Objective: To compare guidelines from eight high-income countries on prevention and management of postpartum haemorrhage (PPH), with a particular focus on severe PPH.Design: Comparative study... Show moreObjective: To compare guidelines from eight high-income countries on prevention and management of postpartum haemorrhage (PPH), with a particular focus on severe PPH.Design: Comparative study.Setting: High-resource countries.Population: Women with PPH.Methods: Systematic comparison of guidance on PPH from eight high-income countries.Main outcome measures: Definition of PPH, prophylactic management, measurement of blood loss, initial PPH-management, second-line uterotonics, non-pharmacological management, resuscitation/transfusion management, organisation of care, quality/methodological rigour.Conclusions: Our study highlights areas where strong evidence is lacking. There is need for a universal definition of (severe) PPH. Consensus is required on how and when to quantify blood loss to identify PPH promptly. Future research may focus on timing and sequence of second-line uterotonics and non-pharmacological interventions and how these impact maternal outcome. Until more data are available, different transfusion strategies will be applied. The use of clear transfusion-protocols are nonetheless recommended to reduce delays in initiation. There is a need for a collaborative effort to develop standardised, evidence-based PPH guidelines.Results: Definitions of (severe) PPH varied as to the applied cut-off of blood loss and incorporation of clinical parameters. Dose and mode of administration of prophylactic uterotonics and methods of blood loss measurement were heterogeneous. Recommendations on second-line uterotonics differed as to type and dose. Obstetric management diverged particularly regarding procedures for uterine atony. Recommendations on transfusion approaches varied with different thresholds for blood transfusion and supplementation of haemostatic agents. Quality of guidelines varied considerably. Show less
Heemelaar, J.C.; Heemelaar, S.; Hertel, S.N.; Jukema, J.W.; Sueters, M.; Louwerens, M.; Antoni, M.L. 2023
Background: Childhood cancer survivors (CCS) are at increased risk of cardiomyopathy during pregnancy if they have prior cardiotoxic exposure. Currently, there is no consensus on the necessity,... Show moreBackground: Childhood cancer survivors (CCS) are at increased risk of cardiomyopathy during pregnancy if they have prior cardiotoxic exposure. Currently, there is no consensus on the necessity, timing and modality of cardiac monitoring during and after pregnancy. Therefore, we examined cardiac function using contemporary echocardiographic parameters during pregnancy in CCS with cardiotoxic treatment exposure, and we observed obstetric outcomes in CCS, including in women without previous cardiotoxic treatment exposure. Method: A single-center retrospective cohort study was conducted among 39 women enrolled in our institution's cancer survivorship outpatient clinic. Information on potential cardiotoxic exposure in childhood, cancer diagnosis and outcomes of all pregnancies were collected through interviews and review of health records. Echocardiographic exams before and during pregnancy were retrospectively analyzed for left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) if available. The primary outcomes were (i) left ventricular dysfunction (LVD) during pregnancy, defined as LVEF < 50% or a decline of >= 10% in LVEF below normal (< 54%), and (ii) symptomatic heart failure (HF). Rate of obstetric and fetal complications was compared to the general population through the national perinatal registry (PERINED). Results: All pregnancies (91) of 39 women were included in this study. The most common malignancy was leukemia (N = 17, 43.6%). In 22 patients, echocardiograms were retrospectively analyzed. LVEFbaseline was 55.4 +/- 1.2% and pre-existing subnormal LVEF was common (7/22, 31.8/%). The minimum value of LVEF during pregnancy was 3.8% lower than baseline (p = 0.002). LVD occurred in 9/22 (40.9%) patients and HF was not observed. When GLS was normal at baseline (< -18.0%; N = 12), none of the women developed LVD. Nine of out ten women with abnormal GLS at baseline developed LVD later in pregnancy. In our cohort, the obstetric outcomes seemed comparable with the general population unless patients underwent abdominal irradiation (N = 5), where high rates of preterm birth (only 5/18 born at term) and miscarriage (6/18 pregnancies) were observed. Conclusion: Our study suggests that women with prior cardiotoxic treatment have a low risk of LVD during pregnancy if GLS at baseline was normal. Pregnancy outcomes are similar to the healthy population except when patients underwent abdominal irradiation. Show less
Wind, M.; Akker-van Marle, M.E. van den; Ballieux, B.E.P.B.; Cobbaert, C.M.; Rabelink, T.J.; Lith, J.M.M. van; ... ; Sueters, M. 2022
