products of conception dislodged during the office hysteroscopy, 34 (26.8%) chose expectant or medical management, and 63 (49.6%) chose surgical management. The mean number of days from EPL diagnosis to resolution of pregnancy was significantly higher in patients who elected for expectant management (31 days; RR 1.18, 95% CI 1.02-1.37) or medical management (41 days; RR 1.54, 95% CI 1.25-1.90) when compared with surgical management (27 days). CONCLUSION: In patients with EPL after IVF, office hysteroscopy detected retained products of conception in 24.4% of those with normal pelvic ultrasonogram results. Due to the efficacy of office hysteroscopy in diagnosing and treating retained products of conception, these data support considering office hysteroscopy as an adjunct to ultrasonography in patients with infertility who experience EPL after IVF.

Ultra-low-dose and very-low-dose Lupron downregulation protocols for poor responders based on POSEIDON group 3 and 4 classifications.

PURPOSE: The objective of this study was to assess if very-low-dose Lupron (VLDL) and ultra-low-dose Lupron (ULDL) protocols can have comparable cycle outcomes when compared to other "poor responder" stimulation protocols based on POSEIDON classification groups 3 (PG3) and 4 (PG4). METHODS: A retrospective cohort study at a single, large academic center was performed. Women in PG3 (age < 35, AMH < 1.2 ng/mL) or PG4 (age ≥ 35, AMH < 1.2 ng/mL) undergoing in vitro fertilization using an ULDL (Lupron 0.1 to 0.05 mg daily), VLDL (Lupron 0.2 to 0.1 mg daily), microflare (Lupron 0.05 mg twice a day), estradiol priming/antagonist, antagonist, or minimal stimulation protocols from 2012 to 2021 were included. The primary outcome was the number of mature oocytes (MII) obtained. The secondary outcome was live birth rate (LBR). RESULTS: The cohort included 3601 cycles. The mean age was 38.1 ± 3.8 years. In the PG3 group, ULDL and VLDL protocols produced a comparable number of MIIs (5.8 ± 4.3 and 5.9 ± 5.4, respectively) and live births (33.3% and 33.3%, respectively) when compared to other protocols. In the PG4 group, ULDL and VLDL protocols resulted in a higher percentage of MIIs when compared to microflare or minimal stimulation (Microflare/ULDL: adjusted relative risk (aRR) 0.78 (95% CI 0.65, 0.95); min stim/ULDL: aRR 0.47 (95% CI 0.38, 0.58); microflare/VLDL: aRR 0.77 (95% CI 0.63, 0.95); min stim/VLDL: aRR 0.47 (95% CI 0.38, 0.95)). There were no significant differences in LBR. CONCLUSION: Dilute Lupron downregulation protocols have comparable outcomes to other poor responder protocols and are reasonable to use.

First and second trimester maternal serum markers for prenatal aneuploidy screening: An update on the adjustment factors for race, smoking, and insulin dependent diabetes mellitus.

OBJECTIVES: The concentrations of maternal serum markers for aneuploidy screening are influenced by maternal characteristics such as race, smoking, insulin dependent diabetes mellitus (IDDM), and in vitro fertilization (IVF). Accurate risk estimation requires adjustment of initial values for these characteristics. This study aims to update and validate adjustment factors for race, smoking, and IDDM. METHODS: The study included singleton pregnancies that received multiple marker screening in Ontario, Canada between January 2012, and December 2018, and had their information collected in the Better Outcomes Registry & Network (BORN) Ontario. Serum markers assessed included first trimester pregnancy-associated plasma protein A (PAPP-A), free ß and total human chorionic gonadotropin (hCG), placental growth factor (PlGF) and αlpha-fetoprotein (AFP); second trimester AFP, unconjugated estriol (uE3), total hCG and inhibin A. The Mann-Whitney U test was used to assess the differences in the median multiple of the median (MoM) of serum markers between study and reference groups. New adjustment factors were generated by dividing the median MoM of a particular race, individuals who smoke tobacco, or have IDDM by those of the reference groups. RESULTS: The study included 624,789 pregnancies. There were statistically significant differences in serum marker concentrations among pregnant individuals who were Black, Asian, or First Nations compared to a White group, those who smoked compared to Non-smoking individuals, and those with IDDM compared to Non-IDDM group. New adjustment factors for race, smoking, and IDDM were validated by comparing median MoM of serum markers corrected using the current adjustment factors and new adjustment factors generated in this study. CONCLUSION: The adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

