Predicting the chances of having a baby with or without treatment at different time points in couples with unexplained subfertility.

STUDY QUESTION: Can we develop a prediction model that can estimate the chances of conception leading to live birth with and without treatment at different points in time in couples with unexplained subfertility? SUMMARY ANSWER: Yes, a dynamic model was developed that predicted the probability of conceiving under expectant management and following active treatments (in vitro fertilisation (IVF), intrauterine insemination with ovarian stimulation (IUI + SO), clomiphene) at different points in time since diagnosis. WHAT IS KNOWN ALREADY: Couples with no identified cause for their subfertility continue to have a realistic chance of conceiving naturally, which makes it difficult for clinicians to decide when to intervene. Previous fertility prediction models have attempted to address this by separately estimating either the chances of natural conception or the chances of conception following certain treatments. These models only make predictions at a single point in time and are therefore inadequate for informing continued decision-making at subsequent consultations. STUDY DESIGN, SIZE, DURATION: A population-based study of 1316 couples with unexplained subfertility attending a regional clinic between 1998 and 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: A dynamic prediction model was developed that estimates the chances of conception within 6 months from the point when a diagnosis of unexplained subfertility was made. These predictions were recomputed each month to provide a dynamic assessment of the individualised chances of conception while taking account of treatment status in each month. Conception must have led to live birth and treatments included clomiphene, IUI + SO, and IVF. Predictions for natural conception were externally validated using a prospective cohort from The Netherlands. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 554 (42%) couples started fertility treatment within 2 years of their first fertility consultation. The natural conception leading to live birth rate was 0.24 natural conceptions per couple per year. Active treatment had a higher chance of conception compared to those who remained under expectant management. This association ranged from weak with clomiphene to strong with IVF [clomiphene, hazard ratio (HR) = 1.42 (95% confidence interval, 1.05 to 1.91); IUI + SO, HR = 2.90 (2.06 to 4.08); IVF, HR = 5.09 (4.04 to 6.40)]. Female age and duration of subfertility were significant predictors, without clear interaction with the relative effect of treatment. LIMITATIONS, REASONS FOR CAUTION: We were unable to adjust for other potentially important predictors, e.g. measures of ovarian reserve, which were not available in the linked Grampian dataset that may have made predictions more specific. This study was conducted using single centre data meaning that it may not be generalizable to other centres. However, the model performed as well as previous models in reproductive medicine when externally validated using the Dutch cohort. WIDER IMPLICATIONS OF THE FINDINGS: For the first time, it is possible to estimate the chances of conception following expectant management and different fertility treatments over time in couples with unexplained subfertility. This information will help inform couples and their clinicians of their likely chances of success, which may help manage expectations, not only at diagnostic workup completion but also throughout their fertility journey. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a Chief Scientist Office postdoctoral training fellowship in health services research and health of the public research (ref PDF/12/06). B.W.M. is supported by an NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck, and Guerbet. None of the other authors declare any conflicts of interest.

Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder.

ANK3, encoding the adaptor protein Ankyrin-G (AnkG), has been implicated in bipolar disorder by genome-wide association studies. ANK3 has multiple alternative first exons, and a bipolar disorder-associated ANK3 variant has been shown to reduce the expression of exon 1b. Here we identify mechanisms through which reduced ANK3 exon 1b isoform expression disrupts neuronal excitation-inhibition balance. We find that parvalbumin (PV) interneurons and principal cells differentially express ANK3 first exon subtypes. PV interneurons express only isoforms containing exon 1b, whereas excitatory principal cells express exon 1e alone or both 1e and 1b. In transgenic mice deficient for exon 1b, PV interneurons lack voltage-gated sodium channels at their axonal initial segments and have increased firing thresholds and diminished action potential dynamic range. These mice exhibit an Ank3 gene dosage-dependent phenotype including behavior changes modeling bipolar disorder, epilepsy and sudden death. Thus ANK3's important association with human bipolar susceptibility may arise from imbalance between AnkG function in interneurons and principal cells and resultant excessive circuit sensitivity and output. AnkG isoform imbalance is a novel molecular endophenotype and potential therapeutic target.

Prolonged concurrent hypotension and low bispectral index ('double low') are associated with mortality, serious complications, and prolonged hospitalization after cardiac surgery.

