Risk Factors for Thyroid Dysfunction in Pregnancy: An Individual Participant Data Meta-Analysis.

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.

A comparison of morphokinetic models and morphological selection for prioritizing euploid embryos: a multicentre cohort study.

STUDY QUESTION: Are morphokinetic models better at prioritizing a euploid embryo for transfer over morphological selection by an embryologist? SUMMARY ANSWER: Morphokinetic algorithms lead to an improved prioritization of euploid embryos when compared to embryologist selection. WHAT IS KNOWN ALREADY: PREFER (predicting euploidy for embryos in reproductive medicine) is a previously published morphokinetic model associated with live birth and miscarriage. The second model uses live birth as the target outcome (LB model). STUDY DESIGN, SIZE, DURATION: Data for this cohort study were obtained from 1958 biopsied blastocysts at nine IVF clinics across the UK from January 2021 to December 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: The ability of the PREFER and LB models to prioritize a euploid embryo was compared against arbitrary selection and the prediction of four embryologists using the timelapse video, blinded to the morphokinetic time stamp. The comparisons were made using calculated percentages and normalized discounted cumulative gain (NDCG), whereby an NDCG score of 1 would equate to all euploid embryos being ranked first. In arbitrary selection, the ploidy status was randomly assigned within each cycle and the NDGC calculated, and this was then repeated 100 times and the mean obtained. MAIN RESULTS AND THE ROLE OF CHANCE: Arbitrary embryo selection would rank a euploid embryo first 37% of the time, embryologist selection 39%, and the LB and PREFER ploidy morphokinetic models 46% and 47% of the time, respectively. The AUC for LB and PREFER model was 0.62 and 0.63, respectively. Morphological selection did not significantly improve the performance of both morphokinetic models when used in combination. There was a significant difference between the NDGC metric of the PREFER model versus embryologist selection at 0.96 and 0.87, respectively (t = 14.1, P < 0.001). Similarly, there was a significant difference between the LB model and embryologist selection with an NDGC metric of 0.95 and 0.87, respectively (t = 12.0, P < 0.001). All four embryologists ranked embryos similarly, with an intraclass coefficient of 0.91 (95% CI 0.82-0.95, P < 0.001). LIMITATIONS, REASONS FOR CAUTION: Aside from the retrospective study design, limitations include allowing the embryologist to watch the time lapse video, potentially providing more information than a truly static morphological assessment. Furthermore, the embryologists at the participating centres were familiar with the significant variables in time lapse, which could bias the results. WIDER IMPLICATIONS OF THE FINDINGS: The present study shows that the use of morphokinetic models, namely PREFER and LB, translates into improved euploid embryo selection. STUDY FUNDING/COMPETING INTEREST(S): This study received no specific grant funding from any funding agency in the public, commercial or not-for-profit sectors. Dr Alison Campbell is minor share holder of Care Fertility. All other authors have no conflicts of interest to declare. Time lapse is a technology for which patients are charged extra at participating centres. TRIAL REGISTRATION NUMBER: N/A.

Myoinositol or D-chiro-inositol for PCOS symptoms in adolescents: a narrative review.

BACKGROUND: Polycystic ovary syndrome (PCOS) treatment in adolescents currently focuses on lifestyle interventions, with pharmacological treatment options often limited to hormonal contraceptives. Several of these carry broad side-effect profiles and are not always accepted by young girls. There is growing interest in non-hormonal therapies for PCOS. We aimed to collate the evidence on the use of myoinositol or D-chiro-inositol in the improvement of PCOS symptoms in symptomatic adolescents. CONTENT: A systematic literature review identifying key articles from inception to March 2023. Participants: Female adolescents (aged 12-19 years) with PCOS or PCOS-like features. Intervention: Myoinositol or D-chiro-inositol with or without additional interventions. Comparison: Any other treatment, including lifestyle interventions, hormonal therapy, metformin or no treatment. The main outcome measure were improvement in symptoms, quality of life and adverse effects. SUMMARY: Eight studies were included: two randomised open-label trials, one quasi-randomised and three non-randomised interventional studies, one case-control study and one cohort study. All studies showed improvements in some biochemical markers, metabolic parameters or clinical symptoms, but these were not reproducible across all studies. OUTLOOK: The benefit of myoinositol in adolescents with PCOS remains unclear, with limited high-quality evidence. This review highlights the need for robustly conducted research to inform clinical practice.