Background: This study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia. Methods: This was a... Show moreBackground: This study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia. Methods: This was a prospective cohort study performed in a tertiary referral centre. Based on the combination of PCr (< 30) and sFlt-1/PlGF (& LE;38) results, four groups were described: a double negative result, group A-/-; a negative PCr and positive sFlt-1/PlGF, group B-/+; a positive PCr and negative sFlt-1/PlGF, group C+/-; and a double positive result, group D+/+. The primary outcome was the proportion of false negatives of the combined tests in comparison with PCr alone in the first week after baseline. Secondary, a cost analysis comparing the costs and savings of adding the sFlt-1/PlGF ratio was performed for different follow-up scenarios. Results: A total of 199 women were included. Pre-eclampsia in the first week was observed in 2 women (2%) in group A-/-, 12 (26%) in group B-/+, 4 (27%) in group C+/-, and 12 (92%) in group D+/+. The proportion of false negatives of 8.2% [95% CI 4.9-13.3] with the PCr alone was significantly reduced to 1.6% [0.4-5.7] by adding a negative sFlt-1/PlGF ratio. Furthermore, the addition of the sFlt-1/PlGF ratio to the spot urine PCr, with telemonitoring of women at risk, could result in a reduction of 41% admissions and 36% outpatient visits, leading to a cost reduction of euro46,- per patient. Conclusions: Implementation of the sFlt-1/PlGF ratio in addition to the spot urine PCr, may lead to improved selection of women at low risk and a reduction of hospital care for women with suspected pre-eclampsia. Show less
Wind, M.; Akker-van Marle, M.E. van den; Ballieux, B.E.P.B.; Cobbaert, C.M.; Rabelink, T.J.; Lith, J.M.M. van; ... ; Sueters, M. 2022
BackgroundThis study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia.MethodsThis was a... Show moreBackgroundThis study investigated the clinical value of adding the sFlt-1/PlGF ratio to the spot urine protein/creatinine ratio (PCr) in women with suspected pre-eclampsia.MethodsThis was a prospective cohort study performed in a tertiary referral centre. Based on the combination of PCr (< 30) and sFlt-1/PlGF (≤38) results, four groups were described: a double negative result, group A−/−; a negative PCr and positive sFlt-1/PlGF, group B−/+; a positive PCr and negative sFlt-1/PlGF, group C+/−; and a double positive result, group D+/+. The primary outcome was the proportion of false negatives of the combined tests in comparison with PCr alone in the first week after baseline. Secondary, a cost analysis comparing the costs and savings of adding the sFlt-1/PlGF ratio was performed for different follow-up scenarios.ResultsA total of 199 women were included. Pre-eclampsia in the first week was observed in 2 women (2%) in group A−/−, 12 (26%) in group B−/+, 4 (27%) in group C+/−, and 12 (92%) in group D+/+. The proportion of false negatives of 8.2% [95% CI 4.9–13.3] with the PCr alone was significantly reduced to 1.6% [0.4–5.7] by adding a negative sFlt-1/PlGF ratio. Furthermore, the addition of the sFlt-1/PlGF ratio to the spot urine PCr, with telemonitoring of women at risk, could result in a reduction of 41% admissions and 36% outpatient visits, leading to a cost reduction of €46,- per patient.ConclusionsImplementation of the sFlt-1/PlGF ratio in addition to the spot urine PCr, may lead to improved selection of women at low risk and a reduction of hospital care for women with suspected pre-eclampsia. Show less
Landman, A.J.E.M.C.; Boer, M.A. de; Visser, L.; Nijman, T.A.J.; Hemels, M.A.C.; Naaktgeboren, C.N.; ... ; Oudijk, M.A. 2022
Background: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our... Show moreBackground: Preterm birth is the leading cause of neonatal morbidity and mortality. The recurrence rate of spontaneous preterm birth is high, and additional preventive measures are required. Our objective was to assess the effectiveness of low-dose aspirin compared to placebo in the prevention of preterm birth in women with a previous spontaneous preterm birth. Methods and findings: We performed a parallel multicentre, randomised, double-blinded, placebo-controlled trial (the APRIL study). The study was performed in 8 tertiary and 26 secondary care hospitals in the Netherlands. We included women with a singleton pregnancy and a history of spontaneous preterm birth of a singleton between 22 and 37 weeks. Participants were randomly assigned to aspirin 80 mg daily or placebo initiated between 8 and 16 weeks of gestation and continued until 36 weeks or delivery. Randomisation was computer generated, with allocation concealment by using sequentially numbered medication containers. Participants, their healthcare providers, and researchers were blinded for treatment allocation. The primary outcome was preterm birth <37 weeks of gestation. Secondary outcomes included a composite of poor neonatal outcome (bronchopulmonary dysplasia, periventricular leukomalacia > grade 1, intraventricular hemorrhage > grade 2, necrotising enterocolitis > stage 1, retinopathy of prematurity, culture proven sepsis, or perinatal death). Analyses were performed by intention to treat.From May 31, 2016 to June 13, 2019, 406 women were randomised to aspirin (n = 204) or placebo (n = 202). A total of 387 women (81.1% of white ethnic origin, mean age 32.5 +/- SD 3.8) were included in the final analysis: 194 women were allocated to aspirin and 193 to placebo. Preterm birth <37 weeks occurred in 41 (21.2%) women in the aspirin group and 49 (25.4%) in the placebo group (relative risk (RR) 0.83, 95% confidence interval (CI) 0.58 to 1.20, p= 0.32). In women with >80% medication adherence, preterm birth occurred in 24 (19.2%) versus 30 (24.8%) women (RR 0.77, 95% CI 0.48 to 1.25, p = 0.29). The rate of the composite of poor neonatal outcome was 4.6% (n = 9) versus 2.6% (n = 5) (RR 1.79, 95% CI 0.61 to 5.25, p = 0.29). Among all randomised women, serious adverse events occurred in 11 out of 204 (5.4%) women allocated to aspirin and 11 out of 202 (5.4%) women allocated to placebo. None of these serious adverse events was considered to be associated with treatment allocation. The main study limitation is the underpowered sample size due to the lower than expected preterm birth rates. Conclusions: In this study, we observed that low-dose aspirin did not significantly reduce the preterm birth rate in women with a previous spontaneous preterm birth. However, a modest reduction of preterm birth with aspirin cannot be ruled out. Further research is required to determine a possible beneficial effect of low-dose aspirin for women with a previous spontaneous preterm birth. Show less