Premature progesterone elevation during the early and mid-follicular phases in fresh in vitro fertilization (IVF) cycles is associated with lower live birth, clinical pregnancy, and implantation rates.

PURPOSE: Evaluate follicular phase progesterone elevation (≥ 1.5 ng/mL) prior to trigger during IVF stimulation and its effects on live birth rate (LBR), clinical pregnancy rate (CPR), and implantation rate (IR) in fresh IVF cycles. METHODS: This was a retrospective cohort study within an academic clinic. A total of 6961 fresh IVF and IVF/ICSI cycles from October 1, 2015 to June 30, 2021 were included and grouped by progesterone (PR) prior to trigger: PR < 1.5 ng/mL (low PR group) and PR ≥ 1.5 ng/mL (high PR group). Main outcome measures included LBR, CPR, and IR. RESULTS: Among all cycle starts, 1568 (22.5%) were in the high PR group and 5393 (77.5%) were in the low PR group. Of the cycles which proceeded to an embryo transfer, 416 (11.1%) were in the high PR group and 3341 (88.9%) were in the low PR group. The high PR group had significantly lower IR (RR 0.75; 95% CI 0.64-0.88), CPR (aRR 0.74; 95% CI 0.64-0.87), and LBR (aRR 0.71; 95% CI 0.59-0.85) compared to the low PR group. When stratified by progesterone on the day of trigger (TPR), there was a clinically notable decrease in IR (16.8% vs 23.3%), CPR (28.1% vs 36.0%), and LBR (22.8% vs 28.9%) in the high PR group compared to the low PR group even when TPR < 1.5 ng/mL. CONCLUSIONS: In fresh IVF cycles in which TPR < 1.5 ng/mL, progesterone elevation ≥ 1.5 ng/mL at any point in time prior to trigger negatively impacts IR, CPR, and LBR. This data supports testing of serum progesterone in the follicular phase prior to trigger, as these patients may benefit from a freeze-all approach.

Day of trophectoderm biopsy and embryo quality are associated with outcomes following euploid embryo transfer.

PURPOSE: To compare clinical outcomes following transfer of euploid blastocysts of varying quality biopsied on day 5 versus day 6. METHODS: Retrospective cohort study to evaluate embryo transfer outcomes for women undergoing autologous cryopreserved next generation sequencing euploid single embryo transfer from 10/2015 to 2/2022 at an academic IVF program. The primary outcome was live birth rate (LBR). Secondary outcomes included ongoing pregnancy rate (OPR), implantation rate (IR), and miscarriage rate (SAB rate). RESULTS: Five hundred and fifty-five transfers from 418 patients were analyzed. Euploid embryos biopsied on day 5 resulted in higher LBR compared to those biopsied on day 6 (62.3% vs. 49.6%; aRR 0.81 95% CI 0.65-0.996). When stratified by biopsy day and blastocyst quality, there was no difference in IR, OPR, and SAB rate for good, fair, and poor quality blastocysts biopsied on day 5 versus day 6. However, day 5 good quality embryos were associated with a higher LBR compared to day 6 good quality embryos (74.3% vs. 51.3%; aRR 0.69; 95% CI 0.48-0.999). There were no significant differences in LBR for fair and poor quality embryos biopsied on day 5 versus day 6. CONCLUSION: Overall LBR are higher for euploid embryos biopsied on day 5 versus day 6. When stratified by embryo quality and day of biopsy, LBR are significantly higher for good quality day 5 versus day 6 embryos. When choosing between multiple euploid embryos, day 5 biopsied good quality embryos should be preferentially selected for transfer over day 6 embryos of the same quality.

