The Management of Nausea and Vomiting in Pregnancy and Hyperemesis Gravidarum (Green-top Guideline No. 69).

An objective and validated index of nausea and vomiting such as the Pregnancy-Unique Quantification of Emesis (PUQE) and HyperEmesis Level Prediction (HELP) tools can be used to classify the severity of NVP and HG. [Grade C] Ketonuria is not an indicator of dehydration and should not be used to assess severity. [Grade A] There are safety and efficacy data for first line antiemetics such as anti (H1) histamines, phenothiazines and doxylamine/pyridoxine (Xonvea®) and they should be prescribed initially when required for NVP and HG (Appendix III). [Grade A] There is evidence that ondansetron is safe and effective. Its use as a second line antiemetic should not be discouraged if first line antiemetics are ineffective. Women can be reassured regarding a very small increase in the absolute risk of orofacial clefting with ondansetron use in the first trimester, which should be balanced with the risks of poorly managed HG. [Grade B] Metoclopramide is safe and effective and can be used alone or in combination with other antiemetics. [Grade B] Because of the risk of extrapyramidal effects metoclopramide should be used as second-line therapy. Intravenous doses should be administered by slow bolus injection over at least 3 minutes to help minimise these. [Grade C] Women should be asked about previous adverse reactions to antiemetic therapies. If adverse reactions occur, there should be prompt cessation of the medications. [GPP] Normal saline (0.9% NaCl) with additional potassium chloride in each bag, with administration guided by daily monitoring of electrolytes, is the most appropriate intravenous hydration. [Grade C] Combinations of different drugs should be used in women who do not respond to a single antiemetic. Suggested antiemetics for UK use are given in Appendix III. [GPP] Thiamine supplementation (either oral 100 mg tds or intravenous as part of vitamin B complex (Pabrinex®)) should be given to all women admitted with vomiting, or severely reduced dietary intake, especially before administration of dextrose or parenteral nutrition. [Grade D] All therapeutic measures should have been tried before considering termination of pregnancy. [Grade C].

Ondansetron and metoclopramide as second-line antiemetics in women with nausea and vomiting in pregnancy: the EMPOWER pilot factorial RCT.

BACKGROUND: Around one-third of pregnant women suffer from moderate to severe nausea and vomiting, causing physical and emotional distress and reducing their quality of life. There is no cure for nausea and vomiting in pregnancy. Management focuses on relieving symptoms and preventing morbidity, and often requires antiemetic therapy. National guidelines make recommendations about first-, second- and third-line antiemetic therapies, although care varies in different hospitals and women report feeling unsupported, dissatisfied and depressed. OBJECTIVES: To determine whether or not, in addition to intravenous rehydration, ondansetron compared with no ondansetron and metoclopramide compared with no metoclopramide reduced the rate of treatment failure up to 10 days after drug initiation; improved symptom severity at 2, 5 and 10 days after drug initiation; improved quality of life at 10 days after drug initiation; and had an acceptable side effect and safety profile. To estimate the incremental cost per treatment failure avoided and the net monetary benefits from the perspectives of the NHS and women. DESIGN: This was a multicentre, double-dummy, randomised, double-blinded, dummy-controlled 2 × 2 factorial trial (with an internal pilot phase), with qualitative and health economic evaluations. PARTICIPANTS: Thirty-three patients (who were < 17 weeks pregnant and who attended hospital with nausea and vomiting after little or no improvement with first-line antiemetic medication) who attended 12 secondary care NHS trusts in England, 22 health-care professionals and 21 women participated in the qualitative evaluation. INTERVENTIONS: Participants were randomly allocated to one of four treatment groups (1 : 1 : 1: 1 ratio): (1) metoclopramide and dummy ondansetron; (2) ondansetron and dummy metoclopramide; (3) metoclopramide and ondansetron; or (4) double dummy. Trial medication was initially given intravenously and then continued orally once women were able to tolerate oral fluids for a maximum of 10 days of treatment. MAIN OUTCOME MEASURES: The primary end point was the number of participants who experienced treatment failure, which was defined as the need for further treatment because symptoms had worsened between 12 hours and 10 days post treatment. The main economic outcomes were incremental cost per additional successful treatment and incremental net benefit. RESULTS: Of the 592 patients screened, 122 were considered eligible and 33 were recruited into the internal pilot (metoclopramide and dummy ondansetron, n = 8; ondansetron and dummy metoclopramide, n = 8; metoclopramide and ondansetron, n = 8; double dummy, n = 9). Owing to slow recruitment, the trial did not progress beyond the pilot. Fifteen out of 30 evaluable participants experienced treatment failure. No statistical analyses were performed. The main reason for ineligibility was prior treatment with trial drugs, reflecting an unpredicted change in prescribing practice at several points along the care pathway. The qualitative evaluation identified the requirements of the study protocol, in relation to guidelines on anti-sickness drugs, and the diversity of pathways to care as key hurdles to recruitment while the role of research staff was a key enabler. No important adverse events or side effects were reported. LIMITATIONS: The pilot trial failed to achieve the recruitment target owing to unforeseen changes in the provision of care. CONCLUSIONS: The trial was unable to provide evidence to support clinician decisions about the best choice of second-line antiemetic for nausea and vomiting in pregnancy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16924692 and EudraCT 2017-001651-31. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 63. See the NIHR Journals Library website for further project information.