BACKGROUND: Low bispectral index (BIS) and low mean arterial pressure (MAP) are associated with worse outcomes after surgery. We tested the hypothesis that a combination of these risk factors, a 'double low', is associated with death and major complications after cardiac surgery. METHODS: We used data from 8239 cardiac surgical patients from two US hospitals. The primary outcomes were 30-day mortality and a composite of in-hospital mortality and morbidity. We examined whether patients who had a case-averaged double low, defined as time-weighted average BIS and MAP (calculated over an entire case) below the sample mean but not in the reference group, had increased risk of the primary outcomes compared with patients whose BIS and/or MAP were at or higher than the sample mean. We also examined whether a prolonged cumulative duration of a concurrent double low (simultaneous low MAP and BIS) increased the risk of the primary outcomes. RESULTS: Case-averaged double low was not associated with increased risk of 30-day mortality {odds ratio [OR] 1.73 [95% confidence interval (CI) 0.94-3.18] vs reference; P =0.01} or the composite of in-hospital mortality and morbidity [OR 1.47 (95% CI 0.98-2.20); P =0.01] after correction for multiple outcomes. A prolonged concurrent double low was associated with 30-day mortality [OR 1.06 (95% CI 1.01-1.11) per 10-min increase; P =0.001] and the composite of in-hospital mortality and morbidity [OR 1.04 (95% CI 1.01-1.07), P =0.004]. CONCLUSIONS: A prolonged concurrent double low, but not a case-averaged double low, was associated with higher morbidity and mortality after cardiac surgery.

Biomarkers for wound healing and their evaluation.

A biological marker (biomarker) is a substance used as an indicator of biological state. Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Research has identified several cellular events and mediators associated with wound healing that can serve as biomarkers. Macrophages, neutrophils, fibroblasts and platelets release cytokines molecules including TNF-α, interleukins (ILs) and growth factors, of which platelet-derived growth factor (PDGF) holds the greatest importance. As a result, various white cells and connective tissue cells release both matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). Studies have demonstrated that IL-1, IL-6, and MMPs, levels above normal, and an abnormally high MMP/TIMP ratio are often present in non-healing wounds. Clinical examination of wounds for these mediators could predict which wounds will heal and which will not, suggesting use of these chemicals as biomarkers of wound healing. There is also evidence that the application of growth factors like PDGF will alleviate the recuperating process of chronic, non-healing wounds. Finding a specific biomarker for wound healing status would be a breakthrough in this field and helping treat impaired wound healing.

Correlation between measures of hypoglycemia and glycemic improvement in sulfonylurea treated patients with type 2 diabetes in India: results from the OBSTACLE hypoglycemia study.

BACKGROUND: This study aimed to assess correlation between measures of hypoglycemia and glycemic control in patients with type 2 diabetes mellitus (T2DM) treated with sulfonylureas. MATERIALS AND METHODS: T2DM patients being initiated on a sulfonylurea (SU) on background of a failing oral antihyperglycemic regimen were followed up for 12 weeks. (HbA1c) was measured at baseline and end of follow-up. Hypoglycemia was assessed using Stanford Hypoglycemia Questionnaire at week 12. RESULTS: Of the total 1069 patients enrolled, 950 were considered evaluable. A weak negative correlation was observed between end of follow-up HbA1c values and hypoglycemia score, using both linear regression analysis (correlation coefficient -0.12; P = 0.0002) and negative binomial regression (ß slope -0.09; P = 0.0010). A similar correlation was also observed between change in HbA1c from baseline and hypoglycemia score (ß slope -0.07; P = 0.0048). Mean HbA1c reduction was lowest (0.65 ± 2.27%) in patients not reporting any hypoglycemia and highest (1.28 ± 2.40%) in patients with hypoglycemia score greater than median of 2 (P = 0.0031). There was no correlation between hypoglycemia frequency and end of follow-up HbA1c values (P = 0.4111). CONCLUSION: With addition of SU on a background of a failing oral anti-hyperglycemic regimen, the extent of glycemic control correlates directly with measures of patient reported hypoglycemia.

Emerging artificial intelligence-aided diagnosis and management methods for ischemic strokes and vascular occlusions: A comprehensive review.

