Risk factors for pre-eclampsia in clinical practice guidelines: Comparison with the evidence.

OBJECTIVE: To compare pre-eclampsia risk factors identified by clinical practice guidelines (CPGs) with risk factors from hierarchical evidence review, to guide pre-eclampsia prevention. DESIGN: Our search strategy provided hierarchical evidence of relationships between risk factors and pre-eclampsia using Medline (Ovid), searched from January 2010 to January 2021. SETTING: Published studies and CPGs. POPULATION: Pregnant women. METHODS: We evaluated the strength of association and quality of evidence (GRADE). CPGs (n = 15) were taken from a previous systematic review. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Of 78 pre-eclampsia risk factors, 13 (16.5%) arise only during pregnancy. Strength of association was usually 'probable' (n = 40, 51.3%) and the quality of evidence was low (n = 35, 44.9%). The 'major' and 'moderate' risk factors proposed by 8/15 CPGs were not well aligned with the evidence; of the ten 'major' risk factors (alone warranting aspirin prophylaxis), associations with pre-eclampsia were definite (n = 4), probable (n = 5) or possible (n = 1), based on moderate (n = 4), low (n = 5) or very low (n = 1) quality evidence. Obesity ('moderate' risk factor) was definitely associated with pre-eclampsia (high-quality evidence). The other ten 'moderate' risk factors had probable (n = 8), possible (n = 1) or no (n = 1) association with pre-eclampsia, based on evidence of moderate (n = 1), low (n = 5) or very low (n = 4) quality. Three risk factors not identified by the CPGs had probable associations (high quality): being overweight; 'prehypertension' at booking; and blood pressure of 130-139/80-89 mmHg in early pregnancy. CONCLUSIONS: Pre-eclampsia risk factors in CPGs are poorly aligned with evidence, particularly for the strongest risk factor of obesity. There is a lack of distinction between risk factors identifiable in early pregnancy and those arising later. A refresh of the strategies advocated by CPGs is needed.

An evidence review and nutritional conceptual framework for pre-eclampsia prevention.

Pre-eclampsia is a serious complication of pregnancy, and maternal nutritional factors may play protective roles or exacerbate risk. The tendency to focus on single nutrients as a risk factor obscures the complexity of possible interactions, which may be important given the complex nature of pre-eclampsia. An evidence review was conducted to compile definite, probable, possible and indirect nutritional determinants of pre-eclampsia to map a nutritional conceptual framework for pre-eclampsia prevention. Determinants of pre-eclampsia were first compiled through an initial consultation with experts. Second, an expanded literature review was conducted to confirm associations, elicit additional indicators and evaluate evidence. The strength of association was evaluated as definite relative risk (RR) < 0·40 or ≥3·00, probable RR 0·40-0·69 or 1·50-2·99, possible RR 0·70-0·89 or 1·10-1·49 or not discernible RR 0·90-1·09. The quality of evidence was evaluated using Grading of Recommendations, Assessment, Development and Evaluation. Twenty-five nutritional factors were reported in two umbrella reviews and twenty-two meta-analyses. Of these, fourteen were significantly associated with pre-eclampsia incidence. Higher serum Fe emerged as a definite nutritional risk factors for pre-eclampsia incidence across populations, while low serum Zn was a risk factor in Asia and Africa. Maternal vitamin D deficiency was a probable risk factor and Ca and/or vitamin D supplementation were probable protective nutritional factors. Healthy maternal dietary patterns were possibly associated with lower risk of developing pre-eclampsia. Potential indirect pathways of maternal nutritional factors and pre-eclampsia may exist through obesity, maternal anaemia and gestational diabetes mellitus. Research gaps remain on the influence of household capacities and socio-cultural, economic and political contexts, as well as interactions with medical conditions.

The PRECISE-DYAD protocol: linking maternal and infant health trajectories in sub-Saharan Africa.

Background: PRECISE-DYAD is an observational cohort study of mother-child dyads running in urban and rural communities in The Gambia and Kenya. The cohort is being followed for two years and includes uncomplicated pregnancies and those that suffered pregnancy hypertension, fetal growth restriction, preterm birth, and/or stillbirth. Methods: The PRECISE-DYAD study will follow up ~4200 women and their children recruited into the original PRECISE study. The study will add to the detailed pregnancy information and samples in PRECISE, collecting additional biological samples and clinical information on both the maternal and child health.Women will be asked about both their and their child's health, their diets as well as undertaking a basic cardiology assessment. Using a case-control approach, some mothers will be asked about their mental health, their experiences of care during labour in the healthcare facility. In a sub-group, data on financial expenditure during antenatal, intrapartum, and postnatal periods will also be collected. Child development will be assessed using a range of tools, including neurodevelopment assessments, and evaluating their home environment and quality of life. In the event developmental milestones are not met, additional assessments to assess vision and their risk of autism spectrum disorders will be conducted. Finally, a personal environmental exposure model for the full cohort will be created based on air and water quality data, combined with geographical, demographic, and behavioural variables. Conclusions: The PRECISE-DYAD study will provide a greater epidemiological and mechanistic understanding of health and disease pathways in two sub-Saharan African countries, following healthy and complicated pregnancies. We are seeking additional funding to maintain this cohort and to gain an understanding of the effects of pregnancies outcome on longer-term health trajectories in mothers and their children.

