Treatment of Gestational Diabetes Mellitus Diagnosed Early in Pregnancy.

BACKGROUND: Whether treatment of gestational diabetes before 20 weeks' gestation improves maternal and infant health is unclear. METHODS: We randomly assigned, in a 1:1 ratio, women between 4 weeks' and 19 weeks 6 days' gestation who had a risk factor for hyperglycemia and a diagnosis of gestational diabetes (World Health Organization 2013 criteria) to receive immediate treatment for gestational diabetes or deferred or no treatment, depending on the results of a repeat oral glucose-tolerance test [OGTT] at 24 to 28 weeks' gestation (control). The trial included three primary outcomes: a composite of adverse neonatal outcomes (birth at <37 weeks' gestation, birth trauma, birth weight of ≥4500 g, respiratory distress, phototherapy, stillbirth or neonatal death, or shoulder dystocia), pregnancy-related hypertension (preeclampsia, eclampsia, or gestational hypertension), and neonatal lean body mass. RESULTS: A total of 802 women underwent randomization; 406 were assigned to the immediate-treatment group and 396 to the control group; follow-up data were available for 793 women (98.9%). An initial OGTT was performed at a mean (±SD) gestation of 15.6±2.5 weeks. An adverse neonatal outcome event occurred in 94 of 378 women (24.9%) in the immediate-treatment group and in 113 of 370 women (30.5%) in the control group (adjusted risk difference, -5.6 percentage points; 95% confidence interval [CI], -10.1 to -1.2). Pregnancy-related hypertension occurred in 40 of 378 women (10.6%) in the immediate-treatment group and in 37 of 372 women (9.9%) in the control group (adjusted risk difference, 0.7 percentage points; 95% CI, -1.6 to 2.9). The mean neonatal lean body mass was 2.86 kg in the immediate-treatment group and 2.91 kg in the control group (adjusted mean difference, -0.04 kg; 95% CI, -0.09 to 0.02). No between-group differences were observed with respect to serious adverse events associated with screening and treatment. CONCLUSIONS: Immediate treatment of gestational diabetes before 20 weeks' gestation led to a modestly lower incidence of a composite of adverse neonatal outcomes than no immediate treatment; no material differences were observed for pregnancy-related hypertension or neonatal lean body mass. (Funded by the National Health and Medical Research Council and others; TOBOGM Australian New Zealand Clinical Trials Registry number, ACTRN12616000924459.).

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial.

BACKGROUND: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks' gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. METHODS: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks' gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. FINDINGS: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference -3·39%, 90% CI -8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. INTERPRETATION: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks' gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. FUNDING: UK Medical Research Council and Indian Department of Biotechnology.

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy: A systematic review and meta-analysis.

BACKGROUND: Treatment with vaginal progesterone reduces the risk of miscarriage and preterm birth in selected high-risk women. The hypothesis that vaginal progesterone can reduce the risk of hypertensive disorders of pregnancy (HDP) is unexplored. OBJECTIVES: To summarise the evidence on the effectiveness of vaginal progesterone to reduce the risk of HDP. SEARCH STRATEGY: We searched Embase (OVID), MEDLINE (OVID), PubMed, CENTRAL and clinicaltrials.gov from inception until 20 June 2023. SELECTION CRITERIA: We included placebo-controlled randomised trials (RCTs) of vaginal progesterone for the prevention or treatment of any pregnancy complications. DATA COLLECTION AND ANALYSIS: We extracted absolute event numbers for HDP and pre-eclampsia in women receiving vaginal progesterone or placebo, and meta-analysed the data with a random effects model. We appraised the certainty of the evidence using GRADE methodology. MAIN RESULTS: The quantitative synthesis included 11 RCTs, of which three initiated vaginal progesterone in the first trimester, and eight in the second or third trimesters. Vaginal progesterone started in the first trimester of pregnancy lowered the risk of any HDP (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53-0.93, 2 RCTs, n = 4431 women, I2 = 0%; moderate-certainty evidence) and pre-eclampsia (RR 0.61, 95% CI 0.41-0.92, 3 RCTs, n = 5267 women, I2 = 0%; moderate-certainty evidence) when compared with placebo. Vaginal progesterone started in the second or third trimesters was not associated with a reduction in HDP (RR 1.19, 95% CI 0.67-2.12, 3 RCTs, n = 1602 women, I2 = 9%; low-certainty evidence) or pre-eclampsia (RR 0.97, 95% CI 0.71-1.31, 5 RCTs, n = 4274 women, I2 = 0%; low-certainty evidence). CONCLUSIONS: Our systematic review found first-trimester initiated vaginal micronised progesterone may reduce the risk of HDP and pre-eclampsia.

