Anti-Müllerian hormone levels are associated with time to pregnancy in a prospective cohort study of 3,150 women.

OBJECTIVE: To study the association between AMH and time to pregnancy. While it has been hypothesized that serum anti-Müllerian hormone (AMH) levels may indicate the chance of conception, findings have been mixed. Given that any association is expected to be modest, and it is possible that previous studies have been underpowered, we investigated this relationship in the largest prospective cohort to date. DESIGN: Prospective time-to-pregnancy cohort study. SUBJECTS: 3,150 US women who had been trying to conceive for less than 3 months and had purchased a Modern Fertility Hormone Test. EXPOSURE: We developed a discrete time-to-event model utilizing a binomial complementary log-log error structure within a generalized additive modeling framework, adjusting for confounding factors such as age, BMI, parity, smoking status, PCOS, and others. Sensitivity analyses were performed in women with regular menstrual cycles (21-35 days), who did not report using fertility treatments, using alternate AMH categories (<0.7, 0.7-8.5, >8.5 ng/mL), and AMH as a continuous measure. MAIN OUTCOME MEASURES: Primary outcomes included cumulative conception probability within 12 cycles and relative fecundability per menstrual cycle. Conception was defined by a self-reported positive pregnancy test. RESULTS: Participants contributed 7.21 ± 5.32 cycles, with 1,325 (42.1%) achieving a pregnancy. Women with low AMH (<1ng/mL, n=427) had a lower chance of natural conception (Adjusted Hazard Ratio (adjHR 0.77, 95%CI 0.64, 0.94, p=0.009) compared to women with a normal AMH (1 - 5.5ng/mL). There was no difference between high (5.5+ ng/ml) and normal AMH categories (adjHR 1.11, 95% CI 0.94, 1.31, p=0.2). The inclusion of AMH improved the model (net reclassification index 0.10 [ 0.06 - 0.14); P<0.001). The instantaneous probability of conception was highest in cycle 4 across all AMH categories: the probability of natural conception was 11.2% (95% CI 9.0, 14.0) for low AMH, 14.3% (95% CI 12.3, 16.5) for normal AMH, and 15.7% (95%CI 12.9, 19.0) for high AMH. In the regular cycles sensitivity analysis (n=1,791), the low AMH group had a lower chance of conception (adjHR 0.77 95% CI 0.61, 0.97, p = 0.028) in the low AMH group compared to normal AMH, and similarly in the continuous model (adjHR 0.90; 95% CI 0.85-0.95, p<0.0001). CONCLUSION: Low AMH levels (<1 ng/ml) are independently associated with a modest but significant reduction in the chance of conception.

Epidural analgesia in labour: separating fact from fiction for autism and neurodevelopment.

Having epidural analgesia in labour has been associated with a later diagnosis of autism spectrum disorder in the offspring, resulting in concerns about childhood wellbeing. Neurodevelopmental changes are inconsistently reported in the literature, creating challenges in the interpretation of these findings. Here we explore the limitations of the current evidence base, and why findings differ between studies, concluding that the current body of evidence does not support a causal association between use of epidural analgesia in labour and autism spectrum disorder.

Price transparency at the point of prescribing with real-time prescription benefits.