Nausea and vomiting in pregnancy cause physical and emotional distress, and up to 30% of affected women require medical treatment. Guidelines on the use of anti-sickness drugs exist, but evidence is limited about which drugs work the best. The EMPOWER (EMesis in Pregnancy ­ Ondansetron With mEtoClopRamide) trial aimed to compare the clinical effectiveness and cost-effectiveness of two anti-sickness drugs [metoclopramide (metoclopramide hydrochloride, Actavis UK Ltd, Barnstable, UK; IV Ratiopharm GmbH, Ulm, Germany) and ondansetron (ondansetron hydrochloride dehydrate, Wockhardt UK Ltd, Wrexham, UK; IV Hameln Pharma plus GmbH, Hameln)] for the treatment of nausea and vomiting in pregnancy. Women who were < 17 weeks pregnant with severe nausea and vomiting who attended hospital because their first anti-sickness drug had failed to improve their symptoms were asked to take part in the trial. Participants received fluids and, with consent, were randomly allocated to one of four groups: (1) metoclopramide and dummy ondansetron, (2) ondansetron and dummy metoclopramide, (3) metoclopramide and ondansetron or (4) double dummy. Trial drugs were administered into a vein and then by tablet for 10 days. On advice from sufferers, the trial focused on treatment failure, but other outcomes, including drug side effects, costs and pregnancy outcome, were collected. The trial was unable to recruit enough women and, therefore, did not progress. Nearly 600 women at 11 hospitals were screened, of whom 122 (21%) were eligible and 33 were recruited. The main reason for ineligibility (68%) was prior use of trial drug (mostly ondansetron). Overall, 15 out of 30 evaluable women experienced treatment failure. Interviews with 21 women who were approached about the trial and 22 research staff identified complex hurdles to and enablers of recruitment. The main hurdles were the requirements of the study protocol in relation to guidelines on anti-sickness drugs and the diversity of pathways to care. The role of research staff was a key enabler. The trial was too small to draw useful conclusions and it highlights the challenges of conducting complex studies on sick pregnant women. Subsequent concerns about the safety of ondansetron highlight the need for further studies to help inform women and the NHS about the best care for nausea and vomiting in pregnancy.

Uterine fibroids: current perspectives.

Uterine fibroids are a major cause of morbidity in women of a reproductive age (and sometimes even after menopause). There are several factors that are attributed to underlie the development and incidence of these common tumors, but this further corroborates their relatively unknown etiology. The most likely presentation of fibroids is by their effect on the woman's menstrual cycle or pelvic pressure symptoms. Leiomyosarcoma is a very rare entity that should be suspected in postmenopausal women with fibroid growth (and no concurrent hormone replacement therapy). The gold standard diagnostic modality for uterine fibroids appears to be gray-scale ultrasonography, with magnetic resonance imaging being a close second option in complex clinical circumstances. The management of uterine fibroids can be approached medically, surgically, and even by minimal access techniques. The recent introduction of selective progesterone receptor modulators (SPRMs) and aromatase inhibitors has added more armamentarium to the medical options of treatment. Uterine artery embolization (UAE) has now been well-recognized as a uterine-sparing (fertility-preserving) method of treating fibroids. More recently, the introduction of ultrasound waves (MRgFUS) or radiofrequency (VizAblate™ and Acessa™) for uterine fibroid ablation has added to the options of minimal access treatment. More definite surgery in the form of myomectomy or hysterectomy can be performed via the minimal access or open route methods. Our article seeks to review the already established information on uterine fibroids with added emphasis on contemporary knowledge.

