Prevención de la preeclampsia: desde la dieta hasta la aspirina: revisión de la literatura / Prevention of preeclampsia: from diet to aspirin: review of the literature

Introducción y objetivo: Explorar las estrategias de prevención de la preeclampsia que se han propuesto a lo largo de la historia. Método: Revisión narrativa de la literatura sobre la evidencia científica histórica disponible entre 2016 y 2023 acerca de la aspirina y otras estrategias de prevención de la preeclampsia, en bases de datos bibliográficas computarizadas de estudios publicados en revistas indexadas. Resultados: Varios estudios confirman la efectividad de la aspirina para prevenir la preeclampsia en población de alto riesgo, siendo un medicamento con bajo riesgo de complicaciones, con mayor evidencia de efectividad si se inicia antes de las 16 semanas de gestación y con un aparente efecto dependiente de la dosis. Intervenciones como la disminución del consumo de sal, el reposo en cama, la suplementación con ácidos grasos, antioxidantes, L-arginina, zinc o magnesio, y el uso de diuréticos o de inhibidores de la bomba de protones, no han mostrado su utilidad en la prevención de la preeclampsia. Conclusiones: La aspirina a dosis baja es un medicamento seguro en el embarazo y efectivo para prevenir la preeclampsia en población de alto riesgo. Es la estrategia de prevención más ampliamente estudiada a lo largo de la historia para la disfunción endotelial durante la gestación.

Introduction and objective: To explore the different prevention strategies for preeclampsia that have been proposed throughout the history. Method: A narrative review of the historical, scientific evidence available between 2016 and 2021 on aspirin and other preeclampsia prevention strategies in computerized bibliographic databases of studies published in indexed journals. Results: Several studies confirm the effectiveness of aspirin to prevent preterm preeclampsia in high-risk populations, considering this as a safe drug with low risk of complications, with greater evidence of effectiveness when started before 16 weeks of gestation and apparently with a dose-dependent effect. Interventions such as reducing salt intake, bed rest, supplementation with fatty acids, antioxidants, L-arginine, zinc, magnesium, the use of diuretics or proton pump inhibitors have not shown its usefulness in the prevention of high risk preeclampsia patients. Conclusions: Low-dose aspirin is a safe drug in pregnancy and is effective to prevent preeclampsia in high-risk populations. Is the most widely studied throughout history prevention strategy for endothelial dysfunction during pregnancy.

The Influence of Vitamin D on Pregnancy and Outcomes: Current Knowledge and Future Perspectives.

INTRODUCTION: The purpose of the research was to explore the relationship between pathology and pregnancy outcomes with serum 25-hydroxycholecalciferol levels and vitamin D supplementation. METHODS: A literature search was performed for systematic literature reviews published between January 2018 and February 2023. Forty-two publications were selected for further analysis. RESULTS: This study demonstrates that elevated maternal serum 25(OH)D levels are associated with a decreased risk of preterm labour and various pregnancy-related health issues, highlighting the protective benefits of adequate vitamin D during pregnancy. CONCLUSION: Vitamin D supplementation during pregnancy at a dose of 2,000 IU or higher is preventive for pre-eclampsia, insulin resistance, and the development of bronchial asthma in early childhood. Vitamin D screening is indicated for all pregnant women. Dosages of vitamin D preparations should be determined individually, considering laboratory tests and risk factors.

Calcium supplementation for the prevention of pre-eclampsia: Challenging the evidence from meta-analyses.

OBJECTIVE: To investigate the validity of the conclusion from Cochrane reviews and meta-analyses that treatment with calcium supplementation during pregnancy reduces the risk for pre-eclampsia by 55%, which has been influential in international guidelines and future research. DESIGN: Sensitivity analysis of data from Cochrane reviews of trials evaluating high-dose calcium supplementation (of at least 1 g/day) for reduction of pre-eclampsia risk. SETTING: Systematic review and meta-analysis. POPULATION: The Cochrane reviews and meta-analyses included 13 trials enrolling a total of 15 730 women. Random-effects meta-analysis of these studies resulted in a mean risk ratio (RR, calcium/placebo) of 0.45 (95% confidence interval [CI] 0.31-0.65; p < 0.0001). METHODS: We carried out a sensitivity analysis of evidence from the relevant Cochrane review, to examine the impact of study size. MAIN OUTCOME MEASURES: pre-eclampsia. RESULTS: In the three largest studies, accounting for 13 815 (88%) of total recruitment, mean RR was 0.92 (95% CI 0.80-1.06) and there was no evidence of heterogeneity between studies (I2 = 0). With inclusion of the smaller studies, mean RR decreased to 0.45 and I2 increased to 70%. CONCLUSIONS: In assessment of the effect of calcium supplementation on pre-eclampsia risk, the naive focus on the mean of the random-effects meta-analysis in the presence of substantial heterogeneity is highly misleading.

