Revolutionising healing: Gene Editing's breakthrough against sickle cell disease.

Recent advancements in gene editing illuminate new potential therapeutic approaches for Sickle Cell Disease (SCD), a debilitating monogenic disorder caused by a point mutation in the ß-globin gene. Despite the availability of several FDA-approved medications for symptomatic relief, allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole curative option, underscoring a persistent need for novel treatments. This review delves into the growing field of gene editing, particularly the extensive research focused on curing haemoglobinopathies like SCD. We examine the use of techniques such as CRISPR-Cas9 and homology-directed repair, base editing, and prime editing to either correct the pathogenic variant into a non-pathogenic or wild-type one or augment fetal haemoglobin (HbF) production. The article elucidates ways to optimize these tools for efficacious gene editing with minimal off-target effects and offers insights into their effective delivery into cells. Furthermore, we explore clinical trials involving alternative SCD treatment strategies, such as LentiGlobin therapy and autologous HSCT, distilling the current findings. This review consolidates vital information for the clinical translation of gene editing for SCD, providing strategic insights for investigators eager to further the development of gene editing for SCD.

Placental growth factor testing at 19-23 weeks of gestation as a guide to subsequent care in pregnancy: A prospective observational study.

OBJECTIVE: To determine whether serum placental growth factor (PlGF) at 19-23 weeks of gestation can improve the identification of risk for adverse outcomes. DESIGN: Prospective observational cohort study. SETTING: Two English maternity units. POPULATION: Unselected singleton pregnancies attending routine ultrasound at 19-23 weeks of gestation. METHODS: Outcomes ascertained by health record review. Diagnostic test properties evaluated clinical risk factors for pre-eclampsia (according to National Institute of Care Excellence) or fetal growth restriction (according to Royal College of Obstetricians and Gynaecologists), low PlGF at 19-23 weeks of gestation (<5th percentile) or both. MAIN OUTCOME MEASURES: Pre-eclampsia, gestational hypertension, stillbirth, birthweight below third percentile or neonatal intensive care unit (NICU) admission for ≥48 h. RESULTS: In 30 013 pregnancies, risk factors were present in 9941 (33.1%), low PlGF was present in 1501 (5.0%) and both ('two-stage' screening) were present in 547 (1.8%) pregnancies. Risk factors detected 41.7%-54.7% of adverse outcomes, and could not meaningfully revise the risk (all positive likelihood ratios, +LR, <5.0; all negative likelihood ratios, -LR, ≥0.2). Low PlGF detected 8.5%-17.4% of adverse outcomes, but meaningfully increased risks (other than NICU admission) associated with delivery <37 weeks of gestation (+LR = 5.03-15.55); all -LRs were ≥0.2. 'Two-stage' screening detected 4.2%-8.9% of adverse outcomes, with meaningful +LRs (6.28-18.61) at <37 weeks of gestation, except for NICU admission of ≥48 h, which had an +LR of 7.56 at <34 weeks of gestation; all -LRs were ≥0.2. No screening strategy meaningfully increased or decreased the detection of adverse outcome risk at term. CONCLUSIONS: Clinical risk factor screening has a high screen-positive rate and a poor detection of adverse outcomes. False positives cannot be reduced by PlGF testing at 19-23 weeks of gestation; therefore, this cannot be recommended as a useful strategy on its own.

Maternal vascular indices at 36 weeks' gestation in the prediction of preeclampsia.