A summary of the 2023 Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) hypertension in pregnancy guideline.

INTRODUCTION: Hypertensive disorders of pregnancy (HDP) affect up to 10% of all pregnancies annually and are associated with an increased risk of maternal and fetal morbidity and mortality. This guideline represents an update of the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) guidelines for the management of hypertensive disorders of pregnancy 2014 and has been approved by the National Health and Medical Research Council (NHMRC) under section 14A of the National Health and Medical Research Council Act 1992. In approving the guideline recommendations, NHMRC considers that the guideline meets NHMRC's standard for clinical practice guidelines. MAIN RECOMMENDATIONS: A total of 39 recommendations on screening, preventing, diagnosing and managing HDP, especially preeclampsia, are presented in this guideline. Recommendations are presented as either evidence-based recommendations or practice points. Evidence-based recommendations are presented with the strength of recommendation and quality of evidence. Practice points were generated where there was inadequate evidence to develop specific recommendations and are based on the expertise of the working group. CHANGES IN MANAGEMENT RESULTING FROM THE GUIDELINE: This version of the SOMANZ guideline was developed in an academically robust and rigorous manner and includes recommendations on the use of combined first trimester screening to identify women at risk of developing preeclampsia, 14 pharmacological and two non-pharmacological preventive interventions, clinical use of angiogenic biomarkers and the long term care of women who experience HDP. The guideline also includes six multilingual patient infographics which can be accessed through the main website of the guideline. All measures were taken to ensure that this guideline is applicable and relevant to clinicians and multicultural women in regional and metropolitan settings in Australia and New Zealand.

Hypertensive Disorders of Pregnancy.

Hypertensive disorders of pregnancy are a major contributor to maternal morbidity and mortality in the United States and include chronic and gestational hypertension, preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, eclampsia, and chronic hypertension with superimposed preeclampsia. For patients with chronic hypertension, oral antihypertensive therapy should be initiated or titrated at a blood pressure threshold of 140/90 mm Hg or greater. Gestational hypertension and preeclampsia without severe features can be managed with blood pressure monitoring, laboratory testing for disease progression, antenatal testing for fetal well-being, and delivery at 37 weeks' gestation. The use of antihypertensive drugs to control nonsevere hypertension in the setting of gestational hypertension and preeclampsia does not improve outcomes and is not recommended. Antihypertensive therapy should be initiated expeditiously for acute-onset severe hypertension to prevent hemorrhagic stroke. Preeclampsia with severe features requires immediate stabilization and inpatient treatment with magnesium sulfate for seizure prophylaxis and antenatal corticosteroids (if preterm). Patients in the preterm period should receive antenatal corticosteroids without delaying delivery to complete courses. Hypertensive disorders of pregnancy can worsen or initially present after delivery and account for up to 44% of pregnancy-related deaths in the first six days postpartum. Patients should be monitored closely in the early postpartum period. Hypertensive disorders of pregnancy are linked to poor long-term maternal and fetal outcomes, including increased maternal lifetime risk of cardiovascular disease. Daily low-dose aspirin therapy starting at 12 to 16 weeks' gestation is safe and effective for reducing the risk of preeclampsia for patients with risk factors.

First-trimester preterm preeclampsia prediction model for prevention with low-dose aspirin.

INTRODUCTION: Preeclampsia (PE) is a major maternal and fetal threat. Previous risk-scoring methods in guidelines lacked precision. The Fetal Medicine Foundation (FMF) proposed a first-trimester PE screening model using Bayes' theorem. PE PREDICTION MODEL: FMF prediction model combines maternal characteristics and medical/obstetrical history to determine prior risk and further incorporate maternal blood pressure, maternal serum biomarkers, and uterine Doppler pulsatility index expressed as multiples of the median (MoM) to estimate posterior risk. LOW-DOSE ASPIRIN PREVENTION: Low-dose aspirin is one of the potential PE prevention strategies. Initiating it before 16 weeks is crucial. Aspirin's antiplatelet and anti-inflammatory properties align with PE's pathophysiology. Dosing and resistance warrant further study, but a standard regimen of 150 mg nightly, starting before 16 weeks, is widely supported. PE PREVENTION IN PRACTICE: Clinical trials, including ASPRE, affirm aspirin's role in PE prevention. Starting aspirin based on FMF screening significantly reduces preterm PE and associated complications. ADVANCEMENTS AND PROSPECTS: Emerging research explores predictors like maternal ophthalmic arterial waveform. Regional variations, especially in Asian populations, are considered. Machine learning and AI show promise, but examiner expertise remains essential for accurate prediction. In conclusion, integrating FMF's first-trimester PE screening with low-dose aspirin offers a promising strategy. Further advancements may enhance precision and broaden prevention efforts.