Pre-eclampsia training needs of midwives in a Ghanaian tertiary hospital: A cross-sectional study.

AIM: This study aimed to assess the specific clinical and non-clinical training needs of midwives and determine their preferred approach to enhancing performance. BACKGROUND: Pre-eclampsia remains one of the leading causes of maternal deaths in low and middle-income countries. Pre-eclampsia-related deaths may be due to reduced midwifery knowledge and inadequate management. Therefore, a training needs assessment is vital in identifying gaps in practice, especially, in poorly resourced settings for maximal use of training resources. DESIGN: A hospital-based cross-sectional study. SETTING: The largest tertiary hospital in Ghana. METHODS: An online version of the validated WHO Hennessy-Hicks Training Needs Analysis questionnaire was used to assess midwives' training needs on the management of pre-eclampsia. The tool has good psychometric properties and was used to assess 1) midwives' confidence in performing tasks, 2) the importance of the task to their role and 3) their preferred performance improvement approach. Data analysis adhered to the guidelines specified in the Hennessy-Hicks Training Needs Analysis Questionnaire and the priority training requirements of the midwives were assessed through descriptive statistics and a series of independent t-tests. RESULTS: Among the 250 midwives who responded, most possessed 1-5 years of experience (74.7 %). All 28 tasks were viewed by midwives as essential responsibilities in pre-eclampsia management. Midwives had the greatest need for training in research/audit and clinical skills domains respectively (p < 0.001, 95 % confidence interval: 1.08-1.47, Cohen's-D = 1.27; and p < 0.001, 95 % confidence interval: 0.69-1.06, Cohen's-D = 0.87). The foremost primary training necessity, as recognised by midwives, was undertaking health promotion activities, including antenatal health education (MD= 0.43, 95 % confidence interval: 0.29-0.57). Training courses were identified as the preferred approach to address training needs and improve overall proficiency. CONCLUSION: Midwives in Ghana require comprehensive training covering research and clinical-based competencies to improve pre-eclampsia management. Considering the pivotal role of Ghanaian midwives in safeguarding maternal well-being, there is a compelling need to enhance the calibre of midwifery services. These findings can guide stakeholders in countries with comparable healthcare contexts in creating effective, resource-efficient training programs that avoid counterproductivity, ultimately supporting national initiatives to enhance pre-eclampsia management and the quality of care.

Effects of calcium supplementation on changes in the IL2, IL4, IL6, IL10 axes and oxidative stress in pregnant women at risk for pre-eclampsia.

BACKGROUND: Pregnant women with hypertensive disorders are at increased risk for inflammatory diseases and oxidative stress. The dilemma raised by the best dosage of calcium supplementation on these factors is evident. The aim of the current study was to examine the effects of calcium on biomarkers of the purinergic system, inflammation and oxidative stress, which are factors contributing to vascular damage in pregnant women at high risk of pre-eclampsia. METHODS: A prospective, double-blind and placebo-controlled study conducted with 101 women at risk of pre-eclampsia were randomized to take 500 mg calcium/day or 1,500 mg calcium/day or placebo for 6 weeks from the 20th gestational week until delivery. Fasting blood samples were collected at the beginning of the study and 6 weeks after the intervention. RESULTS: Taking calcium supplements (500 mg calcium/day) led to a significant increase in ATP hydrolysis (p < 0.05), NTPDase activity with increased hydrolysis of ADP and AMP nucleotides in platelets and lymphocytes. In the intragroup analysis IL-2, IL-6, IL-4 and interferon-É£ presented lower values in the calcium 1,500 mg/day group (p < 0.005). Oxidative stress was assessed by TBARS pro-oxidant marker, with an increase for the calcium groups when compared to the placebo group. The Vitamin C antioxidant marker presented a significant increase (p < 0.005) for the group that received high calcium doses. CONCLUSIONS: Calcium administration for 6 weeks had antioxidant action and positively modulated the purinergic system and inflammatory markers in pregnant women at risk of pre-eclampsia.

The effects of synbiotic supplementation on blood pressure and other maternal outcomes in pregnant mothers with mild preeclampsia: a triple-blinded randomized controlled trial.