BACKGROUND: Epidemiological studies have shown that women with preeclampsia (PE) are at increased long term cardiovascular risk. This risk might be associated with accelerated vascular ageing process but data on vascular abnormalities in women with PE are scarce. OBJECTIVE: This study aimed to identify the most discriminatory maternal vascular index in the prediction of PE at 35 to 37 weeks' gestation and to examine the performance of screening for PE by combinations of maternal risk factors and biophysical and biochemical markers at 35 to 37 weeks' gestation. STUDY DESIGN: This was a prospective observational nonintervention study in women attending a routine hospital visit at 35 0/7 to 36 6/7 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices, and hemodynamic parameters obtained by a noninvasive operator-independent device (pulse wave velocity, augmentation index, cardiac output, stroke volume, central systolic and diastolic blood pressures, total peripheral resistance, and fetal heart rate), mean arterial pressure, uterine artery pulsatility index, and serum concentration of placental growth factor and soluble fms-like tyrosine kinase-1. The performance of screening for delivery with PE at any time and at <3 weeks from assessment using a combination of maternal risk factors and various combinations of biomarkers was determined. RESULTS: The study population consisted of 6746 women with singleton pregnancies, including 176 women (2.6%) who subsequently developed PE. There were 3 main findings. First, in women who developed PE, compared with those who did not, there were higher central systolic and diastolic blood pressures, pulse wave velocity, peripheral vascular resistance, and augmentation index. Second, the most discriminatory indices were systolic and diastolic blood pressures and pulse wave velocity, with poor prediction from the other indices. However, the performance of screening by a combination of maternal risk factors plus mean arterial pressure was at least as high as that of a combination of maternal risk factors plus central systolic and diastolic blood pressures; consequently, in screening for PE, pulse wave velocity, mean arterial pressure, uterine artery pulsatility index, placental growth factor, and soluble fms-like tyrosine kinase-1 were used. Third, in screening for both PE within 3 weeks and PE at any time from assessment, the detection rate at a false-positive rate of 10% of a biophysical test consisting of maternal risk factors plus mean arterial pressure, uterine artery pulsatility index, and pulse wave velocity (PE within 3 weeks: 85.2%; 95% confidence interval, 75.6%-92.1%; PE at any time: 69.9%; 95% confidence interval, 62.5%-76.6%) was not significantly different from a biochemical test using the competing risks model to combine maternal risk factors with placental growth factor and soluble fms-like tyrosine kinase-1 (PE within 3 weeks: 80.2%; 95% confidence interval, 69.9%-88.3%; PE at any time: 64.2%; 95% confidence interval, 56.6%-71.3%), and they were both superior to screening by low placental growth factor concentration (PE within 3 weeks: 53.1%; 95% confidence interval, 41.7%-64.3%; PE at any time: 44.3; 95% confidence interval, 36.8%-52.0%) or high soluble fms-like tyrosine kinase-1-to-placental growth factor concentration ratio (PE within 3 weeks: 65.4%; 95% confidence interval, 54.0%-75.7%; PE at any time: 53.4%; 95% confidence interval, 45.8%-60.9%). CONCLUSION: First, increased maternal arterial stiffness preceded the clinical onset of PE. Second, maternal pulse wave velocity at 35 to 37 weeks' gestation in combination with mean arterial pressure and uterine artery pulsatility index provided effective prediction of subsequent development of preeclampsia.

Prediction of adverse outcome by ophthalmic artery Doppler and angiogenic markers in pregnancies with new onset hypertension.

OBJECTIVES: To compare the ophthalmic artery Doppler peak systolic velocity ratio (OA PSV-ratio) and soluble fms-like tyrosine kinase-1/placental growth factor ratio (sFlt-1/PlGF ratio) in predicting adverse maternal and perinatal outcomes in women presenting with new onset hypertension. STUDY DESIGN: Prospective cohort study in a specialist hypertension clinic, within a tertiary referral centre. MAIN OUTCOME MEASURES: Comparison between the OA PSV-ratio and sFlt-1/PlGF ratio in predicting delivery within one week from presentation and adverse maternal and perinatal outcomes e.g. severe hypertension, neonatal unit admission, small for gestational age. RESULTS: Women who delivered within one week, compared to those who did not, had a higher OA PSV-ratio (0.82 vs 0.71, p < 0.01) and sFlt-1/PlGF ratio (93.3 vs 40.5, p = 0.08). Independent predictors of the OA PSV-ratio included mean arterial pressure and maternal weight and predictors of the sFlt-1/PlGF ratio included diastolic blood pressure and use of antihypertensive medications. Prediction of adverse outcomes with both ratios were similar and only modest e.g. AUROC for predicting delivery within one week for OA PSV-ratio was 0.57 (95% CI 0.47-0.67) and for sFlt-1/PlGF ratio was 0.61 (95% CI 0.52-0.70) (p = 0.53). CONCLUSIONS: In women presenting with new onset hypertension, the OA PSV-ratio and sFlt-1/PlGF ratio have similar and modest performance in predicting adverse outcomes.