Treatment of obstructive sleep apnea in high risk pregnancy: a multicenter randomized controlled trial.

BACKGROUND: Obstructive sleep apnea (OSA) during pregnancy is a risk factor for preeclampsia possibly through a link to placental physiology. This study evaluates the efficacy of continuous positive airway pressure (CPAP) on the modulation of blood pressure and the reduction in preeclampsia in women with high-risk pregnancy and OSA. METHODS: A multicenter open-label, randomized controlled trial comparing CPAP treatment versus usual antenatal care was conducted in three academic hospitals in Bangkok, Thailand. Participants included singleton pregnant women aged older than 18 years with any high-risk condition (i.e., chronic hypertension, obesity, history of preeclampsia or gestational diabetes in the previous pregnancy, or diabetes), and OSA (respiratory disturbance index 5-29.99 events/hour by polysomnography), who presented either in the first trimester (gestational age, GA 0-16 weeks) or subsequently developed OSA during the 2nd trimester (GA 24-28 weeks). The primary endpoint was blood pressure during antenatal care. Secondary endpoints included the incidence of preeclampsia. An intention-to-treat analysis was performed with additional per-protocol and counterfactual analyses for handling of nonadherence. RESULTS: Of 340 participants, 96.5% were recruited during the first trimester. Thirty participants were later excluded leaving 153 and 157 participants in the CPAP and usual-care groups for the modified-intention-to-treat analysis. CPAP adherence rate was 32.7% with average use of 2.5 h/night. Overall, CPAP treatment significantly lowered diastolic blood pressure (DBP) by - 2.2 mmHg [95% CI (- 3.9, - 0.4), p = 0.014], representing approximately - 0.5 mmHg per hour of CPAP use [95%CI (- 0.89, - 0.10), p = 0.013]. CPAP treatment also altered the blood pressure trajectory by continuously lowering DBP throughout pregnancy with mean differences (95% CI) of - 3.09 (- 5.34, - 0.93), - 3.49 (- 5.67, - 1.31) and - 3.03 (- 5.20, - 0.85) mmHg at GA 18-20, 24-28, and 32-34 weeks, respectively compared to 0-16 weeks. Preeclampsia rate was 13.1% (20/153 participants) in the CPAP and 22.3% (35/157 participants) in the usual-care group with a risk difference (95% CI) of - 9% (- 18%, - 1%, p-value = 0.032) and a number-needed-to-treat (95% CI) of 11 (1, 21). CONCLUSIONS: CPAP treatment in women with even mild-to-moderate OSA and high-risk pregnancy demonstrated reductions in both DBP and the incidence of preeclampsia. CPAP treatment also demonstrated a sustained reduction in DBP throughout gestation. Trial registration ClinicalTrial.GovNCT03356106, retrospectively registered November 29, 2017.

Society for Maternal-Fetal Medicine Special Statement: Prophylactic low-dose aspirin for preeclampsia prevention-quality metric and opportunities for quality improvement.

Prophylactic low-dose aspirin reduces the rates of preeclampsia, preterm birth, fetal growth restriction, and perinatal death in patients with risk factors for preeclampsia. Despite recommendations from the US Preventive Services Task Force, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine, low-dose aspirin use is reported in <50% of patients with high-risk factors and <25% of patients with >1 moderate-risk factor. These low use rates represent an important "quality gap" and demonstrate the need for quality improvement activities. In this article, we outline the specifications for a process metric to standardize the measurement of the rate of aspirin use. Furthermore, we outline an approach to conducting a quality improvement project to increase the use of aspirin by patients with risk factors for preeclampsia.

National and international guidelines on the management of twin pregnancies: a comparative review.

