Deep learning versus manual morphology-based embryo selection in IVF: a randomized, double-blind noninferiority trial.

To assess the value of deep learning in selecting the optimal embryo for in vitro fertilization, a multicenter, randomized, double-blind, noninferiority parallel-group trial was conducted across 14 in vitro fertilization clinics in Australia and Europe. Women under 42 years of age with at least two early-stage blastocysts on day 5 were randomized to either the control arm, using standard morphological assessment, or the study arm, employing a deep learning algorithm, intelligent Data Analysis Score (iDAScore), for embryo selection. The primary endpoint was a clinical pregnancy rate with a noninferiority margin of 5%. The trial included 1,066 patients (533 in the iDAScore group and 533 in the morphology group). The iDAScore group exhibited a clinical pregnancy rate of 46.5% (248 of 533 patients), compared to 48.2% (257 of 533 patients) in the morphology arm (risk difference -1.7%; 95% confidence interval -7.7, 4.3; P = 0.62). This study was not able to demonstrate noninferiority of deep learning for clinical pregnancy rate when compared to standard morphology and a predefined prioritization scheme. Australian New Zealand Clinical Trials Registry (ANZCTR) registration: 379161 .

Antimüllerian hormone levels are associated with time to pregnancy in a cohort study of 3,150 women.

OBJECTIVE: To study the association between antimüllerian hormone (AMH) levels and time of pregnancy. Although it has been hypothesized that serum 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. SETTING: Community. PATIENT(S): A total of 3,150 US women who had been trying to conceive for <3 months and had purchased a Modern Fertility hormone test. INTERVENTION(S): We developed a discrete time-to-event model using a binomial complementary log-log error structure within a generalized additive modeling framework, adjusting for confounding factors such as age, body mass index, parity, smoking status, polycystic ovary syndrome, 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 level categories (<0.7, 0.7-8.5, >8.5 ng/mL), and AMH levels as a continuous measure. MAIN OUTCOME MEASURE(S): 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. RESULT(S): Participants contributed 7.21 ± 5.32 cycles, with 1,325 (42.1%) achieving a pregnancy. Women with low AMH levels (<1 ng/mL, n = 427) had a lower chance of natural conception (adjusted hazard ratio [adjHR], 0.77; 95% confidence interval [CI], 0.64-0.94) compared with women with normal AMH levels (1-5.5 ng/mL). There was no difference between high (5.5+ ng/mL) and normal AMH level categories (adjHR, 1.11; 95% CI, 0.94-1.31). The inclusion of AMH improved the model (net reclassification index 0.10 [0.06-0.14]). The instantaneous probability of conception was highest in cycle four across all AMH categories: the probability of natural conception was 11.2% (95% CI, 9.0-14.0) for low AMH levels, 14.3% (95% CI, 12.3-16.5) for normal AMH levels, and 15.7% (95% CI, 12.9-19.0) for high AMH levels. 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) in the low AMH group compared with normal AMH, and similarly in the continuous model (adjHR, 0.90; 95% CI, 0.85-0.95). CONCLUSION(S): Low AMH levels (<1 ng/mL) are independently associated with a modest but significant reduction in the chance of conception.

Defining gestational thyroid dysfunction through modified non-pregnancy reference intervals: an individual participant meta-analysis.

BACKGROUND: Establishing local trimester-specific reference intervals for gestational TSH and FT4 is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific non-pregnancy reference intervals as compared to trimester-specific reference intervals. METHODS: We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the non-pregnancy reference intervals included an absolute modification (per 0.1 mU/L TSH or 1 pmol/L FT4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 to 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity and positive predictive value (PPV) of aforementioned methodologies with population-based trimester-specific reference intervals. RESULTS: The final study population comprised 52,496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity 0.70, confidence interval [CI] 0.47-0.86; PPV 0.64, CI 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity 0.91, CI 0.67-0.98; PPV 0.71, CI 0.58-0.80). Absolute and fixed modifications yielded similar results. Confidence intervals were wide, limiting generalizability. CONCLUSION: We could not identify modifications of non-pregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned towards studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

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.

