Individualised dosing of follitropin delta affects live birth and safety in IVF: an individual participant data meta-analysis of randomised controlled trials.

IMPORTANCE: For women undertaking assisted conception, the dose of gonadotropin has historically been driven by clinical experience. A different and individualised strategy was developed for follitropin delta, a human cell line derived recombinant follicle stimulating hormone, with dose based on anti-Müllerian hormone (AMH) stratification; for women with a high ovarian reserve (AMH ≥15pmol/l; approx. 2.1ng/ml) the dose is based on the combination of AMH and body weight in a continuous manner. The clinical effectiveness of this approach to dosing for ovarian stimulation on live birth and safety is unknown. OBJECTIVE: Undertake a one-stage meta-analysis of individual patient data from randomised trials comparing individualised dosing of follitropin delta versus other forms of follitropin (alpha, beta) for live birth rates and safety parameters in women undergoing ovarian stimulation for IVF. EVIDENCE REVIEW: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify eligible phase 3 trials between Jan 1 2000 and Feb 1 2023. All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drug interacting with log(AMH), age, and random effects for country and trial to compare the primary efficacy and safety outcomes of live birth 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. FINDINGS: Three trials met inclusion criteria and included 2685 women undertaking 2,682 cycles between October 2013, and May 2020, with live birth follow-up through to February 1, 2023. For women with an elevated AMH (≥15 pmol/L), there was high quality evidence that the use of individualised dosing of follitropin delta was associated with an increased live birth rate (adjusted OR 1.64, 95%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 (-48.7µg, 95%CI -53.7, -43.8) and no adjustments in the daily dose. In contrast, similar live birth 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 <15pmol/l. There were no clinical meaningful differences in neonatal outcomes. CONCLUSION AND RELEVANCE: Using follitropin delta in an AMH and weight-based algorithm rather than conventional licenced dosing of follitropin alpha or beta for ovarian stimulation women is associated with improved live birth rates and safety outcomes for women with elevated AMH levels.

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.

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.

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.

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.

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.

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.

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.

Anti-Müllerian hormone for the diagnosis and prediction of menopause: a systematic review.

BACKGROUND: The early onset of menopause is associated with increased risks of cardiovascular disease and osteoporosis. As a woman's circulating anti-Müllerian hormone (AMH) concentration reflects the number of follicles remaining in the ovary and declines towards the menopause, serum AMH may be of value in the early diagnosis and prediction of age at menopause. OBJECTIVE AND RATIONALE: This systematic review was undertaken to determine whether there is evidence to support the use of AMH alone, or in conjunction with other markers, to diagnose menopause, to predict menopause, or to predict and/or diagnose premature ovarian insufficiency (POI). SEARCH METHODS: A systematic literature search for publications reporting on AMH in relation to menopause or POI was conducted in PubMed®, Embase®, and the Cochrane Central Register of Controlled Trials up to 31 May 2022. Data were extracted and synthesized using the Synthesis Without Meta-analysis for diagnosis of menopause, prediction of menopause, prediction of menopause with a single/repeat measurement of AMH, validation of prediction models, short-term prediction in perimenopausal women, and diagnosis and prediction of POI. Risk-of-bias was evaluated using the Tool to Assess Risk of Bias in Cohort Studies protocol and studies at high risk of bias were excluded. OUTCOMES: A total of 3207 studies were identified, and 41, including 28 858 women, were deemed relevant and included. Of the three studies that assessed AMH for the diagnosis of menopause, one showed that undetectable AMH had equivalent diagnostic accuracy to elevated FSH (>22.3 mIU/ml). No study assessed whether AMH could be used to shorten the 12 months of amenorrhoea required for a formal diagnosis of menopause. Studies assessing AMH with the onset of menopause (27 publications [n = 23 835 women]) generally indicated that lower age-specific AMH concentrations are associated with an earlier age at menopause. However, AMH alone could not be used to predict age at menopause with precision (with estimates and CIs ranging from 2 to 12 years for women aged <40 years). The predictive value of AMH increased with age, as the interval of prediction (time to menopause) shortened. There was evidence that undetectable, or extremely low AMH, may aid early diagnosis of POI in young women with a family history of POI, and women presenting with primary or secondary amenorrhoea (11 studies [n = 4537]). WIDER IMPLICATIONS: The findings of this systematic review support the use of serum AMH to study the age of menopause in population studies. The increased sensitivity of current AMH assays provides improved accuracy for the prediction of imminent menopause, but diagnostic use for individual patients has not been rigorously examined. Prediction of age at menopause remains imprecise when it is not imminent, although the finding of very low AMH values in young women is both of clinical value in indicating an increased risk of developing POI and may facilitate timely diagnosis.

