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
Teng, Y.K.O.; Bredewold, E.O.W.; Rabelink, T.J.; Huizinga, T.W.J.; Eikenboom, H.C.J.; Limper, M.; ... ; Sueters, M. 2018