LNG-IUS versus oral progestogen treatment for endometrial hyperplasia: a long-term comparative cohort study.

STUDY QUESTION: What are the regression and hysterectomy rates for women treated with the levonorgestrel-releasing intrauterine system (LNG-IUS) compared with oral progestogens for endometrial hyperplasia (EH)? SUMMARY ANSWER: The LNG-IUS achieves higher regression and lower hysterectomy rates than oral progestogens in the treatment of complex and atypical hyperplasia. WHAT IS KNOWN ALREADY: The LNG-IUS and oral progestogens are both equally used to treat women with EH. There is uncertainty about whether the LNG-IUS is a better therapy for EH. STUDY DESIGN, SIZE, DURATION: This comparative cohort study included 344 women recruited from August 1998 until December 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with complex non-atypical or atypical EH were treated with the LNG-IUS (n = 250) or oral progestogens (n = 94) in a tertiary referral hospital. We evaluated the proportion of women who regressed or underwent hysterectomy after treatment with the LNG-IUS compared with oral progestogens by logistic regression adjusting for confounding. The time from diagnosis to regression was explored through a survival analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The follow-up rate was 95.3%. The mean length of follow-up in the two groups was 66.9 ± SD 35.1 months for the LNG-IUS and 87.2 ± SD 45.5 months for the oral progestogen group. Regression of hyperplasia was achieved in 94.8% (237/250) of patients with the LNG-IUS compared with 84.0% (79/94) of patients treated with oral progestogens (adjusted odds ratio (OR) = 3.04, 95% CI 1.36-6.79, P = 0.001). Hysterectomy rates were lower in the LNG-IUS group during follow-up (22.1, 55/250 versus 37.2%, 35/94, adjusted OR = 0.48, 95% CI 0.28-0.81, P < 0.004). Endometrial cancer was diagnosed in 8 (33%) women who had hysterectomy because of a failure to regress to normal histology during follow-up (n = 24). LIMITATIONS, REASONS FOR CAUTION: The observational design cannot exclude residual confounding from unmeasured variables. WIDER IMPLICATIONS OF THE FINDINGS: In treating EH, LNG-IUS achieves higher regression rates and lower hysterectomy rates than oral progestogens and should be the first-line therapy. Failure to achieve regression carries a high risk of underlying endometrial cancer and hysterectomy is advised.

Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up.