INTRODUCTION: Preeclampsia affects a significant percentage of pregnancies which is a leading cause of premature birth. Probiotics have the potential to affect inflammatory factors, and oxidative stress, which are linked to the development of preeclampsia. The study aimed to compare the effect of synbiotic and placebo on blood pressure and pregnancy duration as primary outcomes, and other pregnancy outcomes. METHODS: This study comprised 128 pregnant women with mild preeclampsia and gestational ages exceeding 24 weeks who were referred to the high-risk pregnancy clinic. It was a randomized, controlled, phase III, triple-blinded clinical experiment. The intervention and control groups were distributed to the participants at random. Intervention group received one oral synbiotic capsule, and control group received placebo daily until delivery. Based on gestational age at the time of diagnosis, preeclampsia was stratificated as early (< 34 weeks) or late (≥ 34 weeks). Data obtained from questionnaires, and biochemical serum factors were analyzed using SPSS software version 23 software. RESULTS: With the exception of the history of taking vitamin D3, there were no statistically significant variations in socio-demographic variables between the research groups. After the intervention, the means of systolic blood pressure (adjusted mean difference: -13.54, 95% CI: -5.01 to -22.07), and diastolic blood pressure (adjusted mean difference: -10.30, 95% CI: -4.70 to -15.90) were significantly lower in the synbiotic-supplemented group than in the placebo group. Compared to the placebo group, the incidence of severe PE (p < 0.001), proteinuria (p = 0.044), and mean serum creatinine level (p = 0.005) significantly declined in the synbiotic-supplemented group after the intervention. However, our analysis found no significant association for other outcomes. CONCLUSION: Based on our results, synbiotic had beneficial effects on some pregnancy outcomes. Further studies with larger samples are needed to verify the advantages of synbiotic supplementation for high-risk pregnancies, particularly with regards to higher doses, and longer intervention periods. TRIAL REGISTRATION: IRCT20110606006709N20.

Gelatin-PVP dissolving microneedle-mediated therapy for controlled delivery of nifedipine for rapid antihypertension treatment.

Nifedipine has exhibited to be the oldest primary drug having promising therapeutic potential for hypertension, angina pectoris, and pre-eclampsia treatment which are the most emergency serious complications worldwide. Moreover, for long-term treatment transdermal route of delivery using polymeric dissolving microneedles (DMNs) patches has shown greater advantages, thus enhancing treatment compliance, painless, reducing the daily number of doses, prolonged release in a controlled manner, and variable bioavailability making this an ideal candidate for the transdermal therapeutic system. Here, we fabricated DMN patches made of gelatin and PVP using PDMS molds loaded with nifedipine drugs for a controlled painless delivery for a longer stable duration. The prepared gelatin-PVP (gel-PVP) DMN patches loaded with nifedipine were fabricated by centrifugation casting method. The characterization results displayed excellent mechanical strength of the needles to penetrate the skin. SEM and confocal microscopy showed penetration of the needles up to 567-600 µm using rhodamine B applied to the hairless punctured skin site. FTIR study exhibited no degradation of the drug was observed while fabricating the DMNs patch at different pH 7.4 and 4. Skin resealing test proved that there was immediate resealing of the skin observed within 10-15 min. Further in-vitro drug release profile study was carried out by dissolution method at different pH 7.4 and 4 showed sustained release of the drug up to 96 ± 2% till 48-72 h avoiding polymer or drug loss which was quantified by UV vis spectrophotometer at 235 nm absorbance showed stable release of the drug upto 48-72 h. A stability study carried out by the HPLC method showed the DMN patches loaded with the drug were found to be stable for up to 30 days at 25 °C. This novel preliminary data are the first study to our knowledge introducing these fabricated nifedipine gel-PVP DMN patches were found to be very efficient and showed prolonged controlled release up to 48-72 h thereby treating hypertension in a convenient, painless manner. This DMN patch-formulated design might act as a potential approach leading to a controllable, self-administrative, and rapid transdermal delivery system.

Midwives' experiences of providing pre-eclampsia care in a low- and middle-income country - A qualitative study.

PROBLEM: Like other low- and middle-income countries, Ghana has high maternal mortality stemming from pre-eclampsia. Ghanaian midwives are frontline service providers of emergency care in obstetric complications and have the greatest potential to maximise pre-eclampsia outcomes. Little is known about the potential barriers and challenges to midwives' capacity to provide quality care in pre-eclampsia in Ghana. Therefore, we aimed to explore and gain insights into midwives' experiences of pre-eclampsia care including their knowledge, skills, and psychological aspects such as midwives' resilience. BACKGROUND: There is a rising global incidence of pre-eclampsia. Quality midwifery care in inter-professional collaborative practice is crucial to reducing pre-eclampsia-related morbidity and mortality. METHODS: A qualitative descriptive exploratory study. In-depth semi-structured interviews (n = 35) were performed in 2021 and analysed by thematic analysis. FINDINGS: There were three main themes. 1) Competence and Confidence in care; midwives provided timely and appropriate care based on sound knowledge and skills; they explained how pre-eclampsia care was organised within a multidisciplinary context and described collaborative working amongst midwives for mutual learning and support. 2) Emotional concerns and empathy; midwives' described fulfillment in achieving positive pre-eclampsia outcomes. In contrast, maternal loss was distressing and traumatic. 3) Call for improved care resources for pre-eclampsia; midwives recommended expansion of continuing professional development opportunities, appropriate infrastructure, resources, tailored public education, and a review of pre-service education to support their participation in pre-eclampsia care. CONCLUSION: To improve the quality of care in pre-eclampsia, midwives should be capacitated, systems should promptly address barriers, and prioritise midwives' emotional well-being.