Interventions to prevent miscarriage.

The physical and psychological impact of miscarriage can be devastating. There are many lifestyle and therapeutic interventions that may prevent a miscarriage. In this review, we have outlined the key areas for health optimization to prevent pregnancy loss, drawing on the most up-to-date evidence available. The 3 key areas identified are lifestyle optimization in women, lifestyle optimization in men, and therapeutic interventions. The evidence demonstrates that the treatments to consider are first-trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies.

Genetic causes of sporadic and recurrent miscarriage.

Approximately 80% of miscarriages happen within the first 12 weeks of gestation. More than half of early losses result from genetic defects, usually presenting as abnormal chromosome numbers or gene rearrangements in the embryo. However, the impact of genetics on pregnancy loss goes well beyond embryonic aneuploidy. For example, the use of big data has recently led to the discovery of specific gene mutations that may be implicated in sporadic and recurrent miscarriages. Further, emerging data suggest that genetic factors play a role in conditions for which there is a causative association with recurrent pregnancy loss. Here, we summarize the evidence on the genetics of miscarriage and provide an overview of the diagnosis and prevention of genetic causes associated with sporadic and recurrent pregnancy loss.

Association between a morphokinetic ploidy prediction model risk score and miscarriage and live birth: a multicentre cohort study.

OBJECTIVE: To determine whether the aneuploidy risk score from a morphokinetic ploidy prediction model, Predicting Euploidy for Embryos in Reproductive Medicine (PREFER), is associated with miscarriage and live birth outcomes. DESIGN: Multicentre cohort study. SETTING: Nine in vitro fertilization clinics in the United Kingdom. PATIENTS: Data were obtained from the treatment of patients from 2016-2019. A total of 3587 fresh single embryo transfers were included; preimplantation genetic testing for aneuploidy) cycles were excluded. INTERVENTION: PREFER is a model developed using 8,147 biopsied blastocyst specimens to predict ploidy status using morphokinetic and clinical biodata. A second model using only morphokinetic (MK) predictors was developed, P PREFER-MK. The models will categorize embryos into the following three risk score categories for aneuploidy: "high risk," "medium risk," and "low risk." MAIN OUTCOME MEASURES: The primary outcomes are miscarriage and live birth. Secondary outcomes include biochemical clinical pregnancy per single embryo transfer. RESULTS: When applying PREFER, the miscarriage rates were 12%, 14%, and 22% in the "low risk," "moderate risk," and "high risk" categories, respectively. Those embryos deemed "high risk" had a significantly higher egg provider age compared with "low risk," and there was little variation in risk categories in patients of the same age. The trend in miscarriage rate was not seen when using PREFER-MK; however, there was an association with live birth, increasing from 38%-49% and 50% in the "high risk," "moderate risk," and "low risk" groups, respectively. An adjusted logistic regression analysis demonstrated that PREFER-MK was not associated with miscarriage when comparing "high risk" to "moderate risk" embryos (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.63-1.63) or "high risk" to "low risk" embryos (OR, 1.07; 95% CI, 0.79-1.46). An embryo deemed "low risk" by PREFER-MK was significantly more likely to result in a live birth than those embryos graded "high risk" (OR, 1.95; 95% CI, 1.65-2.25). CONCLUSION: The PREFER model's risk scores were significantly associated with live births and miscarriages. Importantly, this study also found that this model applied too much weight to clinical factors, such that it could no longer rank a patient's embryos effectively. Therefore, a model including only MKs would be preferred; this was similarly associated with live birth but not miscarriage.

The association between dietary patterns and risk of miscarriage: a systematic review and meta-analysis.