Prediction of ovarian response using the automated Elecsys anti-Müllerian hormone assay in gonadotrophin-releasing hormone antagonist cycles.

RESEARCH QUESTION: What is the capability of serum anti-Müllerian hormone (AMH) measured using the automated Elecsys® AMH immunoassay to (Roche Diagnostics International Ltd) determine ovarian response after fertility treatment? DESIGN: Single-centre, retrospective, observational, cohort study including women undergoing ovarian stimulation. Serum AMH concentrations were determined using the Elecsys AMH immunoassay based on one blood sample drawn 6 months or less before treatment. Stimulation was conducted in accordance with a gonadotrophin-releasing hormone (GnRH) antagonist protocol. Patients were divided into four ovarian response categories based on their oocyte yield: low (0-3), suboptimal (4-9), optimal (10-15) and high (>15). Areas under the curve were calculated for each ovarian response group. RESULTS: Overall, 1248 patients were enrolled. The AMH concentration had a strong positive correlation with oocyte yield (Spearman's rho = 0.74, P < 0.001). Areas under the curve (95% CI) for AMH predicting ovarian response were 0.85 (0.83 to 0.88) for low and 0.89 (0.87 to 0.91) for high response. Optimal serum AMH cut-offs for predicting a low and high response using the Elecsys AMH immunoassay were 6.4 pmol/l (0.89 ng/ml) and 14.2 pmol/l (1.99 ng/ml), respectively. Multivariable regression analysis showed that 47% (R2 = 0.470) of variation in ovarian response could be attributed to AMH alone, increasing to 50.9% (R2 = 0.509) with the addition of age, body weight, and total dose of gonadotrophin. CONCLUSION: Ovarian response and oocyte yield after stimulation in a GnRH antagonist cycle can be predicted with high accuracy using a single determination of serum AMH before ovarian stimulation.

General health in a cohort of children conceived after assisted reproductive technology in the United Kingdom: a population-based record-linkage study.

BACKGROUND: Assisted reproductive technology use is increasing annually; however, data on long-term child health outcomes including hospital admissions are limited. OBJECTIVE: This study aimed to examine the potential effects of assisted reproductive technology on any and cause-specific hospital admissions unrelated to perinatal diagnoses. STUDY DESIGN: This was a population-based record-linkage study that included a previously established cohort of children born after assisted reproductive technology in the United Kingdom between 1997 and 2009 (n=63,877), their naturally conceived siblings (n=11,343), and matched naturally conceived population controls (n=127,544) linked to their postnatal health outcomes up to March 31, 2016 to provide robust risk estimates of the potential effects of assisted reproductive technology on any and cause-specific hospital admissions unrelated to perinatal diagnoses. In addition, comparison of hospital admissions by type of treatment was made. Cox regression was used to estimate the risk of hospital admission, and negative binomial regression was used to compare the number of hospital admissions per year. RESULTS: This study had 1.6 million person-years of follow-up (mean, 12.9 years; range, 0-19 years), and the mean age at the time of first hospital admission was 6.5 years (range, 0-19 years). Singletons born after assisted reproductive technology had increased risk of any hospital admission compared with naturally conceived population controls (hazard ratio, 1.08; 95% confidence interval, 1.05-1.10) but not naturally conceived siblings (hazard ratio, 1.01; 95% confidence interval, 0.94-1.09). We observed increased risk of diagnoses related to neoplasms and diseases of the respiratory, musculoskeletal, digestive, and genitourinary systems, and lower risk of injury, poisoning, and consequences of external causes compared with naturally conceived population controls. Children born after intracytoplasmic sperm injection had a lower risk of hospital admission compared with those born after in vitro fertilization, although no such differences were observed between children born after fresh embryo transfers and those born after frozen embryo transfers. CONCLUSION: Children born after assisted reproductive technology had greater numbers of hospital admissions compared with naturally conceived population controls. Attenuation of these differences in relation to their naturally conceived siblings suggested that this could be partially attributed to the influence of parental subfertility on child health, increased parental concerns, and an actual increase in morbidity in children born after assisted conception.