Efeitos da suplementação do cálcio sobre marcadores da pré-eclâmpsia: ensaio clínico randomizado / Efectos de los suplementos de calcio en marcadores de preeclampsia: ensayo clínico aleatorizado / Effects of calcium supplementation on markers of preeclampsia: randomized clinical trial

Resumo Objetivo Analisar os efeitos da suplementação de cálcio nos marcadores da pré-eclâmpsia ao longo do tempo, comparando o uso de cálcio em alta e baixa dosagem em mulheres grávidas com hipertensão. Métodos Trata-se de ensaio clínico randomizado com três grupos paralelos, placebo controlado, realizado no ambulatório de referência para o pré-natal de alto risco na Região Sul do Brasil, com análise de intenção de tratar e seguimento após quatro e oito semanas. A intervenção consistiu na ingestão de cálcio 500mg/dia, cálcio 1500mg/dia e placebo. Os dados foram analisados segundo um modelo generalizado de estimação de equações mistas adotando α 0,05. Resultados O efeito do cálcio em baixa e alta dosagem na evolução ao longo do tempo foi mantido entre os grupos, mesmo após o ajuste para os fatores de confusão. Houve diferença significativa nos parâmetros analisados na interação tempo e grupo (p <0,000) e diminuição nas médias de 12,3mmHg na PAS, 9,2 mmHg na PAD, 3,2 mg/dl creatinina e 7,2 mg/dl proteinúria para o grupo cálcio 500mg/dia. Os resultados foram semelhantes para o grupo com suplementação máxima. Conclusão O cálcio melhorou o prognóstico vascular em mulheres grávidas com hipertensão ao reduzir os níveis pressóricos e os marcadores da pré-eclâmpsia.

Resumen Objetivo Analizar los efectos de los suplementos de calcio en los marcadores de preeclampsia a lo largo del tiempo, comparando el uso de calcio en dosis altas y bajas en mujeres embarazadas con hipertensión. Métodos Se trata de un ensayo clínico aleatorizado con tres grupos paralelos, placebo controlado realizado en consultorios externos de referencia en el control prenatal de alto riesgo en la Región Sur de Brasil, con análisis de intención de tratar y seguimiento luego de cuatro y ocho semanas. La intervención consistió en la ingesta de calcio 500 mg/día, calcio 1500 mg/día y placebo. Los datos se analizaron de acuerdo con un modelo generalizado de estimación de ecuaciones mixtas adoptando α 0,05. Resultados El efecto del calcio en dosis bajas y altas en la evolución a lo largo del tiempo se mantuvo entre los grupos, inclusive después de los ajustes por los factores de confusión. Hubo diferencia significativa en los parámetros analizados en la interacción tiempo y grupo (p <0,000) y reducción de los promedios de 12,3 mmHg en la PAS, 9,2 mmHg en la PAD, 3,2 mg/dl creatinina y 7,2 mg/dl proteinuria en el grupo calcio 500 mg/día. Los resultados fueron parecidos en el grupo con suplemento en dosis máxima. Conclusión El calcio mejoró el pronóstico vascular en mujeres embarazadas con hipertensión al reducir los niveles de presión y los marcadores de preeclampsia. Registro Brasileiro de Ensaios Clínicos: RBR-9ngb95

Abstract Objective To analyze the effects of calcium supplementation on markers of preeclampsia over time by comparing the use of high- and low-dose calcium in hypertensive pregnant women. Methods This is a randomized clinical trial, placebo controlled, with three parallel groups carried out at the reference outpatient clinic for high-risk prenatal care in the South Region of Brazil, with intention-to-treat analysis and follow-up after four and eight weeks. The intervention consisted of ingesting calcium 500mg/day, calcium 1500mg/day and placebo. Data were analyzed according to a generalized mixed equation estimation model adopting α 0.05. Results The effect of low- and high-dose calcium on evolution over time was maintained between groups, even after adjustment for confounding factors. There was a significant difference in the parameters analyzed in the time and group interaction (p <0.000) and a decrease in the means of 12.3 mmHg in SBP, 9.2 mmHg in DBP, 3.2 mg/dl creatinine and 7.2 mg/dl proteinuria for the 500mg calcium/day group. The results were similar for the maximal supplementation group. Conclusion Calcium improved vascular prognosis in hypertensive pregnant women by reducing blood pressure levels and markers of preeclampsia. Brazilian Registry of Clinical Trials: RBR-9ngb95

Exploring the Complex Interplay of Trace Elements and Their Association with the Risk of Development of Pre-eclampsia in Pregnancy: a Case-Control.