PURPOSE: Real-time prescription benefits (RTPB) shows prescribers patient-, medication-, and pharmacy-specific information on medication pricing, prior authorization requirements, and lower-cost alternatives. RTPB is intended to improve patient satisfaction and prescription fill rates by decreasing out-of-pocket costs for prescriptions. Therefore, we evaluated how RTPB affects prescribing patterns by examining acceptance and subsequent fill rates for RTPB alternative suggestions. METHODS: RTPB was implemented in February 2022 using external vendor interfaces. Prescribing data from March 2022 to March 2023 were analyzed. RTPB displayed alerts for medications requiring prior authorization or when alternative medications would result in cost savings. Patients were included if their prescription received an RTPB response and they had a subsequent encounter with pharmacy fill data. Primary outcomes were alert acceptance rates and prescription fill rates across RTPB alert groups, with a secondary outcome of monthly copay savings for accepted alerts. RESULTS: RTPB requests received a response for 88% of prescriptions, with price estimates provided for 77.9% of them. Lower-cost alternatives accounted for 67.2% of alerts, while prior authorization requirements represented 15% of alerts. Prescribers selected a lower-cost alternative 32% of the time. For those with an RTPB alert, patients filled prescriptions 68% of the time when an alternative was chosen, compared to 59% of the time when the original prescription was retained (odds ratio, 1.5; 95% confidence interval, 1.5-1.6; P < 0.001). Patients saved an average of $27.77 per month on copay costs when alternatives were selected. CONCLUSION: Implementation of RTPB was found to result in significant improvements in prescription fill rates and decrease patient copay costs, despite low alert acceptance rates.

Epidural analgesia during labour and severe maternal morbidity: population based study.

OBJECTIVES: To determine the effect of labour epidural on severe maternal morbidity (SMM) and to explore whether this effect might be greater in women with a medical indication for epidural analgesia during labour, or with preterm labour. DESIGN: Population based study. SETTING: All NHS hospitals in Scotland. PARTICIPANTS: 567 216 women in labour at 24+0 to 42+6 weeks' gestation between 1 January 2007 and 31 December 2019, delivering vaginally or through unplanned caesarean section. MAIN OUTCOME MEASURES: The primary outcome was SMM, defined as the presence of ≥1 of 21 conditions used by the US Centers for Disease Control and Prevention (CDC) as criteria for SMM, or a critical care admission, with either occurring at any point from date of delivery to 42 days post partum (described as SMM). Secondary outcomes included a composite of ≥1 of the 21 CDC conditions and critical care admission (SMM plus critical care admission), and respiratory morbidity. RESULTS: Of the 567 216 women, 125 024 (22.0%) had epidural analgesia during labour. SMM occurred in 2412 women (4.3 per 1000 births, 95% confidence interval (CI) 4.1 to 4.4). Epidural analgesia was associated with a reduction in SMM (adjusted relative risk 0.65, 95% CI 0.50 to 0.85), SMM plus critical care admission (0.46, 0.29 to 0.73), and respiratory morbidity (0.42, 0.16 to 1.15), although the last of these was underpowered and had wide confidence intervals. Greater risk reductions in SMM were detected among women with a medical indication for epidural analgesia (0.50, 0.34 to 0.72) compared with those with no such indication (0.67, 0.43 to 1.03; P<0.001 for difference). More marked reductions in SMM were seen in women delivering preterm (0.53, 0.37 to 0.76) compared with those delivering at term or post term (1.09, 0.98 to 1.21; P<0.001 for difference). The observed reduced risk of SMM with epidural analgesia was increasingly noticeable as gestational age at birth decreased in the whole cohort, and in women with a medical indication for epidural analgesia. CONCLUSION: Epidural analgesia during labour was associated with a 35% reduction in SMM, and showed a more pronounced effect in women with medical indications for epidural analgesia and with preterm births. Expanding access to epidural analgesia for all women during labour, and particularly for those at greatest risk, could improve maternal health.

Individualized dosing of follitropin delta affects live birth and safety in in vitro fertilization treatment: an individual participant data meta-analysis of randomized controlled trials.