STUDY QUESTION: What is the risk of relapse for women with endometrial hyperplasia treated with levonorgestrel-releasing intrauterine system (LNG-IUS) or oral progestogens? SUMMARY ANSWER: Relapse of complex endometrial hyperplasia after initial regression occurs often and it occurs less often in women treated with LNG-IUS than with oral progestogens. WHAT IS KNOWN ALREADY: The LNG-IUS and oral progestogens are used to treat women with endometrial hyperplasia and achieve regression. There is uncertainty over whether further surveillance for these women is necessary as the risk for relapse is unknown. STUDY DESIGN, SIZE, DURATION: A cohort study of 219 women with complex non-atypical or atypical endometrial hyperplasia who were treated and achieved initial regression with LNG-IUS (n = 153) or oral progestogens (n = 66) from August 1998 until December 2007 and followed up for >5 years. The mean length of follow-up was 74.7 ± SD 31.8 months for the LNG-IUS versus 87.6 ± SD 42.2 months for the oral progestogen group. PARTICIPANTS/MATERIALS, SETTING, METHODS: We evaluated the proportion of women who relapsed or had hysterectomy after initial regression with LNG-IUS compared with oral progestogens by logistic regression and adjusting for confounding. The time from regression to relapse was explored through a survival analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Relapse of hyperplasia occurred in 13.7% (21/153) of women treated with LNG-IUS compared with 30.3% (20/66) of women treated with oral progestogens [adjusted odds ratio (OR) = 0.34, 95% confidence interval (CI): 0.17-0.7, P = 0.005]. Relapse rates over long-term follow-up were lower for complex non-atypical hyperplasia compared with atypical hyperplasia for both LNG-IUS (12.7%, 18/142 versus 27.3%, 3/11, respectively; P ≤ 0.001) and oral progestogens (28.3%, 17/60 versus 50%, 3/6, respectively; P ≤ 0.001). The survival analysis indicates that relapse occurred less often with LNG-IUS at 12, 24, 36, 48, 60 and >60 months of follow-up (hazard ratio 0.37, 95% CI: 0.2-0.7, P = 0.0013). There were no events of relapse after 48 months from regression with oral progestogens, but 5 women treated with LNG-IUS relapsed after 60 months when treatment was discontinued. Hysterectomy rates were lower in the LNG-IUS than oral progestogen group during follow-up (19.6%, 30/153 versus 31.8%, 21/66, respectively, OR = 0.52, 95% CI: 0.27-1, P = 0.05). Endometrial cancer was diagnosed in 2 (11.8%) women who had hysterectomy (n = 17) because of relapse. LIMITATIONS, REASONS FOR CAUTION: We are unable to accurately estimate the cancer risk in women who relapse during follow-up as only 17 out of 41 who relapsed underwent hysterectomy. WIDER IMPLICATIONS OF THE FINDINGS: Relapse of endometrial hyperplasia after initial regression occurs often and long-term follow-up is advised. STUDY FUNDING/COMPETING INTEREST(S): Ioannis D. Gallos and this study were funded through a grant from Wellbeing of Women (ELS022). No competing interests.

Predicting success in graduate entry medical students undertaking a graduate entry medical program.

BACKGROUND: Success in undergraduate medical courses in the UK can be predicted by school exit examination (A level) grades. There are no documented predictors of success in UK graduate entry medicine (GEM) courses. This study looks at the examination performance of GEM students to identify factors which may predict success; of particular interest was A level score. METHODS: Data was collected for students graduating in 2004, 2005 and 2006, including demographic details (age and gender), details of previous academic achievement (A level total score and prior degree) and examination results at several points during the degree course. RESULTS: Study group comprised 285 students. Statistical analyses identified no significant variables when looking at clinical examinations. Analysis of pass/fail data for written examinations showed no relationship with A level score. However, both percentage data for the final written examination and the analysis of the award of honours showed A level scores of AAB or higher were associated with better performance (p<0.001). DISCUSSION: A prime objective of introducing GEM programs was to diversify admissions to medical school. In trying to achieve this, medical schools have changed selection criteria. The findings in this study justify this by proving that A level score was not associated with success in either clinical examinations or passing written examinations. Despite this, very high achievements at A level do predict high achievement during medical school. CONCLUSIONS: This study shows that selecting graduate medical students with the basic requirement of an upper-second class honours degree is justifiable and does not disadvantage students who may not have achieved high scores in school leaver examinations.

Position in the second stage of labour for women without epidural anaesthesia.

