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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., Trial Registration Number: NTR6134; Pre-results., Competing Interests: Competing interests: JHD sits on advisory boards for Novo Nordisk A/S. BWM is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). BWM reports consultancy for ObsEva, Merck KGaA and Guerbet., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate if immediate catheter removal (ICR) after laparoscopic hysterectomy is associated with similar retention outcomes compared with delayed removal (DCR)., Study Design: Non-inferiority randomised controlled trial., Population: Women undergoing laparoscopic hysterectomy in six hospitals in the Netherlands., Methods: Women were randomised to ICR or DCR (between 18 and 24 hours after surgery)., Primary Outcome: The inability to void within 6 hours after catheter removal., Results: One hundred and fifty-five women were randomised to ICR (n = 74) and DCR (n = 81). The intention-to-treat and per-protocol analysis could not demonstrate the non-inferiority of ICR: ten women with ICR could not urinate spontaneously within 6 hours compared with none in the delayed group (risk difference 13.5%, 5.6-24.8, P = 0.88). However, seven of these women could void spontaneously within 9 hours without additional intervention. Regarding the secondary outcomes, eight women from the delayed group requested earlier catheter removal because of complaints (9.9%). Three women with ICR (4.1%) had a urinary tract infection postoperatively versus eight with DCR (9.9%, risk difference -5.8%, -15.1 to 3.5, P = 0.215). Women with ICR mobilised significantly earlier (5.7 hours, 0.8-23.3 versus 21.0 hours, 1.4-29.9; P ≤ 0.001)., Conclusion: The non-inferiority of ICR could not be demonstrated in terms of urinary retention 6 hours after procedure. However, 70% of the women with voiding difficulties could void spontaneously within 9 hours after laparoscopic hysterectomy. It is therefore questionable if all observed urinary retention cases were clinically relevant. As a result, the clinical advantages of ICR may still outweigh the risk of bladder retention and it should therefore be considered after uncomplicated laparoscopic hysterectomy., Tweetable Abstract: The advantages of immediate catheter removal after laparoscopic hysterectomy seem to outweigh the risk of bladder retention., (© 2018 The Authors BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Objective: To determine whether maternal allopurinol treatment during suspected fetal hypoxia would reduce the release of biomarkers associated with neonatal brain damage., Design: A randomised double-blind placebo controlled multicentre trial., Patients: We studied women in labour at term with clinical indices of fetal hypoxia, prompting immediate delivery., Setting: Delivery rooms of 11 Dutch hospitals., Intervention: When immediate delivery was foreseen based on suspected fetal hypoxia, women were allocated to receive allopurinol 500 mg intravenous (ALLO) or placebo intravenous (CONT)., Main Outcome Measures: Primary endpoint was the difference in cord S100ß, a tissue-specific biomarker for brain damage., Results: 222 women were randomised to receive allopurinol (ALLO, n=111) or placebo (CONT, n=111). Cord S100ß was not significantly different between the two groups: 44.5 pg/mL (IQR 20.2-71.4) in the ALLO group versus 54.9 pg/mL (IQR 26.8-94.7) in the CONT group (difference in median -7.69 (95% CI -24.9 to 9.52)). Post hoc subgroup analysis showed a potential treatment effect of allopurinol on the proportion of infants with a cord S100ß value above the 75th percentile in girls (ALLO n=5 (12%) vs CONT n=10 (31%); risk ratio (RR) 0.37 (95% CI 0.14 to 0.99)) but not in boys (ALLO n=18 (32%) vs CONT n=15 (25%); RR 1.4 (95% CI 0.84 to 2.3)). Also, cord neuroketal levels were significantly lower in girls treated with allopurinol as compared with placebo treated girls: 18.0 pg/mL (95% CI 12.1 to 26.9) in the ALLO group versus 32.2 pg/mL (95% CI 22.7 to 45.7) in the CONT group (geometric mean difference -16.4 (95% CI -24.6 to -1.64))., Conclusions: Maternal treatment with allopurinol during fetal hypoxia did not significantly lower neuronal damage markers in cord blood. Post hoc analysis revealed a potential beneficial treatment effect in girls., Trial Registration Number: NCT00189007, Dutch Trial Register NTR1383., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: There is little knowledge about neonatal complications in GH and PE and induction at term, we aim to assess whether they can be predicted from clinical data., Methods: We used data of the HYPITAT trial and evaluated whether adverse neonatal outcome (Apgar score < 7, pH < 7.05, NICU admission) could be predicted from clinical data. Logistic regression, ROC analysis and calibration were used to identify predictors and evaluate the predictive capacity in an antepartum and intrapartum model., Results: We included 1153 pregnancies, of whom 76 (6.6%) had adverse neonatal outcome. Parity (primipara OR 2.75), BMI (OR 1.06), proteinuria (dipstick +++ OR 2.5), uric acid (OR 1.4) and creatinine (OR 1.02) were independent antepartum predictors; In the intrapartum model, meconium stained amniotic fluid (OR 2.2), temperature (OR 1.8), duration of first stage of labour (OR 1.15), proteinuria (dipstick +++ OR 2.7), creatinine (OR 1.02) and uric acid (OR 1.5) were predictors of adverse neonatal outcome. Both models showed good discrimination (AUC 0.75 and 0.78), but calibration was limited (Hosmer-Lemeshow p = 0.41, and p = 0.20)., Conclusions: In women with GH or PE at term, it is difficult to predict neonatal complications, possibly since they are rare in the term pregnancy. However, the identified individual predictors may guide physicians to anticipate requirements for neonatal care.