OBJECTIVE: To undertake a one-stage meta-analysis of individual patient data from randomized trials comparing individualized dosing of follitropin delta vs. other forms of follitropin (alpha and beta) for live birth (LB) rates (LBR) and safety parameters in women undergoing ovarian stimulation for in vitro fertilization treatment. DESIGN: Systematic review with individual patient data meta-analysis. SETTING: Not applicable. PATIENTS: Women undergoing ovarian stimulation for in vitro fertilization treatment. INTERVENTIONS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Web of Science to identify eligible phase 3 trials between January 1, 2000, and February 1, 2023. MAIN OUTCOME MEASURES: All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drugs interacting with log (AMH) level, age, and random effects for country and trial to compare the primary efficacy and safety outcomes of LB and early ovarian hyperstimulation syndrome (OHSS) and/or the need for OHSS preventative measures, with ovarian stimulation parameters and neonatal outcomes also assessed. PROSPERO registration: CRD42023399711. RESULTS: Three trials met inclusion criteria and included 2,685 women undertaking 2,682 cycles between October 2013 and May 2020, with LB follow-up through to February 1, 2023. For women with an elevated AMH level (≥15 pmol/L), there was high-quality evidence that the use of individualized dosing of follitropin delta was associated with an increased LB rate (adjusted odds ratio [adj OR] 1.64, 95% confidence interval [CI] 1.14, 2.36). Safety outcomes were also improved with a reduced risk of both early OHSS and/or the need for preventative interventions (adj OR 0.27, 95% CI 0.15, 0.49) and early moderate or severe OHSS (adj OR 0.30, 95% CI 0.16, 0.58). These improvements in outcomes were obtained with a lower total dose of gonadotropin (-48.7 µg, 95% CI -53.7, -43.8) and no adjustments in the daily dose. In contrast, similar LB rates (adj OR 0.86, 95% CI 0.63, 1.17) and safety outcomes (adj OR 1.92, 95% CI 0.76, 4.87) were observed for women with an AMH level of <15 pmol/L. There were no clinically meaningful differences in neonatal outcomes. CONCLUSION: Using follitropin delta in an AMH level and weight-based algorithm rather than conventional licensed dosing of follitropin alpha or beta for ovarian stimulation in women is associated with improved LB rates and safety outcomes for women with elevated AMH levels.

Improving Medication Management for Inpatients with a Secondary Diagnosis of Parkinson Disease.

ABSTRACT: Patients who have Parkinson disease require individualized medication regimens to optimize care. A review of the medication management of patients admitted to a tertiary care hospital with a secondary diagnosis of Parkinson disease found significant departures from the patients' home regimen. Medication regimens are often altered by health care teams unfamiliar with Parkinson disease-specific care in order to conform to standard hospital medication orders and administration times, potentially resulting in increased patient falls, delirium, and mortality.A nurse-led multidisciplinary team consisting of pharmacy, nursing, informatics, neurology, and quality personnel implemented a quality improvement (QI) project between July 2020 and July 2022 to identify patients with Parkinson disease, including those with a secondary diagnosis and those undergoing deep brain stimulation, and customize medication management in order to reduce length of stay, mortality, falls, falls with harm, and 30-day readmissions. The QI project team also evaluated patient satisfaction with medication management.Among patients with a secondary diagnosis of Parkinson disease, the proportion who had medication histories conducted by a pharmacy staff member increased from a baseline of 53% to more than 75% per month. For all patients with Parkinson disease, those whose medication history was taken by a pharmacy staff member had orders matching their home regimen 89% of the time, whereas those who did not had orders matching the home regimen only 40% of the time. Among patients with a secondary diagnosis of Parkinson disease, the length-of-stay index decreased from a baseline of 1 to 0.94 and observed-to-expected mortality decreased from 1.03 to 0.78. The proportion of patients experiencing a fall decreased from an average of 5% to 4.08% per quarter, while the proportion of patients experiencing a fall with harm decreased from an average of 1% to 0.75% per quarter. The rate of 30-day readmissions decreased from 10.81% to 4.53% per quarter. Patient satisfaction scores were 1.95 points higher for patients who had medication histories taken by pharmacy than for those who did not (5 versus 3.05).

Latent Epstein-Barr virus infection collaborates with Myc over-expression in normal human B cells to induce Burkitt-like Lymphomas in mice.