Pre-eclampsia, a hypertensive disorder occurring during pregnancy, poses significant risks to maternal and fetal health worldwide. Despite extensive research, the precise cause of pre-eclampsia remains unknown. Recent studies have indicated that trace elements, essential minerals crucial for various biological processes, might be significant factors in the development of pre-eclampsia. This study examines the intricate relationship between trace elements (magnesium, copper, zinc, calcium, phosphorus, and iron) and the severity of pre-eclampsia. The study involves a total of 150 participants, categorized into three distinct groups: 50 individuals with mild pre-eclampsia, 50 with severe pre-eclampsia, and 50 healthy pregnant controls. Specifically, out of the 100 pre-eclampsia cases, 5 were identified as early-onset and 95 as late-onset. Participants were recruited from a tertiary care hospital based on stringent inclusion and exclusion criteria. All the trace elements were quantitatively measured by direct colorimetric method using the Beckman Coulter AU480 analyzer system (Beckman Coulter, USA). Pre-eclampsia cases exhibited a significantly lowered level of magnesium (2.02 mg/dL), zinc (57.62 mg/dL), calcium (8.02 mg/dL), and phosphorus (3.93 mg/dL). These levels were approximately 14.4%, 20.2%, 21.1%, and 22.6% lower when compared to healthy pregnant women. Conversely, copper (151.67 mg/dL) and iron (53 µg/dL) levels were significantly elevated in pre-eclampsia cases. Age emerged as a significant risk factor, correlating with heightened pre-eclampsia susceptibility. Magnesium showed a protective effect, correlating negatively with age and positively with gestational age. The complex relationships between trace elements, age, and pre-eclampsia underline the need for personalized interventions, potentially including magnesium supplementation, in high-risk pregnancies.

Classification of preeclampsia according to molecular clusters with the goal of achieving personalized prevention.

The prevention of pre-eclampsia is difficult due to the syndromic nature and multiple underlying mechanisms of this severe complication of pregnancy. The current clinical distinction between early- and late-onset disease, although clinically useful, does not reflect the true nature and complexity of the pathologic processes leading to pre-eclampsia. The current gaps in knowledge on the heterogeneous molecular pathways of this syndrome and the lack of adequate, specific diagnostic methods are major obstacles to early screening and tailored preventive strategies. The development of novel diagnostic tools for detecting the activation of the identified disease pathways would enable early, accurate screening and personalized preventive therapies. We implemented a holistic approach that includes the utilization of different proteomic profiling methods of maternal plasma samples collected from various ethnic populations and the application of systems biology analysis to plasma proteomic, maternal demographic, clinical characteristic, and placental histopathologic data. This approach enabled the identification of four molecular subclasses of pre-eclampsia in which distinct and shared disease mechanisms are activated. The current review summarizes the results and conclusions from these studies and the research and clinical implications of our findings.

Let's talk aspirin: A survey of barriers and facilitators faced by midwives when engaging in conversations about aspirin with women at risk of pre-eclampsia.

OBJECTIVE: Adherence to low-dose aspirin is key in preventing pre-eclampsia. Midwives are well positioned to support women to take aspirin as prescribed. This study aimed to understand the barriers and facilitators that midwives face during consultations with pregnant women about prophylactic aspirin. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional, UK-wide, quantitative and qualitative study of midwives was conducted between November 2020 and April 2021 using social media platforms. The survey was designed using the Theoretical Domains Framework by a team of researchers experienced in using it. An open-ended question was embedded in the survey to allow midwives to expand on matters related to the study subject. FINDINGS: Out of 160 responders, 37.5 % indicated inadequate engagement in conversations with women about aspirin prophylaxis. Domains 'Knowledge' (OR 13.7, 95 %CI 5.7-32.7, p < 0.001), 'Professional role and Identity' (OR 15.3, 95 %CI 6.4-36.7, p < 0.001) and 'Beliefs about capabilities' (OR 13.6, 95 %CI 6.1-30.6, p < 0.001) were most prominently associated with effective engagement. Best fit model was comprised of 'Beliefs about Capabilities', 'Social/professional role and identity', and 'Knowledge'. Midwives' comments focused on barriers within 'environmental context' related to 'conflicting views' and 'deficit in resources' that compromise positive reinforcement of aspirin use. Responders also provided helpful 'Top tips' that streamline their daily practice. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Beliefs about Capabilities, Social/professional role and identity, Knowledge, and Environmental Context and resources are key domains related to midwives' engagement in conversations about aspirin in pregnancy. Clear, up-to date information for midwives and the public should be available in an easy access format to allow provision of unequivocal advice related to the use of aspirin in pregnancy.

Advances in Folic Acid Biosensors and Their Significance in Maternal, Perinatal, and Paediatric Preventive Medicine.