Rennert, K.N.; Breuking, S.H.; Schuit, E.; Bekker, M.N.; Woiski, M.; Boer, M.A. de; ... ; Hermans, F.J.R. 2021
Objective To assess the association between preterm birth and cervical length after arrested preterm labor in high-risk pregnant women.Methods In this post-hoc analysis of a randomized clinical... Show moreObjective To assess the association between preterm birth and cervical length after arrested preterm labor in high-risk pregnant women.Methods In this post-hoc analysis of a randomized clinical trial, transvaginal cervical length was measured in women whose contractions had ceased 48 h after admission for threatened preterm labor. At admission, women were defined as having a high risk of preterm birth based on a cervical length of < 15 mm or a cervical length of 15-30 mm with a positive fetal fibronectin test. Logistic regression analysis was used to investigate the association of cervical length measured at least 48 h after admission and of the change in cervical length between admission and at least 48 h later, with preterm birth before 34 weeks' gestation and delivery within 7 days after admission.Results A total of 164 women were included in the analysis. Women whose cervical length increased between admission for threatened preterm labor and 48 h later (32%; n=53) were found to have a lower risk of preterm birth before 34weeks compared with women whose cervical length did not change (adjusted odds ratio (aOR), 0.24 (95% CI, 0.09-0.69)). The risk in women with a decrease in cervical length between the two time points was not different from that in women with no change in cervical length (aOR, 1.45 (95% CI, 0.62-3.41)). Moreover, greater absolute cervical length after 48 h was associated with a lower risk of preterm birth before 34 weeks (aOR, 0.90 (95% CI, 0.84-0.96)) and delivery within 7 days after admission (aOR, 0.91 (95% CI, 0.82-1.02)). Sensitivity analysis in women randomized to receive no intervention showed comparable results.Conclusion Our study suggests that the risk of preterm birth before 34weeks is lower in women whose cervical length increases between admission for threatened preterm labor and at least 48 h later when contractions had ceased compared with women in whom cervical length does not change or decreases. (C) 2021 The Authors. Show less
Wind, M.; Hendriks, M.; Brussel, B.T.J. van; Eikenboom, J.; Allaart, C.F.; Lamb, H.J.; ... ; Teng, Y.K.O. 2021
Objectives SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk... Show moreObjectives SLE and/or antiphospholipid syndrome (SLE/APS) are complex and rare systemic autoimmune diseases that predominantly affect women of childbearing age. Women with SLE/APS are at high risk of developing complications during pregnancy. Therefore, clinical practice guidelines recommend that patients with SLE/APS should receive multidisciplinary counselling before getting pregnant. We investigated the clinical effectiveness of implementing a multidisciplinary clinical pathway including prepregnancy counselling of patients with SLE/APS. Methods A clinical pathway with specific evaluation and prepregnancy counselling for patients with SLE/APS was developed and implemented in a tertiary, academic hospital setting. Patients were prospectively managed within the clinical pathway from 2014 onwards and compared with a retrospective cohort of patients that was not managed in a clinical pathway. Primary outcome was a combined outcome of disease flares for SLE and thromboembolic events for APS. Secondary outcomes were maternal and fetal pregnancy complications. Results Seventy-eight patients with 112 pregnancies were included in this study. The primary combined outcome was significantly lower in the pathway cohort (adjusted OR (aOR) 0.20 (95% CI 0.06 to 0.75)) which was predominantly determined by a fivefold risk reduction of SLE flares (aOR 0.22 (95% CI 0.04 to 1.09)). Maternal and fetal pregnancy complications were not different between the cohorts (respectively, aOR 0.91 (95% CI 0.38 to 2.17) and aOR 1.26 (95% CI 0.55 to 2.88)). Conclusions The outcomes of this study suggest that patients with SLE/APS with a pregnancy wish benefit from a multidisciplinary clinical pathway including prepregnancy counselling. Show less
Jansen, S.; Lopriore, E.; Naaktgeboren, C.; Sueters, M.; Limpens, J.; Leeuwen, E. van; Bekker, V. 2020
Background: While epidural analgesia (EA) is associated with maternal fever during labor, the impact on the risk for maternal and/or neonatal sepsis is unknown. Objectives: The aim of this... Show moreBackground: While epidural analgesia (EA) is associated with maternal fever during labor, the impact on the risk for maternal and/or neonatal sepsis is unknown. Objectives: The aim of this systematic review was to investigate the effect of epidural-related intrapartum fever on maternal and neonatal outcomes. Methods: OVID MEDLINE, OVID Embase, the Cochrane Library, Cochrane Controlled Register of Trials, and clinical trial registries were searched for randomized controlled trials (RCT) and observational cohort studies from inception to November 2018. A total of 761 studies were identified with 100 eligible for full-text review. Only articles investigating the relationship between EA and maternal fever during labor were eligible for inclusion. Study quality was assessed using the Cochrane's Risk of Bias tool and National Institute of Health Quality Assessment Tool. Two meta-analyses - one each for the RCT and observational cohort