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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?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.Overall, 1248 patients were enrolled. The AMH concentration had a strong positive correlation with oocyte yield (Spearman's rho = 0.74, P0.001). 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% (ROvarian 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.

Does anti-Müllerian hormone (AMH) differ between healthy European and Indian women, and are potential ethnic differences modified by infertility diagnosis?Cross-sectional analysis of three prospectively recruited cohorts (n = 2758); healthy European women (n = 758), healthy community cohort from Kolhapur, India (n = 400) and infertility cohort from Kolhapur, India (n = 1600). AMH was determined by assay. Ethnicity, age and cause of infertility were modelled using additive quantile regression models.Healthy Indian women had lower AMH than their healthy European counterparts (population estimates 20.0% lower [95% CI 7.2-36.5]), with increasing discordance with increasing age; at 25 years AMH was 11.9% lower (95% CI 9.4-14.1), increasing to 40.0% lower (95% CI 0-64.6) by age 45. Comparison of healthy and infertile Indian women revealed differences that were related to cause of infertility. Women whose male partner had severe oligoasthenoteratozoospermia (n = 95) had similar AMH to controls; women with polycystic ovary syndrome (n = 220) had higher AMH, especially in those30 years, and in women with a principal diagnosis of unexplained infertility (n = 757) AMH was lower (median difference 22.6% lower; 95% CI 9.1-37.7) than controls.AMH is substantially lower in healthy Indian women at all ages than their European counterparts. Infertile Indian women have variable differences in AMH from healthy Indian controls, with the extent and direction of differences primarily reflecting the underlying cause of infertility. Recognition of ethnic and cause-specific differences are critical to ensure accurate contextualizing of results and clinical outcomes for patients.

Context Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. Objective (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. Methods (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. Results (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody–positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from –10.8% to –21.8% for TSH and –1.2% to –13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. Conclusion We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

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 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.

RESEARCH QUESTION Is ovarian response associated with individualized follitropin delta dosing regimen comparable across different ethnic populations? DESIGN Post-hoc analysis of ovarian response in 800 IVF/intracytoplasmic sperm injection (ICSI) patients (170 Japanese women and 630 White women) undergoing stimulation with individualized follitropin delta dosing based on serum anti-Mullerian hormone concentration and body weight in two randomized controlled trials conducted in Japan (NCT03228680) and in Europe, North America and South America (NCT01956110). RESULTS On average, Japanese women weighed 10 kg less, which affected the total follitropin delta dose, compared with White women (83.5 ± 28.9 versus 90.2 ± 25.2 µg). At the end of stimulation, serum FSH concentrations were not significantly different between Japanese and White women (median 14.3 versus 14.0 IU/l), whereas serum oestradiol concentrations were significantly higher in Japanese women (median 6517 versus 5298 pmol/l, P < 0.0001). Japanese and White women had a similar number of oocytes retrieved with no significant differences among all women who started stimulation (9.3 ± 5.4 versus 9.5 ± 5.7), potential low responders (7.2 ± 3.7 versus 7.6 ± 4.6) or potential high responders (10.8 ± 5.9 versus 11.0 ± 6.0). At each level of ovarian response, serum oestradiol concentrations were significantly higher in Japanese women (P = 0.024). The incidence of early ovarian hyperstimulation syndrome was significantly higher in Japanese women compared with White women; overall (10.0% versus 2.2%, P = 0.0124) and at similar serum oestradiol concentrations (P = 0.0137). CONCLUSIONS The individualized follitropin delta dosing provides similar serum FSH concentrations and similar oocyte yield in Japanese and White IVF/ICSI patients, but the oestradiol response is higher in Japanese women.

IntroductionThis protocol outlines aims to test the wider impacts of the COVID-19 pandemic on pregnancy and birth outcomes and inequalities in Scotland.Method and analysisWe 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 disseminationNHS 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.

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 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.