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.

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.

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.

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.

Association between perinatal mortality and morbidity and customised and non-customised birthweight centiles in Denmark, Finland, Norway, Wales, and England: comparative, population based, record linkage study.

Objectives: To compare the risk of adverse perinatal outcomes according to infants who are born small for gestational age (SGA; <10th centile) or large for gestational age (LGA; >90th centile), as defined by birthweight centiles that are non-customised (ie, standardised by sex and gestational age only) and customised (by sex, gestational age, maternal weight, height, parity, and ethnic group). Design: Comparative, population based, record linkage study with meta-analysis of results. Setting: Denmark, Finland, Norway, Wales, and England (city of Bradford), 1986-2019. Participants: 2 129 782 infants born at term in birth registries. Main outcome measures: Stillbirth, neonatal death, infant death, admission to neonatal intensive care unit, and low Apgar score (<7) at 5 minutes. Results: Relative to those infants born average for gestational age (AGA), both SGA and LGA births were at increased risk of all five outcomes, but observed relative risks were similar irrespective of whether non-customised or customised charts were used. For example, for SGA versus AGA births, when non-customised and customised charts were used, relative risks pooled over countries were 3.60 (95% confidence interval 3.29 to 3.93) versus 3.58 (3.02 to 4.24) for stillbirth, 2.83 (2.18 to 3.67) versus 3.32 (2.05 to 5.36) for neonatal death, 2.82 (2.07 to 3.83) versus 3.17 (2.20 to 4.56) for infant death, 1.66 (1.49 to 1.86) versus 1.54 (1.30 to 1.81) for low Apgar score at 5 minutes, and (based on Bradford data only) 1.97 (1.74 to 2.22) versus 1.94 (1.70 to 2.21) for admission to the neonatal intensive care unit. The estimated sensitivity of combined SGA or LGA births to identify the three mortality outcomes ranged from 31% to 34% for non-customised charts and from 34% to 38% for customised charts, with a specificity of 82% and 80% with non-customised and customised charts, respectively. Conclusions: These results suggest an increased risk of adverse perinatal outcomes of a similar magnitude among SGA or LGA term infants when customised and non-customised centiles are used. Use of customised charts for SGA/LGA births-over and above use of non-customised charts for SGA/LGA births-is unlikely to provide benefits in terms of identifying term births at risk of these outcomes.

Beyond the Umbrella: A Systematic Review of the Interventions for the Prevention of and Reduction in the Incidence and Severity of Ovarian Hyperstimulation Syndrome in Patients Who Undergo In Vitro Fertilization Treatments.

Ovarian hyperstimulation syndrome (OHSS) is the main severe complication of ovarian stimulation for in vitro fertilization (IVF) cycles. The aim of the current study was to identify the interventions for the prevention of and reduction in the incidence and severity of OHSS in patients who undergo IVF not included in systematic reviews with meta-analyses of randomized controlled trials (RCTs) and assess and grade their efficacy and evidence base. The best available evidence for each specific intervention was identified, analyzed in terms of safety/efficacy ratio and risk of bias, and graded using the Oxford Centre for Evidence-Based Medicine (CEBM) hierarchy of evidence. A total of 15 interventions to prevent OHSS were included in the final analysis. In the IVF population not at a high risk for OHSS, follitropin delta for ovarian stimulation may reduce the incidence of early OHSS and/or preventive interventions for early OHSS. In high-risk patients, inositol pretreatment, ovulation triggering with low doses of urinary hCG, and the luteal phase administration of a GnRH antagonist may reduce OHSS risk. In conclusion, even if not supported by systematic reviews with homogeneity of the RCTs, several treatments/strategies to reduce the incidence and severity of OHSS have been shown to be promising.

Interventions to prevent or reduce the incidence and severity of ovarian hyperstimulation syndrome: a systematic umbrella review of the best clinical evidence.