Association between serum estradiol level on day of progesterone start and outcomes from frozen blastocyst transfer cycles utilizing oral estradiol.

PURPOSE: Supraphysiologic serum estradiol levels may negatively impact the likelihood of conception and live birth following IVF. The purpose of this study is to determine if there is an association between serum estradiol level on the day of progesterone start and clinical outcomes following programmed frozen blastocyst transfer cycles utilizing oral estradiol. METHODS: This is a retrospective cohort study at an academic fertility center analyzing 363 patients who underwent their first autologous single (SET) or double frozen embryo transfer (DET) utilizing oral estradiol and resulting in blastocyst transfer from June 1, 2012, to June 30, 2018. Main outcome measures included implantation, clinical pregnancy, live birth, and miscarriage rates. Cycles were stratified by quartile of serum estradiol on the day of progesterone start and separately analyzed for SET cycles only. Poisson and Log binomial regression were used to calculate relative risks (RR) with 95% confidence intervals (CI) for implantation, clinical pregnancy, live birth, and miscarriage with adjustments made for age and BMI. RESULTS: Cycles with the highest quartile of estradiol (mean 528 pg/mL) were associated with lower risks of implantation (RR 0.66, CI 0.50-0.86), ongoing pregnancy (RR 0.66, CI 0.49-0.88), and live birth (RR 0.70, CI 0.52-0.94) compared with those with the lowest estradiol quartile (mean 212 pg/mL). Similar findings were seen for analyses limited to SETs. There was no significant difference in miscarriage rate or endometrial thickness between groups. CONCLUSION: High levels of serum estradiol on the day of progesterone start may be detrimental to implantation, pregnancy, and live birth following frozen blastocyst transfer.

Predictors of Adverse Pregnancy Outcomes in Pregnant Women Living with Obesity: A Systematic Review.

Obesity is a well-recognized risk factor for pregnancy complications. Most studies to date are in large cohorts, with results presented in a way that assumes all women living with obesity are at equal risk. This study investigates which women living with obesity are at higher risk of specific pregnancy complications. A systematic search of MEDLINE and Embase identified 7894 prospective or retrospective cohort studies exploring predictors of adverse outcomes among pregnant women living with obesity. Following screening, 61 studies were deemed eligible. Studies were selected if the effects of exposure to any predictor amongst pregnant women living with obesity could be collected. Maternal characteristics assessed for association with adverse outcomes included maternal age, race/ethnicity, maternal height, mode of conception, complement activation factors, and history of various comorbidities/procedures. Gestational diabetes mellitus was the most studied outcome (n = 32), followed by preterm birth (n = 29), preeclampsia (n = 27), low birthweight infants (n = 20), small for gestational age newborns (n = 12), and stillbirth (n = 7). This review identified important characteristics that should be considered during the screening and follow-up sessions of pregnant women living with obesity, including pre-existing type 1 diabetes, maternal age < 20 years or ≥35 years, non-White ethnicity, abdominal adiposity obesity, and history of bariatric surgery.

Oocyte cryopreservation review: outcomes of medical oocyte cryopreservation and planned oocyte cryopreservation.