IMPORTANCE: The evidence on the association between diet and miscarriage risk is scant and conflicting. OBJECTIVE: To summarize the evidence on the association between periconceptual diet and miscarriage risk in healthy women of reproductive age. DATA SOURCES: Electronic databases were searched from inception to August 2022 without restriction of regions, publication types, or languages. STUDY SELECTION AND SYNTHESIS: Experimental or observational studies were considered for inclusion. The population was healthy women of reproductive age. Exposure was periconception diet. Study quality was assessed using the modified Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for each food category. MAIN OUTCOMES: Miscarriage rate (as defined by primary studies). RESULTS: We included 20 studies (11 cohort and 9 case-control), of which 6 presented data suitable for meta-analysis (2 cohort and 4 case-control, n = 13,183 women). Our primary analyses suggest a reduction in miscarriage odds with high intake of the following food groups: fruit (OR, 0.39; 95% CI, 0.33-0.46), vegetables (OR, 0.59; 95% CI, 0.46-0.76), fruit and vegetables (OR, 0.63; 95% CI, 0.50-0.81), seafood (OR, 0.81; 95% CI, 0.71-0.92), dairy products (OR, 0.63; 95% CI, 0.54-0.73), eggs (OR, 0.81; 95% CI, 0.72-0.90), and cereal (grains) (OR, 0.67; 95% CI, 0.52-0.87). The evidence was uncertain for meat, red meat, white meat, fat and oil, and sugar substitutes. We did not find evidence of an association between adherence to predefined dietary patterns and miscarriage risk. However, a whole diet containing healthy foods as perceived by the trialists, or with a high Dietary Antioxidant Index score (OR, 0.43; 95% CI, 0.20-0.91) may be associated with a reduction in miscarriage risk. In contrast, a diet rich in processed food was demonstrated to be associated with increased miscarriage risk (OR, 1.97; 95% CI, 1.36-3.34). CONCLUSION AND RELEVANCE: A diet abundant in fruit, vegetables, seafood, dairy, eggs, and grain may be associated with lower miscarriage odds. Further interventional studies are required to accurately assess the effectiveness of periconception dietary modifications on miscarriage risk. PROSPERO REGISTRATION: CRD42020218133.

A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.

A comparison of 12 machine learning models developed to predict ploidy, using a morphokinetic meta-dataset of 8147 embryos.

STUDY QUESTION: Are machine learning methods superior to traditional statistics in predicting blastocyst ploidy status using morphokinetic and clinical biodata? SUMMARY ANSWER: Mixed effects logistic regression performed better than all machine learning methods for ploidy prediction using our dataset of 8147 embryos. WHAT IS KNOWN ALREADY: Morphokinetic timings have been demonstrated to be delayed in aneuploid embryos. Machine learning and statistical models are increasingly being built, however, until now they have been limited by data insufficiency. STUDY DESIGN, SIZE, DURATION: This is a multicentre cohort study. Data were obtained from 8147 biopsied blastocysts from 1725 patients, treated from 2012 to 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: All embryos were cultured in a time-lapse system at nine IVF clinics in the UK. A total of 3004 euploid embryos and 5023 aneuploid embryos were included in the final verified dataset. We developed a total of 12 models using four different approaches: mixed effects multivariable logistic regression, random forest classifiers, extreme gradient boosting, and deep learning. For each of the four algorithms, two models were created, the first consisting of 22 covariates using 8027 embryos (Dataset 1) and the second, a dataset of 2373 embryos and 26 covariates (Dataset 2). Four final models were created by switching the target outcome from euploid to aneuploid for each algorithm (Dataset 1). Models were validated using internal-external cross-validation and external validation. MAIN RESULTS AND THE ROLE OF CHANCE: All morphokinetic variables were significantly delayed in aneuploid embryos. The likelihood of euploidy was significantly increased the more expanded the blastocyst (P < 0.001) and the better the trophectoderm grade (P < 0.01). Univariable analysis showed no association with ploidy status for morula or cleavage stage fragmentation, morula grade, fertilization method, sperm concentration, or progressive motility. Male age did not correlate with the percentage of euploid embryos when stratified for female age. Multinucleation at the two-cell or four-cell stage was not associated with ploidy status. The best-performing model was logistic regression built using the larger dataset with 22 predictors (F1 score 0.59 for predicting euploidy; F1 score 0.77 for predicting aneuploidy; AUC 0.71; 95% CI 0.67-0.73). The best-performing models using the algorithms from random forest, extreme gradient boosting, and deep learning achieved an AUC of 0.68, 0.63, and 0.63, respectively. When using only morphokinetic predictors the AUC was 0.61 for predicting ploidy status, whereas a model incorporating only embryo grading was unable to discriminate aneuploid embryos (AUC = 0.52). The ploidy prediction model's performance improved with increasing age of the egg provider. LIMITATIONS, REASONS FOR CAUTION: The models have not been validated in a prospective study design or yet been used to determine whether they improve clinical outcomes. WIDER IMPLICATIONS OF THE FINDINGS: This model may aid decision-making, particularly where pre-implantation genetic testing for aneuploidy is not permitted or for prioritizing embryos for biopsy. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was sought for this study; university funds supported the first author. A.Ca. is a minor shareholder of participating centres. TRIAL REGISTRATION NUMBER: N/A.