groups - were performed using the random-effects model of Mantel-Haenszel to produce summary risk ratios (RR) with 95% CI. Results: Twelve RCTs and 16 observational cohort studies involving 579,157 parturients were included. RRs for maternal fever for the RCT and cohort analyses were 3.54 (95% CI 2.61-4.81) and 5.60 (95% CI 4.50-6.97), respectively. Meta-analyses of RR for maternal infection in both groups were infeasible given few occurrences. Meta-analysis of data from observational studies showed an increased risk for maternal antibiotic treatment in the epidural group (RR 2.60; 95% CI 1.31-5.17). For both analyses, neonates born to women with an epidural were not evaluated more often for suspected sepsis. Neither analysis reported an increased rate of neonatal bacteremia or neonatal antibiotic treatment after EA, although data precluded conclusiveness. Conclusion: EA increases the risk of intrapartum fever and maternal antibiotic treatment. However, a definite conclusion on whether EA increases the risk for a proven maternal and/or neonatal bacteremia cannot be drawn due to the low quality of data. Further research on whether epidural-related intrapartum fever is of infectious origin or not is therefore needed. Show less
This randomized clinical trial examines whether sildenafil reduces the risk of perinatal mortality or morbidity vs placebo in children of pregnant women with severe early onset fetal growth... Show moreThis randomized clinical trial examines whether sildenafil reduces the risk of perinatal mortality or morbidity vs placebo in children of pregnant women with severe early onset fetal growth restriction.Question Does sildenafil reduce the risk of perinatal mortality or morbidity in children of pregnant women with severe early onset fetal growth restriction? Findings In this randomized clinical trial including 216 pregnant women, perinatal mortality or major morbidity was not statistically different and occurred in the offspring of 60.2% of participants allocated to sildenafil vs 54.2% of those allocated to placebo. Pulmonary hypertension occurred in 18.8% of neonates in the sildenafil group compared with 5.1% of neonates in the placebo group, which was statistically significantly different. Meaning These findings suggest that treatment of severe early onset fetal growth restriction by maternal sildenafil did not reduce the risk of perinatal mortality or major neonatal morbidity, but increased neonatal pulmonary hypertension was observed.Importance Severe early onset fetal growth restriction caused by placental dysfunction leads to high rates of perinatal mortality and neonatal morbidity. The phosphodiesterase 5 inhibitor, sildenafil, inhibits cyclic guanosine monophosphate hydrolysis, thereby activating the effects of nitric oxide, and might improve uteroplacental function and subsequent perinatal outcomes. Objective To determine whether sildenafil reduces perinatal mortality or major morbidity. Design, Setting, and Participants This placebo-controlled randomized clinical trial was conducted at 10 tertiary referral centers and 1 general hospital in the Netherlands from January 20, 2015, to July 16, 2018. Participants included pregnant women between 20 and 30 weeks of gestation with severe fetal growth restriction, defined as fetal abdominal circumference below the third percentile or estimated fetal weight below the fifth percentile combined with Dopplers measurements outside reference ranges or a maternal hypertensive disorder. The trial was stopped early owing to safety concerns on July 19, 2018, whereas benefit on the primary outcome was unlikely. Data were analyzed from January 20, 2015, to January 18, 2019. The prespecified primary analysis was an intention-to-treat analysis including all randomized participants. Interventions Participants were randomized to sildenafil, 25 mg, 3 times a day vs placebo. Main Outcomes and Measures The primary outcome was a composite of perinatal mortality or major neonatal morbidity until hospital discharge. Results Out of 360 planned participants, a total of 216 pregnant women were included, with 108 women randomized to sildenafil (median gestational age at randomization, 24 weeks 5 days [interquartile range, 23 weeks 3 days to 25 weeks 5 days]; mean [SD] estimated fetal weight, 458 [160] g) and 108 women randomized to placebo (median gestational age, 25 weeks 0 days [interquartile range, 22 weeks 5 days to 26 weeks 3 days]; mean [SD] estimated fetal weight, 464 [186] g). In July 2018, the trial was halted owing to concerns that sildenafil may cause neonatal pulmonary hypertension, whereas benefit on the primary outcome was unlikely. The primary outcome, perinatal mortality or major neonatal morbidity, occurred in the offspring of 65 participants (60.2%) allocated to sildenafil vs 58 participants (54.2%) allocated to placebo (relative risk, 1.11; 95% CI, 0.88-1.40; P = .38). Pulmonary hypertension, a predefined outcome important for monitoring safety, occurred in 16 neonates (18.8%) in the sildenafil group vs 4 neonates (5.1%) in the placebo group (relative risk, 3.67; 95% CI, 1.28-10.51; P = .008). Conclusions and Relevance These findings suggest that antenatal maternal sildenafil administration for severe early onset fetal growth restriction did not reduce the risk of perinatal mortality or major neonatal morbidity. The results suggest that sildenafil may increase the risk of neonatal pulmonary hypertension. Show less
Petrus, A.H.J.; Jongert, B.L.; Kies, P.; Sueters, M.; Jongbloed, M.R.M.; Vliegen, H.W.; ... ; Akker, T. van den 2020