Twin gestations are associated with increased risk of pregnancy complications. However, high-quality evidence regarding the management of twin pregnancies is limited, often resulting in inconsistencies in the recommendations of various national and international professional societies. In addition, some recommendations related to the management of twin gestations are often missing from the clinical guidelines dedicated to twin pregnancies and are instead included in the practice guidelines on specific pregnancy complications (eg, preterm birth) of the same professional society. This can make it challenging for care providers to easily identify and compare recommendations for the management of twin pregnancies. This study aimed to identify, summarize, and compare the recommendations of selected professional societies from high-income countries on the management of twin pregnancies, highlighting areas of both consensus and controversy. We reviewed clinical practice guidelines of selected major professional societies that were either specific to twin pregnancies or were focused on pregnancy complications or aspects of antenatal care that may be relevant for twin pregnancies. We decided a priori to include clinical guidelines from 7 high-income countries (United States, Canada, United Kingdom, France, Germany, and Australia and New Zealand grouped together) and from 2 international societies (International Society of Ultrasound in Obstetrics and Gynecology and the International Federation of Gynecology and Obstetrics). We identified recommendations regarding the following care areas: first-trimester care, antenatal surveillance, preterm birth and other pregnancy complications (preeclampsia, fetal growth restriction, and gestational diabetes mellitus), and timing and mode of delivery. We identified 28 guidelines published by 11 professional societies from the 7 countries and 2 international societies. Thirteen of these guidelines focus on twin pregnancies, whereas the other 16 focus on specific pregnancy complications predominantly in singletons but also include some recommendations for twin pregnancies. Most of the guidelines are recent, with 15 of the 29 guidelines published over the past 3 years. We identified considerable disagreement among guidelines, primarily in 4 key areas: screening and prevention of preterm birth, using aspirin to prevent preeclampsia, defining fetal growth restriction, and the timing of delivery. In addition, there is limited guidance on several important areas, including the implications of the "vanishing twin" phenomenon, technical aspects and risks of invasive procedures, nutrition and weight gain, physical and sexual activity, the optimal growth chart to be used in twin pregnancies, the diagnosis and management of gestational diabetes mellitus, and intrapartum care.This consolidation of key recommendations across several clinical practice guidelines can assist healthcare providers in accessing and comparing recommendations on the management of twin pregnancies and identifies high-priority areas for future research based on either continued disagreement among societies or limited current evidence to guide care.

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 great obstetrical syndromes and the placenta.

Although historically pre-eclampsia, preterm birth, abruption, fetal growth restriction and stillbirth have been viewed as clinically distinct entities, a growing body of literature has demonstrated that the placenta and its development is the root cause of many cases of these conditions. This has led to the term 'the great obstetrical syndromes' being coined to reflect this common origin. Although these conditions mostly manifest in the second half of pregnancy, a failure to complete deep placentation (the transition from histiotrophic placentation to haemochorial placenta at 10-18 weeks of gestation via a second wave of extravillous trophoblast invasion), is understood to be key to the pathogenesis of the great obstetrical syndromes. While the reasons that the placenta fails to achieve deep placentation remain active areas of investigation, maternal inflammation and thrombosis have been clearly implicated. From a clinical standpoint these mechanisms provide a biological explanation of how low-dose aspirin, which affects the COX-1 receptor (thrombosis) and the COX-2 receptor (inflammation), prevents not just pre-eclampsia but all the components of the great obstetrical syndromes if initiated early in pregnancy. The optimal dose of low-dose aspirin that is maximally effective in pregnancy remains a question open for further research. Additionally, other candidate medications have been identified that may also prevent pre-eclampsia, and further study of them may offer therapeutic options beyond low-dose aspirin. Interestingly, three of the eight identified compounds (hydroxychloroquine, metformin and pravastatin) are known to decrease inflammation.

ASPRE trial: effects of aspirin on mean arterial blood pressure and uterine artery pulsatility index trajectories in pregnancy.

OBJECTIVES: The mechanism by which aspirin prevents pre-eclampsia is poorly understood, and its effects on biomarkers throughout pregnancy are unknown. We aimed to investigate the effects of aspirin on mean arterial pressure (MAP) and mean uterine artery pulsatility index (UtA-PI) using repeated measures from women at increased risk of preterm pre-eclampsia. METHODS: This was a longitudinal secondary analysis of the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Pre-eclampsia Prevention (ASPRE) trial using repeated measures of MAP and UtA-PI. In the trial, 1620 women at increased risk of preterm pre-eclampsia were identified using the Fetal Medicine Foundation algorithm at 11 + 0 to 13 + 6 weeks, of whom 798 were randomly assigned to receive 150 mg/day aspirin and 822 were assigned to receive placebo daily from 11-14 weeks to 36 weeks of gestation or delivery, whichever came first. MAP and UtA-PI were measured at baseline and follow-up visits at 19-24, 32-34 and 36 weeks of gestation. Generalized additive mixed models with treatment by gestational age interaction terms were used to investigate the effects of aspirin on MAP and UtA-PI trajectories over time. RESULTS: Among 798 participants in the aspirin group and 822 in the placebo group, there were 5951 MAP and 5942 UtA-PI measurements. Trajectories of raw and multiples of the median (MoM) values of MAP did not differ significantly between the two groups (MAP MoM analysis: P-value for treatment by gestational age interaction, 0.340). In contrast, trajectories of raw and MoM values of UtA-PI showed a significantly steeper decline in the aspirin group than in the placebo group, with the difference mainly driven by a more pronounced reduction before 20 weeks of gestation (UtA-PI MoM analysis: P-value for treatment by gestational age interaction, 0.006). CONCLUSIONS: In women at increased risk of preterm pre-eclampsia, 150 mg/day aspirin initiated in the first trimester does not affect MAP but is associated with a significant decrease in mean UtA-PI, particularly before 20 weeks of gestation. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prediction of fetal and neonatal outcomes after preterm manifestations of placental insufficiency: systematic review of prediction models.