Evaluating the Progression to Hypothyroidism in Preconception Euthyroid Thyroid Peroxidase Antibody-Positive Women.

CONTEXT: Thyroid peroxidase antibody (TPOAb) positivity is prevalent in women of reproductive age and predisposes to thyroid dysfunction, particularly hypothyroidism, which has adverse effects on pregnancy. OBJECTIVE: This study aimed to report the rate of development of abnormal thyroid function among initially euthyroid TPOAb-positive women recruited into the TABLET trial, to identify factors associated with the development of hypothyroidism, and to compare outcomes between euthyroid and treated hypothyroid individuals. METHODS: This observational cohort study, conducted at 49 UK hospitals between 2011 and 2016, included euthyroid TPOAb-positive women 16 to 40 years of age with a history of miscarriage or subfertility, planning pregnancy, randomized to levothyroxine 50 mcg daily or placebo. Abnormal thyroid function, conception rate, and live birth rate (LBR) ≥34 weeks were analyzed. RESULTS: Among the women, 70/940 (7.4%) developed subclinical (SCH) or overt (OH) hypothyroidism: 27/470 taking levothyroxine and 43/470 placebo (relative risk [RR] 0.63; 95% CI, 0.39-1.00; P = 0.05); 83% of cases emerged prepregnancy. Baseline median serum TSH concentrations and TPOAb titers were significantly higher in those who developed hypothyroidism vs those who did not (P < 0.001). Treated SCH/OH demonstrated a higher failure-to-conceive rate compared with euthyroid women (adjusted RR 2.02 [1.56-2.62]; P < 0.001). The LBR ≥ 34 weeks was similar in the treated SCH/OH and euthyroid groups (adjusted RR 1.09 [0.77-1.55]; P = 0.6). CONCLUSION: Approximately 7% of euthyroid TPOAb-positive women will develop hypothyroidism within 1 year preconception or in pregnancy. Conception rates are lower in women with treated SCH/OH compared with euthyroid women, but LBR are comparable. Thyroid function in TPOAb-positive women should be monitored regularly, when trying to conceive, to ensure prompt diagnosis and appropriate treatment initiation.

Preconception Counseling and Care for Pregnant Women with Thyroid Disease.

Thyroid disease is associated with adverse maternal and fetal outcomes. Appropriate reference ranges should be used for the interpretation of test results, although universal screening for thyroid dysfunction is not warranted. Overt thyroid dysfunction requires careful consideration of medication adjustments and close monitoring. Mild thyroid hypofunction has been linked to adverse pregnancy outcomes including preterm delivery, and poor neurocognition in the offspring. This review summarizes the most recent evidence on the counseling and management of women with thyroid disease before and during pregnancy and highlights the areas of controversy in need of further research.

Subclinical hypothyroidism and antithyroid autoantibodies in women with subfertility or recurrent pregnancy loss: Scientific Impact Paper No. 70 June 2022: Scientific Impact Paper No. 70 June 2022.

The thyroid is a gland located in the neck and is important for many processes in the body. Problems with the thyroid gland are common in women of reproductive age. It is essential to have a normal working thyroid gland in order to achieve a successful pregnancy. One of the most common problems with the thyroid is underactivity (known as hypothyroidism). An early, mild form of an underactive thyroid is called subclinical hypothyroidism. Often people with this condition do not have any symptoms. Another common problem is thyroid autoimmunity. Here, the immune system attacks the thyroid gland, sometimes leading to the development of abnormal thyroid function. This can be diagnosed by the presence of proteins in the bloodstream called antibodies. Mild thyroid problems and the presence of high levels of thyroid antibodies have been linked to miscarriage and premature birth. There is debate in medicine about whether there should be routine testing of thyroid function both in the general population and in individuals who are trying for a baby. In addition, the strategies used to manage certain thyroid problems are questioned. Discussions around testing and subsequent management particularly relate to women with a history of subfertility or repeated miscarriages. This Scientific Impact Paper provides information on thyroid testing and the management of mild thyroid problems and thyroid antibodies in women with a history of subfertility or recurrent miscarriages, using the latest evidence and guidelines. It concludes that there may be a role for treating these women with thyroxine tablets (the hormone produced by the thyroid gland) when subclinical hypothyroidism is present, and gives guidance on the cut-off levels for treatment.

