The Use of Expanded Carrier Screening in Reproductive Medicine: Scientific Impact Paper No. 74.

Expanded carrier screening (ECS) is a genetic screening test carried out by analysing a blood sample. This screen can be used to detect whether the individual unknowingly carries gene variants associated with common genetic conditions, such as cystic fibrosis, that may be passed on to their children. It is typically performed in reproductive medicine for those who are considering having a family either naturally or via fertility treatment. Many donor sperm and egg banks, particularly in the USA and Europe, also perform blanket ECS testing on all their prospective sperm and egg donors. ECS is not currently routine practice in the UK, but a growing number of patients are requesting it before treatment. All of us carry gene variants of some sort that may cause autosomal recessive disease in their children if their partner or donor also carry a variant in the same gene. An autosomal recessive disease means two copies of an abnormal gene must be present in order for the disease or trait (such as cystic fibrosis or sickle cell disease) to develop. One copy of the variant means the person is a carrier but does not have the condition. Two copies, i.e. from the mother and father, means the child has a 25% chance of having the genetic disease. Carrying a gene variant does not mean that the individual would necessarily have any symptoms of the disease or any features of the condition. Genetic tests for specific conditions are currently available either before or during pregnancy for prospective parents who have a family or personal history of a genetic condition, or for those from ethnic backgrounds where certain conditions - such as haemoglobinopathies (blood disorders) - are common, prompting referral to a clinical genetics department. Expanded carrier screens may test for more than 100 genetic conditions. The list of conditions screened for is called a panel. Common panels are 250 or 600 genes. Not all expanded carrier screens that are available analyse the same genes. Some may test for genes that do not cause serious disease, or cause diseases that occur in later life; others test for genes that cause severe conditions in childhood. There is no agreement as to which panel of genes should be tested for in an ECS. Understanding the screening that is being offered, and the meaning of any results, is complicated and requires support from appropriately trained professionals to best inform the prospective parent or parents.

Fertility Preservation in Female Patients with Cancer.

Advances in cancer treatment with resultant dramatic improvements in long-term survival have led to increasing awareness of the wide range of medical and social issues faced by survivors of malignancy. The potential deleterious effects on fertility are a significant worry of women and trans gender men, and the rising trend in delaying childbearing and the higher proportion of patients who have not completed their family at the time of diagnosis increases the demand for an optimised fertility-preservation service. Fertility preservation for this group following a diagnosis of cancer is a rapidly expanding area of reproductive medicine, although provision for such treatment often varies by region. In the past, there were few treatment options, but with dramatic improvements in oocyte cryopreservation and, more recently, ovarian tissue cryopreservation, this area of fertility care has broadened substantially. This review will be exploring areas that apply to all cisgender women, but not necessarily all trans men and non-binary individuals. There are specific considerations in fertility preservation for trans people, which are beyond the scope of this paper. All individuals with female reproductive organs should be offered the opportunity to discuss fertility preservation prior to starting potential gonadotoxic treatment. Failure to do this may negatively influence their anticancer treatment choices and adherence to treatment regimens. There are currently few networks streamlined around offering this service and as demand for these treatment options increases, it is recognised that these complex patients require specialist management within recognised care pathways. Here we are looking to describe some of the unique challenges associated with providing a state-of-the-art service, particularly in a financially unpredictable climate in the midst of the COVID-19 pandemic.

Symptomatology and Serum Nuclear Magnetic Resonance Metabolomics; Do They Predict Endometriosis in Fertile Women Undergoing Laparoscopic Sterilisation? A Prospective Cross-sectional Study.

Endometriosis is a common, chronic inflammatory condition, thought to have a higher incidence in symptomatic women, yet, commonly associated symptoms do not always correlate with the presence or severity of disease and diagnosis requires surgery. We prospectively collected data and assessed symptomology and NMR spectroscopy-based metabolomics of 102 women undergoing laparoscopic sterilisation at a tertiary referral centre in a cross-sectional study. Twelve women were incidentally diagnosed with endometriosis (11.7%). According to the pre-operative questionnaire, presence and absence of many symptoms usually attributed to endometriosis were declared at similar frequencies in women with or without endometriosis. Women with endometriosis reported apparently more persistent heavy periods (50% vs 18.9%), prolonged periods (25% versus 7.8%) and problems conceiving (27.3% versus 9%) than those without endometriosis. NMR could not discern any distinguishable differences in the serum metabolome between those with and without endometriosis. Our paper highlights the complex symptomology experienced by women, regardless of a surgical diagnosis of endometriosis. Previous literature and the current study failed to identify clear, distinguishable symptoms or biomarkers pertinent to surgically confirmed endometriosis in the general population. Therefore, development of effective, non-invasive tests for identifying this heterogenous benign condition, endometriosis, is likely to be challenging.