OBJECTIVES: To identify all prediction models for fetal and neonatal outcomes in pregnancies with preterm manifestations of placental insufficiency (gestational hypertension, pre-eclampsia, HELLP syndrome or fetal growth restriction with its onset before 37 weeks' gestation) and to assess the quality of the models and their performance on external validation. METHODS: A systematic literature search was performed in PubMed, Web of Science and EMBASE. Studies describing prediction models for fetal/neonatal mortality or significant neonatal morbidity in patients with preterm placental insufficiency disorders were included. Data extraction was performed using the CHARMS checklist. Risk of bias was assessed using PROBAST. Literature selection and data extraction were performed by two researchers independently. RESULTS: Our literature search yielded 22 491 unique publications. Fourteen were included after full-text screening of 218 articles that remained after initial exclusions. The studies derived a total of 41 prediction models, including four models in the setting of pre-eclampsia or HELLP, two models in the setting of fetal growth restriction and/or pre-eclampsia and 35 models in the setting of fetal growth restriction. None of the models was validated externally, and internal validation was performed in only two studies. The final models contained mainly ultrasound (Doppler) markers as predictors of fetal/neonatal mortality and neonatal morbidity. Discriminative properties were reported for 27/41 models (c-statistic between 0.6 and 0.9). Only two studies presented a calibration plot. The risk of bias was assessed as unclear in one model and high for all other models, mainly owing to the use of inappropriate statistical methods. CONCLUSIONS: We identified 41 prediction models for fetal and neonatal outcomes in pregnancies with preterm manifestations of placental insufficiency. All models were considered to be of low methodological quality, apart from one that had unclear methodological quality. Higher-quality models and external validation studies are needed to inform clinical decision-making based on prediction models. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

The long-term risk of cardiovascular disease among women with a history of hypertensive disorders of pregnancy: a systematic review of clinical practice guidelines.

BACKGROUND: The lifelong risks of cardiovascular disease following preeclampsia and gestational hypertension are well-established. However, it is unclear whether this evidence has been translated into clinical practice guidelines. Thus, this review aimed to assess the quality and content of Australian clinical practice guidelines regarding the risk of cardiovascular disease following gestational hypertension and preeclampsia. METHODS: We conducted a systematic search of MEDLINE (Ovid), EMBASE (Ovid), and CINAHL databases, as well as hospital, obstetric society, and medical college websites. Publications were included if: they were a clinical practice guideline; were published in the previous ten years; and included recommendations for the management of future cardiovascular disease risk following hypertensive disorders of pregnancy. Quality assessment was performed using Appraisal of Guidelines for Research and Evaluation Instrument Version Two (AGREE-II) and AGREE Recommendations Excellence Instrument (AGREE-REX). RESULTS: Eighteen guidelines were identified, and of these, less than half (n = 8) included recommendations for managing future cardiovascular risk following hypertensive disorders of pregnancy. Across these eight, four main counselling recommendations were found regarding (1) risk of future cardiovascular disease; (2) risk factor screening; (3) lifestyle interventions; and (4) prenatal counselling for future pregnancies. The quality and content of these recommendations varied significantly, and the majority of guidelines (87.5%) were assessed as low to moderate quality. CONCLUSIONS: There are limited Australian clinical practice guidelines providing appropriate advice regarding future risk of cardiovascular disease following hypertensive disorders of pregnancy. The quality and content of these guidelines varied significantly. These findings highlight the need for improved translation from evidence-based research to enhance clinical care and guidance.

Aspirin in pregnancy: a review of indications, timing, dosing and efficacy.

