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

Surviving mothers and lost babies - burden of stillbirths and neonatal deaths among women with maternal near miss in eastern Ethiopia:a prospective cohort study

Background: Although maternal near miss (MNM) is often considered a 'great save' because the woman survived life-threatening complications, these complications may have resulted in loss of a child or severe neonatal morbidity. The objective of this study was to assess proportion of perinatal mortality (stillbirths and early neonatal deaths) in a cohort of women with MNM in eastern Ethiopia. In addition, we compared perinatal outcomes among women who fulfilled the World Health Organization (WHO) and the sub-Saharan African (SSA) MNM criteria. Methods: In a prospective cohort design, women with potentially life-threatening conditions (PLTC) (severe postpartum hemorrhage, severe pre-(eclampsia), sepsis/severe systemic infection, and ruptured uterus) were identified every day from January 1st, 2016, to April 30th, 2017, and followed until discharge in the two main hospitals in Harar, Ethiopia. Maternal and perinatal outcomes were collected using both sets of criteria. Numbers and proportions of stillbirths and early neonatal deaths were computed and compared. Results: Of 1054 women admitted with PTLC during the study period, 594 women fulfilled any of the MNM criteria. After excluding near misses related to abortion, ectopic pregnancy or among undelivered women, 465 women were included, in whom 149 (32%) perinatal deaths occurred: 132 (88.6%) stillbirths and 17 (11.4%) early neonatal deaths. In absolute numbers, the SSA criteria picked up more perinatal deaths compared to the WHO criteria, but the proportion of perinatal deaths was lower in SSA group compared to the WHO (149/465, 32% vs 62/100, 62%). Perinatal mortality was more likely among near misses with antepartum hemorrhage (adjusted odds ratio (aOR) = 4.81; 95% CI = 1.76-13.20), grand multiparous women (aOR = 4.31; 95% confidence interval CI = 1.23-15.25), and women fulfilling any of the WHO near miss criteria (aOR = 4.89; 95% CI = 2.17-10.99). Conclusion: WHO MNM criteria pick up fewer perinatal deaths, although perinatal mortality occurred in a larger proportion of women fulfilling the WHO MNM criteria compared to the SSA MNM criteria. As women with MNM have increased risk of perinatal deaths (in both definitions), a holistic care addressing the needs of the mother and baby should be considered in management of women with MNM

Severe Hypertensive Disorders of Pregnancy in Eastern Ethiopia:Comparing the Original WHO and Adapted sub-Saharan African Maternal Near-Miss Criteria

Objectives: To assess life-threatening complications among women admitted with severe hypertensive disorders of pregnancy and compare applicability of World Health Organization (WHO) maternal near-miss (MNM) criteria and the recently adapted sub-Saharan African (SSA) MNM criteria in eastern Ethiopia.Methods: Of 1,054 women admitted with potentially life-threatening conditions between January 2016 and April 2017, 562 (53.3%) had severe preeclampsia/eclampsia. We applied the definition of MNM according to the WHO MNM criteria and the SSA MNM criteria. Logistic regression was performed to identify factors associated with severe maternal outcomes (MNMs and maternal deaths).Results: The SSA MNM criteria identified 285 cases of severe maternal outcomes: 271 MNMs and 14 maternal deaths (mortality index 4.9%). The WHO criteria identified 50 cases of severe maternal outcomes: 36 MNMs and 14 maternal deaths (mortality index 28%). The MNM ratio was 36.6 per 1,000 livebirths according to the SSA MNM criteria and 4.9 according to the WHO criteria. More than 80% of women in both groups had MNM events on arrival or within 12 hours after admission. Women without antenatal care, from rural areas, referred from other facilities, and with concomitant hemorrhage more often developed severe maternal outcomes.Conclusion: Regarding hypertensive disorders of pregnancy, the SSA tool is more inclusive than the WHO tool, while still maintaining a considerably high mortality index indicating severity of included cases. This may enable more robust audits. Strengthening the referral system and improving prevention and management of obstetric hemorrhage in women with hypertensive disorders of pregnancy are required to avert severe maternal outcomes.</p