BACKGROUND: The utilization of oocyte cryopreservation (OC) has become popularized with increasing numbers of reproductive-aged patients desiring to maintain fertility for future family building. OC was initially used for fertility preservation in postmenarchal patients prior to gonadotoxic therapies; however, it is now available to patients to circumvent age-related infertility and other diagnoses associated with early loss of ovarian reserve. The primary aim of this paper is to provide a narrative review of the most recent and robust data on the utilization and outcomes of OC in both patient populations. OC results in similar oocyte yield in patients facing gonadotoxic therapies and patients undergoing planned OC. Available data are insufficient to predict the live birth rates or the number of oocytes needed to result in live birth. However, oocyte yield and live birth rates are best among patients < 37.5 years old or with anti-mullerian hormone levels > 1.995 ng/dL, at the time of oocyte retrieval. There is a high 'no use' rate (58.9%) in patients using planned OC with 62.5% returning to use frozen oocytes with a spouse. The utilization rate in medical OC patients is < 10%. There is currently no data on the effects of BMI, smoking, or ethnicity on planned OC outcomes. CONCLUSION: It is too early to draw any final conclusions on outcomes of OC in medical OC and planned OC; however, preliminary data supports that utilization of OC in both groups result in preservation of fertility and subsequent live births in patients who return to use their cryopreserved eggs. Higher oocyte yield, with fewer ovarian stimulation cycles, and higher live birth rates are seen in patients who seek OC at younger ages, reinforcing the importance of age on fertility preservation. More studies are needed in medical OC and planned OC to help guide counseling and decision-making in patients seeking these services.

The impact of fertility preservation on the timing of breast cancer treatment, recurrence, and survival.

BACKGROUND: Many young women with breast cancer undergo fertility preservation (FP) before cancer treatment. This study examined the impact of FP on breast cancer outcomes. METHODS: The authors performed a retrospective cohort study of 272 women aged 20 to 45 years with newly diagnosed stage 0 to III breast cancer who underwent an FP consultation between 2005 and 2017. Among these women, 123 (45.2%) underwent FP (fertility preservation-positive [FP+]). The remaining 149 women did not undergo FP (fertility preservation-negative [FP-]). RESULTS: The characteristics at enrollment were similar with the exception of ethnicity (FP+, 87.8% White; FP-, 67.8% White; P = .002) and BRCA status (FP+, 27.7% BRCA+; FP-, 15.5% BRCA+; P = .021). The median follow-up was approximately 4 years. Women who underwent FP had longer times to first treatment (FP+, 37 days; FP-, 31 days; adjusted hazard ratio [aHR], 0.74; confidence interval [CI], 0.56-0.99) and neoadjuvant chemotherapy (FP+, 36 days; FP-, 26 days; aHR, 0.41; CI, 0.24-0.68) and from surgery to adjuvant chemotherapy (FP+, 41 days; FP-, 33 days; aHR, 0.58; CI, 0.38-0.90). Adjusted 3- and 5-year invasive disease-free survival (IDFS) rates were comparable between the 2 groups (3-year IDFS: FP+, 85.4%; FP-, 79.4%; P = .411; 5-year IDFS: FP+, 73.7%; FP-, 67.1%; P = .288). Similarly, no difference in overall survival (OS) was observed between the 2 groups (3-year OS: FP+, 95.5%; FP-, 93.5%; P = .854; 5-year OS: FP+, 84.2%; FP-, 81.4%; P = .700). CONCLUSIONS: FP after a breast cancer diagnosis delays the time to treatment by a small amount, but this delay does not lead to inferior IDFS or OS.

Quality of embryos on day 7 after medium refreshment on day 6: a prospective trial.