ImportanceMenstrual cycle characteristics may be associated with an increased risk of cardiovascular disease (CVD). However, existing studies are limited, and few have explored the mediating role of established CVD risk factors.ObjectiveTo explore the associations of menstrual cycle characteristics across the reproductive lifespan with the risk of CVD and to what extent these associations were mediated by hypercholesterolemia, chronic hypertension, and type 2 diabetes.Design, Setting, and ParticipantsThis cohort study prospectively followed Nurses’ Health Study II participants between 1993 and 2017 who reported menstrual cycle regularity and length for ages 14 to 17 years and 18 to 22 years at enrollment in 1989 and updated current cycle characteristics in 1993 (at ages 29 to 46 years). Data analysis was performed from October 1, 2019, to January 1, 2022.ExposuresMenstrual cycle regularity and length across the reproductive lifespan.Main Outcomes and MeasuresIncident CVD events of interest, including fatal and nonfatal coronary heart disease (CHD; myocardial infarction [MI] or coronary revascularization) and stroke.ResultsA total of 80 630 Nurses’ Health Study II participants were included in the analysis, with a mean (SD) age of 37.7 (4.6) years and body mass index of 25.1 (5.6) at baseline. Over 24 years of prospective follow-up, 1816 women developed their first CVD event. Multivariable Cox proportional hazards models showed that, compared with women reporting very regular cycles at the same ages, women who had irregular cycles or no periods at ages 14 to 17, 18 to 22, or 29 to 46 years had hazard ratios for CVD of 1.15 (95% CI, 0.99-1.34), 1.36 (95% CI, 1.06-1.75), and 1.40 (95% CI, 1.14-1.71), respectively. Similarly, compared with women reporting a cycle length of 26 to 31 days, women reporting a cycle length 40 days or more or a cycle too irregular to estimate from ages 18 to 22 or 29 to 46 years had hazard ratios for CVD of 1.44 (95% CI, 1.13-1.84) and 1.30 (95% CI, 1.09-1.57), respectively. Mediation analyses showed that subsequent development of hypercholesteremia, chronic hypertension, and type 2 diabetes only explained 5.4% to 13.5% of the observed associations.Conclusions and RelevanceIn this cohort study, both irregular and long menstrual cycles were associated with increased rates of CVD, which persisted even after accounting for subsequently established CVD risk factors.

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.

Introduction: \ud Illicit opioid use in pregnancy is associated with adverse maternal, neonatal, and childhood outcomes. Opioid substitution is recommended, but whether methadone or buprenorphine is the optimal agent remains unclear.\ud \ud Methods: \ud We searched EMBASE, PubMed, Web of Science, Scopus, Open Gray, CINAHL and the Cochrane Central Registry of Controlled Trials (CENTRAL) from inception to April 2020 for randomized controlled trials (RCTs) and cohort studies comparing methadone and buprenorphine treatment for opioid-using mothers. Included studies assessed maternal and or neonatal outcomes. We used random-effects meta-analyses to estimate summary measures for outcomes and report these separately for RCTs and cohort studies.\ud \ud Results: \ud Of 408 abstracts screened, 20 papers were included (4 RCTs, 16 cohort, 223 and 7028 participants respectively). All RCTs (4/4) had a high risk of bias and median (IQR) Newcastle Ottawa Scale for cohort studies was 7.5 (6–9). In both RCTs and cohort studies, buprenorphine was associated with; greater offspring birth weight (weighted mean difference [WMD] 343 g (95% CI: 40–645 g) in RCT and 184 g (95% CI: 121–247 g) in cohort studies); body length at birth (WMD 2.28 cm (95% CI: 1.06–3.49 cm) in RCTs and 0.65 cm (95% CI: 0.31–0.98 cm) in cohort studies); and reduced risk of prematurity (risk ratio [RR] 0.41 (95% CI: 0.18–0.93) in RCTs and 0.63 [95% CI: 0.53–0.75] in cohort studies) when compared to methadone. All other clinical outcomes were comparable.\ud \ud Conclusions: \ud Compared to methadone, buprenorphine was consistently associated with improved birthweight and gestational age, however given potential biases, results should be interpreted with caution.