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threating iatrogenic complication of the early luteal phase and/or early pregnancy after in vitro fertilization (IVF) treatment. The aim of the current study was to identify the most effective methods for preventing of and reducing the incidence and severity of OHSS in IVF patients. A systematic review of systematic reviews of randomized controlled trials (RCTs) with meta-analysis was used to assess each potential intervention (PROSPERO website, CRD 268626) and only studies with the highest quality were included in the qualitative analysis. Primary outcomes included prevention and reduction of OHSS incidence and severity. Secondary outcomes were maternal death, incidence of hospital admission, days of hospitalization, and reproductive outcomes, such as incidence of live-births, clinical pregnancies, pregnancy rate, ongoing pregnancy, miscarriages, and oocytes retrieved. A total of specific interventions related to OHSS were analyzed in 28 systematic reviews of RCTs with meta-analyses. The quality assessment of the included studies was high, moderate, and low for 23, 2, and 3 studies, respectively. The certainty of evidence (CoE) for interventions was reported for 37 specific situations/populations and resulted high, moderate, and low-to-very low for one, 5, and 26 cases, respectively, while it was not reported in 5 cases. Considering the effective interventions without deleterious reproductive effects, GnRH-ant co-treatment (36 RCTs; OR 0.61, 95% C 0.51 to 0.72, n = 7,944; I2 = 31%) and GnRH agonist triggering (8 RCTs; OR 0.15, 95% CI 0.05 to 0.47, n = 989; I2 = 42%) emerged as the most effective interventions for preventing OHSS with a moderate CoE, even though elective embryo cryopreservation exhibited a low CoE. Furthermore, the use of mild ovarian stimulation (9 RCTs; RR 0.26, CI 0.14 to 0.49, n = 1,925; I2 = 0%), and dopaminergic agonists (10 RCTs; OR 0.32, 95% CI 0.23 to 0.44, n = 1,202; I2 = 13%) coadministration proved effective and safe with a moderate CoE. In conclusion, the current study demonstrates that only a few interventions currently can be considered effective to reduce the incidence of OHSS and its severity with high/moderate CoE despite the numerous published studies on the topic. Further well-designed RCTs are needed, particularly for GnRH-a down-regulated IVF cycles.

Setting a tariff for IVF and ICSI treatment: a cost analysis.

In-vitro fertilisation (IVF) and intra-cytoplasmatic sperm injection (ICSI) are available in Scotland through the National Health Service (NHS) according to specific criteria. There is no standardised NHS tariff for these treatments in Scotland, and variation exists amongst different centres providing NHS services. The aim of this study was to calculate the mean cost of IVF and ICSI cycles for NHS-funded treatment in Scotland. A detailed cost analysis of fresh and frozen cycles was performed, and a breakdown of the various cost components was presented. A deterministic approach was applied using NHS-funded individual cycle data from 2015-2018 and aggregate data. All costs were calculated in UK pounds sterling (£- using 2018 prices). Resource use was assigned to individual cycles based on cycle-level data or expert-informed assumptions; whenever needed, average aggregate costs were assigned to cycles. A total of 9442 NHS-funded cycles were included in the analysis. The average cost of fresh IVF and ICSI cycles was £3247 [£1526-£4215] and £3473 [£1526-£4416], respectively. Frozen cycles averaged £938 [£272-£1085]. This data can be useful to decision-makers, especially where IVF/ICSI is publicly funded, as it delivers a detailed IVF/ICSI cost breakdown. It is an opportunity for other authorities to estimate IVF/ICSI costs, as the methods applied are clear and reproducible.

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis.

AIMS: To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. METHODS AND RESULTS: Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. CONCLUSION: These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

Contraceptive-specific antimüllerian hormone values in reproductive-age women: a population study of 42,684 women.