Large-vessel occlusion (LVO) stroke is a promising field for the use of AI, especially machine learning (ML) because optimal results are highly dependent on timely diagnosis, communication, and treatment. In order to better understand the current state of artificial intelligence (AI) in relation to LVO strokes, its efficacy, and potential future applications, we searched relevant literature to perform a comprehensive evaluation of the topic. The databases PubMed, Embase, and Scopus were extensively searched for this review. Studies were then screened using title and abstract criteria and duplicate studies were excluded. By using pre-established inclusion and exclusion criteria, it was decided whether or not to include full-text papers in the final analysis. The studies were analyzed, and the relevant information was retrieved. In recognizing LVO on computed tomography, ML approaches were very accurate. There is a shortage of AI applications for thrombectomy patient selection, despite the fact that certain research accurately evaluates individual patient eligibility for endovascular therapy. Machine learning algorithms may reasonably predict clinical and angiographic outcomes as well as associated factors. AI has shown promise in the diagnosis and treatment of people who have just suffered a stroke. However, the usefulness of AI in management and forecasting remains restricted, necessitating more studies into machine learning applications that can guide decision making in the future.

Elective frozen replacement cycles for all: ready for prime time?

Conventionally, most in vitro fertilization (IVF) embryos are transferred in fresh treatment cycles with freezing reserved for spare ones. Improvement in cryopreservation facilities over time has encouraged the greater use of this technology with the success rate of frozen replacement cycles approaching that associated with fresh embryo transfer. Data from observational studies suggest that obstetric and perinatal outcomes are better in pregnancies resulting from frozen replacement cycles. In the interests of promoting feto-maternal safety is it therefore time to avoid fresh embryo transfers in IVF, freeze all available embryos and replace them in subsequent cycles? In this article we explore the biological plausibility of this concept, appraise the evidence underpinning it and consider the implications of adopting such a strategy in routine clinical practice. The outcomes of existing randomized trials appear to favour a strategy of frozen embryo transfer, but larger trials are needed before a major change in clinical practice can be considered.

Dexamethasone, light anaesthesia, and tight glucose control (DeLiT) randomized controlled trial.

BACKGROUND: The inflammatory response to surgical tissue injury is associated with perioperative morbidity and mortality. We tested the primary hypotheses that major perioperative morbidity is reduced by three potential anti-inflammatory interventions: (i) low-dose dexamethasone, (ii) intensive intraoperative glucose control, and (iii) lighter anaesthesia. METHODS: We enrolled patients having major non-cardiac surgery who were ≥40 yr old and had an ASA physical status ≤IV. In a three-way factorial design, patients were randomized to perioperative i.v. dexamethasone (a total of 14 mg tapered over 3 days) vs placebo, intensive vs conventional glucose control 80-110 vs 180-200 mg dl(-1), and lighter vs deeper anaesthesia (bispectral index target of 55 vs 35). The primary outcome was a collapsed composite of 15 major complications and 30 day mortality. Plasma high-sensitivity (hs) C-reactive protein (CRP) concentration was measured before operation and on the first and second postoperative days. RESULTS: The overall incidence of the primary outcome was about 20%. The trial was stopped after the second interim analysis with 381 patients, at which all three interventions crossed the futility boundary for the primary outcome. No three-way (P=0.70) or two-way (all P>0.52) interactions among the interventions were found. There was a significantly smaller increase in hsCRP in patients given dexamethasone than placebo [maximum 108 (64) vs 155 (69) mg litre(-1), P<0.001], but none of the other two interventions differentially influenced the hsCRP response to surgery. CONCLUSIONS: Among our three interventions, dexamethasone alone reduced inflammation. However, no intervention reduced the risk of major morbidity or 1 yr mortality. TRIAL REGISTRATION IDENTIFIER: NCT00433251 at www.clinicaltrials.gov.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with endometrial cancer was published in 2022. It was therefore decided, by both the ESMO and the Indian Society of Medical and Paediatric Oncology (ISMPO), to convene a virtual meeting in July 2022 to adapt the ESMO 2022 guidelines to take into account the variations in the management of endometrial cancer in Asia. These guidelines represent the consensus opinion of a panel of Asian experts representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). Voting was based on scientific evidence and was conducted independently of the current treatment practices and treatment access constraints in the different Asian countries, which were discussed when appropriate. The aim of this guideline manuscript is to provide guidance for the optimisation and harmonisation of the management of patients with endometrial cancer across the different regions of Asia, drawing on the evidence provided by Western and Asian trials whilst respecting the variations in clinical presentation, diagnostic practices including molecular profiling and disparities in access to therapeutic options, including drug approvals and reimbursement strategies.

Maintenance therapy with a poly(ADP-ribose) polymerase inhibitor in patients with newly diagnosed advanced epithelial ovarian cancer: individual patient data and trial-level meta-analysis.