BackgroundThe fetus is vulnerable to maternal drug exposure. We determined associations of exposure to spinal, epidural, or general anesthesia on neonatal and childhood development outcomes during the first 1000 days of life.MethodsPopulation-based study of all singleton, cesarean livebirths of 24+0 to 43+6 weeks gestation between January 2007 and December 2016 in Scotland, stratified by urgency with follow-up to age 2 years. Models were adjusted for: maternal age, weight, ethnicity, socioeconomic status, smoking, drug-use, induction, parity, previous cesarean or abortion, pre-eclampsia, gestation, birth weight, and sex.Results140 866 mothers underwent cesarean section (41.2% (57,971/140,866) elective, 58.8% (82,895/140,866) emergency) with general anesthesia used in 3.2% (1877/57,971) elective and 9.8% (8158/82,895) of emergency cases. In elective cases, general anesthesia versus spinal was associated with: neonatal resuscitation (crude event rate 16.2% vs 1.9% (adjusted RR 8.20, 95% CI 7.20 to 9.33), Apgar ConclusionsGeneral anesthesia for cesarean section, irrespective of urgency, is associated with neonatal resuscitation, low Apgar, and neonatal unit admission. Associations were strongest in non-urgent cases and at term. Further evaluation of long-term outcomes is warranted.

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.

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT(4)), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT(4) concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT(4) concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.

Research question:\ud Chinese women are known to have an earlier age of natural menopause than their European counterparts, but whether they also have a lower functional ovarian reserve is unknown. This study was designed to assess whether there are ethnic differences in anti-Müllerian hormone (AMH) concentrations in women of reproductive age.\ud \ud Design:\ud Women in China and Europe with regular menstrual cycles, not on hormonal contraception and with no medical history of note, were recruited to provide a day 2–5 early follicular phase sample. AMH concentration was determined using the Roche Elecsys assay. Decline in AMH was modelled with linear, quadratic and quadratic with interaction on age equations to assess the impact of ethnicity.\ud \ud Results:\ud A total of 887 European and 461 Chinese women participated in the study. Despite the Chinese population being slightly younger (34.1 ± 8.4 years) than their European counterparts (34.8±8.9 years), their median AMH was lower, at 1.87 ng/ml (interquartile range [IQR] 0.28–3.64) compared with 2.11 ng/ml (IQR 0.73–3.96), with evidence of increasing discordance from age 25 years. In all regression models of the age-related decline in AMH, there was evidence of a difference between Chinese and European women. Although AMH was 28.1% (95% confidence interval [CI] 18.2–36.7%) lower in the Chinese population at age 30, this decline increased to 79.4% (95% CI 75.4– 82.9%) at age 45.\ud \ud Conclusions:\ud There were independent effects of age and ethnicity on serum AMH concentrations, with Chinese women having a substantially lower AMH in adult life than their European counterparts from age 25 onwards.

STUDY QUESTION How did coronavirus disease 2019 (COVID-19) impact on medically assisted reproduction (MAR) services in Europe during the COVID-19 pandemic (March to May 2020)? SUMMARY ANSWER MAR services, and hence treatments for infertile couples, were stopped in most European countries for a mean of 7 weeks. WHAT IS KNOWN ALREADY With the outbreak of COVID-19 in Europe, non-urgent medical care was reduced by local authorities to preserve health resources and maintain social distancing. Furthermore, ESHRE and other societies recommended to postpone ART pregnancies as of 14 March 2020. STUDY DESIGN, SIZE, DURATION A structured questionnaire was distributed in April among the ESHRE Committee of National Representatives, followed by further information collection through email. PARTICIPANTS/MATERIALS, SETTING, METHODS The information was collected through the questionnaire and afterwards summarised and aligned with data from the European Centre for Disease Control on the number of COVID-19 cases per country. MAIN RESULTS AND THE ROLE OF CHANCE By aligning the data for each country with respective epidemiological data, we show a large variation in the time and the phase in the epidemic in the curve when MAR/ART treatments were suspended and restarted. Similarly, the duration of interruption varied. Fertility preservation treatments and patient supportive care for patients remained available during the pandemic. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Data collection was prone to misinterpretation of the questions and replies, and required further follow-up to check the accuracy. Some representatives reported that they, themselves, were not always aware of the situation throughout the country or reported difficulties with providing single generalised replies, for instance when there were regional differences within their country. WIDER IMPLICATIONS OF THE FINDINGS The current article provides a basis for further research of the different strategies developed in response to the COVID-19 crisis. Such conclusions will be invaluable for health authorities and healthcare professionals with respect to future similar situations. STUDY FUNDING/COMPETING INTEREST(S) There was no funding for the study, apart from technical support from ESHRE. The authors had no COI to disclose.