Automated anti-Mullerian hormone measurement: data review to provide insights and interpretation.

RESULTS: AMH results were pooled and a table with 2.5 and 97.5 percentiles for each age group constructed. Based on Youden index, the optimal cut off for low responders (0-3 eggs), was 5.5 pmol/l (87% sensitivity, 55% specificity) and for high responders (>15 eggs) 15.6 pmol/l (78% sensitivity, 57% specificity). AMH correlated with number of eggs collected (r = 0.48) and clinical pregnancies (r = 0.14), (p < .0001). CONCLUSIONS: The table of AMH levels measured using the Access 2 fully automated immunoassay system according to age may be used as a reference and cutoff levels for high and poor responders are clearly defined to help tailor controlled ovarian stimulation, maximizing efficiency and ensuring patient safety. The use of a random access automated immunoassay system means that blood sampled on arrival can produce an AMH result in 40 mins by the time the subject enters the doctor's clinic together with other relevant endocrine markers.

The practical role of anti-Müllerian hormone in assisted reproduction.

The objective of this study was to offer a brief critical summary of the literature on the role of AMH in the subfertility work up and during ART, while exploring its role in predicting ART success.

Intrauterine insemination practice in the UK.

Intrauterine insemination (IUI) is a recognised treatment for infertility. The overall success rate of IUI remains controversial and depends on several factors. There is a wide variation in the practice of IUI across the country. A postal survey was conducted to determine the attitudes to the factors influencing IUI practice. A questionnaire containing 22 factors was sent to 150 reproductive medicine units in the UK. Practitioners were requested to rate each parameter on the scale of 1-10, where 1 was least important and 10 very important. A total of 101 practitioners replied. Over 50% of the corresponding practitioners were Consultants, 32% were Infertility Nurse Specialists and 12% were other clinicians. The factor with the highest rating was the number of the follicles on the day of human chorionic gonadotrophin (hCG) injection, followed by the size of the follicle and the total sperm count. The fourth critical factor voted was the need for a standardised protocol for all the unit staff. The wide variation in the approach to IUI probably explains the great variance in pregnancy rates. Further properly designed studies are needed to ascertain the role of the factors in determining the success of IUI and the most successful protocols.

Adnexal torsion, a medical complication of in vitro fertilization.

With the expanding use of assisted reproductive technologies, general obstetricians and gynaecologists must maintain a high index of suspicion for complications of in vitro fertilization. We present the case of a pregnant woman with unilateral adnexal torsion following in vitro fertilization and its diagnostic implications in an emergency setting.

Low-dose aspirin for in vitro fertilisation.

BACKGROUND: Low-dose aspirin is sometimes used to improve the outcome in women undergoing in vitro fertilisation, despite inconsistent evidence of efficacy and the potential risk of significant side affects. The most appropriate time to commence aspirin therapy and length of treatment required is also still to be determined. OBJECTIVES: To determine the effectiveness of low-dose aspirin for improving the outcome of in vitro fertilisation and intracytoplasmic sperm injection treatment cycles. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (April 2007), MEDLINE (1966 to March 2007) and EMBASE (1980 to March 2007) databases using the following research terms: "(aspirin OR acetylsalicylic acid) AND (in-vitro fertilisation OR intracytoplasmic sperm injection)" combined with the Cochrane Menstrual Disorders and Subfertility Group's search strategy for identifying randomised controlled trials for reports which appeared to describe randomised controlled trials of low-dose aspirin for women undergoing in vitro fertilisation. SELECTION CRITERIA: Prospective randomised controlled trials, published or unpublished, which addressed the objectives of the review. Quasi-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies to include in the review, extracted data and assessed trial quality. MAIN RESULTS: The searches identified nine trials which were eligible for inclusion in the review, including a total of 1449 participants. No significant differences were found between the treatment and control groups for any of the outcomes assessed. Only two studies (involving 401 participants) investigated the effect of low-dose aspirin on live birth rate, and no significant difference was found between the treatment and control groups (RR 0.94, 95% CI 0.63 to 1.39). No significant difference was found in clinical pregnancy rate between treatment and control groups, based on results from 1240 participants in seven studies (RR 1.09, 95% CI 0.83 to 1.43). No data were reported on adverse events related to aspirin treatment in any of the included studies. AUTHORS' CONCLUSIONS: Use of low-dose aspirin for women undergoing in vitro fertilisation cannot currently be recommended due to lack of adequate trial data. There is a need for randomised controlled trials investigating the use of low-dose aspirin for different patient groups undergoing in vitro fertilisation. We used control group data from the largest trial included in this review to determine that a sample size of 350 women in each group would be required in order to demonstrate a 10% improvement from the use of aspirin with 80% power at the 5% significance level. Until evidence from appropriately powered trials is available, this treatment can not be recommended.