Auxotrophic primates like human beings rely on exogenous dietary vitamin B9 supplementation to meet their metabolic demands. Folates play a crucial role in nucleotide synthesis and DNA methylation. Maternal folate deficiency causes several pregnancy-related complications, perinatal defects, and early childhood cognitive impairments. New evidence suggests excess FA is a potential risk factor resulting in unfavourable genomic and epigenomic alterations. Thus, it is essential to revisit the need to consistently monitor maternal folate levels during pregnancy. Yet, to date, no point-of-care folate-monitoring biosensor is commercially available. Here, we critically appraise the advances in folate biosensors to understand the translational gaps in biosensor design. Further, our review sheds light on the potential role of folate biosensors in strengthening maternal, perinatal, and child healthcare.

Orchestrated feedback regulation between melatonin and sex hormones involving GPER1-PKA-CREB signaling in the placenta.

Maintaining placental endocrine homeostasis is crucial for a successful pregnancy. Pre-eclampsia (PE), a gestational complication, is a leading cause of maternal and perinatal morbidity and mortality. Aberrant elevation of testosterone (T0 ) synthesis, reduced estradiol (E2 ), and melatonin productions have been identified in preeclamptic placentas. However, the precise contribution of disrupted homeostasis among these hormones to the occurrence of PE remains unknown. In this study, we established a strong correlation between suppressed melatonin production and decreased E2 as well as elevated T0 synthesis in PE placentas. Administration of the T0 analog testosterone propionate (TP; 2 mg/kg/day) to pregnant mice from E7.5 onwards resulted in PE-like symptoms, along with elevated T0 production and reduced E2 and melatonin production. Notably, supplementation with melatonin (10 mg/kg/day) in TP-treated mice had detrimental effects on fetal and placental development and compromised hormone synthesis. Importantly, E2 , but not T0 , actively enhanced melatonin synthetase AANAT expression and melatonin production in primary human trophoblast (PHT) cells through GPER1-PKA-CREB signaling pathway. On the other hand, melatonin suppressed the level of estrogen synthetase aromatase while promoting the expressions of androgen synthetic enzymes including 17ß-HSD3 and 3ß-HSD1 in PHT cells. These findings reveal an orchestrated feedback mechanism that maintains homeostasis of placental sex hormones and melatonin. It is implied that abnormal elevation of T0 synthesis likely serves as the primary cause of placental endocrine disturbances associated with PE. The suppression of melatonin may represent an adaptive strategy to correct the imbalance in sex hormone levels within preeclamptic placentas. The findings of this study offer novel evidence that identifies potential targets for the development of innovative therapeutic strategies for PE.

Determinants of pre-eclampsia among pregnant women attending antenatal care and delivery services at Bahir Dar public hospitals, northwest Ethiopia: A case-control study.

Background and Aims: Pre-eclampsia (PE) is a pregnancy-related syndrome that occurs after 20 weeks of pregnancy. The current study was designed to evaluate the determinants of PE in pregnant women following antenatal and delivery services. Methods: An institution-based case-control study was performed in governmental hospitals of Bahir Dar city. The data were collected using an interview-administered questionnaire and analyzed by SPSS version 20 software. Bivariate and multivariable logistic regression models were utilized for the analysis of variables. A p < 0.05 was used to declare the level of significance. Results: In this study, the mean ages (in years) of cases and controls were 28.20 ± 5.66 and 27.52 ± 4.70, respectively. Factors such as: being primiparous (adjusted odds ratio [AOR]: 3.19 at 95% confidence interval [CI]: 1.71, 5.97), family history of hypertension (HTN) (AOR: 4.14 at 95% CI: 1.71, 10.05), previous history of PE (AOR: 7.97 at 95% CI: 2.42, 26.63), number of antenatal care (ANC) visits (AOR: 5.43 at 95% CI: 2.86, 10.33), not taking iron and folic acid supplement (AOR: 4.46 at 95% CI: 1.59, 12.48), body mass index ≥25 kg/m2 (AOR: 3.47 at 95% CI: 1.78, 6.77), not consuming vegetables (AOR: 1.99 at 95% CI: 1.07, 3.69) and not consuming egg, milk and milk products (AOR: 3.00 at 95% CI: 1.47, 6.11) were the determinants of PE. Conclusion: In this study, different determinants of PE were identified. Hence, special attention should be given for primiparous women, women having previous history of PE and family history of HTN. Moreover, nutritional counseling should be given for pregnant women during ANC visits. Besides, higher officials should design an appropriate strategy to increase the number of mothers to complete their ANC visits and to take iron and folic acid supplements. Furthermore, to verify the determinants of PE, community-based cohort studies are warranted.

A randomized controlled trial of loading dose alone versus pritchard regimen of magnesium sulphate, for seizure prophylaxis in severe preeclampsia.

