Incidence and Predictors of Maternal Cardiovascular Mortality and Severe Morbidity in the Netherlands: A Prospective Cohort Study

Objective: To assess incidence and possible risk factors of severe maternal morbidity and mortality from cardiovascular disease in the Netherlands. Design: A prospective population based cohort study. Setting: All 98 maternity units in the Netherlands. Population: All women delivering in the Netherlands between August 2004 and August 2006 (n = 371,021) Methods: Cases of severe maternal morbidity and mortality from cardiovascular disease were prospectively collected during a two-year period in the Netherlands. Women with cardiovascular complications during pregnancy or postpartum who were admitted to the ward, intensive care or coronary care unit were included. Cardiovascular morbidity was defined as cardiomyopathy, valvular disease, ischaemic heart disease, arrhythmias or aortic dissection. All women delivering in the same period served as a reference cohort. Main outcome measures: Incidence, case fatality rates and possible risk factors. Results: Incidence of severe maternal morbidity due to cardiovascular disease was 2.3 per 10,000 deliveries (84/358,874). Maternal mortality rate from cardiovascular disease was 3.0 per 100,000 deliveries (11/358,874). Case fatality rate in women with severe maternal morbidity due to cardiovascular disease was 13% (11/84). Case fatality rate was highes

Exogenous Ligand-Free Nickel-Catalyzed Carboxylate O-Arylation:Insight into Ni^I/Ni^III Cycles**

Nickel-catalyzed cross-coupling reactions have become a powerful methodology to construct C-heteroatom bonds. However, many protocols suffer from competitive off-cycle reaction pathways and require non-equimolar amounts of coupling partners to suppress them. Here, we report on mechanistic examination of carboxylate O-arylation under thermal conditions, in both the presence and absence of an exogeneous bipyridine-ligand. Furthermore, spectroscopic studies of the novel ligand-free carboxylate O-arylation reaction unveiled the resting state of the nickel catalyst, the crucial role of the alkylamine base and the formation of an off-cycle NiI−NiII dimer upon reduction. This study provides insights into the competition between productive catalysis and deleterious pathways (comproportionation and protodehalogenation) in the commonly proposed self-sustained NiI/NiIII catalytic cycle. Thereby we show that for productive nickel-catalyzed carboxylate O-arylation a choice must be made between either mild conditions or equimolar ratios of substrates

Clinical Validation of a Dried Blood Spot Assay for 8 Antihypertensive Drugs and 4 Active Metabolites

BACKGROUND: Drug nonadherence is one of the major challenges faced by resistant hypertension patients, and identification of this problem is needed for optimizing pharmacotherapy. Dried blood spot (DBS) sampling is a minimally invasive method designed to detect and determine the degree of nonadherence. In this study, a DBS method for qualifying 8 antihypertensive drugs (AHDs) and 4 active metabolites was developed and validated using ultra high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). METHOD: The DBS assay was validated analytically and clinically, in accordance with FDA requirements. Analytical validation was accomplished using UHPLC-MS/MS. For clinical validation, paired peak and trough levels of DBS and plasma samples were simultaneously collected and comparatively analyzed using Deming regression and Bland-Altman analyses. All concentrations below the set lower limit were excluded. Deming regression analysis was used to predict comparison bias between the collected plasma and DBS samples, with DBS concentrations corrected accordingly. RESULTS: The UHPLC-MS/MS method for simultaneously measuring 8 AHDs and their metabolites in DBS, was successfully validated. With Deming regression no bias was observed in N = 1; constant bias was seen in N = 6 and proportional bias in N = 11 of the AHDs and metabolites. After correction for bias, only one metabolite (canrenone) met the 20% acceptance limit for quantification, after Bland-Altman analyses. In addition, amlodipine, valsartan, and [enalaprilate] met the 25% acceptance limit. CONCLUSIONS: A novel DBS assay for simultaneously qualifying and quantifying 8 AHDs and their metabolites, has been successfully developed and validated. The DBS assay is therefore a suitable method to detect drug nonadherence. However, with the exception of canrenone, the interchangeable use of plasma and DBS sa

Adaptation of the WHO maternal near miss tool for use in sub-Saharan Africa:An International Delphi study