PURPOSE OF REVIEW: The aim of this study was to evaluate the recent literature examining the utility of low-dose daily aspirin (LDA) in the prevention of preeclampsia and other potential adverse perinatal sequelae. The evidence supporting various aspirin doses and timing of initiation of treatment for this purpose will be examined. The potential benefits of LDA therapy in pregnancy will be discussed weighing against any potential associated harm. RECENT FINDINGS: Findings from several recent meta-analyses of randomized controlled trials are consistent with prior studies in showing a reduction in risk for preeclampsia with LDA use in individuals at an increased risk for this complication. Some studies suggest aspirin at a dose greater than the current recommended 81 mg is associated with the highest reduction in preterm PE.Several studies have demonstrated a reduction in risk for preterm birth, small for gestational age (SGA) infant or intrauterine growth restriction (IUGR), and a reduction in the risk of perinatal mortality associated with aspirin use. The findings of reduced preterm birth (PTB) and IUGR were also demonstrated among low-risk patients.Identifying patients at risk was re-evaluated, with resulting changes to existing United States Preventive Services Task Force (USPSTF) guidelines. SUMMARY: This review of recent evidence suggests a decreased rate of preeclampsia at aspirin doses higher than the standardly used 81 mg when treatment is initiated prior to 16 weeks of gestation. Although LDA use seems promising for other outcomes such as preterm delivery and IUGR, further studies to strengthen recommendations are warranted.

Alternative magnesium sulphate regimens for women with pre-eclampsia and eclampsia.

BACKGROUND: Magnesium sulphate is the drug of choice for the prevention and treatment of women with eclampsia. Regimens for administration of this drug have evolved over the years, but there is no clarity on the comparative benefits or harm of alternative regimens. This is an update of a review first published in 2010. OBJECTIVES: To assess if one magnesium sulphate regimen is better than another when used for the care of women with pre-eclampsia or eclampsia, or both, to reduce the risk of severe morbidity and mortality for the woman and her baby. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (29 April 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised trials and cluster-randomised trials comparing different regimens for administration of magnesium sulphate used in women with pre-eclampsia or eclampsia, or both. Comparisons included different dose regimens, intramuscular versus intravenous route for maintenance therapy, and different durations of therapy. We excluded studies with quasi-random or cross-over designs. We included abstracts of conference proceedings if compliant with the trustworthiness assessment. DATA COLLECTION AND ANALYSIS: For this update, two review authors assessed trials for inclusion, performed risk of bias assessment, and extracted data. We checked data for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: For this update, a total of 16 trials (3020 women) met our inclusion criteria: four trials (409 women) compared regimens for women with eclampsia, and 12 trials (2611 women) compared regimens for women with pre-eclampsia. Most of the included trials had small sample sizes and were conducted in low- and middle-income countries. Eleven trials reported adequate randomisation and allocation concealment. Blinding of participants and clinicians was not possible in most trials. The included studies were for the most part at low risk of attrition and reporting bias. Treatment of women with eclampsia (four comparisons) One trial compared a loading dose-alone regimen with a loading dose plus maintenance dose regimen (80 women). It is uncertain whether either regimen has an effect on the risk of recurrence of convulsions or maternal death (very low-certainty evidence). One trial compared a lower-dose regimen with standard-dose regimen over 24 hours (72 women). It is uncertain whether either regimen has an effect on the risk of recurrence of convulsion, severe morbidity, perinatal death, or maternal death (very low-certainty evidence). One trial (137 women) compared intravenous (IV) versus standard intramuscular (IM) maintenance regimen. It is uncertain whether either route has an effect on recurrence of convulsions, death of the baby before discharge (stillbirth and neonatal death), or maternal death (very low-certainty evidence). One trial (120 women) compared a short maintenance regimen with a standard (24 hours after birth) maintenance regimen. It is uncertain whether the duration of the maintenance regimen has an effect on recurrence of convulsions, severe morbidity, or side effects such as nausea and respiratory failure. A short maintenance regimen may reduce the risk of flushing when compared to a standard 24 hours maintenance regimen (risk ratio (RR) 0.27, 95% confidence interval (CI) 0.08 to 0.93; 1 trial, 120 women; low-certainty evidence). Many of our prespecified critical outcomes were not reported in the included trials. Prevention of eclampsia for women with pre-eclampsia (five comparisons) Two trials (462 women) compared loading dose alone with loading dose plus maintenance therapy. Low-certainty evidence suggests an uncertain effect with either regimen on the risk of eclampsia (RR 2.00, 95% CI 0.61 to 6.54; 2 trials, 462 women) or perinatal death (RR 0.50, 95% CI 0.19 to 1.36; 2 trials, 462 women). One small trial (17 women) compared an IV versus IM maintenance regimen for 24 hours. It is uncertain whether IV or IM maintenance regimen has an effect on eclampsia or stillbirth (very low-certainty evidence). Four trials (1713 women) compared short postpartum maintenance regimens with continuing for 24 hours after birth. Low-certainty evidence suggests there may be a wide range of benefit or harm between groups regarding eclampsia (RR 1.99, 95% CI 0.18 to 21.87; 4 trials, 1713 women). Low-certainty evidence suggests there may be little or no effect on severe morbidity (RR 0.96, 95% CI 0.71 to 1.29; 2 trials, 1233 women) or side effects such as respiratory depression (RR 0.80, 95% CI 0.25 to 2.61; 2 trials, 1424 women). Three trials (185 women) compared a higher-dose maintenance regimen versus a lower-dose maintenance regimen. It is uncertain whether either regimen has an effect on eclampsia (very low-certainty evidence). Low-certainty evidence suggests that a higher-dose maintenance regimen has little or no effect on side effects when compared to a lower-dose regimen (RR 0.79, 95% CI 0.61 to 1.01; 1 trial 62 women). One trial (200 women) compared a maintenance regimen by continuous infusion versus a serial IV bolus regimen. It is uncertain whether the duration of the maintenance regimen has an effect on eclampsia, side effects, perinatal death, maternal death, or other neonatal morbidity (very low-certainty evidence). Many of our prespecified critical outcomes were not reported in the included trials. AUTHORS' CONCLUSIONS: Despite the number of trials evaluating various magnesium sulphate regimens for eclampsia prophylaxis and treatment, there is still no compelling evidence that one particular regimen is more effective than another. Well-designed randomised controlled trials are needed to answer this question.