BACKGROUND: We synthesize the efficacy and toxicity of poly(ADP-ribose) polymerase inhibitors (PARPis) in patients with newly diagnosed advanced ovarian cancer. PATIENTS AND METHODS: We manually extracted individual patient data (IPD) for progression-free survival (PFS) from published survival curves of randomized controlled trials (RCTs) that compared PARPi versus placebo as maintenance therapy in first-line treatment, for whole study populations and subgroups, based on BRCA1/BRCA2 mutation (germline and/or somatic) and homologous recombination deficiency (HRD) status, using WebPlotDigitizer software. The respective PFS curves for each study and combined population were reconstructed from extracted IPD. The primary outcome was PFS in combined whole population and subgroups. RESULTS: In IPD analysis of combined population from three RCTs, with 2296 patients and 1287 events, PFS was significantly longer in PARPi versus placebo [median 20.4 (95% confidence interval (CI) 18.6-21.9) versus 14.9 (95% CI 13.9-16.5) months, respectively; hazard ratio (HR) 0.67, 95% CI 0.60-0.75; P < 0.001]. In IPD subgroup analyses from four eligible RCTs (2687 patients and 1485 events), median PFS was significantly longer in PARPi versus placebo arm, in the BRCA-mutated (45.7 versus 17.7 months, respectively; HR 0.38, 95% CI 0.32-0.46; P < 0.001), HRD-positive including BRCA-mutated (34.7 versus 17.9 months, respectively; HR 0.45, 95% CI 0.38-0.54; P < 0.001), and HRD positive excluding BRCA-mutated (22.3 versus 13.1 months, respectively; HR 0.47, 95% CI 0.34-0.65; P < 0.001) subgroups, but not in the HRD-negative (15.0 versus 11.3 months, respectively; HR 0.90, 95% CI 0.76-1.05; P = 0.75) subgroup. Results of trial-level meta-analysis were concordant with IPD analysis in whole population and subgroups. CONCLUSIONS: Among newly diagnosed ovarian cancer patients, PARPi maintenance therapy significantly improves PFS in those with germline and/or somatic BRCA mutation and/or HRD-positive tumor but not in those with HRD-negative tumor.

Should a hysterosalpingogram be a first-line investigation to diagnose female tubal subfertility in the modern subfertility workup?

Tubal assessment is an integral part of female fertility evaluation. While diagnostic laparoscopy is gold standard, it is not suitable to be used as a screening test. Hysterosalpingogram (HSG) has been advocated as first-line investigation historically. With advances in diagnostics, more tests are available, such as hysterosalpingo contrast sonography (HyCoSy) and Chlamydia antibody titre (CAT) are available. The CAT test is much cheaper, less invasive and can be performed at any time during the cycle. The CAT test can also be used as a means of identifying which patients need further evaluation. HyCoSy has same diagnostic accuracy as HSG, without exposing women to radiation. We argue that HSG is out of date and has no place in a modern infertility evaluation. We also suggest a pathway (based on history, clinical and ultrasound evaluation) for investigations to screen for and diagnose tubal pathology.

Psychological assessment and lived experiences of recovered COVID-19 patients who presented for convalescent plasma donation.

BACKGROUND: Increasingly, it has been seen that patients recovering from COVID-19 may face a second battle of coping with its mental health ramifications. These psychological issues can even be experienced by patients who were asymptomatic or had mild to moderate symptoms, potentially impacting their quality of life. METHODOLOGY: This was a prospective observational study to analyse the psychological impact of COVID-19 in recovered patients who presented as prospective convalescent plasma (CP) donors. An interview for the psychological assessment of the prospective donors was carried out. Depression and anxiety in the participants were assessed by HAM-A, and HAM-D scores and Quality of Life were assessed using the WHOQOL-BREF scale. RESULTS: A total of 51 prospective donors were assessed, with a mean age of 34.37 (±9.08) years, with the majority being males (46). No clinically significant depression and anxiety were found on the basis of HAM-D and HAM-A scores. The worst affected quality of life parameter, based on the WHOQOL-BREF scale, was physical quality of life followed by environmental, psychological, and social relationships. Moreover, due to infection, social stigma was experienced by 49.02% of the donors, while 21.97% had anxiety related to convalescent plasma donation as a common livid experience. CONCLUSION: Poor quality of life and social stigma during the recovery phase is prevalent in COVID-19 recovered patients, for which formulation of holistic support strategies are the need of the hour.

Use of insulin glargine during pregnancy: A review.

