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.

MRI in the diagnosis of fetal developmental brain abnormalities: the MERIDIAN diagnostic accuracy study.

BACKGROUND: Ultrasonography has been the mainstay of antenatal screening programmes in the UK for many years. Technical factors and physical limitations may result in suboptimal images that can lead to incorrect diagnoses and inaccurate counselling and prognostic information being given to parents. Previous studies suggest that the addition of in utero magnetic resonance imaging (iuMRI) may improve diagnostic accuracy for fetal brain abnormalities. These studies have limitations, including a lack of an outcome reference diagnosis (ORD), which means that improvements could not be assessed accurately. OBJECTIVES: To assess the diagnostic impact, acceptability and cost consequence of iuMRI among fetuses with a suspected fetal brain abnormality. DESIGN: A pragmatic, prospective, multicentre, cohort study with a health economics analysis and a sociological substudy. SETTING: Sixteen UK fetal medicine centres. PARTICIPANTS: Pregnant women aged ≥ 16 years carrying a fetus (at least 18 weeks' gestation) with a suspected brain abnormality detected on ultrasonography. INTERVENTIONS: Participants underwent iuMRI and the findings were reported to their referring fetal medicine clinician. MAIN OUTCOME MEASURES: Pregnancy outcome was followed up and an ORD from postnatal imaging or postmortem autopsy/imaging collected when available. Developmental data from the Bayley Scales of Infant Development and questionnaires were collected from the surviving infants aged 2-3 years. Data on the management of the pregnancy before and after the iuMRI were collected to inform the economic evaluation. Two surveys collected data on patient acceptability of iuMRI and qualitative interviews with participants and health professionals were undertaken. RESULTS: The primary analysis consisted of 570 fetuses. The absolute diagnostic accuracies of ultrasonography and iuMRI were 68% and 93%, respectively [a difference of 25%, 95% confidence interval (CI) 21% to 29%]. The difference between ultrasonography and iuMRI increased with gestational age. In the 18-23 weeks group, the figures were 70% for ultrasonography and 92% for iuMRI (difference of 23%, 95% CI 18% to 27%); in the ≥ 24 weeks group, the figures were 65% for ultrasonography and 94% for iuMRI (difference of 29%, 95% CI 23% to 36%). Patient acceptability was high, with at least 95% of respondents stating that they would have iuMRI again in a similar situation. Health professional interviews suggested that iuMRI was acceptable to clinicians and that iuMRI was useful as an adjunct to ultrasonography, but not as a replacement. Across a range of scenarios, iuMRI resulted in additional costs compared with ultrasonography alone. The additional cost was consistently < £600 per patient and the cost per management decision appropriately changed was always < £3000. There is potential for reporting bias from the referring clinicians on the diagnostic and prognostic outcomes. Lower than anticipated follow-up rates at 3 years of age were observed. CONCLUSIONS: iuMRI as an adjunct to ultrasonography significantly improves the diagnostic accuracy and confidence for the detection of fetal brain abnormalities. An evaluation of the use of iuMRI for cases of isolated microcephaly and the diagnosis of fetal spine abnormalities is recommended. Longer-term follow-up studies of children diagnosed with fetal brain abnormalities are required to fully assess the functional significance of the diagnoses. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27626961. 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. 23, No. 49. See the NIHR Journals Library website for further project information.

Ultrasonography is routine in pregnancy to check that the baby's brain is developing as expected. However, no medical test is perfect and ultrasonography may miss some brain abnormalities, may get some brain abnormalities wrong or may diagnose an abnormality that is not really present. Magnetic resonance imaging (MRI) may help clarify difficult cases during pregnancy. We wanted to find out if MRI was better than ultrasonography alone in making an accurate diagnosis. We recruited pregnant women whose ultrasound scan, performed by an expert, suggested that their baby had a brain abnormality, and referred them for a MRI scan. The results of the two tests were compared with each other and to the final outcome of the pregnancy. Our results showed that using MRI in addition to ultrasonography improved the accuracy of the diagnosis in about one in four pregnancies. It changed the prediction of how the baby would develop in at least one in five cases. In many cases, the pregnancy was managed differently because of the MRI result. The MRI was acceptable to women, with 95% saying that they would have MRI again in a similar situation. Neither MRI nor ultrasonography accurately identified children who went on to have delayed development at the age of 2­3 years, but MRI was better than ultrasonography at ruling out developmental problems at this age. The MRI cost more than ultrasonography alone; therefore, whether or not it is worthwhile depends on the value placed on the decisions that changed as a result of its use.