Gestational diabetes in women with obesity; an analysis of clinical history and simple clinical/anthropometric measures.

AIM: We assessed clinical risk factors, anthropometric measures of adiposity and weight gain to determine associations with development of GDM in a cohort of pregnant women with obesity. METHODS: This was a secondary analysis of the UPBEAT trial of a complex lifestyle intervention in pregnant women with obesity (ISRCTN89971375). Clinical risk factors, and measures of adiposity and weight were assessed in the early 2nd trimester (mean 17 +0 weeks), and adiposity and weight repeated in the early 3rd trimester (mean 27 +5 weeks'). RESULTS: Of the 1117 women (median BMI 35.0 kg/m2) with complete data, 25.8% (n = 304) developed GDM (IADPSG criteria, OGTT 24-28weeks). Using multivariable analysis, early clinical risk factors associated with later development of GDM included age (adj OR 1.06 per year; 95% CI 1.04-1.09), previous GDM (3.27; 1.34-7.93) and systolic blood pressure (per 10mmHg, 1.34; 1.18-1.53). Anthropometric measures positively associated with GDM included second trimester (mean 17+0 weeks) subscapular skinfold thickness, (per 5mm, 1.12; 1.05-1.21), and neck circumference (per cm, 1.11; 1.05-1.18). GDM was not associated with gestational weight gain, or changes in skinfolds thicknesses or circumferences between visits. CONCLUSIONS: In this cohort of women with obesity, we confirmed clinical risk factors for GDM, (age, systolic blood pressure) previously identified in heterogeneous weight women but add to these indices of adiposity which may provide a discriminatory approach to GDM risk assessment in this group. This study also underscores the need to focus on modifiable factors pre-pregnancy as an opportunity for GDM prevention, as targeting gestational weight gain and adiposity during pregnancy is likely to be less effective.

Changes in women's physical function in mid-life by reproductive age and hormones: a longitudinal study.

BACKGROUND: Whether women's physical function in mid-life is related to their reproductive age is not known. The objectives of this study were to examine and compare changes in physical function in women by reproductive age, measured as time since final menstrual period (FMP), and chronological age, and to explore associations with repeatedly assessed levels of reproductive hormones. METHODS: We used data from 2319 UK women with up to three repeated measurements of physical function (median length of follow up: 2 years), focusing on changes occurring in women experiencing a natural menopausal transition. The main outcome was a composite physical function score that incorporated assessments of strength (grip strength), balance (one-leg stand) and cardiorespiratory fitness (timed chair rises). Associations with time since FMP, age, and time-updated measures of anti-Müllerian hormone, follicle-stimulating hormone and luteinizing hormone were assessed by multilevel models and generalised estimating equations models adjusted for the underlying effects of chronological age and confounding by education, age at first birth and smoking. RESULTS: The results showed that, adjusted for these confounders, time since FMP (- 0.21 SD per 10 years, 95% CI - 0.37, - 0.06) and chronological age (- 0.31 SD per 10 years, 95% CI - 0.46, - 0.15) were inversely associated with the physical function composite score. Grip strength seemed to be the main contributor to the decline in the composite score by time since FMP. There was no strong evidence of associations between any of the three reproductive hormones and the composite score. CONCLUSIONS: Physical function in women in mid-life declined with both chronological and reproductive age. The decline with reproductive age was independent of chronological age but did not seem to be driven by changes in reproductive hormones.