BACKGOUND AND AIMS: Hyperglycemia during pregnancy is increasing globally. Insulin therapy is considered the standard of care for its optimum management. Insulin glargine, in spite of widespread use in non-pregnant adults, lacks randomized controlled trial evidence as safe basal insulin during pregnancy. Aim of this review is to discuss major available evidences and recommendations on the use of insulin glargine during pregnancy. METHODS: Evidences related to use of insulin glargine during pregnancy, including animal studies, placental transfer studies, case reports as well as observational studies were retrieved using PUBMED & Google scholar. Recommendations regarding use of insulin glargine during pregnancy by international and Indian organizations were reviewed. RESULTS: Trans-placental transfer studies show that insulin glargine does not cross placenta when used at therapeutic concentrations. Although there are no randomized controlled trials on insulin glargine in pregnancy, it's use during pregnancy is not associated with any adverse maternal or neonatal outcomes as shown in many case reports and observational studies (both prospective and retrospective). It's use during pregnancy is hence considered safe by many organizations across the globe. CONCLUSIONS: Insulin glargine can be continued safely during pregnancy in women who are already taking it prior to pregnancy and have achieved good glycemic control with it. However we require preferably randomized controlled trials or large prospective observational studies to establish it as first line or preferred basal insulin for management of hyperglycemia during pregnancy.

Current Opinion on Peritoneal Carcinomatosis Treatment: a Survey of the Indian Society of Peritoneal Surface Malignancies (ISPSM).

PURPOSE: Patients with peritoneal carcinomatosis (PC) are increasingly treated with multidisciplinary combined approaches. The study aim was to assess current practice and perceptions of treatment modalities of PC. METHODS: Indian Society of Peritoneal Surface Malignancies (ISPSM) members were invited to complete an online survey. Current practice and perceptions of treatment modalities were assessed through 19 closed questions. Scores were assessed using a Likert scale (0: not important, 5: very important). Treatment modality satisfaction was assessed using a semantic scale (frustrated: 0, perfectly happy: 10). Participants were sent 3 reminders at 4-week intervals. RESULTS: Fifty-seven out of 182 members completed the survey (31%). Forty percent of participants had an experience of at least 10 years, and 75% stated treating less than 20 PC patients per year. Main treatment goals for patients with PC were cure (5/5) and symptom relief (4/5). Participant's satisfaction with treatment modalities for ovarian, colorectal, and gastric PC were 6/10, 5/10, and 2/10, respectively. Hyperthermic intraperitoneal chemotherapy (HIPEC) for ovarian (57%) and colorectal (44%) origins were considered to be useful. Clinical usefulness of chemotherapy for gastric PC was rated to be low (17%). CONCLUSIONS: Current treatment modalities fall short to satisfy the needs (cure, symptom relief) of patients with PC. Alternative systemic and intraperitoneal treatment modalities should be assessed.

Predicting the disaster - The role of CRP in acetabular surgery.

OBJECTIVES: Acetabular fractures represent a complex surgical challenge. Given the heterogenous fracture pattern, the patient characteristics and spectrum of complications demand individual solutions. Surgical site infections (SSI) threaten osteosynthesis, and early detection of them and treatment remain crucial. What is the value of postoperative C-reactive protein (CRP) in this group of patients as well as its normal course? DESIGN & METHODS: 115 patients with isolated fractures of the acetabulum were retrospectively evaluated. CRP, white blood cell count (WBC) and fracture patterns as well as patient characteristics were assessed for 20 days following operative fixation of the acetabular fracture (n = 71) and in fractures that were managed conservatively (n = 44). RESULTS: Twelve patients suffered an infectious complication. With a one-phase decay, 70.55% of the variance of postoperative CRP kinetics was predicted. To anticipate maximum CRP as well as an infection, the preoperative CRP represented the best prognostic parameter. To predict an infection, the single variable "peak CRP value above 100 mg/l" resulted in a sensitivity and specificity of 91.67% and 36.21%, respectively. Combining a second peak of CRP with maximum CRP and day 5 CRP value for receiver-operating characteristic (ROC) analysis resulted in 83.3% and 88.1%, respectively. CONCLUSIONS: Predicting surgical site infections after an acetabular fracture is most predictive when analyzing the maximum overall CRP, the second peak and the CRP after day 5. With a combination of these parameters, a sensitivity and specificity of 83.3% and 88.1% to detect an infection was achieved.

Should access to fertility treatment be determined by female body mass index?