Objective: Pregnancies complicated by intrauterine growth restriction (IUGR) are at increased risk for neonatal morbidity and mortality. The Dutch nationwide disproportionate intrauterine growth intervention trial at term (DIGITAT trial) showed that induction of labour and expectant monitoring were comparable with respect to composite adverse neonatal outcome and operative delivery. In this study we compare the costs of both strategies., Study Design: A cost analysis was performed alongside the DIGITAT trial, which was a randomized controlled trial in which 650 women with a singleton pregnancy with suspected IUGR beyond 36 weeks of pregnancy were allocated to induction or expectant management. Resource utilization was documented by specific items in the case report forms. Unit costs for clinical resources were calculated from the financial reports of participating hospitals. For primary care costs Dutch standardized prices were used. All costs are presented in Euros converted to the year 2009., Results: Antepartum expectant monitoring generated more costs, mainly due to longer antepartum maternal stays in hospital. During delivery and the postpartum stage, induction generated more direct medical costs, due to longer stay in the labour room and longer duration of neonatal high care/medium care admissions. From a health care perspective, both strategies generated comparable costs: on average €7106 per patient for the induction group (N=321) and €6995 for the expectant management group (N=329) with a cost difference of €111 (95%CI: €-1296 to 1641)., Conclusion: Induction of labour and expectant monitoring in IUGR at term have comparable outcomes immediately after birth in terms of obstetrical outcomes, maternal quality of life and costs. Costs are lower, however, in the expectant monitoring group before 38 weeks of gestation and costs are lower in the induction of labour group after 38 weeks of gestation. So if induction of labour is considered to pre-empt possible stillbirth in suspected IUGR, it is reasonable to delay until 38 weeks, with watchful monitoring., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Gestational hypertension (GH) and preeclampsia (PE) are major contributors to maternal and neonatal morbidity and mortality. In GH or PE, labor may be either induced or monitored expectantly. We studied maternal health-related quality of life (HR-QoL) after induction of labor versus expectant monitoring in GH or PE at term. We performed the HR-QoL study alongside a multicenter randomized controlled trial comparing induction of labor to expectant monitoring in women with GH or PE after 36 weeks., Methods: We used written questionnaires, covering background characteristics, condition-specific issues, and validated measures: the Short-Form (SF-36), European Quality of Life (EuroQoL 6D3L), Hospital Anxiety and Depression Scale (HADS), and Symptom Checklist (SCL-90). Measurements were at the following time points: baseline, 6 weeks postpartum, and 6 months postpartum. A multivariate mixed model with repeated measures was defined to assess the effect of the treatments on the physical component score (PCS) and mental component score (MCS) of the SF-36. Analysis was by intention to treat., Results: We analyzed the data of 491 randomized and 220 nonrandomized women. We did not find treatment effect on long-term HR-QoL (PCS: p = 0.09; MCS: p = 0.82). The PCS improved over time (p < 0.001) and was better in nonrandomized patients (p = 0.02)., Conclusion: Despite a clinical benefit of induction of labor, long-term HR-QoL is equal after the induction of labor and expectant management in women with GH or PE beyond 36 weeks of gestation.