Background: Assessments of maternal near miss (MNM) are increasingly used in addition to those of maternal mortality measures. The World Health Organization (WHO) has introduced an MNM tool in 2009, but this tool was previously found to be of limited applicability in several low-resource settings. The aim of this study was to identify adaptations to enhance applicability of the WHO MNM tool in sub-Saharan Africa. Methods: Using a Delphi consensus methodology, existing MNM tools were rated for applicability in sub-Saharan Africa over a series of three rounds. Maternal health experts from sub-Saharan Africa or with considerable knowledge of the context first rated importance of WHO MNM parameters using Likert scales, and were asked to suggest additional parameters. This was followed by two confirmation rounds. Parameters accepted by at least 70% of the panel members were accepted for use in the region. Results: Of 58 experts who participated from study onset, 47 (81%) completed all three rounds. Out of the 25 WHO MNM parameters, all 11 clinical, four out of eight laboratory, and four out of six management-based parameters were accepted, while six parameters (PaO2/FiO2 <200 mmHg, bilirubin > 100 mu mol/l or > 6.0 mg/dl, pH <7.1, lactate > 5 mu mol/l, dialysis for acute renal failure and use of continuous vasoactive drugs) were deemed to not be applicable. An additional eight parameters (uterine rupture, sepsis/severe systemic infection, eclampsia, laparotomy other than caesarean section, pulmonary edema, severe malaria, severe complications of abortions and severe pre-eclampsia with ICU admission) were suggested for inclusion into an adapted sub-Saharan African MNM tool. Conclusions: All WHO clinical criteria were accepted for use in the region. Only few of the laboratory-and management based were rated applicable. This study brought forward important suggestions for adaptations in the WHO MNM criteria to enhance its applicability in sub-Saharan Africa and possibly other low-resource settings

Amniotic fluid embolism incidence, risk factors and outcomes: a review and recommendations

<p>Abstract</p> <p>Background</p> <p>Amniotic fluid embolism (AFE) is a rare but severe complication of pregnancy. A recent systematic review highlighted apparent differences in the incidence, with studies estimating the incidence of AFE to be more than three times higher in North America than Europe. The aim of this study was to examine population-based regional or national data from five high-resource countries in order to investigate incidence, risk factors and outcomes of AFE and to investigate whether any variation identified could be ascribed to methodological differences between the studies.</p> <p>Methods</p> <p>We reviewed available data sources on the incidence of AFE in Australia, Canada, the Netherlands, the United Kingdom and the USA. Where information was available, the risk factors and outcomes of AFE were examined.</p> <p>Results</p> <p>The reported incidence of AFE ranged from 1.9 cases per 100 000 maternities (UK) to 6.1 per 100 000 maternities (Australia). There was a clear distinction between rates estimated using different methodologies. The lowest estimated incidence rates were obtained through validated case identification (range 1.9-2.5 cases per 100 000 maternities); rates obtained from retrospective analysis of population discharge databases were significantly higher (range 5.5-6.1 per 100 000 admissions with delivery diagnosis). Older maternal age and induction of labour were consistently associated with AFE.</p> <p>Conclusions</p> <p>Recommendation 1: Comparisons of AFE incidence estimates should be restricted to studies using similar methodology. The recommended approaches would be either population-based database studies using additional criteria to exclude false positive cases, or tailored data collection using existing specific population-based systems.</p> <p>Recommendation 2: Comparisons of AFE incidence between and within countries would be facilitated by development of an agreed case definition and an agreed set of criteria to minimise inclusion of false positive cases for database studies.</p> <p>Recommendation 3: Groups conducting detailed population-based studies on AFE should develop an agreed strategy to allow combined analysis of data obtained using consistent methodologies in order to identify potentially modifiable risk factors.</p> <p>Recommendation 4: Future specific studies on AFE should aim to collect information on management and longer-term outcomes for both mothers and infants in order to guide best practice, counselling and service planning.</p

Association of Timing of Plasma Transfusion With Adverse Maternal Outcomes in Women With Persistent Postpartum Hemorrhage