STUDY QUESTION: Are embryos that fail to meet biopsy or freezing criteria on day 6 (D6) more likely to meet these criteria on day 7 (D7) if cultured in fresh medium from D6 to D7? SUMMARY ANSWER: Refreshment of medium on D6 did not increase the proportion of usable embryos on D7, with an adverse effect for women ≥40 years old. WHAT IS KNOWN ALREADY: Embryo development in continuous single-step medium, from fertilization to the blastocyst stage, is equivalent to that using a sequential media protocol. However, there remains a theoretical benefit of refreshing the culture environment by transitioning slowly developing D6 embryos to a fresh medium droplet of the same composition, with a renewed source of nutrients and a milieu free of metabolic toxins. STUDY DESIGN, SIZE, DURATION: This was a prospective trial of culture media exposure in which embryos were randomized on D6 to remain in the same culture medium from D3 to D7 (continuous, n = 620) or be moved to fresh medium (fresh, n = 603) on D6, with re-evaluation on D7. Data were collected from IVF cycles, with or without ICSI, between 29 March 2019 and 17 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Embryos from 298 women, aged 18-44 years, from cycles with or without preimplantation genetic testing (PGT) that did not meet criteria for biopsy and/or freeze on D6 were included in the study. Embryos were only included if there was a minimum of two embryos meeting the inclusion criteria in any cohort. Only the first cycle undertaken by each woman in the study period from which embryos were randomized was included. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 1254 embryos were randomized from 312 cycles (209 non-PGT and 103 PGT) including 200 women undergoing IVF without PGT and 98 women who underwent PGT. The proportion of usable blastocysts on D7 did not differ between groups: 10.1% (61/603) in fresh versus 9.7% (60/620) in continuous medium (relative risk (RR) 1.05, 95% CI 0.74-1.47)). Embryos from women ≥40 years old had a significantly decreased likelihood of achieving a usable blastocyst on D7 after culture in fresh versus continuous medium: 3.5% versus 12.2%; RR 0.29, 95% CI 0.08-0.98. In total, 9.9% of embryos otherwise discarded on D6 met the criteria for biopsy and/or freeze on D7. LIMITATIONS, REASONS FOR CAUTION: Future work investigating implantation, clinical pregnancy and miscarriage rates with D7 embryos is still needed. WIDER IMPLICATIONS OF THE FINDINGS: Refreshment of medium on D6 did not increase the proportion of usable embryos on D7 overall. Younger women were more likely to develop D7 embryos after refreshment of medium on D6, while an adverse effect was seen in women ≥40 years old. However, by extending the culture of embryos to D7, additional blastocysts become available for clinical use. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided through the Department of Obstetrics and Gynecology at Brigham and Women's Hospital. I.G.I. works with Teladoc Health. A.L. has no disclosures. E.S.G. works as a consultant for Teladoc Health, and a writer and editor for UpToDate and BioMed Central. C.R. is a board member of the American Society for Reproductive Medicine and works with UpToDate. TRIAL REGISTRATION NUMBER: N/A.

The impact of polycystic ovary syndrome and body mass index on the absorption of recombinant human follicle stimulating hormone.

PURPOSE: Women with polycystic ovary syndrome (PCOS) have an increased ovarian responsiveness to exogenous recombinant follicle stimulating hormone (rFSH) but also have high rates of obesity, which is known to affect serum FSH concentrations following exogenous injection. The purpose of this study was to compare rFSH absorption and ovarian response between lean and overweight/obese PCOS subjects and normo-ovulatory controls. METHODS: Fourteen women with PCOS aged 18-42 years old with a BMI of 18.5-24.9 kg/m2 (normal) or 25.0-40.0 kg/m2 (overweight/obese) and eleven normo-ovulatory controls matched by age and BMI were included. After downregulation with oral contraceptives, participants were administered a single subcutaneous injection of 225 IU rFSH and underwent serial blood draws over 72 h. RESULTS: Lean PCOS subjects exhibited a significantly higher area under the curve (AUC) of baseline-corrected serum FSH over 72 h when compared with overweight/obese PCOS subjects (183.3 vs 139.8 IU*h/L, p = 0.0002), and lean, normo-ovulatory women had a significantly higher AUC FSH when compared with overweight/obese, normo-ovulatory women (193.3 vs 93.8 IU*h/L, p < 0.0001). Within overweight/obese subjects, those with PCOS had a significantly higher AUC FSH compared with normo-ovulatory controls (p = 0.0002). Lean PCOS subjects similarly had the highest AUC of baseline-corrected estradiol (6095 pg h/mL), compared with lean normo-ovulatory subjects (1931 pg h/mL, p < 0.0001) and overweight/obese PCOS subjects (2337 pg h/mL, p < 0.0001). CONCLUSION: Lean PCOS subjects exhibited significantly higher baseline-corrected FSH and estradiol levels following rFSH injection compared with overweight/obese PCOS subjects with similar ovarian reserve markers. Amongst overweight/obese subjects, those with PCOS had significantly higher FSH and E2 levels when compared with normo-ovulatory controls.

