SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

SARS-CoV-2 infection in pregnancy during the first wave of COVID-19 in the Netherlands: a prospective nationwide population-based cohort study (NethOSS)

Objective To describe characteristics, risk factors and maternal, obstetric and neonatal outcomes of pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Design Multi-centre prospective population-based cohort study. Setting Nationwide study in the Netherlands. Population Pregnant women with confirmed SARS-CoV-2 infection admitted to hospital or in home-isolation: 1 March 2020 to 31 August 2020. Methods Pregnant women with positive polymerase chain reaction or antibody tests were registered using the Netherlands Obstetrics Surveillance System (NethOSS). (Selective) testing occurred according to national guidelines. Data from the national birth registry (pregnant pre-coronavirus disease 2019 [COVID-19] cohort) and an age-matched cohort of COVID-19-positive women (National Institute for Public Health and the Environment; fertile age COVID-19 cohort) were used as reference. Main outcome measures Incidence of SARS-CoV-2 infection in pregnant women. Maternal, obstetric and neonatal outcomes including hospital and intensive care admission. Results Of 376 registered pregnant women with confirmed SARS-CoV-2 infection, 20% (74/376) were admitted to hospital, of whom 84% (62/74) were due to SARS-CoV-2; 10% (6/62) were admitted to intensive care and 15% (9/62) to obstetric high-care units. Risk factors for admission were non-European country of origin (odds ratio [OR] 1.73, 95% CI 1.01-2.96) and being overweight/obese (OR 1.86, 95% CI 1.51-3.20). No maternal or perinatal deaths occurred. Caesarean section after labour-onset was increased (OR 1.58, 95% CI 1.09-2.28). Hospital and intensive care admission were higher compared with the fertile age COVID-19 cohort (OR 6.75, 95% CI 5.18-8.81 and OR 2.52, 95% CI 1.11-5.77, respectively). Conclusions Non-European country of origin and being overweight/obese are risk factors for severe course of SARS-CoV-2 infection in pregnancy, risk of caesarean section and hospital and intensive care unit admission are increased. Tweetable abstract Pregnant women with SARS-CoV-2 in the Netherlands show increased hospital/ICU admission and caesarean section

Spontaneous haemoperitoneum in pregnancy: nationwide surveillance and Delphi audit system

Objective: To evaluate the incidence, diagnostic management strategies and clinical outcomes of women with spontaneous haemoperitoneum in pregnancy (SHiP) and reassess the definition of SHiP.Design: A population-based cohort study using the Netherlands Obstetric Surveillance System (NethOSS).Setting: Nationwide, the Netherlands.Population: All pregnant women between April 2016 and April 2018.Methods: This is a case study of SHiP using the monthly registry reports of NethOSS. Complete anonymised case files were obtained. A newly introduced online Delphi audit system (DAS) was used to evaluate each case, to make recommendations on improving the management of SHiP and to propose a new definition of SHiP.Main outcome measures: Incidence and outcomes, lessons learned about clinical management and the critical appraisal of the current definition of SHiP.Results: In total, 24 cases were reported. After a Delphi procedure, 14 cases were classified as SHiP. The nationwide incidence was 4.9 per 100 000 births. Endometriosis and conceiving after artificial reproductive techniques were identified as risk factors. No maternal and three perinatal deaths occurred. Based on the DAS, adequate imaging of free intra-abdominal fluid, and identifying and treating women with signs of hypovolemic shock could improve the early detection and management of SHiP. A revised definition of SHiP was proposed, excluding the need for surgical or radiological intervention.Conclusions: SHiP is a rare and easily misdiagnosed condition that is associated with high perinatal mortality. To improve care, better awareness among healthcare workers is needed. The DAS is a sufficient tool to audit maternal morbidity and mortality.Research into fetal development and medicin

Maternal and neonatal consequences of treated and untreated asymptomatic bacteriuria in pregnancy: a prospective cohort study with an embedded randomised controlled trial