Objective: To compare the effect of induction of labour with a policy of expectant monitoring for intrauterine growth restriction near term., Design: Multicentre randomised equivalence trial (the Disproportionate Intrauterine Growth Intervention Trial At Term (DIGITAT))., Setting: Eight academic and 44 non-academic hospitals in the Netherlands between November 2004 and November 2008., Participants: Pregnant women who had a singleton pregnancy beyond 36+0 weeks' gestation with suspected intrauterine growth restriction., Interventions: Induction of labour or expectant monitoring., Main Outcome Measures: The primary outcome was a composite measure of adverse neonatal outcome, defined as death before hospital discharge, five minute Apgar score of less than 7, umbilical artery pH of less than 7.05, or admission to the intensive care unit. Operative delivery (vaginal instrumental delivery or caesarean section) was a secondary outcome. Analysis was by intention to treat, with confidence intervals calculated for the differences in percentages or means., Results: 321 pregnant women were randomly allocated to induction and 329 to expectant monitoring. Induction group infants were delivered 10 days earlier (mean difference -9.9 days, 95% CI -11.3 to -8.6) and weighed 130 g less (mean difference -130 g, 95% CI -188 g to -71 g) than babies in the expectant monitoring group. A total of 17 (5.3%) infants in the induction group experienced the composite adverse neonatal outcome, compared with 20 (6.1%) in the expectant monitoring group (difference -0.8%, 95% CI -4.3% to 3.2%). Caesarean sections were performed on 45 (14.0%) mothers in the induction group and 45 (13.7%) in the expectant monitoring group (difference 0.3%, 95% CI -5.0% to 5.6%)., Conclusions: In women with suspected intrauterine growth restriction at term, we found no important differences in adverse outcomes between induction of labour and expectant monitoring. Patients who are keen on non-intervention can safely choose expectant management with intensive maternal and fetal monitoring; however, it is rational to choose induction to prevent possible neonatal morbidity and stillbirth., Trial Registration: International Standard Randomised Controlled Trial number ISRCTN10363217.

Background: Hypoxic-ischaemic encephalopathy is associated with development of cerebral palsy and cognitive disability later in life and is therefore one of the fundamental problems in perinatal medicine. The xanthine-oxidase inhibitor allopurinol reduces the formation of free radicals, thereby limiting the amount of hypoxia-reperfusion damage. In case of suspected intra-uterine hypoxia, both animal and human studies suggest that maternal administration of allopurinol immediately prior to delivery reduces hypoxic-ischaemic encephalopathy., Methods/design: The proposed trial is a randomized double blind placebo controlled multicenter study in pregnant women at term in whom the foetus is suspected of intra-uterine hypoxia.Allopurinol 500 mg IV or placebo will be administered antenatally to the pregnant woman when foetal hypoxia is suspected. Foetal distress is being diagnosed by the clinician as an abnormal or non-reassuring foetal heart rate trace, preferably accompanied by either significant ST-wave abnormalities (as detected by the STAN-monitor) or an abnormal foetal blood scalp sampling (pH < 7.20).Primary outcome measures are the amount of S100B (a marker for brain tissue damage) and the severity of oxidative stress (measured by isoprostane, neuroprostane, non protein bound iron and hypoxanthine), both measured in umbilical cord blood. Secondary outcome measures are neonatal mortality, serious composite neonatal morbidity and long-term neurological outcome. Furthermore pharmacokinetics and pharmacodynamics will be investigated.We expect an inclusion of 220 patients (110 per group) to be feasible in an inclusion period of two years. Given a suspected mean value of S100B of 1.05 ug/L (SD 0.37 ug/L) in the placebo group this trial has a power of 90% (alpha 0.05) to detect a mean value of S100B of 0.89 ug/L (SD 0.37 ug/L) in the 'allopurinol-treated' group (z-test2-sided). Analysis will be by intention to treat and it allows for one interim analysis., Discussion: In this trial we aim to answer the question whether antenatal allopurinol administration reduces hypoxic-ischaemic encephalopathy in neonates exposed to foetal hypoxia., Trial Registration Number: Clinical Trials, protocol registration system: NCT00189007.