Potential biological therapies for severe preeclampsia: a systematic review and meta-analysis.

BACKGROUND: Preeclampsia remains a significant danger to both mother and child and current prevention and treatment management strategies are limited. The objective of this systematic review was to investigate the current literature on evidence for the use of the regenerative capacity of mesenchymal stem cell (MSC) therapy, the anticoagulant activity of antithrombin (AT), or the free radical scavenging activity of alpha-1-microglobulin (A1M) as potential novel treatments for severe preeclampsia and Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP). METHOD: We conducted a systematic review of potential biological therapies for preeclampsia. We screened MEDLINE and Embase from inception through May 2017 for studies using AT, A1M or MSCs as potential treatments for preeclampsia and/or HELLP. A meta-analysis was performed to pool data from randomized control trials (RCTs) with homogenous outcomes using the inverse variance method. The Newcastle-Ottawa Scale, the Cochrane risk of bias tool for RCTs, and SYRCLE's risk of bias tool for animal studies were used to investigate potential bias of studies. RESULTS: The literature search retrieved a total of 1015 articles, however, only 17 studies met the selection criteria: AT (n = 9, 8 human and 1 animal); A1M (n = 4, 3 animal and 1 ex-vivo); and, MSCs (n = 4, 3 animal and 1 ex-vivo). A meta-analysis of AT therapy versus placebo and a meta-analysis for AT therapy with heparin versus heparin alone did not show significant differences between study groups. Animal and ex-vivo studies demonstrated significant benefits in relevant outcomes for A1M and MSCs versus control treatments. Most RCT studies were rated as having a low risk of bias across categories with some studies showing an unclear risk of bias in some categories. The two cohort studies both received a total of four out of nine stars (a rating of "poor" quality). Most animal studies had an unclear risk of bias across most categories, with some studies having a low risk of bias in some categories. CONCLUSIONS: The findings of this review are strengthened by rigorous systematic search and review of the literature. Results of our meta-analyses do not currently warrant further exploration of AT as a treatment of preeclampsia in human trials. Results of animal and ex-vivo studies of A1M and MSCs were encouraging and supportive of initiating human investigations.

Prevalence and predictors of 6-month exclusive breastfeeding among Canadian women: a national survey.

BACKGROUND: In spite of the evidence supporting the importance of breastfeeding during the first year of life, data on breastfeeding practices remain limited in Canada. The study aimed to examine the prevalence and predictors of 6-month exclusive breastfeeding among Canadian women. METHODS: The analysis was based on the Maternity Experience Survey targeting women aged >or= 15 years who had singleton live births between February 2006 - May 2006 in the Canadian provinces and November 2005 - February 2006 in the territories. The main outcome was exclusive breastfeeding based on the World Health Organization definition. Socioeconomic, demographic, maternal, pregnancy and delivery related variables were considered for a multivariate logistic regression using stepwise modeling. Bootstrapping was performed to account for the complex sampling design. RESULTS: The sample size in this study was 5,615 weighted to represent 66,810 Canadian women. While ever breastfeeding was 90.3%, the 6-month exclusive breastfeeding rate was 13.8%. Based on the regression model, having higher years of education, residing in the Northern territories and Western provinces, living with a partner, having had previous pregnancies, having lower pre-pregnancy body mass index and giving birth at older age were associated with increased likelihood of 6-month exclusive breastfeeding. Moreover, smoking during pregnancy, Caesarean birth, infant's admission to the intensive care unit and maternal employment status before 6 months of infant's age were negatively associated with exclusive breastfeeding. Mothers choosing to deliver at home were more likely to remain exclusively breastfeeding for 6 months (Odds Ratio: 5.29, 95% Confidence Interval: 2.95-9.46). CONCLUSIONS: The 6-month exclusive breastfeeding rate is low in Canada. The study results constitute the basis for designing interventions that aim to bridge the gap between the current practices of breastfeeding and the World Health Organization recommendation.