Background: Preeclampsia poses a significant risk of maternal and neonatal morbidity and mortality. Magnesium sulfate superiority for seizure prophylaxis in severe preeclampsia has been proven globally. However, the search for the lowest effective dose is an area of continuing research. Aim: The aim of this study was to compare the effectiveness of loading dose with the Pritchard regimen of magnesium sulfate for seizure prophylaxis in severe preeclampsia. Materials and Methods: A total of 138 eligible women after 28-week gestation with severe preeclampsia were randomized to either receiving a single loading dose of MgSO4 (study arm: n = 69) or Pritchard regimen of MgSO4 (control: n = 69). The effectiveness was assessed by the development of seizure. The results obtained were analyzed using SPSS version 21. Categorical variables were analyzed using the Chi-square test and normally distributed continuous variables were analyzed with t-test and Fisher's exact test. P < 0.05 was considered statistical significance. Results: There were no significant differences between those who received only the loading dose when compared with those who had Pritchard regimen other than a single recorded convulsion among the control group (P = 0.316). Similarly, except for the duration of hospital stay which was significantly longer in the Pritchard group (P = 0.019), both the arms of the study shared similar maternal and fetal outcomes. Conclusion: This study suggests the effectiveness of just the loading dose of magnesium sulfate when compared with the standardized Pritchard regimen in the prevention of seizure among women with severe preeclampsia. The study also demonstrated safety and similarity in fetal-maternal outcome. The loading dose only had an added advantage of shorter duration of hospital stay.

Résumé Contexte: La prééclampsie pose un risque important de morbidité et de mortalité maternelle et néonatale. La supériorité du sulfate de magnésium pour 15 prophylaxies épileptiques dans la prééclampsie sévère a été prouvée à l'échelle mondiale. Cependant, la recherche de la dose efficace la plus faible est un domaine de recherche continue. Objectif: L'objectif de cette étude était de comparer l'efficacité de la dose de charge avec le schéma de Pritchard de sulfate de magnésium pour la prophylaxie de 17 épilepsies dans la prééclampsie sévère. Matériels et méthodes: Un total de 138 femmes éligibles après 28 semaines de gestation atteintes de 18 prééclampsie ont été randomisés pour recevoir soit une dose de charge unique de MgSO4 (groupe d'étude : n = 69) soit un régime de Pritchard de MgSO4 (contrôle : n = 69). L'efficacité a été évaluée par le développement de saisie. Les résultats obtenus ont été analysés à l'aide de SPSS version 21. Les 19 variables catégorielles ont été analysées à l'aide du test du chi carré et les variables continues normalement distribuées ont été analysées à l'aide du test t et du test exact de Fisher. 20 P < 0,05 était considéré comme une signification statistique. Résultats: Il n'y avait pas de différences significatives entre ceux qui n'avaient reçu que la dose de charge 21 par rapport à ceux qui avaient reçu le régime de Pritchard autre qu'une seule convulsion enregistrée parmi le groupe témoin (P = 0,316). 22 De même, à l'exception de la durée du séjour à l'hôpital qui était significativement plus longue dans le groupe Pritchard (P = 0,019), les deux bras de l'étude 23 partageaient des résultats maternels et fœtaux similaires. Conclusion: Cette étude suggère l'efficacité de la seule dose de charge de sulfate de magnésium par rapport au régime de Pritchard standardisé dans la prévention des convulsions chez les femmes atteintes de prééclampsie sévère. L'étude a également démontré 24 l'innocuité et la similarité des résultats fœto-maternels. La dose de charge n'avait qu'un avantage supplémentaire de durée d'hospitalisation plus courte. 25. Mots-clés: Éclampsie, dose de charge, sulfate de magnésium, régime de Pritchard, prophylaxie des crises, prééclampsie sévère.

Vitamin D in pregnancy (GRAVITD) - a randomised controlled trial identifying associations and mechanisms linking maternal Vitamin D deficiency to placental dysfunction and adverse pregnancy outcomes - study protocol.

BACKGROUND: The prevalence of vitamin D deficiency is high among pregnant women. Vitamin D deficiency in pregnancy is associated with increased risk of adverse pregnancy outcomes especially complications related to placental dysfunction and insulin resistance. The objective of this study is to investigate if a higher dose of vitamin D supplementation in pregnancy reduces the prevalence of vitamin D deficiency and prevents adverse pregnancy outcome with special emphasize on preeclampsia, foetal growth restriction and gestational diabetes. METHODS: GRAVITD is a double-blinded randomised trial with parallel groups where all pregnant women attending the free of charge national nuchal translucency scan programme in gestational week 10-14 at Randers Regional Hospital are invited to participate. Enrolment started in June 2020. Participants are randomised in a two armed randomization with a 1:1 allocation ratio into 1) control group - receives 10 µg of vitamin D or 2) intervention group - receives 90 µg of vitamin D. A total of 2000 pregnant women will be included. Maternal blood samples and questionnaires describing life-style habits are collected upon enrolment. For half of the participants blood samples and questionnaires will be repeated again in 3rd trimester. Blood samples will be analysed for 25-hydroxy-vitamin D using high-performance liquid chromatography coupled with tandem mass spectrometry. Upon delivery, placental tissue and umbilicalcord blood will be collected and information on maternal and fetal outcomes will be exstracted from medical records. The primary outcomes are serum levels of 25-hydroxy-vitamin D ≥ 75 nmol/L and the rate of preeclampsia, foetal growth restriction and gestational diabetes. Secondary outcome includes identification and impact on placental functions related to vitamin D. A tertiary outcome is to initiate a cohort of children born from mothers in the trial for future follow-up of the effects of vitamin D on childhood health. DISCUSSION: Provided that this trial finds beneficial effects of a higher dose of vitamin D supplementation in pregnancies, official recommendations can be adjusted accordingly. This will provide a low-cost and easily implementable adjustment of prenatal care which can improve health for both mother and child during pregnancy and beyond. TRIAL REGISTRATION: ClinicalTrial.gov: NCT04291313 . Registered February 17, 2020.