PurposeTo generate a large cohort of children born after assisted reproductive technology (ART) in the UK between 1992 and 2009, their naturally conceived siblings (NCS) and matched naturally conceived population (NCP) controls and linking this with health outcome data to allow exploration of the effects of ART. The effects of fresh and frozen embryo transfer on birth weight (BW) were analysed to test the validity of the cohort.ParticipantsChildren recorded on the Human Fertilisation and Embryology Authority (HFEA) register as being born after ART between 1992 and 2009, their NCS and matched NCP controls linked to Office for National Statistics birth registration dataset (HFEA-ONS cohort). This cohort was further linked to the UK Hospital Episode Statistics database to allow monitoring of the child’s post-natal health outcomes up to 2015 (HFEA-ONS-HES subcohort).Findings to dateThe HFEA-ONS cohort consisted of 75 348 children born after non-donor ART carried out in the UK between 1 April 1992 and 31 July 2009 and successfully linked to birth registration records, 14 763 NCS and 164 823 matched NCP controls. The HFEA-ONS-HES subcohort included 63 877 ART, 11 343 NCS and 127 544 matched NCP controls further linked to health outcome data. The exemplar analysis showed that children born after fresh embryo transfers were lighter (BW difference: −131 g, 95% CI: −140 to –123) and those born after frozen embryo transfers were heavier (BW difference: 35 g, 95% CI: 19 to 52) than the NCP controls. The within-sibling analyses were directionally consistent with the population control analyses, but attenuated markedly for the fresh versus natural conception (BW difference: −54 g; 95% CI: −72 to –36) and increased markedly for the frozen versus natural conception (BW difference: 152 g; 95% CI: 113 to 190) analyses.Future plansTo use this cohort to explore the relationship between ART conception and short-term and long-term health outcomes in offspring.

Study question In men and women undergoing IVF are preconceptual circulating metabolites associated with ongoing pregnancy rates? Summary answer Preconceptual serum histidine levels, in both women and men were associated with ongoing pregnancy. Several amino acids and lipoproteins exhibited possible sex-specific associations. What is known already Preconceptual maternal health has been associated with pregnancy outcomes after IVF. The extent to which this is because of pre-existing metabolic factors related to infertility and the role of paternal metabolic health is unclear. Study design, size, duration Cohort of 398 women and 325 male partners prospectively recruited between 1 April 2017 and 31 March 2019. Participants/materials, setting, methods Women and their male partners intending to undergo assisted conception at a University Hospital, had detailed pre-treatment phenotyping including non-fasting serum lipids, lipoprotein subclasses, and low-molecular weight metabolites (including amino acids, glycolysis and inflammatory markers) (155 metabolites) quantified by NMR spectroscopy. Multivariable linear and logistic regression were used to examine the associations of pre-treatment serum metabolic profiles, with ongoing pregnancy at 20 weeks gestation with adjustment for confounders. Main results and the role of chance 392 women and 322 men proceeded to IVF treatment, with an overall ongoing pregnancy rate of 47.2% (95% CI 0.42, 0.52) per cycle started and a multiple pregnancy rate of 1.1% (95%CI 0.0, 0.04). In both females and males in confounder adjusted analyses histidine was associated with the chance of ongoing pregnancy, with similar magnitudes in each parent (OR 1.28 (95% CI 1.03, 1.60) per one standard deviation (SD) increase for males and OR 1.26 (95% CI 0.99, 1.60) per one SD increase for females). In females Alanine (OR = 1.31 (1.05, 1.64)), Isoleucine (OR = 1.28 (1.02, 1.61)) and Leucine (OR = 1.24 (0.99, 1.55)) had a positive association with ongoing pregnancy, while in males, pyruvate (OR = 1.30 (1.02,1.66)) exhibited a positive association with ongoing pregnancy. In both parents, associations of lipids, lipoproteins sub-particles and fatty acids with pregnancy were closer to the null. Limitations, reasons for caution Suggestive parental differences could be due to chance. Patients were relatively homogenous undertaking their first IVF cycle and the results may not be generalisable to other clinical populations. Wider implications of the findings: This study provides data on a range of metabolic pathways and their association with ongoing pregnancy following IVF. The identification of potentially relevant clinical effect sizes in both men and women warrants further exploration. Trial registration number Not applicable