Resource allocation towards fertility treatment has been extensively debated in countries where fertility treatment is publicly-funded. Medical, social and ethical aspects have been evaluated prior to allocation of resources. Analysis of cost-effectiveness, risks and benefits and poor success rates have led to calls of restricting fertility treatment to obese women. In this debate article, we critically appraise the evidence underlying this issue and highlight the problems with such a policy. Poor success rate of treatment is unsubstantiated as there is insufficient evidence to link high body mass index (BMI) to reduction in live birth. Obstetric complications have a linear relationship with BMI but are significantly influenced by maternal age. The same is true for miscarriage rates which are influenced by the confounding factors of polycystic ovary syndrome and age. Studies have shown that the direct costs per live birth are no greater for overweight and obese women. With changing demographics over half the reproductive-age population is overweight or obese. Restricting fertility treatment on the grounds of BMI would cause stigmatization and lead to inequity, feelings of injustice and social tension as affluent women manage to bypass these draconian restrictions. Time lost and poor success of conventional weight loss strategies would jeopardize the chances of conception for many women.

Should non-mosaic Klinefelter syndrome men be labelled as infertile in 2009?

BACKGROUND: Klinefelter syndrome is a common genetic condition. Affected non-mosaic men are azoospermic and have been labelled as infertile. Despite reports that these men can have children using assisted reproduction techniques, it is not common practice in the UK to offer sperm retrieval to these men. METHODS: Medline and EMBASE (1980-2009) were searched independently by two authors and all studies involving surgical sperm retrieval in non-mosaic Klinefelter syndrome were included. The primary outcome was success of surgical sperm retrieval and the secondary outcome was live birth rate. RESULTS: The overall success rate for sperm retrieval was 44%, with a higher rate of success using micro-dissection testicular sperm aspiration (micro-TESE) (55%). This, along with ICSI, has led to the birth of 101 children. However, there are no known predictors for successful sperm retrieval. Although there are concerns about genetic risk to the offspring of non-mosaic Klinefelter patients, this risk has not been found to be greater than that of patients with non-obstructive azoospermia with normal karyotype. CONCLUSIONS: It is possible for a man with non-mosaic Klinefelter to father a child. However, before these techniques are offered, some ethical issues need to be explored.

Maternal and perinatal outcome in women with threatened miscarriage in the first trimester: a systematic review.

BACKGROUND: Threatened miscarriage is a common complication in the first trimester of pregnancy and is often associated with anxiety regarding pregnancy outcome. OBJECTIVE: We undertook a systematic review to explore the effects of threatened miscarriage in the first trimester on maternal and perinatal outcomes. SEARCH STRATEGY: An electronic literature search using MEDLINE and EMBASE, and bibliographies of retrieved primary articles. No language restrictions were applied. SELECTION CRITERIA: All studies analysing outcomes of first-trimester bleeding where viability was confirmed on ultrasound or the pregnancy continued beyond viability. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies and extracted data on study characteristics, quality and accuracy. Meta-analysis was performed using Review Manager software. MAIN OUTCOME MEASURES: The outcome was broadly categorised into maternal and perinatal outcomes. The chief maternal outcomes included pre-eclampsia/eclampsia or pregnancy-induced hypertension, antepartum haemorrhage, preterm prelabour rupture of membranes (PPROM) and mode of delivery. The perinatal outcomes evaluated were preterm delivery, low birthweight, intrauterine growth restriction, perinatal mortality, indicators of perinatal morbidity (Apgar scores and neonatal unit admission) and presence of congenital anomalies. MAIN RESULTS: Fourteen studies met the inclusion criteria. Women with threatened miscarriage had a significantly higher incidence of antepartum haemorrhage due to placenta praevia [odds ratio (OR) 1.62, 95% CI 1.19, 2.22] or antepartum haemorrhage of unknown origin (OR 2.47, 95% CI 1.52, 4.02) when compared with those without first-trimester bleeding. They were more likely to experience PPROM (OR 1.78, 95% CI 1.28, 2.48), preterm delivery (OR 2.05, 95% CI 1.76, 2.4) and to have babies with intrauterine growth restriction (OR 1.54, 95% CI 1.18, 2.00). First-trimester bleeding was associated with significantly higher rates of perinatal mortality (OR 2.15, 95% CI 1.41, 3.27) and low-birthweight babies (OR 1.83, 95% CI 1.48, 2.28). AUTHORS' CONCLUSIONS: Threatened miscarriage in the first trimester is associated with increased incidence of adverse maternal and perinatal outcome.