Item does not contain fulltextBACKGROUND: Existing approaches for the screening and treatment of asymptomatic bacteriuria in pregnancy are based on trials that were done more than 30 years ago. In this study, we reassessed the consequences of treated and untreated asymptomatic bacteriuria in pregnancy. METHODS: In this multicentre prospective cohort study with an embedded randomised controlled trial, we screened women (aged >/=18 years) at eight hospitals and five ultrasound centres in the Netherlands with a singleton pregnancy between 16 and 22 weeks' gestation for asymptomatic bacteriuria. Screening was done with a single dipslide and two culture media. Dipslides were judged positive when the colony concentration was at least 1x10(5) colony-forming units (CFU) per mL of a single microorganism or when two different colony types were present but one had a concentration of at least 1x10(5) CFU per mL. Asymptomatic bacteriuria-positive women were eligible to participate in the randomised controlled trial comparing nitrofurantoin with placebo treatment. In this trial, participants were randomly assigned 1:1 to receive either nitrofurantoin 100 mg or identical placebo tablets, and were instructed to self-administer these tablets twice daily for 5 consecutive days. Randomisation was done by a web-based application with a computer-generated list with random block sizes of two, four, or six participants rendered by an independent data manager. 1 week after the end of treatment, they provided us with a follow-up dipslide. Women, treating physicians, and researchers all remained unaware of the bacteriuria status and treatment allocation. Women who refused to participate in the randomised controlled trial did not receive any antibiotics, but their outcomes were collected for analysis in the cohort study. We compared untreated and placebo-treated asymptomatic bacteriuria-positive women with asymptomatic bacteriuria-negative women and nitrofurantoin-treated asymptomatic bacteriuria-positive women. The primary endpoint was a composite of pyelonephritis with or without preterm birth at less than 34 weeks, analysed by intention to treat at 6 weeks post-partum. This trial is registered with the Dutch Trial Registry, number NTR3068. FINDINGS: Between Oct 11, 2011, and June 10, 2013, we enrolled 5621 women into our screening cohort, of whom 5132 were eligible for screening. After exclusions for contaminated dipslides and patients lost to follow-up, in our final cohort of 4283 women, 248 were asymptomatic bacteriuria positive, of whom 40 were randomly assigned to nitrofurantoin and 45 to placebo for the randomised controlled trial, whereas the other 163 asymptomatic bacteriuria-positive women were followed without treatment. The proportion of women with pyelonephritis, preterm birth, or both did not differ between untreated or placebo-treated asymptomatic bacteriuria-positive women and asymptomatic bacteriuria-negative women (6 [2.9%] of 208 vs 77 [1.9%] of 4035; adjusted odds ratio [OR] 1.5, 95% CI 0.6-3.5) nor between asymptomatic bacteriuria-positive women treated with nitrofurantoin versus those who were untreated or received placebo (1 [2.5%] of 40 vs 6 [2.9%] of 208; risk difference -0.4, 95% CI -3.6 to 9.4). Untreated or placebo-treated asymptomatic bacteriuria-positive women developed pyelonephritis in five [2.4%] of 208 cases, compared with 24 [0.6%] of 4035 asymptomatic bacteriuria-negative women (adjusted OR 3.9, 95% CI 1.4-11.4). INTERPRETATION: In women with an uncomplicated singleton pregnancy, asymptomatic bacteriuria is not associated with preterm birth. Asymptomatic bacteriuria showed a significant association with pyelonephritis, but the absolute risk of pyelonephritis in untreated asymptomatic bacteriuria is low. These findings question a routine screen-treat-policy for asymptomatic bacteriuria in pregnancy. FUNDING: ZonMw (the Netherlands Organisation for Health Research and Development)

Early enteral tube feeding in optimizing treatment of hyperemesis gravidarum: the Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER) randomized controlled trial

Item does not contain fulltextBackground: Hyperemesis gravidarum (HG) leads to dehydration, poor nutritional intake, and weight loss. HG has been associated with adverse pregnancy outcomes such as low birth weight. Information about the potential effectiveness of treatments for HG is limited.Objective: We hypothesized that in women with HG, early enteral tube feeding in addition to standard care improves birth weight.Design: We performed a multicenter, open-label randomized controlled trial [Maternal and Offspring outcomes after Treatment of HyperEmesis by Refeeding (MOTHER)] in 19 hospitals in the Netherlands. A total of 116 women hospitalized for HG between 5 and 20 wk of gestation were randomly allocated to enteral tube feeding for >/=7 d in addition to standard care with intravenous rehydration and antiemetic treatment or to standard care alone. Women were encouraged to continue tube feeding at home. On the basis of our power calculation, a sample size of 120 women was anticipated. Analyses were performed according to the intention-to-treat principle.Results: Between October 2014 and March 2016 we randomly allocated 59 women to enteral tube feeding and 57 women to standard care. The mean +/- SD birth weight was 3160 +/- 770 g in the enteral tube feeding group compared with 3200 +/- 680 g in the standard care group (mean difference: -40 g, 95% CI: -230, 310 g). Secondary outcomes, including maternal weight gain, duration of hospital stay, readmission rate, nausea and vomiting symptoms, decrease in quality of life, psychological distress, prematurity, and small-for-gestational-age, also were comparable. Of the women allocated to enteral tube feeding, 28 (47%) were treated according to protocol. Enteral tube feeding was discontinued within 7 d of placement in the remaining women, primarily because of its adverse effects (34%).Conclusions: In women with HG, early enteral tube feeding does not improve birth weight or secondary outcomes. Many women discontinued tube feeding because of discomfort, suggesting that it is poorly tolerated as an early routine treatment of HG. This trial was registered at www.trialregister.nl as NTR4197