Research QuestionDiscontinuation of in vitro fertilisation (IVF) cycles has been part of the radical transformation of healthcare provision to enable reallocation of staff and resources to deal with the COVID-19 pandemic. We sought to estimate the impact of cessation of treatment on individual prognosis and United States population live-birth rates.DesignData from 271,438 ovarian stimulation UK IVF cycles was used to model the effect of age as a continuous, yet non-linear, function on cumulative live-birth rate. We recalibrated this model to cumulative live-birth rates reported for the 135,6733 stimulation cycles undertaken in the USA in 2016, with live-birth follow-up to October 2018. We calculated the effect of a one-month, three-month and six-month shutdown in IVF treatment as the effect of the equivalent increase in a woman’s age, stratified by age group. ResultsThe average reduction in cumulative live-birth rate would be 0.3% [95% CI: 0.3, 0.3], 0.8% [0.8, 0.8] and 1.6% [1.6, 1.6] for a one-month, three-month and six-month shutdown, respectively. This corresponds to a reduction of 369 [95% CI; 360, 378), 1,098 [1071, 1123] and 2,166 [2,116, 2,216] live-births in the cohort, respectively. The greatest contribution to this reduction was from older mothers. ConclusionsWe demonstrate that the discontinuation of fertility treatment for even 1 month in the USA could result in 369 fewer women having a live-birth, due to the increase in patients’ age during the shutdown. As a result of reductions in cumulative live-birth rate, more cycles may be required to overcome infertility at an individual and population level.

Objective: We sought to examine the association of menopausal hot flashing with vascular reactivity in two different vascular beds in the same cohort of postmenopausal women and explore the relationship between hot flashing and cardiovascular disease (CVD) risk profile. Methods: A cross-sectional study of 79 healthy postmenopausal women, 23 of whom have never had menopausal hot flashes and 56 of whom have reported hot flashes. Endothelial function at a microvascular level was measured with Laser Doppler Imaging with Iontophoresis which assesses the response to both acetylcholine (Ach, endothelium dependent) and sodium-nitroprusside (SNP, endothelium independent). Reactive Hyperemia Index (RHI) was measured with peripheral arterial tonometry as a marker of endothelial function mainly at a macrovascular level. Metabolic biomarkers including insulin sensitivity were assessed. Results: Women with hot flashes had enhanced microvascular response to Ach by ∼30% (P = 0.04) and to SNP by ∼31% (P = 0.02), but lower RHI by ∼13% (P = 0.05) compared with women without flashes. Hot flashing was associated with enhanced response to SNP and lower RHI after adjustment for confounders and conventional CVD risk factors. Women with hot flashes were more insulin resistant than nonflashers (HOMAIR: 1.9 (1.2-2.6) vs 1.4 (0.8-1.9), P = 0.03). Conclusions: Our data support the association of hot flashing with greater insulin resistance and lower macrovascular response. The paradoxical enhanced microvascular response in hot flashers could be the result of the net effect of thermoregulatory and nonnitric oxide-related pathways rather than of endothelial integrity.