IMPORTANCE Early plasma transfusion for women with severe postpartum hemorrhage (PPH) is recommended to prevent coagulopathy. However, there is no comparative, quantitative evidence on the association of early plasma transfusion with maternal outcomes. OBJECTIVE To compare the incidence of adverse maternal outcomes among women who received plasma during the first 60 minutes of persistent PPH vs women who did not receive plasma for similarly severe persistent PPH. DESIGN, SETTING, AND PARTICIPANTS This multicenter cohort study used a consecutive sample of women with persistent PPH, defined as PPH refractory to first-line measures to control bleeding, between January 1, 2011, and January 1, 2013. Time-dependent propensity score matching was used to select women who received plasma during the first 60 minutes of persistent PPH and match each of them with a woman who had shown the same severity and received the same treatment of PPH but who had not received plasma at the moment of matching. Transfusions were not guided by coagulation tests. Statistical analysis was performed from June 2018 to June 2019. EXPOSURES Transfusion of plasma during the first 60 minutes of persistent PPH vs no or later plasma transfusion. MAIN OUTCOMES AND MEASURES Incidence of adverse maternal outcomes, defined as a composite of death, hysterectomy, or arterial embolization. RESULTS This study included 1216 women (mean [SD] age, 31.6 [5.0] years) with persistent PPH, of whom 932 (76.6%) delivered vaginally and 780 (64.1%) had PPH caused by uterine atony. Seven women (0.6%) died because of PPH, 62 women (5.1%) had a hysterectomy, and 159 women (13.1%) had arterial embolizations. Among women who received plasma during the first 60 minutes of persistent PPH, 114 women could be matched with a comparable woman who had not received plasma at the moment of matching. The incidence of adverse maternal outcomes was similar between the women, with adverse outcomes recorded in 24 women (21.2%) who received early plasma transfusion and 23 women (19.9%) who did not receive early plasma transfusion (odds ratio, 1.09; 95% CI, 0.57-2.09). Results of sensitivity analyses were comparable to the primary results. CONCLUSIONS AND RELEVANCE In this cohort study, initiation of plasma transfusion during the first 60 minutes of persistent PPH was not associated with adverse maternal outcomes compared with no or later plasma transfusion, independent of severity of PPH

Confidential enquiry into maternal deaths in the Netherlands, 2006-2018

Introduction To calculate the maternal mortality ratio (MMR) for 2006-2018 in the Netherlands and compare this with 1993-2005, and to describe women's characteristics, causes of death and improvable factors. Material and Methods We performed a nationwide, cohort study of all maternal deaths between January 1, 2006 and December 31, 2018 reported to the Audit Committee Maternal Mortality and Morbidity. Main outcome measures were the national MMR and causes of death. Results Overall MMR was 6.2 per 100 000 live births, a decrease from 12.1 in 1993-2005 (risk ratio [RR] 0.5). Women with a non-western ethnic background had an increased MMR compared with Dutch women (MMR 6.5 vs. 5.0, RR 1.3). The MMR was increased among women with a background from Surinam/Dutch Antilles (MMR 14.7, RR 2.9). Half of all women had an uncomplicated medical history (79/161, 49.1%). Of 171 pregnancy-related deaths within 1 year postpartum, 102 (60%) had a direct and 69 (40%) an indirect cause of death. Leading causes within 42 days postpartum were cardiac disease (n = 21, 14.9%), hypertensive disorders (n = 20, 14.2%) and thrombosis (n = 19, 13.5%). Up to 1 year postpartum, the most common cause of death was cardiac disease (n = 32, 18.7%). Improvable care factors were identified in 76 (47.5%) of all deaths. Conclusions Maternal mortality halved in 2006-2018 compared with 1993-2005. Cardiac disease became the main cause. In almost half of all deaths, improvable factors were identified and women with a background from Surinam/Dutch Antilles had a threefold increased risk of death compared with Dutch women without a background of migration

Nationwide confidential enquiries into maternal deaths because of obstetric hemorrhage in the Netherlands between 2006 and 2019