Epstein-Barr virus (EBV) is an important cause of human lymphomas, including Burkitt lymphoma (BL). EBV+ BLs are driven by Myc translocation and have stringent forms of viral latency that do not express either of the two major EBV oncoproteins, EBNA2 (which mimics Notch signaling) and LMP1 (which activates NF-κB signaling). Suppression of Myc-induced apoptosis, often through mutation of the TP53 (p53) gene or inhibition of pro-apoptotic BCL2L11 (BIM) gene expression, is required for development of Myc-driven BLs. EBV+ BLs contain fewer cellular mutations in apoptotic pathways compared to EBV-negative BLs, suggesting that latent EBV infection inhibits Myc-induced apoptosis. Here we use an EBNA2-deleted EBV virus (ΔEBNA2 EBV) to create the first in vivo model for EBV+ BL-like lymphomas derived from primary human B cells. We show that cord blood B cells infected with both ΔEBNA2 EBV and a Myc-expressing vector proliferate indefinitely on a CD40L/IL21 expressing feeder layer in vitro and cause rapid onset EBV+ BL-like tumors in NSG mice. These LMP1/EBNA2-negative Myc-driven lymphomas have wild type p53 and very low BIM, and express numerous germinal center B cell proteins (including TCF3, BACH2, Myb, CD10, CCDN3, and GCSAM) in the absence of BCL6 expression. Myc-induced activation of Myb mediates expression of many of these BL-associated proteins. We demonstrate that Myc blocks LMP1 expression both by inhibiting expression of cellular factors (STAT3 and Src) that activate LMP1 transcription and by increasing expression of proteins (DNMT3B and UHRF1) known to enhance DNA methylation of the LMP1 promoters in human BLs. These results show that latent EBV infection collaborates with Myc over-expression to induce BL-like human B-cell lymphomas in mice. As NF-κB signaling retards the growth of EBV-negative BLs, Myc-mediated repression of LMP1 may be essential for latent EBV infection and Myc translocation to collaboratively induce human BLs.

Why do users override alerts? Utilizing large language model to summarize comments and optimize clinical decision support.

OBJECTIVES: To evaluate the capability of using generative artificial intelligence (AI) in summarizing alert comments and to determine if the AI-generated summary could be used to improve clinical decision support (CDS) alerts. MATERIALS AND METHODS: We extracted user comments to alerts generated from September 1, 2022 to September 1, 2023 at Vanderbilt University Medical Center. For a subset of 8 alerts, comment summaries were generated independently by 2 physicians and then separately by GPT-4. We surveyed 5 CDS experts to rate the human-generated and AI-generated summaries on a scale from 1 (strongly disagree) to 5 (strongly agree) for the 4 metrics: clarity, completeness, accuracy, and usefulness. RESULTS: Five CDS experts participated in the survey. A total of 16 human-generated summaries and 8 AI-generated summaries were assessed. Among the top 8 rated summaries, five were generated by GPT-4. AI-generated summaries demonstrated high levels of clarity, accuracy, and usefulness, similar to the human-generated summaries. Moreover, AI-generated summaries exhibited significantly higher completeness and usefulness compared to the human-generated summaries (AI: 3.4 ± 1.2, human: 2.7 ± 1.2, P = .001). CONCLUSION: End-user comments provide clinicians' immediate feedback to CDS alerts and can serve as a direct and valuable data resource for improving CDS delivery. Traditionally, these comments may not be considered in the CDS review process due to their unstructured nature, large volume, and the presence of redundant or irrelevant content. Our study demonstrates that GPT-4 is capable of distilling these comments into summaries characterized by high clarity, accuracy, and completeness. AI-generated summaries are equivalent and potentially better than human-generated summaries. These AI-generated summaries could provide CDS experts with a novel means of reviewing user comments to rapidly optimize CDS alerts both online and offline.

The prospect of artificial intelligence to personalize assisted reproductive technology.