Beyond No Blame:Practical Challenges of Conducting Maternal and Perinatal Death Reviews in Eastern Ethiopia

Performing effective maternal death reviews as part of the maternal death surveillance and response program has been hindered by challenges including poor attendance, defensive attitudes, and blame shifting. Reviews of maternal and perinatal deaths should be based on a “no blame” principle. Emphasis should be on learning lessons and health professionals should feel safe to discuss the circumstances surrounding death. Meaningful reduction in maternal mortality requires a depoliticizing paradigm shift, a professional body to address patients’ worries, and clear medicolegal guidance to encourage providers to identify care deficiencies

Introduction of Criterion-Based Audit of Postpartum Hemorrhage in a University Hospital in Eastern Ethiopia:Implementation and Considerations

With postpartum hemorrhage (PPH) continuing to be the leading cause of maternal mortality in most low-resource settings, an audit of the quality of care in health facilities is essential. The purpose of this study was to identify areas of substandard care and establish recommendations for the management of PPH in Hiwot Fana Specialized University Hospital, eastern Ethiopia. Using standard criteria (n = 8) adapted to the local hospital setting, we audited 45 women with PPH admitted from August 2018 to March 2019. Four criteria were agreed as being low: IV line-setup (32 women, 71.1%), accurate postpartum vital sign monitoring (23 women, 51.1%), performing typing and cross-matching (22 women, 48.9%), and fluid intake/output chart maintenance (6 women, 13.3%). In only 3 out of 45 women (6.7%), all eight standard criteria were met. Deficiencies in the case of note documentation and clinical monitoring, non-availability of medical resources and blood for transfusion, as well as delays in clinical management were identified. The audit created awareness, resulting in self-reflection of current practice and promoted a sense of responsibility to improve care among hospital staff. Locally appropriate recommendations and an intervention plan based on available resources were formulated

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

Society and synthetic cells:A position paper by the Future Panel on Synthetic Life