Interventions to enhance medication adherence in pregnancy- a systematic review.

BACKGROUND: Sub-optimal medication adherence in pregnant women with chronic disease and pregnancy-related indications has the potential to adversely affect maternal and perinatal outcomes. Adherence to appropriate medications is advocated during and when planning pregnancy to reduce risk of adverse perinatal outcomes relating to chronic disease and pregnancy-related indications. We aimed to systematically identify effective interventions to promote medication adherence in women who are pregnant or planning to conceive and impact on perinatal, maternal disease-related and adherence outcomes. METHODS: Six bibliographic databases and two trial registries were searched from inception to 28th April 2022. We included quantitative studies evaluating medication adherence interventions in pregnant women and women planning pregnancy. Two reviewers selected studies and extracted data on study characteristics, outcomes, effectiveness, intervention description (TIDieR) and risk of bias (EPOC). Narrative synthesis was performed due to study population, intervention and outcome heterogeneity. RESULTS: Of 5614 citations, 13 were included. Five were RCTs, and eight non-randomised comparative studies. Participants had asthma (n = 2), HIV (n = 6), inflammatory bowel disease (IBD; n = 2), diabetes (n = 2) and risk of pre-eclampsia (n = 1). Interventions included education +/- counselling, financial incentives, text messaging, action plans, structured discussion and psychosocial support. One RCT found an effect  of the tested intervention on self-reported antiretroviral adherence but not objective adherence. Clinical outcomes were not evaluated. Seven non-randomised comparative studies found an association between the tested intervention and at least one outcome of interest: four found an association between receiving the intervention and both improved clinical or perinatal outcomes and adherence in women with IBD, gestational diabetes mellitus (GDM), and asthma. One study in women with IBD reported an association between receiving the intervention and maternal outcomes but not for self-reported adherence. Two studies measured only adherence outcomes and reported an association between receiving the intervention and self-reported and/or objective adherence in women with HIV and risk of pre-eclampsia. All studies had high or unclear risk of bias. Intervention reporting was adequate for replication in two studies according to the TIDieR checklist. CONCLUSIONS: There is a need for high-quality RCTs reporting replicable interventions to evaluate medication adherence interventions in pregnant women and those planning pregnancy. These should assess both clinical and adherence outcomes.

Molecular subclasses of preeclampsia characterized by a longitudinal maternal proteomics study: distinct biomarkers, disease pathways and options for prevention.

OBJECTIVES: The heterogeneous nature of preeclampsia is a major obstacle to early screening and prevention, and a molecular taxonomy of disease is needed. We have previously identified four subclasses of preeclampsia based on first-trimester plasma proteomic profiles. Herein, we expanded this approach by using a more comprehensive panel of proteins profiled in longitudinal samples. METHODS: Proteomic data collected longitudinally from plasma samples of women who developed preeclampsia (n=109) and of controls (n=90) were available from our previous report on 1,125 proteins. Consensus clustering was performed to identify subgroups of patients with preeclampsia based on data from five gestational-age intervals by using select interval-specific features. Demographic, clinical, and proteomic differences among clusters were determined. Differentially abundant proteins were used to identify cluster-specific perturbed KEGG pathways. RESULTS: Four molecular clusters with different clinical phenotypes were discovered by longitudinal proteomic profiling. Cluster 1 involves metabolic and prothrombotic changes with high rates of early-onset preeclampsia and small-for-gestational-age neonates; Cluster 2 includes maternal anti-fetal rejection mechanisms and recurrent preeclampsia cases; Cluster 3 is associated with extracellular matrix regulation and comprises cases of mostly mild, late-onset preeclampsia; and Cluster 4 is characterized by angiogenic imbalance and a high prevalence of early-onset disease. CONCLUSIONS: This study is an independent validation and further refining of molecular subclasses of preeclampsia identified by a different proteomic platform and study population. The results lay the groundwork for novel diagnostic and personalized tools of prevention.