Infertility affects 1-in-6 couples, with repeated intensive cycles of assisted reproductive technology (ART) required by many to achieve a desired live birth. In ART, typically, clinicians and laboratory staff consider patient characteristics, previous treatment responses, and ongoing monitoring to determine treatment decisions. However, the reproducibility, weighting, and interpretation of these characteristics are contentious, and highly operator-dependent, resulting in considerable reliance on clinical experience. Artificial intelligence (AI) is ideally suited to handle, process, and analyze large, dynamic, temporal datasets with multiple intermediary outcomes that are generated during an ART cycle. Here, we review how AI has demonstrated potential for optimization and personalization of key steps in a reproducible manner, including: drug selection and dosing, cycle monitoring, induction of oocyte maturation, and selection of the most competent gametes and embryos, to improve the overall efficacy and safety of ART.

A Randomized Trial of Two Remote Health Care Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study.

BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).

Leveraging explainable artificial intelligence to optimize clinical decision support.

OBJECTIVE: To develop and evaluate a data-driven process to generate suggestions for improving alert criteria using explainable artificial intelligence (XAI) approaches. METHODS: We extracted data on alerts generated from January 1, 2019 to December 31, 2020, at Vanderbilt University Medical Center. We developed machine learning models to predict user responses to alerts. We applied XAI techniques to generate global explanations and local explanations. We evaluated the generated suggestions by comparing with alert's historical change logs and stakeholder interviews. Suggestions that either matched (or partially matched) changes already made to the alert or were considered clinically correct were classified as helpful. RESULTS: The final dataset included 2 991 823 firings with 2689 features. Among the 5 machine learning models, the LightGBM model achieved the highest Area under the ROC Curve: 0.919 [0.918, 0.920]. We identified 96 helpful suggestions. A total of 278 807 firings (9.3%) could have been eliminated. Some of the suggestions also revealed workflow and education issues. CONCLUSION: We developed a data-driven process to generate suggestions for improving alert criteria using XAI techniques. Our approach could identify improvements regarding clinical decision support (CDS) that might be overlooked or delayed in manual reviews. It also unveils a secondary purpose for the XAI: to improve quality by discovering scenarios where CDS alerts are not accepted due to workflow, education, or staffing issues.

Clinical compatibility of magnetic resonance imaging with magnetic intramedullary nails: a feasibility study.

INTRODUCTION: The use of magnetic resonance imaging (MRI) with a magnetic intramedullary lengthening nail in place is contraindicated per the manufacturer due to the concern of implant activation and migration. A prior in vitro study did not confirm these complications only noting that a 3.0 T MRI weakened the internal magnet. Therefore, a retrospective analysis of patients who underwent an MRI with a magnetic nail in place was performed to determine if any adverse effects occurred in the clinical setting. MATERIALS AND METHODS: A retrospective review of all patients who underwent an MRI with a magnetic lengthening nail in place was performed. The time spent being imaged in the MRI, number of times the patient entered the MRI suite, and the images obtained were recorded. Radiographs were performed before and after the MRI to determine if any hardware complications occurred. The patients were monitored for any adverse symptoms while they were in the suite. RESULTS: A total of 12 patients with 13 nails were identified. Two patients underwent imaging with a 3.0 T MRI while the remaining 10 underwent imaging with a 1.5 T MRI. Each patient entered the MRI suite 2.1 times and spent an average of 84.7 min being imaged in the MRI (range 21-494). No patients noted any adverse symptoms related to the nail while in the suite and no hardware complications were identified. CONCLUSION: MRI appears to be safe with a magnetic nail in place and did not result in any complications. Given the manufacturer's recommendations, informed consent should be obtained prior to an MRI being performed and a 3.0 T MRI should be avoided when possible if further activation of the nail is required.

Sensitivity of North American grassland birds to weather and climate variability.