Growing concern over the safety of using mobile phones and male fertility.

There are growing concerns about the possible hazards of electromagnetic waves emitted by mobile phones on human health. One of the biggest concerns is their possible association with increased risk of cancer and their possible effects on cellular DNA. Electromagnetic waves can inflict their results through both thermal and non-thermal effects. There are many animal studies that show that electromagnetic waves have a wide range of damaging effects on the male reproductive system and sperm parameters. However, similar studies are quite limited in humans, and the results of animal studies should be interpreted with caution when considering their application to humans. Large controlled studies are required before confirming such possible effects on male fertility.

Cervical stitch (cerclage) for preventing pregnancy loss in women.

BACKGROUND: A cervical stitch has been used to prevent preterm deliveries in women with previous second trimester pregnancy losses, or other risk factors such as short cervix on digital or ultrasound examination. OBJECTIVES: To assess effectiveness and safety of prophylactic cerclage (before the cervix has dilated), emergency cerclage (where cervices have started to shorten and dilate) and then labour halted, and to determine whether a particular technique of stitch insertion is better than others. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group specialised register (July 2002). We handsearched congress proceedings of International and European society meetings of feto-maternal medicine, recurrent miscarriage and reproductive medicine. We contacted researchers in the field. SELECTION CRITERIA: All randomised trials comparing cervical cerclage with expectant management or no cerclage during pregnancy and trials comparing one technique with another or with other interventions were included. Quasi randomised trials were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently used prepared data extraction forms. Any discrepancy was resolved by discussion or by a third reviewer. Further clarification was sought from trial authors when required. Results were reported as relative risks using fixed or random effects model. MAIN RESULTS: Six trials with a total of 2175 women were analysed. Prophylactic cerclage was compared with no cerclage in four trials. There was no overall reduction in pregnancy loss and preterm delivery rates, although a small reduction in births under 33 weeks' gestation was seen in the largest trial (relative risks 0.75, 95% confidence interval 0.58 to 0.98). Cervical cerclage was associated with mild pyrexia, increased use of tocolytic therapy and hospital admissions but no serious morbidity. Two trials examined the role of therapeutic cerclage when ultrasound examination revealed short cervix. Pooled results failed to show a reduction in total pregnancy loss, early pregnancy loss or preterm delivery before 28 and 34 weeks in women assigned to cervical cerclage. REVIEWER'S CONCLUSIONS: The use of a cervical stitch should not be offered to women at low or medium risk of mid trimester loss, regardless of cervical length by ultrasound. The role of cervical cerclage for women who have short cervix on ultrasound remains uncertain as the numbers of randomised women are too few to draw firm conclusions. There is no information available as to the effect of cervical cerclage or its alternatives on the family unit and long term outcome.

Mid-trimester loss--appraisal of a screening protocol.

The main causes for mid-trimester loss are known. There is likely to be overlap with those of first trimester loss, but the proportions may be different. We wished to perform an aetiological survey in a large population of patients with a history of recurrent miscarriage, for possible explanations for their second trimester miscarriages. Database analysis of 636 patients attending a UK University Teaching Hospital dedicated miscarriage clinic between 1991 and 1996 revealed a 25% prevalence (n = 158) for second trimester miscarriage. Results from an investigative screening protocol were positive in 50% of cases: 33% (n = 52) tested positive for antiphospholipid syndrome (APS); 8% (n = 13) fulfilled strict criteria for cervical incompetence; there was a 4% prevalence of uterine anomaly; 3% for infection (n = 5) and 2% of patients (n = 3) proved to be hypothyroid. Importantly, dual pathology was found in 5% of patients with a history of second trimester miscarriage. As idiopathic mid-trimester loss is a diagnosis by exclusion, a high index of suspicion is required, as are modern diagnostic techniques.

Oncogene and tumour suppressor gene products during trophoblast differentiation in the first trimester.