The miR-183/ItgA3 axis is a key regulator of prosensory area during early inner ear development.

MicroRNAs are important regulators of gene expression and are involved in cellular processes such as proliferation or differentiation, particularly during development of numerous organs including the inner ear. However, it remains unknown if miRNAs are required during the earliest stages of otocyst and cochlear duct development. Here, we report that a conditional loss of Dicer expression in the otocyst impairs the early development of the inner ear as a result of the accumulation of DNA damage that trigger p53-mediated apoptosis. Moreover, cochlear progenitors in the prosensory domain do not exit the cell cycle. Our unbiased approach identified ItgA3 as a target of miR-183, which are both enriched in the otic vesicle. We observed that the repression of integrin alpha 3 by miR-183 controls cell proliferation in the developing cochlea. Collectively, our results reveal that Dicer and miRNAs play essential roles in the regulation of early inner ear development.

MicroRNA targeting of CoREST controls polarization of migrating cortical neurons.

The migration of cortical projection neurons is a multistep process characterized by dynamic cell shape remodeling. The molecular basis of these changes remains elusive, and the present work describes how microRNAs (miRNAs) control neuronal polarization during radial migration. We show that miR-22 and miR-124 are expressed in the cortical wall where they target components of the CoREST/REST transcriptional repressor complex, thereby regulating doublecortin transcription in migrating neurons. This molecular pathway underlies radial migration by promoting dynamic multipolar-bipolar cell conversion at early phases of migration, and later stabilization of cell polarity to support locomotion on radial glia fibers. Thus, our work emphasizes key roles of some miRNAs that control radial migration during cerebral corticogenesis.

Huntingtin is required for mitotic spindle orientation and mammalian neurogenesis.

Huntingtin is the protein mutated in Huntington's disease, a devastating neurodegenerative disorder. We demonstrate here that huntingtin is essential to control mitosis. Huntingtin is localized at spindle poles during mitosis. RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein. This leads to increased apoptosis following mitosis of adherent cells in vitro. In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos. This function is conserved in Drosophila, the specific disruption of Drosophila huntingtin in neuroblast precursors leading to spindle misorientation. Moreover, Drosophila huntingtin restores spindle misorientation in mammalian cells. These findings reveal an unexpected role for huntingtin in dividing cells, with potential important implications in health and disease.

Elongator controls the migration and differentiation of cortical neurons through acetylation of alpha-tubulin.

The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.

Benfotiamine, a synthetic S-acyl thiamine derivative, has different mechanisms of action and a different pharmacological profile than lipid-soluble thiamine disulfide derivatives.

BACKGROUND: Lipid-soluble thiamine precursors have a much higher bioavailability than genuine thiamine and therefore are more suitable for therapeutic purposes. Benfotiamine (S-benzoylthiamine O-monophosphate), an amphiphilic S-acyl thiamine derivative, prevents the progression of diabetic complications, probably by increasing tissue levels of thiamine diphosphate and so enhancing transketolase activity. As the brain is particularly sensitive to thiamine deficiency, we wanted to test whether intracellular thiamine and thiamine phosphate levels are increased in the brain after oral benfotiamine administration. RESULTS: Benfotiamine that is practically insoluble in water, organic solvents or oil was solubilized in 200 mM hydroxypropyl-beta-cyclodextrin and the mice received a single oral administration of 100 mg/kg. Though thiamine levels rapidly increased in blood and liver to reach a maximum after one or two hours, no significant increase was observed in the brain. When mice received a daily oral administration of benfotiamine for 14 days, thiamine derivatives were increased significantly in the liver but not in the brain, compared to control mice. In addition, incubation of cultured neuroblastoma cells with 10 muM benfotiamine did not lead to increased intracellular thiamine levels. Moreover, in thiamine-depleted neuroblastoma cells, intracellular thiamine contents increased more rapidly after addition of thiamine to the culture medium than after addition of benfotiamine for which a lag period was observed. CONCLUSION: Our results show that, though benfotiamine strongly increases thiamine levels in blood and liver, it has no significant effect in the brain. This would explain why beneficial effects of benfotiamine have only been observed in peripheral tissues, while sulbutiamine, a lipid-soluble thiamine disulfide derivative, that increases thiamine derivatives in the brain as well as in cultured cells, acts as a central nervous system drug. We propose that benfotiamine only penetrates the cells after dephosphorylation by intestinal alkaline phosphatases. It then enters the bloodstream as S-benzoylthiamine that is converted to thiamine in erythrocytes and in the liver. Benfotiamine, an S-acyl derivative practically insoluble in organic solvents, should therefore be differentiated from truly lipid-soluble thiamine disulfide derivatives (allithiamine and the synthetic sulbutiamine and fursultiamine) with a different mechanism of absorption and different pharmacological properties.