BACKGROUND: For centuries, there has been controversy around whether being upright (sitting, birthing stools, chairs, squatting, kneeling) or lying down have advantages for women delivering their babies. OBJECTIVES: To assess the benefits and risks of the use of different positions during the second stage of labour (i.e. from full dilatation of the uterine cervix). SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (28 February 2012). SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of any upright or lateral position assumed by pregnant women during the second stage of labour compared with supine or lithotomy positions. Secondary comparisons include comparison of different upright positions and the lateral position. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and assessed trial quality. At least two review authors extracted the data. Data were checked for accuracy. MAIN RESULTS: Results should be interpreted with caution as the methodological quality of the 22 included trials (7280 women) was variable.In all women studied (primigravid and multigravid) there was a non-significant reduction in duration of second stage in the upright group (mean difference (MD) -3.71 minutes; 95% confidence interval (CI) -8.78 to 1.37 minutes; 10 trials, 3485 women; random-effects, I(2) = 94%), a significant reduction in assisted deliveries (risk ratio (RR) 0.78; 95% CI 0.68 to 0.90; 19 trials, 6024 women, I(2)= 27%), a reduction in episiotomies (average RR 0.79, 95% CI 0.70 to 0.90, 12 trials, 4541 women; random-effects, I(2) = 7%), an increase in second degree perineal tears (RR 1.35; 95% CI 1.20 to 1.51, 14 trials, 5367 women), increased estimated blood loss greater than 500 ml (RR 1.65; 95% CI 1.32 to 2.60; 13 trials, 5158 women, asymmetric funnel plot indicating publication bias), fewer abnormal fetal heart rate patterns (RR 0.46; 95% CI 0.22 to 0.93; two trials, 617 women). In primigravid women the use of any upright compared with supine positions was associated with: non-significant reduction in duration of second stage of labour (nine trials: mean 3.24 minutes, 95% CI 1.53 to 4.95 minutes) - this reduction was largely due to women allocated to the use of the birth cushion. AUTHORS' CONCLUSIONS: The findings of this review suggest several possible benefits for upright posture in women without epidural, but with the possibility of increased risk of blood loss greater than 500 mL. Until such time as the benefits and risks of various delivery positions are estimated with greater certainty, when methodologically stringent data from trials are available, women should be allowed to make choices about the birth positions in which they might wish to assume for birth of their babies.

Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis.

OBJECTIVE: To conduct a systematic review and metaanalysis of studies evaluating the regression rate of endometrial hyperplasia with oral progestogens and levonorgestrel-releasing intrauterine system. STUDY DESIGN: Searches were conducted on Medline, Embase, Cochrane Library, and Web of Science, and reference lists of relevant articles were examined. The methodologic index for nonrandomized studies was used for quality assessment. Metaanalysis was performed with random effects model. RESULTS: There were 24 observational studies (1001 women), of low methodologic quality, evaluating the outcome of regression of endometrial hyperplasia with oral progestogens or levonorgestrel-releasing intrauterine system. Metaanalysis showed that oral progestogens achieved a lower pooled regression rate compared with levonorgestrel-releasing intrauterine system for complex (pooled rate, 66% vs 92%; P < .01) and atypical hyperplasia (pooled rate, 69% vs 90%; P = .03). There was no statistical difference in simple hyperplasia (pooled rate, 89% vs 96%; P = .41). CONCLUSION: Oral progestogens appear to induce a lower disease regression rate than Levonorgestrel-releasing intrauterine system in the treatment of endometrial hyperplasia.

Comparing the performance of graduate-entry and school-leaver medical students.

OBJECTIVES: Between 2000 and 2006 Leicester-Warwick Medical Schools (LWMS) provided parallel courses for graduate and school-leaver entrants into medicine. The parallel courses were based upon a single curriculum with ;identical teaching programmes and assessment methods over the two sites (Warwick and Leicester). Warwick runs the curriculum over an accelerated 4-year period for its graduate-entry students. LWMS hence provides a unique opportunity to compare outcomes for these two contrasting groups of students. METHODS: We carried out an observational, quantitative cohort study over a 6-year period covering three cohorts of students who graduated in 2004, 2005 and 2006, respectively, using examination scores as outcome measures. We compared the examination performance of school-leaver and graduate-entry students in written and clinical examinations. These included intermediate clinical examinations, final clinical and final written examinations for both sets of students. Examination data were collected from original mark sheets and university databases at Warwick and Leicester. A-level data were collected from the national University College Admissions Service (UCAS) and compared against examination performance throughout medical school examinations. RESULTS: Graduate-entry students performed as well as school-leaver students prior to entering the full-time clinical element of the course despite having significantly lower A-level grades. School-leaver entrants performed better on midpoint examinations, but had lost this advantage by the time they sat final professional examinations. CONCLUSIONS: This is the first large-scale UK study to compare the performance of graduate-entry and school-leaver medical students following the same clinical curriculum and using the same assessments. Graduate-entry students performed as well as undergraduates in final examinations despite lower A-level grades and a shorter 4-year accelerated course.