The BaSyC consortium, whose acronym stands for building a synthetic cell, proposes to develop a synthetic cell from the bottom up. In the context of this joined effort, the Rathenau Instituut and Radboud University Nijmegen have organised the Future Panel on Synthetic Life, consisting of societal experts, to explore the social challenges, dilemmas, and possible societal impacts of synthetic cell research, and to advise how this research may contribute to a fair and sustainable future. The goal for the Future Panel is to create an initial agenda for future political, academic, and public debate on the synthetic cell.The profile of science and technology is two-sided. On the one hand, they act as drivers for problem-solving, progress, and emancipation, but techno-scientific innovation can also give rise to disruptive threats. Therefore, societal reflection should be timely and anticipatory. Rather than asking what risks and benefits are involved, the question will be how to engage society in such a way that synthetic cell research can become a joint endeavour, responsive to societal hopes and concerns. Consequently, the Future Panel aimed to:• map the social challenges and dilemmas in a society where a synthetic cell exists;• identify conditions under which synthetic cell technology can be considered beneficial for society; and• advice on how these conditions can be realised.To contribute to this, the Future Panel discussed the role and perspectives of key stakeholders (academia, government and governance, industry, and civil society), besides more specific issues like public responses, biosafety, biosecurity, and intellectual property rights during multiple online and offline meetings within a period of two years. This position paper summarises the most important points of conversation, shared insights, key challenges, dilemmas that were discussed during these meetings, resulting in four recommendations, as a starting point for further analysis and debate.Key challengesDuring the deliberations, the Future Panel encountered four overarching challenges.1. The novelty of synthetic cell research makes it challenging to devise amethodology capable of anticipating public concerns in a domain where overt public attitudes do not exist as of yet.Society and synthetic cells 132. As long as the existing power structures within the contexts that shape developments in science and technology are not explicitly addressed, the development of a synthetic cell will inevitably reproduce and may even strengthen existing power inequalities.3. In order to involve civil society and allow citizens to articulate their views and concerns, besides factual information, the synthetic cell has to be positioned in a proper context: how to develop a responsible narrative that allows the public to actively relate to these developments?4. Even though the BaSyC project is halfway, there are still many unknowns, even unknown unknowns. A key challenge is to connect social, ethical, and science perspectives, and dilemmas, ambitions, and uncertainties related to the building of a synthetic cell.DilemmasDuring the panel discussions, many reasons have arisen, from different perspectives, for involving the general public, governments, industry and NGOs in an anticipatory way. However, doing this reveals some fundamental dilemmas and tensions that should be addressed.1. The BaSyC project is curiosity-driven, aspiring to deepen our understanding of life. At the same time, our desire to know is driven by an impetus to control. How to practice synthetic cell research as a dialogue with nature rather than an appropriation and instrumentalisation of the living cell?2. Many aspects of synthetic cell research are yet unknown. How to allow space for the unknown while, at the same time, opt for an anticipatory and imaginative approach to take the future social and ethical implications and concerns into account?3. How to make research more inclusive by involving public, politics and policy in such a way that it is fostering and inspirational rather than detrimental for curiosity-driven experimentation and exploration?4. Curiosity-driven science requires a great deal of specialism and thrives on serendipity. How to achieve convergence in science, involving multiple stakeholders and taking into account societal expectations and concerns, without frustrating the process of discovery?5. Deliberation requires a dialogue across disciplines, languages, and levels of information. How to combine different vocabularies, perspectives, socio- cultural and time horizons in a meaningful way?6. Within science and technology, and in particular biotechnology, there has long been a discussion about how to deal with knowledge and intellectual property rights. Should life be considered patentable or should life be seen as a common heritage that belongs to everybody?7. How to deal with researchers who need to make their work openly accessible, and companies, incubators, and organisations that want to protect their invention?8. Within projects of four to five years, researchers are under pressure to focus on and deliver scientific publications, while at the same time being encouraged to actively reflect on and engage with the potential societal impact of their work. How to balance conflicting expectations related to different time horizons?RecommendationsThe Future Panel proposes four recommendations for fostering a socially responsible development of the synthetic cell:1. Ensure that the synthetic cell contributes to a fair and sustainable futureTo foster sustainable synthetic cells, we need co-constructed narratives that allow us to explore how synthetic cells may contribute to a sustainable future. It is not enough to stimulate techno-scientific innovation as such. Governments must simultaneously stimulate social innovation, and promote broad stakeholder involvement in synthetic cell research.2. Organise participation of civil society in synthetic cell researchIn order to ensure that synthetic cell research contributes to a fair and sustainable society, an inclusive and participatory process of reflection is required, open to public intelligence, and sensitive to societal expectations and concerns. This requires innovative methods to engage the wisdom of the crowd. Meetings with societal stakeholders should be organised on relevant issues at different moments of the project and should be designed as in-between spaces in which different meanings, interests, and societal values come together and are made explicit.3. Foster a socially responsive academic ecosystemRather than endorsing the status quo, synthetic cell research emphasises the importance of rethinking the university of the 21st century, where research and education must become more inclusive and interactive, bent on developing long- term partnerships with society: with industry and governmental organisations, but first and foremost with society at large. Societal reflection and interaction with society should be an integral part of academic research and education. Therefore, researchers must be empowered to engage with society in such a way that dialogue and interaction become an inherent part of their work, from design to publication.4. Design social governance experiments aimed at renewing the regulatory landscape for new biotechnologies, including the synthetic cellEnsuring that the synthetic cell may contribute to a more sustainable and socially equitable world requires an adequate social understanding of governance and regulatory systems. The current regulatory system is not prepared for that task. We need a new system, which does not reproduce previous polemics. Besides looking at risks, a more comprehensive regulatory regime would integrate questions concerning sustainability, human rights, ethics, and societal desirability. Governance experiments co-designed with societal actors are needed to gain insight into the contours of such a new regulatory landscape on synthetic biology or new biotechnologies, including the synthetic cell