Objective: Maternal heart disease (HD) complicates 1-4 % of pregnancies and is associated with adverse maternal and fetal outcomes. Although vaginal birth is generally recommended in the guidelines... Show moreObjective: Maternal heart disease (HD) complicates 1-4 % of pregnancies and is associated with adverse maternal and fetal outcomes. Although vaginal birth is generally recommended in the guidelines, cesarean section (CS) rates in women with HD are often high. Aim of the present study was to evaluate mode of birth and pregnancy outcomes in women with HD in a tertiary care hospital in the Netherlands.Study design: The study population consisted of 128 consecutive pregnancies in 99 women with HD, managed by a pregnancy heart team between 2012-2017 and ending in births after 24 weeks' gestation. Pregnancy risk was assessed per modified World Health Organization class. Mode of birth (planned and performed) and maternal and fetal complications (cardiovascular events, postpartum hemorrhage, prematurity, small for gestational age and death) were assessed for each pregnancy.Results: Pregnancy risk was classified as modified World Health Organization class I in 23 %, class II in 50 %, class III in 21 % and class IV in 6% of pregnancies. Planned mode of birth was vaginal in 114 pregnancies (89 %) and CS in 14 (11 %; nine for obstetric and five for cardiac indication). An unplanned CS was performed in 18 pregnancies (16 %; 16 for obstetric and two for cardiac indications). Overall mode of birth was vaginal in 75 % and CS in 25 %. Twelve cardiovascular events occurred in eight pregnancies (6 %), postpartum hemorrhage in nine (7 %) and small for gestational age in 14 (11 %). No maternal or fetal deaths occurred.Conclusions: Findings of this study indicate that - given that pregnancies are managed and mode of birth is meticulously planned by a multidisciplinary pregnancy heart team - vaginal birth is a suitable option for women with HD. (C) 2020 Elsevier B.V. All rights reserved. Show less
Wit, L. de; Rademaker, D.; Voormolen, D.N.; Akerboom, B.M.C.; Kiewiet-Kemper, R.M.; Soeters, M.R.; ... ; Rijn, B.B. van 2019
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... Show moreIntroduction 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. Show less
Nijman, T.A.J.; Baaren, G.J. van; Vliet, E.O.G. van; Kok, M.; Gyselaers, W.; Porath, M.M.; ... ; Oudijk, M.A. 2019
Objective To assess the cost-effectiveness of treatment with nifedipine compared with atosiban in women with threatened preterm birth. Design An economic analysis alongside a randomised clinical... Show moreObjective To assess the cost-effectiveness of treatment with nifedipine compared with atosiban in women with threatened preterm birth. Design An economic analysis alongside a randomised clinical trial (the APOSTEL III study). Setting Obstetric departments of 12 tertiary hospitals and seven secondary hospitals in the Netherlands and Belgium. Population Women with threatened preterm birth between 25 and 34 weeks of gestation, randomised for tocolysis with either nifedipine or atosiban. Methods We performed an economic analysis from a societal perspective. We estimated costs from randomisation until discharge. Analyses for singleton and multiple pregnancies were performed separately. The robustness of our findings was evaluated in sensitivity analyses. Main outcome measures Mean costs and differences were calculated per woman treated with nifedipine or atosiban. Health outcomes were expressed as the prevalence of a composite of adverse perinatal outcomes. Results Mean costs per patients were significantly lower in the nifedipine group [singleton pregnancies: euro34,897 versus euro43,376, mean difference (MD) -euro8479 [95% confidence interval (CI) -euro14,327 to -euro2016)]; multiple pregnancies: euro90,248 versus euro102,292, MD -euro12,044 (95% CI -euro21,607 to euro -1671). There was a non-significantly higher death rate in the nifedipine group. The difference in costs was mainly driven by a lower neonatal intensive care unit admission (NICU) rate in the nifedipine group. Conclusion Treatment with nifedipine in women with threatened preterm birth results in lower costs when compared with treatment with atosiban. However, the safety of nifedipine warrants further investigation. Tweetable abstract In women with threatened preterm birth, tocolysis using nifedipine results in lower costs when compared with atosiban. Show less
Teng, Y.K.O.; Bredewold, E.O.W.; Rabelink, T.J.; Huizinga, T.W.J.; Eikenboom, H.C.J.; Limper, M.; ... ; Sueters, M. 2018
The incidence of spontaneous twinning in the Netherlands is approximately 1%, of which are 70% dizygotic and 30% monozygotic twins. Dizygotic twinning occurs after fertilization of two eggs (non... Show moreThe incidence of spontaneous twinning in the Netherlands is approximately 1%, of which are 70% dizygotic and 30% monozygotic twins. Dizygotic twinning occurs after fertilization of two eggs (non-identical twins). Dizygotic twins almost invariably have two separate placentas (dichorionic) and two separate amnions (diamniotic). Monozygotic twinning occurs after fertilization of one egg that splits into two embryos (identical twins). In 70-75%, these twins share one common placenta (monochorionic) and have two separate amnions (diamniotic). The incidence of monochorionic twinning is 1 in every 400 pregnancies. During gestation, monochorionic twins compared to dichorionic twins are at increased risk of several complications, such as intrauterine fetal death, intrauterine growth restriction, discordant fetal anomalies, and, most severe, twin-to-twin transfusion syndrome (TTTS). TTTS complicates 10 to 15% of monochorionic twin pregnancies. With an annual birth rate of 188 000, between 47 and 67 cases of TTTS are expected in the Netherlands per year. In