OBJECTIVE: To determine how the contraceptive-specific serum antimüllerian hormone (AMH) levels compare across ages and percentiles in a reproductive-age cohort. DESIGN: Cross-sectional analysis of a prospectively recruited cohort. SETTING: Community. PATIENT(S): This study included US-based women of reproductive age who purchased a fertility hormone test and consented to participate in research between May 2018 and November 2021. At the time of hormone testing, participants were users of various contraceptives (combined oral contraceptive [n = 6,850], progestin-only pill [n = 465], hormonal [n = 4,867] or copper [n = 1,268] intrauterine device, implant [n = 834], vaginal ring [n = 886]) or women with regular menstrual cycles (n = 27,514). INTERVENTION(S): Contraceptive use. MAIN OUTCOME MEASURE(S): Age and contraceptive-specific estimates of AMH. RESULT(S): There were contraceptive-specific effects on AMH with effect estimates ranging from 0.83 (95% confidence interval [CI], 0.82-0.85) (17% lower) for the combined oral contraceptive pill to no effect (1.00; 95% CI, 0.98-1.03) for the hormonal intrauterine device. We did not observe age-specific differences in suppression. However, there were differential suppressive effects of the contraceptive method across AMH percentiles, with the greatest effect at lower percentiles and least effect at higher percentiles. For example, for women taking the combined oral contraceptive pill, the AMH level was 32% lower at the 10th percentile (coefficient, 0.68; 95% CI, 0.65-0.71), 19% lower at the 50th percentile (coefficient, 0.81; 95% CI, 0.79-0.84), and 5% lower at the 90th percentile (coefficient, 0.95; 95% CI, 0.92-0.98), with other forms of contraception showing similar discordances. CONCLUSION(S): These findings reinforce the body of literature that shows that hormonal contraceptives have different impacts on the AMH levels at a population level. These results add to this literature that these effects are not consistent; instead, the greatest impact occurs at the lower AMH percentiles. However, these contraceptive-dependent differences are small compared with the known biological variability in ovarian reserve at any given age. These reference values enable robust assessment of an individual's ovarian reserve relative to their peers without requiring cessation or potentially invasive removal of contraception.

Study protocol: examining the impacts of COVID-19 mitigation measures on pregnancy and birth outcomes in Scotland-a linked administrative data study.

INTRODUCTION: This protocol outlines aims to test the wider impacts of the COVID-19 pandemic on pregnancy and birth outcomes and inequalities in Scotland. METHOD AND ANALYSIS: We will analyse Scottish linked administrative data for pregnancies and births before (March 2010 to March 2020) and during (April 2020 to October 2020) the pandemic. The Community Health Index database will be used to link the National Records of Scotland Births and the Scottish Morbidity Record 02. The data will include about 500 000 mother-child pairs. We will investigate population-level changes in maternal behaviour (smoking at antenatal care booking, infant feeding on discharge), pregnancy and birth outcomes (birth weight, preterm birth, Apgar score, stillbirth, neonatal death, pre-eclampsia) and service use (mode of delivery, mode of anaesthesia, neonatal unit admission) during the COVID-19 pandemic using two analytical approaches. First, we will estimate interrupted times series regression models to describe changes in outcomes comparing prepandemic with pandemic periods. Second, we will analyse the effect of COVID-19 mitigation measures on our outcomes in more detail by creating cumulative exposure variables for each mother-child pair using the Oxford COVID-19 Government Response Tracker. Thus, estimating a potential dose-response relationship between exposure to mitigation measures and our outcomes of interest as well as assessing if timing of exposure during pregnancy matters. Finally, we will assess inequalities in the effect of cumulative exposure to lockdown measures on outcomes using several axes of inequality: ethnicity/mother's country of birth, area deprivation (Scottish Index of Multiple Deprivation), urban-rural classification of residence, number of previous children, maternal social position (National Statistics Socioeconomic Classification) and parental relationship status. ETHICS AND DISSEMINATION: NHS Scotland Public Benefit and Privacy Panel for Health and Social Care scrutinised and approved the use of these data (1920-0097). Results of this study will be disseminated to the research community, practitioners, policy makers and the wider public.