Grassland birds in North America have declined sharply over the last 60 years, driven by the widespread loss and degradation of grassland habitats. Climate change is occurring more rapidly in grasslands relative to some other ecosystems, and exposure to extreme and novel climate conditions may affect grassland bird ecology and demographics. To determine the potential effects of weather and climate variability on grassland birds, we conducted a systematic review of relationships between temperature and precipitation and demographic responses in grassland bird species of North America. Based on 124 independent studies, we used a vote-counting approach to quantify the frequency and direction of significant effects of weather and climate variability on grassland birds. Grassland birds tended to experience positive and negative effects of higher temperatures and altered precipitation. Moderate, sustained increases in mean temperature and precipitation benefitted some species, but extreme heat, drought, and heavy rainfall often reduced abundance and nest success. These patterns varied among climate regions, temporal scales of temperature and precipitation (<1 or ≥1 month), and taxa. The sensitivity of grassland bird populations to extreme weather and altered climate variability will likely be mediated by regional climates, interaction with other stressors, life-history strategies of various species, and species' tolerances for novel climate conditions.

Sensibilidad de las aves norteamericanas de pastizales ante la variabilidad climática y el clima Resumen Las aves de los pastizales norteamericanos han declinado gravemente durante los últimos 60 años, principalmente debido a la pérdida generalizada y la degradación del hábitat. El cambio climático ocurre cada vez más rápido en los pastizales en relación con otros ecosistemas, y la exposición a las condiciones climáticas nuevas y extremas puede afectar la demografía y la ecología aviar en los pastizales. Realizamos un análisis sistemático de las relaciones entre la temperatura y la precipitación y las respuestas demográficas de las especies de aves de pastizales en Norteamérica para determinar los efectos potenciales del clima y la variabilidad climática sobre estas aves. Usamos un método de conteo de votos basado en 124 estudios independientes para cuantificar la frecuencia y dirección de los efectos significativos del clima y la variabilidad climática sobre las aves de pastizal. Las aves de pastizal tendieron a experimentar los efectos positivos y negativos de las altas temperaturas y la precipitación alterada. El incremento moderado y sostenido en las medias de temperatura y precipitación beneficiaron a algunas especies, pero el calor extremo, la sequía y las lluvias torrenciales redujeron con frecuencia la abundancia y el éxito de anidación. Estos patrones variaron entre las regiones climáticas, las escalas temporales de temperatura y precipitación (< 1 mes o ≥ 1 mes) y los taxones. La sensibilidad de las poblaciones de aves de pastizal ante el clima extremo y la variabilidad climática alterada probablemente será mediada por los climas regionales, la interacción con otros estresantes, las estrategias de vida de varias especies y la tolerancia de las especies a las condiciones climáticas nuevas.

TSH and FT4 Reference Interval Recommendations and Prevalence of Gestational Thyroid Dysfunction: Quantification of Current Diagnostic Approaches.

CONTEXT: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.

Luteal phase support in assisted reproductive technology.

Infertility affects one in six couples, with in vitro fertilization (IVF) offering many the chance of conception. Compared to the solitary oocyte produced during the natural menstrual cycle, the supraphysiological ovarian stimulation needed to produce multiple oocytes during IVF results in a dysfunctional luteal phase that can be insufficient to support implantation and maintain pregnancy. Consequently, hormonal supplementation with luteal phase support, principally exogenous progesterone, is used to optimize pregnancy rates; however, luteal phase support remains largely 'black-box' with insufficient clarity regarding the optimal timing, dosing, route and duration of treatment. Herein, we review the evidence on luteal phase support and highlight remaining uncertainties and future research directions. Specifically, we outline the physiological luteal phase, which is regulated by progesterone from the corpus luteum, and evaluate how it is altered by the supraphysiological ovarian stimulation used during IVF. Additionally, we describe the effects of the hormonal triggers used to mature oocytes on the degree of luteal phase support required. We explain the histological transformation of the endometrium during the luteal phase and evaluate markers of endometrial receptivity that attempt to identify the 'window of implantation'. We also cover progesterone receptor signalling, circulating progesterone levels associated with implantation, and the pharmacokinetics of available progesterone formulations to inform the design of luteal phase support regimens.