virtually all monochorionic twin placentas, vascular connections between the two twins are present, whereas these almost never occur in dichorionic placentas. Thus, intertwin transfusion is the norm in monochorionic pregnancies and a normal physiological phenomenon as long as blood flow between the fetuses is balanced. TTTS develops when blood flow gets unbalanced. Hypovolemia, oliguria and oligohydramnios develop in the donor twin. The recipient twin suffers from hypervolemia, polyuria and polyhydramnios, which may lead to circulatory volume overload, cardiac failure and, eventually, hydrops. TTTS is diagnosed sonographically by the detection of an oligo/polyhydramnios sequence. Quintero et al. developed a staging system for TTTS based on the oligo/polyhydramnios sequence (Stage 1), and also included absent bladder filling in the donor (Stage 2), pathological Doppler findings in donor or recipient (Stage 3), hydrops (Stage 4), and eventually fetal death (Stage 5). TTTS usually emerges in the second trimester of pregnancy, although first-trimester and early third-trimester cases have been described. Due to massive polyhydramnios, TTTS may lead to maternal discomfort and present with clinical symptoms, such as premature rupture of membranes or contractions. This may result in (extremely) premature birth and high mortality and morbidity rates. If left untreated, mortality rates exceed 80% and survivors are handicapped in 10 to 50%. Since the 1980__s, several forms of treatment have been available, of which fetoscopic laser coagulation of the vascular anastomoses on the monochorionic placenta has been proven to be superior compared to serial amniodrainage in terms of perinatal survival and absence of neurological disease in survivors. Moreover, treatment in the early Quintero stages resulted in better outcome. Since 2000, monochorionic twin pregnancies complicated by TTTS have been treated with fetoscopic laser coagulation of placental anastomoses in the Leiden University Medical Center (LUMC), which is a tertiary medical center in the Netherlands and serves as the national referral center for fetal therapy. Since then, several studies on monochorionic twins with and without TTTS were started. TULIPS, Twins and ULtrasound In Pregnancy Studies, was one of these projects. Between July 2003 and July 2005, 58 monochorionic twins with and without TTTS had an ultrasound examination performed at least biweekly. The aims of our study were to evaluate serial ultrasound examinations combined with patient instructions in achieving timely detection of TTTS in a cohort of monochorionic diamniotic twin pregnancies, and to study the effects of TTTS and fetoscopic laser coagulation of the placental anastomoses on fetal hemodynamics of monochorionic twins. Chapter 1 contains a review of the literature on ultrasound examination in monochorionic twins and twin-to-twin transfusion syndrome during gestation. In part 1 of this chapter, the importance of first-trimester ultrasound examination to diagnose chorionicity is discussed in detail. To assess chorionicity, the intertwin membrane should be imaged at its insertion site to the placental mass. A lambda (_)-, __Y__- or twin peak sign indicates dichorionicity, whereas a __T__ sign must be visualized in monochorionic diamniotic twin pregnancies. The observation of two separate placentas alone is not sufficient to diagnose dichorionicity. A single placental mass does not prove monochorionicity. Thickness of the intertwin membrane and fetal gender are not considered reliable indicators of chorionicity. The complications of monochorionic twinning, such as single intrauterine fetal death, intrauterine growth restriction, discordant fetal anomalies, and TTTS, are outlined in short. Part 2 is focused on ultrasound and TTTS. Current insights in the pathophysiology, diagnosis, treatment and outcome are reviewed. Sonographic markers early in pregnancy that could forecast the development of TTTS are described, such as increased nuchal translucency, abnormal Doppler studies of the ductus venosus, folding of the intertwin membrane, and the sonographic absence of arterioarterial anastomoses. Furthermore, an overview of the most important Doppler studies in TTTS is supplied. Pathological Doppler studies in the donor are consistent with decreased venous return due to hypovolemia and increased cardiac afterload due to increased placental resistance. Pathological Doppler studies in the recipient are caused by congestive heart failure due to hypervolemia. Fetoscopic laser ablation of the placental anastomoses in TTTS affects the fetal and fetoplacental circulation in various ways, such as transient volume overload in donors and improvement of cardiac function in recipients, resulting in changed Doppler studies after therapy. Finally, the fetal heart in TTTS is discussed. Particularly recipients may be affected by prenatal cardiac failure. Donors show no or little cardiac pathology. The exact cause of cardiac dysfunction is unclear, however, primary cardiac pathology, increased preload, or increased afterload are suggested to play a role. In conclusion, most twin pregnancies have an uneventful course, although twins are at greater risk than singletons, particularly those that are monochorionic. TTTS is the most severe complication during gestation. TTTS is diagnosed sonographically, and that is why ultrasound examination is an essential tool in prenatal care for monochorionic twins. In chapter 2 we undertook a study to report the occurrence of bipartite monochorionic twin placentas. Examination of 109 monochorionic placentas delivered at our institution between June 2002 and June 2005 was performed. Placental