Morphological and morphokinetic associations with aneuploidy: a systematic review and meta-analysis.

BACKGROUND: A time lapse system (TLS) is utilized in some fertility clinics with the aim of predicting embryo viability and chance of live birth during IVF. It has been hypothesized that aneuploid embryos display altered morphokinetics as a consequence of their abnormal chromosome complement. Since aneuploidy is one of the fundamental reasons for IVF failure and miscarriage, attention has focused on utilizing morphokinetics to develop models to non-invasively risk stratify embryos for ploidy status. This could avoid or reduce the costs associated with pre-implantation genetic testing for aneuploidy (PGT-A). Furthermore, TLS have provided an understanding of the true prevalence of other dysmorphisms. Hypothetically, the incorporation of morphological features into a model could act synergistically, improving a model's discriminative ability to predict ploidy status. OBJECTIVE AND RATIONALE: The aim of this systematic review and meta-analysis was to investigate associations between ploidy status and morphokinetic or morphological features commonly denoted on a TLS. This will determine the feasibility of a prediction model for euploidy and summarize the most useful prognostic markers to be included in model development. SEARCH METHODS: Five separate searches were conducted in Medline, Embase, PubMed and Cinahl from inception to 1 July 2021. Search terms and word variants included, among others, PGT-A, ploidy, morphokinetics and time lapse, and the latter were successively substituted for the following morphological parameters: fragmentation, multinucleation, abnormal cleavage and contraction. Studies were limited to human studies. OUTCOMES: Overall, 58 studies were included incorporating over 40 000 embryos. All except one study had a moderate risk of bias in at least one domain when assessed by the quality in prognostic studies tool. Ten morphokinetic variables were significantly delayed in aneuploid embryos. When excluding studies using less reliable genetic technologies, the most notable variables were: time to eight cells (t8, 1.13 h, 95% CI: 0.21-2.05; three studies; n = 742; I2 = 0%), t9 (2.27 h, 95% CI: 0.5-4.03; two studies; n = 671; I2 = 33%), time to formation of a full blastocyst (tB, 1.99 h, 95% CI 0.15-3.81; four studies; n = 1640; I2 = 76%) and time to expanded blastocyst (tEB, 2.35 h, 95% CI: 0.06-4.63; four studies; n = 1640; I2 = 83%). There is potentially some prognostic potential in the degree of fragmentation, multinucleation persisting to the four-cell stage and frequency of embryo contractions. Reverse cleavage was associated with euploidy in this meta-analysis; however, this article argues that these are likely spurious results requiring further investigation. There was no association with direct unequal cleavage in an embryo that progressed to a blastocyst, or with multinucleation assessed on Day 2 or at the two-cell stage. However, owing to heterogeneous results and poor-quality evidence, associations between these morphological components needs to be investigated further before conclusions can be reliably drawn. WIDER IMPLICATIONS: This first systematic review and meta-analysis of morphological and morphokinetic associations with ploidy status demonstrates the most useful morphokinetic variables, namely t8, t9 and tEB to be included in future model development. There is considerable variability within aneuploid and euploid embryos making definitively classifying them impossible; however, it is feasible that embryos could be prioritized for biopsy. Furthermore, these results support the mechanism by which algorithms for live birth may have predictive ability, suggesting aneuploidy causes delayed cytokinesis. We highlight significant heterogeneity in our results secondary to local conditions and diverse patient populations, therefore calling for future models to be robustly developed and tested in-house. If successful, such a model would constitute a meaningful breakthrough when accessing PGT-A is unsuitable for couples.

Evaluating interventions and adjuncts to optimize pregnancy outcomes in subfertile women: an overview review.