Introduction: Obstetric hemorrhage-related deaths are rare in high income countries. Yet, with increasing incidences of obstetric hemorrhage in these countries, it is of utmost importance to learn lessons from each obstetric hemorrhage-related death to improve maternity care. Our objective was to calculate the obstetric hemorrhage-related maternal mortality ratio (MMR), assess causes of obstetric hemorrhage-related deaths, and identify lessons learned. Material and methods: Nationwide mixed-methods prospective case-series with confidential enquiries into maternal deaths due to obstetric hemorrhage in the Netherlands from January 1, 2006 to December 31, 2019. Results: The obstetric hemorrhage-related MMR in the Netherlands in 2006–2019 was 0.7 per 100 000 livebirths and was not statistically significantly different compared with the previous MMR of 1.0 per 100 000 livebirths in 1993–2005 (odds ratio 0.70, 95% confidence interval 0.38–1.30). Leading underlying cause of hemorrhage was retained placenta. Early recognition of persistent bleeding, prompt involvement of a senior clinician and timely management tailored to the cause of hemorrhage with attention to coagulopathy were prominent lessons learned. Also, timely recourse to surgical interventions, including hysterectomy, in case other management options fail to stop bleeding came up as an important lesson in several obstetric hemorrhage-related deaths. Conclusions: The obstetric hemorrhage-related MMR in the Netherlands in 2006–2019 has not substantially changed compared to the MMR of the previous enquiry in 1993–2005. Although obstetric hemorrhage is commonly encountered by maternity care professionals, it is important to remain vigilant for possible adverse maternal outcomes and act upon an ongoing bleeding following birth in a more timely and adequate manner. Our confidential enquiries still led to important lessons learned with clinical advice to professionals as how to improve maternity care and avoid maternal deaths. Drawing lessons from maternal deaths should remain a qualitative and moral imperative

Modulation of Conductance and Ion Selectivity of OmpF Porin by La3+ Ions

Background: Auditing is an important tool to identify practice variation and 'best practices'. The Dutch Pancreatic Cancer Audit is mandatory in all 18 Dutch centers for pancreatic surgery. Methods: Performance indicators and case-mix factors were identified by a PubMed search for randomized controlled trials (RCT's) and large series in pancreatic surgery. In addition, data dictionaries of two national audits, three institutional databases, and the Dutch national cancer registry were evaluated. Morbidity, mortality, and length of stay were analyzed of all pancreatic resections registered during the first two audit years. Case ascertainment was cross-checked with the Dutch healthcare inspectorate and key-variables validated in all centers. Results: Sixteen RCT's and three large series were found. Sixteen indicators and 20 case-mix factors were included in the audit. During 2014-2015, 1785 pancreatic resections were registered including 1345 pancreatoduodenectomies. Overall in-hospital mortality was 3.6%. Following pancreatoduodenectomy, mortality was 4.1%, Clavien-Dindo grade >= III morbidity was 29.9%, median (IQR) length of stay 12 (9-18) days, and readmission rate 16.0%. In total 97.2% of >40,000 variables validated were consistent with the medical charts. Conclusions: The Dutch Pancreatic Cancer Audit, with high quality data, reports good outcomes of pancreatic surgery on a national level

Perinatal thalamic injury: MRI predictors of electrical status epilepticus in sleep and long-term neurodevelopment

Objective: Perinatal thalamic injury is associated with epilepsy with electrical status epilepticus in sleep (ESES). The aim of this study was to prospectively quantify the risk of ESES and to assess neuroimaging predictors of neurodevelopment. Methods: We included patients with perinatal thalamic injury. MRI scans were obtained in the neonatal period, around three months of age and during childhood. Thalamic and total brain volumes were obtained from the three months MRI. Diffusion characteristics were assessed. Sleep EEGs distinguished patients into ESES (spike-wave index (SWI) >85%), ESES-spectrum (SWI 50–85%) or no ESES (SWI < 50%). Serial Intelligence Quotient (IQ)/Developmental Quotient (DQ) scores were obtained during follow-up. Imaging and EEG findings were correlated to neurodevelopmental outcome. Results: Thirty patients were included. Mean thalamic volume at three months was 8.11 (±1.67) ml and mean total brain volume 526.45 (±88.99) ml. In the prospective cohort (n = 23) 19 patients (83%) developed ESES (-spectrum) abnormalities after a mean follow-up of 96 months. In the univariate analysis, larger thalamic volume, larger total brain volume and lower SWI correlated with higher mean IQ/DQ after 2 years (Pearson's r = 0.74, p = 0.001; Pearson's r = 0.64, p = 0.005; and Spearman's rho -0.44, p = 0.03). In a multivariable mixed model analysis, thalamic volume was a significant predictor of IQ/DQ (coefficient 9.60 [p < 0.001], i.e., corrected for total brain volume and SWI and accounting for repeated measures within patients, a 1 ml higher thalamic volume was associated with a 9.6 points higher IQ). Diffusion characteristics during childhood correlated with IQ/DQ after 2 years. Significance: Perinatal thalamic injury is followed by electrical status epilepticus in sleep in the majority of patients. Thalamic volume and diffusion characteristics correlate to neurodevelopmental outcome