characteristics on prenatal ultrasound were studied, including single or double appearance and type of intertwin membrane-placental junction (__T__ sign or lambda sign). Monochorionicity was confirmed by postnatal histologic confirmation (diamniotic intertwin membrane without chorionic tissue within the dividing septum). Bipartition was diagnosed when two separate placental masses attached by membranes were identified. Of the 109 monochorionic placentas, three were composed of two separate placental masses. Prenatal ultrasound examination showed two separate placental masses in each case. Monochorionicity was suspected on prenatal ultrasound due to the presence of __T__ sign in two cases and TTTS in another case. Microscopic examination of the dividing septum was consistent with monochorionicity in each case. Vascular anastomoses were present in two of the three placentas, and led in both cases to the development of TTTS. We concluded that two separate placental masses in twin pregnancies are not per se dichorionic and may occur in almost 3% of monochorionic placentas. Second-trimester twin-to-twin transfusion is well known, but first-trimester cases have been rarely described. In chapter 3 we present the case of a monochorionic twin at 11+0 weeks of gestation with single increased nuchal translucency and normal karyotypes. At 12+5 weeks of gestation, double intrauterine death was diagnosed, followed by delivery of a strikingly red and white fetus. In conclusion, TTTS can be seen in various ways at different gestational ages. Besides the well-known risks of severe second-trimester TTTS, we believe that TTTS can cause fetal death or neurological damage, even in the first trimester of pregnancy. The only presenting symptom may be a single increased nuchal translucency. In chapter 4 we assessed the value of serial ultrasound examinations together with patient instructions to report the onset of symptoms in achieving timely detection of TTTS in a cohort of monochorionic diamniotic twin pregnancies, and to evaluate sonographic TTTS predictors. Timely detection of TTTS was defined as diagnosis before severe complications of TTTS occurred, such as preterm prelabor rupture of membranes, very preterm delivery (24-32 weeks of pregnancy), fetal hydrops, or intrauterine fetal death. During a two-year period, a prospective series of 23 monochorionic twin pregnancies was monitored from the first trimester until delivery. At least every two weeks we performed ultrasound and Doppler measurements (nuchal translucency thickness, presence of membrane folding, estimated fetal weight, deepest vertical pocket, bladder filling, and Doppler waveforms of the umbilical artery, ductus venosus, and umbilical vein). Measurements of TTTS cases were compared to those of non-TTTS cases matched for gestational age. Furthermore, patients were informed about the symptoms caused by TTTS, and instructed to consult us immediately in case of rapidly increasing abdominal size or premature contractions. In all four TTTS cases, the diagnosis was timely. At the time of diagnosis, one case was at Quintero Stage 1, two at Quintero Stage 2, and one at Quintero Stage 3. Two of the TTTS cases became apparent after the patients__ feeling of rapidly increasing girth. The identification of TTTS predictors was successful with respect to one parameter: isolated polyhydramnios in one sac, without oligohydramnios in the other, preceded the ultimate diagnosis of TTTS in two of the four TTTS cases. All other ultrasound measurements of TTTS cases, prior to the diagnosis of TTTS, were within the range of measurements of non-TTTS cases. We concluded that biweekly ultrasound examinations, with special attention to amniotic fluid compartments of both fetuses, combined with detailed patient instructions to report the onset of symptoms resulted in timely diagnosis of all TTTS cases and appears to be a safe program for monitoring monochorionic twin pregnancies. In chapter 5 we investigated fetal hemodynamics in monochorionic twins with TTTS before and after fetoscopic laser therapy, focusing on the renal and cerebral blood flow. In a prospective study, we performed Doppler studies in monochorionic twin pregnancies with TTTS. The pulsatility index (PI) and end-diastolic flow (EDF) of the umbilical artery (UA) (recorded as present, absent or reversed); the PI and the peak systolic velocity of the middle cerebral artery (MCA PSV); the maximum flow velocity (V max) and flow pattern of the intrahepatic part of the umbilical vein (UV) (classified as pulsatile or non-pulsatile); the pulsatility index for veins (PIV) and A-wave of the ductus venosus (DV) (recorded as present, absent or reversed); and the PI and PSV of the renal artery (RA) were measured within 24 h before, 12 to 24 h and 4 to 10 days after laser therapy. At each examination, the presence or absence of tricuspid regurgitation (TR) and of hydropic signs (pleural effusion, ascites, pericardial effusion, or skin edema) was recorded. Hemoglobin values and reticulocyte counts were determined at birth. Long-term follow-up was assessed at the age of 2 years. In donor twins (n=34), DV PIV increased significantly 12 to 24 h after laser therapy, however returned to pre-operative values within 4 to 10 days. A significant decrease in UA PI and increase in UV V max was detected after laser treatment. Twenty percent (6/30) showed signs of TR 12 to 24 h after laser therapy, which was resolved completely after 4 to 10 days. The MCA PI and RA PI were significantly decreased 12 to 24 h after laser treatment, however returned to pre-operative values within 4 to 10 days. MCA and RA PSV values were unchanged by fetoscopic laser therapy. In