Impact of free maternity services on outcomes related to hypertensive disorders of pregnancy at Moi Teaching and Referral Hospital in Kenya: a retrospective analysis.

BACKGROUND: Preeclampsia is a major contributor to maternal and neonatal mortality worldwide. Ninety-nine percent of these deaths occur in resource limited settings. One of the greatest barriers to women seeking medical attention remains the cost of care. Kenya implemented a nation-wide policy change in 2013, offering free inpatient maternity services to all women to address this concern. Here, we explore the impact of this policy change on maternal and neonatal outcomes specific to the hypertensive disorders of pregnancy. METHODS: We conducted a retrospective cross-sectional chart review of patients discharged or deceased with a diagnosis of gestational hypertension, preeclampsia, eclampsia or HELLP syndrome at a tertiary referral center in western Kenya one year before (June 1, 2012-May 31, 2013) and one year after (June 1, 2013-May 31, 2014) free maternity services were introduced at public facilities across the country. Demographic information, obstetric history, medical history, details of the current pregnancy, diagnosis on admission and at discharge, antepartum treatment, maternal outcomes, and neonatal outcomes were collected and comparisons were made between the time points. RESULTS: There were more in hospital births after policy change was introduced. The proportion of women diagnosed with a hypertensive disorder of pregnancy was higher in the year before free maternity care although there was a statistically significant increase in the proportion of women diagnosed with gestational hypertension after policy change. Among those diagnosed with hypertensive disorders, there was no difference in the proportion who developed obstetric or medical complications. Of concern, there was a statistically significant increase in the proportion of women dying as a result of their condition. There was a statistically significant increase in the use of magnesium sulfate for seizure prophylaxis. There was no overall difference in the use of anti-hypertensives between groups and no overall difference in the proportion of women who received dexamethasone for fetal lung maturity. CONCLUSIONS: Free maternity services, however necessary, are insufficient to improve maternal and neonatal outcomes related to the hypertensive disorders of pregnancy at a tertiary referral center in western Kenya. Multiple complementary strategies acting in unison are urgently needed.

Analysis of a maternal health medicines pipeline database 2000-2021: New candidates for the prevention and treatment of fetal growth restriction.

OBJECTIVE: The Accelerating Innovation for Mothers project established a new database of candidate medicines under development between 2000 and 2021 for five pregnancy-related conditions, including fetal growth restriction. The objective was to assess medicines for fetal growth restriction and their potential for clinical use globally. DESIGN: Landscape analysis. SETTING: Global (focus on low- and middle-income countries, LMICs). SAMPLE: Drugs, dietary supplements and biologics under investigation for prevention or treatment of fetal growth restriction. METHODS: A research pipeline database of medicines was created through searching AdisInsight, PubMed and various grant and clinical trial databases. Analysis of clinical and preclinical candidates were descriptive. MAIN OUTCOMES MEASURES: Fetal growth restriction candidates in clinical development were identified and ranked as high, medium or low potential based on prespecified criteria, including efficacy, safety and accessibility. RESULTS: Of the 444 unique candidates in the database across all five pregnancy-related conditions, 63 were for fetal growth restriction. Of these, 31 were in clinical development (phases I, II or III) and 32 were in preclinical development. Three candidates, aspirin, l-arginine and vitamin D, were ranked as having high potential as preventive agents. There were no high-potential candidates for treating fetal growth restriction, although five candidates were ranked as having medium potential: allylestrenol, dalteparin, omega-3 fatty acids, tadalafil, and United Nations International Multiple Micronutrient Antenatal Preparation (UNIMMAP). CONCLUSIONS: l-Arginine, aspirin and vitamin D are promising, high-potential preventative agents for fetal growth restriction. Based on the medicines pipeline, new pharmacological agents for fetal growth restriction are unlikely to emerge in the near future.

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.