BACKGROUND: There is a wealth of information regarding interventions for treating subfertility. The majority of studies exploring interventions for improving conception rates also report on pregnancy outcomes. However, there is no efficient way for clinicians, researchers, funding organizations, decision-making bodies or women themselves to easily access and review the evidence for the effect of adjuvant therapies on key pregnancy outcomes in subfertile women. OBJECTIVE AND RATIONALE: The aim was to summarize all published systematic reviews (SRs) of randomized controlled trials (RCTs) of interventions in the subfertile population, specifically reporting on the pregnancy outcomes of miscarriage and live birth. Furthermore, we aimed to highlight promising interventions and areas that need high-quality evidence. SEARCH METHODS: We searched the Cochrane Database of Systematic Reviews and PubMed clinical queries SR filter (inception until July 2021) with a list of key words to capture all SRs specifying or reporting any miscarriage outcome. Studies were included if they were SRs of RCTs. The population was subfertile women (pregnant or trying to conceive) and any intervention (versus placebo or no treatment) was included. We adopted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) for determining the quality of the evidence. Exclusion criteria were overview reviews, reviews that exclusively reported on women conceiving via natural conception, reviews including non-randomized study designs or reviews where miscarriage or live birth outcomes were not specified or reported. OUTCOMES: The primary outcome was miscarriage, defined as pregnancy loss <24 weeks of gestation. Data were also extracted for live birth where available. We included 75 published SRs containing 121 251 participants. There were 14 classes of intervention identified: luteal phase, immunotherapy, anticoagulants, hCG, micronutrients, lifestyle, endocrine, surgical, pre-implantation genetic testing for aneuploidies (PGT-As), laboratory techniques, endometrial injury, ART protocols, other adjuncts/techniques in the ART process and complementary interventions. The interventions with at least moderate-quality evidence of benefit in reducing risk of miscarriage or improving the chance of a live birth are: intrauterine hCG at time of cleavage stage embryo transfer, but not blastocyst transfer, antioxidant therapy in males, dehydroepiandrosterone in women and embryo medium containing high hyaluronic acid. Interventions showing potential increased risk of miscarriage or reduced live birth rate are: embryo culture supernatant injection before embryo transfer in frozen cycles and PGT-A with the use of fluorescence in situ hybridization. WIDER IMPLICATIONS: This review provides an overview of key pregnancy outcomes from published SRs of RCTs in subfertile women. It provides access to concisely summarized information and will help clinicians and policy makers identify knowledge gaps in the field, whilst covering a broad range of topics, to help improve pregnancy outcomes for subfertile couples. Further research is required into the following promising interventions: the dose of progesterone for luteal phase support, peripheral blood mononuclear cells for women with recurrent implantation failure, glucocorticoids in women undergoing IVF, low-molecular-weight heparin for unexplained subfertility, intrauterine hCG at the time of cleavage stage embryo or blastocyst transfer and low oxygen concentrations in embryo culture. In addition, there is a need for high-quality, well-designed RCTs in the field of reproductive surgery. Finally, further research is needed to demonstrate the integrated effects of non-pharmacological lifestyle interventions.

Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5-18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3-11·4%), two miscarriages is 1·9% (1·8-2·1%), and three or more miscarriages is 0·7% (0·5-0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

Sporadic miscarriage: evidence to provide effective care.

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units.

Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

An evaluation of the quality of online information on emergency contraception.

OBJECTIVES: The increasing availability of health information online combined with reduced access to health care providers due to the coronavirus pandemic means that more people are using the internet for health information. However, with no standardised regulation of the internet, the population is vulnerable to misinformation regarding important health information. This review aimed to evaluate the quality and readability of the online information available on emergency contraception (EC) options. STUDY DESIGN: In this descriptive study, a Google search was performed using the term 'emergency contraception options' on 13 April 2020 yielding 232 results. Seventy-one results were excluded (34 inaccessible, 37 contained no medical information). The remaining 161 results were categorised by typology and assessed for credibility (JAMA criteria and HONcode), reliability (DISCERN tool) and readability (Flesch-Kincaid Grade Level and Simple Measure of Gobbledygook). RESULTS: Of all webpages evaluated, the most common typology was governmental. Credibility of web pages was poor (average JAMA score of 1.47 out of 4). Only 10.6% of webpages were HONcode certified. The most common DISCERN category was Fair (29.81%), closely followed by Poor (27.95%) reliability. On average, readability levels were above the recommended grade level for health information. The intrauterine device was discussed least frequently (86.96%) of all the EC options. CONCLUSION: Online information was of low credibility, reliability and written above the recommended reading level. Clinicians should be aware of the poor quality of online information on EC options, and actively educate patients on what makes a source credible.