Tumour suppressor genes may have a role in the control of trophoblast cell population expansion as trophoblast invasion occurs. To investigate this hypothesis, the location of tumour suppressor gene and proto-oncogene products were studied at various stages of trophoblast differentiation and invasion. Trophoblast and decidua were obtained from eight women having a therapeutic termination of pregnancy. Immunohistochemistry was used to localize the products of c-myc, c-erB-2, RB, BCL-2, P21, and P53 genes and anti-cytokeratin was used to identify fetal cells amongst the maternal decidual cells. The most differentiated and furthest invading trophoblast cell type, the multinucleated trophoblast, expressed a combination of genes which may indicate a high apoptotic rate. The other fully differentiated trophoblast, the syncytiotrophoblast, expressed BCL-2 suggesting protection from apoptosis. The co-occurrence of proto-oncogenes and the products of tumour suppressor genes in first trimester trophoblast suggests an important role not only in negative regulation of cellular invasion but also in population expansion through the presence of oncogenes and anti-apoptotic proteins.

The effect of progestagens on the carotid artery pulsatility index in postmenopausal women on oestrogen replacement therapy.

Part of the cardioprotective effect of postmenopausal oestrogen replacement therapy has been attributed to arterial vasodilation. This effect is partially reversed in the uterine artery by the addition of a progestagen. This study was designed to compare the effects of the C21 progestagen, dydrogesterone and the C19 testosterone derivative, norethisterone on the carotid artery pulsatility index (PI) (thought to represent distal impedance to flow) using a randomized double blind cross-over trial. The addition of progestagen resulted in a significant increase in the carotid artery PI from a median value of 1.67 during the oestrogen only phase to 1.77 (P = 0.02) during the combined phase. This trend was seen with both dydrogesterone and norethisterone, but there was no significant difference in the size of the effect caused by either progestagen. The addition of cyclical progestagen to ERT partially antagonizes the reduction in the carotid artery PI.

Intraumbilical oxytocin for the management of retained placenta: a randomized controlled trial.

OBJECTIVE: To evaluate the ability of intraumbilical oxytocin injection as a treatment for retained placenta after vaginal delivery to reduce the incidence of manual removal and postpartum hemorrhage. METHODS: A randomized controlled trial was set up in a university and a district general hospital. We recruited 81 women with singleton pregnancies who underwent vaginal delivery and who failed to deliver the placenta after 20 minutes of active management of the third stage of labor. Study subjects were randomized to receive either 1) an intraumbilical injection of oxytocin (20 IU in 20 mL of saline); 2) an intraumbilical injection of saline (20 mL); or 3) no treatment. Outcome measures were expulsion of the placenta within 45 minutes of delivery, need for manual removal of the placenta under anesthesia, and postpartum hemorrhage (defined as a blood loss greater than 500 mL). RESULTS: Women given an intraumbilical injection of oxytocin had a significant increase in spontaneous expulsion of the placenta within 45 minutes of delivery and fewer manual removals of the placenta, compared with women without treatment (odds ratio [OR] 11.6, 99% confidence interval [CI] 1.4, 272.8; and OR 7.4, 99% CI 1.1, 86.5; respectively). When women given intraumbilical oxytocin were compared with women given only intraumbilical saline, the difference was not statistically significant (OR 6.6, 99% CI 0.9, 77.2 for spontaneous expulsion of the placenta; and OR 4.7, 99% CI 0.8, 39.5 for manual removal). There was no significant difference in the incidence of spontaneous expulsion and manual removal of the placenta between women given intraumbilical saline injection and women without treatment (OR 1.8, 99% CI 0.1, 53.9; and OR 1.6, 99% CI 0.1, 22.4; respectively). CONCLUSION: The results of our study suggest a clinically important beneficial effect of intraumbilical oxytocin injection in the management of retained placenta.

Delivery of twins.

The delivery of twins presents considerable challenges to the obstetric team, particularly in terms of decision-making, technical skills required and the need to respond quickly to changing circumstances. There is a serious lack of sound evidence upon which to base decisions concerning the method of delivery of twins. The trend towards the routine use of caesarean section is not supported by evidence of improved outcome for the infants, while maternal outcome is compromised. Specific circumstances that may have a bearing on the need for caesarean section include gestational age, presentation of the twins and chorionicity/amnionicity. Caesarean section does not eliminate the chance of fetal trauma during delivery, particularly for premature twins. The techniques of twin delivery, whether vaginal or by caesarean section, require thorough preparation for all possible eventualities, and skilled teamwork. Particular attention should be paid to emotional needs during labour, birth and afterwards, of the parents of twins.