Combined Anticoagulant Therapy for Prevention of Preeclampsia and Small for Gestational Age Neonates: A Systematic Review and Meta-analysis.

OBJECTIVE: This systematic review and meta-analysis (SRMA) aims to compare the efficacy of combining low molecular weight heparin (LMWH) and aspirin against aspirin alone in preventing preeclampsia (PE) and small for gestational age (SGA) neonates in women at moderate and high risks. STUDY DESIGN: The included studies were nonrandomized and randomized clinical trials (RCTs) enrolling women at moderate and high risks for developing preeclampsia. PubMed/Medline, Cochrane Library, Embase, and Grey literature (including ClinicalTrials.gov) were searched. RESULTS: Out of 4,762 records, 7 nonrandomized studies and 12 RCTs (enrolling 545 and 1,677 women, respectively) were selected. Although the studies were clinically heterogeneous, the conduction of quantitative analysis was feasible. Regarding RCTs, the odds of early-onset preeclampsia was reduced by 89% (pooled odds ratio [OR] = 0.11, 95% confidence interval [CI]: 0.01-0.93, p = 0.04) in women with thrombophilia, the incidence of SGA neonates below the 5th percentile by 48% (pooled OR = 0.52, 95% CI: 0.28-0.96, p = 0.04) in women with a history of preeclampsia and/or SGA neonates, and the incidence of SGA neonates below the 10th percentile by 31% (pooled OR = 0.69, 95% CI: 0.50-0.96, p = 0.03) in the whole population. CONCLUSION: Concerning the whole studied population, combined anticoagulant therapy is not superior to aspirin alone. However, it may be more effective in preventing early-onset preeclampsia regarding women with thrombophilia, SGA neonates below the 5th percentile regarding women with a history of preeclampsia and/or SGA, and SGA neonates below the 10th percentile in moderate- or high-risk women. The above mixed but promising results need to be envisaged with caution due to the clinical heterogeneity of the included studies which is the main limitation of our research. Nevertheless, the strict and narrow inclusion search criteria, and the appropriate subgroup analysis are its main strengths. More RCTs with homogeneous populations and stricter inclusion criteria are needed to confirm these results. KEY POINTS: · Combined therapy is not superior to aspirin alone.. · Combined therapy in women with thrombophilia may protect against early-onset preeclampsia.. · Combined therapy in moderate/high-risk women may protect against SGA <10th percentile neonates..

Timing of antenatal steroid administration for imminent preterm birth: results of a prospective observational study in Germany.

PURPOSE: To evaluate the timing of antenatal steroid administration and associated medical interventions in women with imminent preterm birth. METHODS: We performed a prospective observational study at a single tertiary center in Germany from September 2018 to August 2019. We included pregnant women who received antenatal steroids for imminent preterm birth and evaluated the interval from administration to birth. 120 women with antenatal steroid application were included into our analysis. Descriptive statistics were performed to analyze factors influencing the timing of antenatal steroids and to evaluate additional medical interventions which women with imminent preterm birth experience. RESULTS: Of the 120 women included into our study, 35.8% gave birth before 34/0 weeks and 64.2% before 37/0 weeks of gestation. Only 25/120 women (20.8%) delivered within the optimal time window of 1-7 days after antenatal steroid application. 5/120 women (4.2%) only received one dose of antenatal steroids before birth and 3/120 (2.5%) gave birth within 8 to 14 days after antenatal steroids. Most women gave birth more than 14 days after steroid application (72.5%, 87/120). Women with preeclampsia (60%), PPROM (31%), and FGR (30%) had the highest rates of delivery within the optimal time window. Women of all timing groups received additional interventions and medications like antibiotics, tocolytics, or anticoagulation. CONCLUSION: Our observational data indicate that most pregnant women do not give birth within 7 days after the administration of antenatal steroids. The timing was best for preterm birth due to preeclampsia, PPROM, and FGR. Especially for women with symptoms of preterm labor and bleeding placenta previa, antenatal steroids should be indicated more restrictively to improve neonatal outcome and reduce untimely and unnecessary interventions.