Homeostatic leukocyte trafficking into and within the female reproductive tract (FRT) contributes to fertility and reproductive health. It is unclear how this process is regulated in the anatomically distinct reproductive tissues, or whether the genes involved are affected by cyclical changes in reproductive hormones. In tissues such as skin and intestine, mouse studies have defined evolutionarily conserved molecular mechanisms for tissue-specific homing, interstitial positioning, and leukocyte egress. Chemokine family members are invariably involved, with the chemokine expression profile of a tissue regulating leukocyte content. Reproductive tissues (ovary, vagina, cervix, uterine horn) of 8 week old virgin female C57BL/6 mice (n = 20) were collected, and expression of mRNA for leukocyte markers and chemokines conducted by qPCR. Lymphocytic and myeloid cell populations within the uterus, cervix, bone marrow and PALN from virgin C57BL/6 mice were determined by flow cytometric analysis. Variation in leukocyte content between reproductive tissues is evident, with the uterus and cervix containing complex mixtures of lymphocytes and myeloid cells. Twenty-six chemokine genes are expressed in the FRT, many by several component tissues, some preferentially by one. Most striking are Xcl1 and Ccl28, which are restricted to the uterus. Ccl20 and genes encoding CXCR2 ligands are primarily transcribed in cervix and vagina. Ovary shows the lowest expression of most chemokine genes, with the notable exception of Ccl21 and Ccl27. We also identify eight chemokines in the vagina whose expression fluctuates substantially across the oestrous cycle. These data reveal complex chemokine networks within the FRT, and provide a framework for future studies of homeostatic leukocyte trafficking into and within these tissues.

Aims/hypothesis Stillbirth risk is increased in pregnancy complicated by diabetes. Fear of stillbirth has major influence on obstetric management, particularly timing of delivery. We analysed population-level data from Scotland to describe timing of stillbirths in women with diabetes and associated risk factors. Methods A retrospective cohort of singleton deliveries to mothers with type 1 (n = 3778) and type 2 diabetes (n = 1614) from 1 April 1998 to 30 June 2016 was analysed using linked routine care datasets. Maternal and fetal characteristics, HbA1c data and delivery timing were compared between stillborn and liveborn groups. Results Stillbirth rates were 16.1 (95% CI 12.4, 20.8) and 22.9 (95% CI 16.4, 31.8) per 1000 births in women with type 1 (n = 61) and type 2 diabetes (n = 37), respectively. In women with type 1 diabetes, higher HbA1c before pregnancy (OR 1.03 [95% CI 1.01, 1.04]; p = 0.0003) and in later pregnancy (OR 1.06 [95% CI 1.04, 1.08]; p 95th centile born to women with type 2 diabetes (n = 15 stillbirths, 402 livebirths). A high proportion of stillborn infants were male among mothers with type 2 diabetes (81.1% vs 50.5% livebirths, p = 0.0002). A third of stillbirths occurred at term, with highest rates in the 38th week (7.0 [95% CI 3.7, 12.9] per 1000 ongoing pregnancies) among mothers with type 1 diabetes and in the 39th week (9.3 [95% CI 2.4, 29.2]) for type 2 diabetes. Conclusions/interpretation Maternal blood glucose levels and BMI are important modifiable risk factors for stillbirth in diabetes. Babies at extremes of weight centiles are at most risk. Many stillbirths occur at term and could potentially be prevented by change in routine care and delivery policies. Electronic supplementary material The online version of this article (10.1007/s00125-019-4943-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background: Phenotype-based assortative mating is well established in humans, with the potential for further convergence through a shared environment. To assess the correlation within infertile couples of physical, social, and behavioural characteristics and 155 circulating metabolic measures. Methods: Cross sectional study at a tertiary medical center of 326 couples undertaking IVF. Serum lipids, lipoprotein subclasses, and low-molecular weight metabolites as quantified by NMR spectroscopy (155 metabolic measures). Multivariable and quantile regression correlations within couples of metabolite profiles.Results: Couples exhibited statistical correlations of varying strength for most physical, social, and behavioural characteristics including age, height, alcohol consumption, education, smoking status, physical activity, family history and ethnicity, with correlation coefficients ranging from 0.22 to 0.73. There was no evidence of within couple associations for BMI and weight, where the correlation coefficients were -0.03 (95%CI -0.14, 0.08) and 0.01 (95%CI -0.10, 0.12), respectively. Within spousal associations of the metabolite measurements were all positive but with weak to modest magnitudes, with the median correlation coefficient across all 155 measures being 0.12 (range 0.01 to 0.37 and interquartile range 0.10 to 0.18). With just four having associations stronger than 0.3: docosahexaenoic acid (0.37, 95%CI 0.22, 0.52), omega-3 fatty acids (0.32, 95%CI 0.20, 0.43) histidine (0.32, 95%CI 0.23, 0.41) and pyruvate (0.32, 95%CI 0.22, 0.43). Conclusions: Infertile couples exhibit spousal similarities for a range of demographic and serum metabolite measures, supporting initial assortative mating, with diet-derived metabolites suggesting possible subsequent convergence of their individual metabolic profile.