Background: Around 80% of intrauterine growth restricted (IUGR) infants are born at term. They have an increase in perinatal mortality and morbidity including behavioral problems, minor developmental delay and spastic cerebral palsy. Management is controversial, in particular the decision whether to induce labour or await spontaneous delivery with strict fetal and maternal surveillance. We propose a randomised trial to compare effectiveness, costs and maternal quality of life for induction of labour versus expectant management in women with a suspected IUGR fetus at term., Methods/design: The proposed trial is a multi-centre randomised study in pregnant women who are suspected on clinical grounds of having an IUGR child at a gestational age between 36+0 and 41+0 weeks. After informed consent women will be randomly allocated to either induction of labour or expectant management with maternal and fetal monitoring. Randomisation will be web-based. The primary outcome measure will be a composite neonatal morbidity and mortality. Secondary outcomes will be severe maternal morbidity, maternal quality of life and costs. Moreover, we aim to assess neurodevelopmental and neurobehavioral outcome at two years as assessed by a postal enquiry (Child Behavioral Check List-CBCL and Ages and Stages Questionnaire-ASQ). Analysis will be by intention to treat. Quality of life analysis and a preference study will also be performed in the same study population. Health technology assessment with an economic analysis is part of this so called Digitat trial (Disproportionate Intrauterine Growth Intervention Trial At Term). The study aims to include 325 patients per arm., Discussion: This trial will provide evidence for which strategy is superior in terms of neonatal and maternal morbidity and mortality, costs and maternal quality of life aspects. This will be the first randomised trial for IUGR at term., Trial Registration: Dutch Trial Register and ISRCTN-Register: ISRCTN10363217.

Background: We have offered, for the first time in The Netherlands, carrier diagnostics for hemoglobinopathies (HbP) to early pregnant women. The aim of this study was to establish whether carrier analysis would be welcome by the public and feasible at the outpatient level., Method: One hundred and thirty-nine randomly selected women were informed and offered basic carrier diagnostics at the first pregnancy control., Results: Carrier diagnostics was accepted by 136 women (97.8%). The population consisted of 31% of recent immigrants and 69% of native Dutch. One carrier of HbS and one of beta-thalassemia were found, both among the group of the recent immigrants. In both cases, partners were tested excluding a couple at risk. In addition, five carriers of alpha(+)-thalassemia were diagnosed at the molecular level, one of them in the native Dutch population. Basic carrier analysis was done both at the Hospital Laboratory and at the Reference Laboratory. No discrepancies were found., Conclusions: This pilot study shows that (1) as predicted the prevalence of risk-related HbP and of alpha(+)-thalassemia is high in the immigrant population. (2) The compliance with carrier analysis in both native Dutch and immigrants is virtually total and (3) carrier diagnosis in early pregnancy and partner analysis in Hospital Laboratories is possible and is an effective tool for primary prevention of HbP in The Netherlands.

Problem: The unusual pattern of human leukocyte antigen (HLA) expression on human trophoblasts could play an important role in successful pregnancy outcome. To determine whether alterations in HLA expression are associated with pregnancy abnormalities we have investigated expression of these antigens on chorionic and extravillous cytotrophoblasts., Methods: Frozen tissue sections of placenta and fetal membranes were collected after pre-term spontaneous delivery, severe pre-eclampsia pre-term Caesarean section, normal term delivery and term Caesarean section. HLA expression was analyzed by immunohistochemistry., Results: We did not observe differences in the expression of HLA on chorionic and extravillous cytotrophoblasts in pregnancy abnormalities. However, we noted higher expression levels of HLA class Ia molecules in amnion epithelial cells in pre-term deliveries. Furthermore, in severe pre-eclampsia the number of extravillous cytotrophoblast islands were elevated when compared with pre-term deliveries., Conclusions: No alterations in expression of HLA class Ia, HLA-G and HLA class II on human trophoblasts in pregnancy abnormalities were seen.

Five case histories illustrate the issue of delayed interval deliveries. In the first two cases, the first child was born at a gestational age of 20 and 18 weeks, respectively. The first woman (40 years old) gave birth to the second child after successful prolongation of pregnancy to a gestational age of 38 weeks. In the second case (28 years old), the attempt to delay delivery failed and the second child was born at 19 weeks of gestation. The third case (32 years old), illustrates the enormous differences in neonatal course between a child born at 26 weeks of gestation, who had to be treated at length for respiratory distress syndrome, hypotension and patent ductus arteriosus, and his twin brother born two weeks later and who recovered more quickly. The fourth case (24 years old) describes delayed delivery to allow administration of antenatal glucocorticoids. The last case (32 years old) deals with a serious maternal complication of placental abruption during an attempt to delay the birth of the second twin. Early tocolytic and antibiotic therapy may delay delivery and, in combination with antenatal glucocorticoids to stimulate lung maturation, may thereby improve the condition of the second twin. The role of cervical cerclage remains controversial. There is an important publication bias in the literature due to under-reporting of the failed attempts of delayed deliveries. In multiple gestation with imminent very preterm birth, delayed delivery of the second child is a feasible management option.