recipient twins (n=32), DV PIV decreased significantly 4 to 10 days after laser therapy. The RA PI increased non-significantly after laser treatment; RA PSV values were unchanged. MCA PI and MCA PSV values increased significantly after laser therapy. After birth, mean hemoglobin values of donors (17.3 _ 4.9 g_/dL) and recipients (16.1 _ 4.2 g_/dL) were comparable (p=0.43). At the age of 2 years, neurodevelopmental impairment was diagnosed in 15% (4/26) of donors and in 10% (2/21) of recipients and was not related to abnormal MCA flow. None of the children suffered from chronic renal failure. We concluded that fetoscopic laser ablation of the placental anastomoses in TTTS affects the fetal and fetoplacental circulation in various ways, such as transient volume overload in donors and improvement of cardiac function in recipients. Cerebral and renal flow changes occur after laser therapy. Whether these are permanent or temporarily fetal adaptations needs further investigation with prolonged follow-up. In our studies, the changes found were not associated with long-term neurological or renal sequelae. In chapter 6 the influence of fetoscopic laser therapy on fetal cardiac size in monochorionic twins complicated by TTTS was evaluated. In a longitudinal, prospective study, we assessed sonographically the fetal cardiac size in monochorionic diamniotic twins with TTTS treated with laser therapy and in monochorionic twins without TTTS. The fetal cardiothoracic ratio (cardiac circumference divided by thoracic circumference) of TTTS twins was determined within 24 h before, 12 to 24 h after and 1 week after laser treatment, and from then on every 2 to 4 weeks until birth. TTTS twins were classified at Quintero Stage 1-2 (n=18) and Stage 3-4 (n=16) and measurements were compared to biweekly measurements of non-TTTS monochorionic twins matched for gestational age (n=38). Cardiomegaly was defined as a cardiothoracic ratio above the 97.5th percentile. Before laser treatment, cardiomegaly was observed in 44% (8/18) and in 50% (8/16) of recipients at Quintero Stage 1-2 and Stage 3-4, respectively. Cardiomegaly occurred in none of the donors before treatment. After laser treatment, cardiomegaly was observed in 76% (13/17) and 50% (7/14) of recipients at Stage 1-2 and Stage 3-4, respectively. Cardiomegaly was found in 17% (3/18) and 13% (2/15) of donors at Stage 1-2 and Stage 3-4, respectively. Non-TTTS monochorionic twins and singletons showed cardiomegaly in 18% (7/38) and 8% (2/25). After laser therapy, cardiothoracic ratios of recipients at Stage 1-2 and Stage 3-4 were not significantly changed (p=0.34 and 0.67, respectively). Cardiothoracic ratios of donors at Stage 1-2 and Stage 3-4 were increased compared to their cardiothoracic ratios before laser therapy (p-values 0.0002 and 0.005, respectively). Cardiothoracic ratios of non-TTTS monochorionic twins were not significantly different from our reference range in singletons throughout gestation, and were smaller as compared to both recipients and donors after laser therapy. It was concluded that recipients show cardiomegaly both before as well as after fetoscopic laser therapy for TTTS. Donors develop cardiomegaly only after laser treatment for TTTS. Our findings emphasize the significant effect of TTTS and fetoscopic laser therapy on the fetal hearts of both recipient and donor twins. In chapter 7 we compared fetal cardiac output (CO) in donor and recipient twins of TTTS pregnancies after fetoscopic laser therapy to monochorionic twins without TTTS and to normal singletons. In a longitudinal, prospective study, we sonographically assessed fetal CO in donors (n=10) and recipients (n=10) with TTTS after fetoscopic laser therapy, in monochorionic twins without TTTS (n=20) and in 20 normal singleton pregnancies. The fetal CO of TTTS twins was determined 1 day and 1 week after laser treatment, and from then on every 2 to 4 weeks until birth. Twins without TTTS were examined biweekly until birth. Singletons were examined twice with an 8-week interval at different gestational ages between 17 and 35 weeks. Absolute CO increased exponentially with advancing gestational age (p<0.001), and was significantly related to fetal weight for all groups (p<0.0001). The median CO/kg in donors after laser therapy, recipients after laser therapy, and non-TTTS monochorionic twins was significantly higher compared to singletons (all p-values <0.001). Median CO/kg in donors after laser therapy, recipients after laser therapy, and non-TTTS monochorionic twins was not significantly different from each other. It was concluded that monochorionic twins with TTTS have an increased CO/kg after laser treatment as compared to normal singletons. These results may be of importance in view of the increasing awareness of fetal origins of adult disease. In conclusion, knowledge about monochorionic twinning and its complications such as TTTS is crucial for clinicians participating in the care of pregnant women and for children born as monochorionic twins. With the studies described in this thesis, we aimed at designing a framework that is helpful in providing high quality prenatal care for monochorionic twins. A first-trimester scan to establish chorionicity is vital and should be followed by biweekly ultrasound examinations and patient instructions. Specific __guidelines__ that may be used both before and after fetoscopic laser treatment for TTTS are provided in the recommendations for clinical practice. We hope that the studies presented in this thesis will contribute to increased awareness of the potential problems and optimization of management of this unique subset of pregnancies: the monochorionic twins. Show less