Prediction of premature ovarian insufficiency (POI) would be of substantial individual benefit, but being a heterogeneous and fluctuating condition, with an extensive range of complex etiologies and arbitrary diagnostic criteria, might make this seem foolhardy. However, contemporary and complementary genetic strategies assessing consanguineous and large POI pedigrees and cohorts with age at natural menopause have shown strong enrichment in genes regulating DNA damage repair, homologous recombination, and meiosis, processes that are critical to oogenesis and folliculogenesis. Recognition of the molecular architecture of POI and its contribution to baseline genotypic risk may enable these estimates to be refined further by estimation of the residual ovarian reserve. Increasing data derived from spontaneous and gonadotoxic-induced POI cohorts demonstrate the utility of anti-Müllerian hormone (AMH) to predict POI. This review presents current understanding of how genetics in combination with AMH may facilitate the prediction of POI.

The menopause and its pathological version, premature ovarian insufficiency (POI), are characterized by the cessation of follicle growth in the ovary, with consequent lack of estrogen production and amenorrhea. The measurement of a specific product of ovarian follicles would therefore be expected to be a valuable biomarker in women with POI, and to be of likely clinical value in the diagnosis and perhaps prediction of POI. Anti-Müllerian hormone (AMH) is produced by the granulosa cells of growing follicles and is therefore likely to be of value in this context. Current data indicate that measurement of AMH is an accurate indicator of POI in many situations and has diagnostic validity and may facilitate more timely diagnosis. AMH seems to be of limited value in predicting age at natural menopause, even with multiple measurements, and there are scarce data regarding prediction of POI, other than when it is imminent, and in some contexts where there is an immediate iatrogenic threat to ovarian function. AMH therefore appears to have considerable value as a diagnostic test for POI, but apart from highlighting broadly those at increased risk, it has inadequate precision to be able to predict accurately the timing of onset of impending POI.

Anti-Müllerian hormone reflects the continuum of the functional ovarian reserve, and as such can predict ovarian response to gonadotropin stimulation and be used to individualize treatment pathways to improve efficacy and safety. However, consistent with other biomarkers and age-based prediction models it has limited ability to predict live birth and should not be used to refuse treatment, but rather to inform counselling and shared decision making. The use of absolute clinical thresholds to stratify patient phenotypes, assess discordance and individualize treatment protocols in non-validated algorithms combined with the lack of standardization of assays may result in inappropriate classification and sub-optimal clinical decision making. We propose that holistic baseline phenotyping, incorporating antral follicle count and other patient characteristics is critical. Treatment decisions driven by validated algorithms that use ovarian reserve biomarkers as continuous measures, reducing the risk of misclassification, are likely to improve overall outcomes for our patients.

Aims: We characterised changes in reproductive hormones – LH, FSH, SHBG and AMH – by chronological age and time around the menopause (reproductive age) in mid-life women and explored their associations with lifestyle and reproductive factors.Methods: We used data from 1,608 women from a UK cohort who had repeat hormone measures and experienced a natural menopause. Multilevel models were used to assess: (i) changes in hormones (outcomes) by reproductive age and chronological age (these age variables being the key exposures) and (ii) associations of body mass index (BMI), smoking, alcohol intake, parity and age at menarche with changes in hormones by reproductive age.Results: Both LH and FSH increased until ~5 and 7 years postmenopause, respectively, after which they declined, but not to premenopausal levels. SHBG decreased slightly until ~4 years postmenopause and increased thereafter. AMH decreased markedly before menopause and remained low subsequently. For all hormones, the best fitting models included both reproductive and chronological age. BMI, smoking and parity were associated with hormone changes; e.g., higher BMI was associated with slower increase in LH and FSH and decrease in AMH. Conclusions: Reproductive and chronological age contribute to changes in LH, FSH, SHBG and AMH across mid-life in women, and BMI, smoking and parity are associated with these hormone changes.