We have examined the hypothesis that regional differences in 15-hydroxyprostaglandin dehydrogenase (PGDH) activities occur within the human fetal membranes. Further, we reasoned that a specific reduction in PGDH in the fetal membranes at the lower uterine segment might occur with labour, providing a potential mechanism for local generation of primary prostaglandins (PG) that could contribute to cervical ripening. Full-thickness membranes were obtained from patients at caesarean section in the presence or absence of labour. Membranes were sampled from three regions: close to the site of placental attachment, in the region of the internal cervical os, and from a 'middle' area between these two. PGDH activities (sum of PGF2 alpha to 15-keto PGF2 alpha and 13, 14-dihydro 15-keto PGF2 alpha conversion) and immunoreactivity varied appreciably between the three regions. PGDH activity was highest in chorion in the cervical region of patients not in labour, but was significantly lower in the chorion from membranes taken closest to the internal os of patients in labour. Loss of PGDH activity was not attributable to a diminution in the number of trophoblast cells in this area. We conclude that regional loss of PGDH in the fetal membranes (chorion) at the lower uterine segment occurs with labour. Reduced PG catabolism could facilitate local generation of bioactive PG at this site for cervical effacement.

There is evidence that intrauterine infection, which stimulates PG synthesis may play a role in the pathogenesis of some preterm labor. Local tissue concentrations of PGs are controlled not only by the rate of synthesis, but also by catabolism, which is regulated by 15-hydroxyprostaglandin dehydrogenase (PGDH). We hypothesized that a decrease of PGDH activity could contribute to an increase in PG output at the time of preterm labor (PTL) especially in association with infection. We measured PGDH activity with a zero order kinetic enzymatic assay, PGDH messenger ribonucleic acid by in situ hybridization and PGDH distribution and localization with immunohistochemistry in human placenta and fetal membranes from women at term before (n = 10) or after (n = 16) labor compared to preterm labor at less than 36 weeks without (n = 16) and with (n = 11) chorioamnionitis. PGDH activity in chorion was significantly lower in PTL than at term and was further reduced when PTL was associated with inflammation. Immunoreactive PGDH and PGDH messenger ribonucleic acid localized predominantly to chorionic trophoblasts at term and were reduced in PTL women with or without infection. These effects were not observed in the placenta. Loss of PGDH with infection was associated with infiltration of chorion by polymorphonuclear leukocytes, resulting in a compromised structural integrity, although the amniotic epithelium was generally intact. We conclude that a reduction in PGDH in the human fetal membranes may occur in some cases of preterm labor and may contribute to an increase in net PG accumulation and drive to myometrial contractility.

Previously we reported that the proportion of trophoblast cells that were immunopositive for 15-OH prostaglandin dehydrogenase (PGDH) in the chorionic membranes was reduced in women in preterm labour without infection, compared with women at term, but was not altered in preterm labour patients with an underlying infective process. Subsequently, we found that PGDH activity and PGDH mRNA were significantly lower in membranes of this latter group of patients than in women at preterm labour without infection or at term. To resolve this issue we used immunohistochemistry to examine the distribution and frequency of immunoreactive (ir)-PGDH positive cells in full-thickness fetal membranes in patients at preterm labour in the presence or absence of infection. Trophoblast and decidual stromal cells were identified using antibodies against cytokeratin and vimentin, respectively. There was considerable variation in the number of chorionic trophoblast cells that were positive for ir-PGDH, but in some patients there was little or no ir-PGDH staining, and this was associated with loss of trophoblast cells from the tissue. The mean intensity and number of ir-PGDH positive cells was significantly lower in membranes from patients in preterm labour with infection than in idiopathic preterm labour at which the diagnosis of infection was not made. We conclude that in the setting of preterm labour with infection there may be loss of trophoblast cells from membranes, with corresponding reduction in the number of ir-PGDH positive cells. Loss of PGDH activity removes the initial step in activating primary prostaglandins, which are then able to pass unmetabolized to the decidua and myometrium, and contribute to the stimulus to preterm birth.