Fetal surgery using fetoscopic endoluminal tracheal occlusion for severe congenital diaphragmatic hernia: a single-center experience.

PURPOSE: To provide a comprehensive report of the experience gained in the prenatal treatment of congenital diaphragmatic hernia (CDH) using fetoscopic endoluminal tracheal occlusion (FETO) following its implementation at a newly established specialized fetal medicine center. METHODS: Mothers of fetuses with severe CDH were offered prenatal treatment by FETO. RESULTS: Between 2018 and 2021, 16 cases of severe CDH underwent FETO. The median gestational age (GA) at balloon insertion was 28.4 weeks (IQR 27.8-28.6). The median GA at delivery was 37 weeks (IQR 34.4-37.8). The survival rate was 8/16 cases (50%). None of the survivors required home oxygen therapy at 6 months of age. Comparison between the survivors and deceased showed that survivors had balloon insertion 1 week earlier (27.8 vs. 28.4 weeks, p = 0.007), a higher amniotic fluid level change between pre- to post-FETO (3.4 vs 1.3, p = 0.024), a higher O/E LHR change between pre- to post-FETO (50.8 vs. 37.5, p = 0.047), and a GA at delivery that was 2 weeks later (37.6 vs. 35.4 weeks, p = 0.032). CONCLUSIONS: The survival rate at 6 months of age in cases of severe CDH treated with FETO in our center was 50%. Our new fetal medicine center matches the performance of other leading international centers.

Maternal Plasma RNA in First Trimester Nullipara for the Prediction of Spontaneous Preterm Birth ≤ 32 Weeks: Validation Study.

The first-trimester prediction of spontaneous preterm birth (sPTB) has been elusive, and current screening is heavily dependent on obstetric history. However, nullipara lack a relevant history and are at higher risk for spontaneous (s)PTB ≤ 32 weeks compared to multipara. No available objective first-trimester screening test has proven a fair predictor of sPTB ≤ 32 weeks. We questioned whether a panel of maternal plasma cell-free (PCF) RNAs (PSME2, NAMPT, APOA1, APOA4, and Hsa-Let-7g) previously validated at 16-20 weeks for the prediction of sPTB ≤ 32 weeks might be useful in first-trimester nullipara. Sixty (60) nulliparous women (40 with sPTB ≤ 32 weeks) who were free of comorbidities were randomly selected from the King's College Fetal Medicine Research Institute biobank. Total PCF RNA was extracted and the expression of panel RNAs was quantitated by qRT-PCR. The analysis employed, primarily, multiple regression with the main outcome being the prediction of subsequent sPTB ≤ 32 weeks. The test performance was judged by the area under the curve (AUC) using a single threshold cut point with observed detection rates (DRs) at three fixed false positive rates (FPR). The mean gestation was 12.9 ± 0.5 weeks (range 12.0-14.1 weeks). Two RNAs were differentially expressed in women destined for sPTB ≤ 32 weeks: APOA1 (p < 0.001) and PSME2 (p = 0.05). APOA1 testing at 11-14 weeks predicted sPTB ≤ 32 weeks with fair to good accuracy. The best predictive model generated an AUC of 0.79 (95% CI 0.66-0.91) with observed DRs of 41%, 61%, and 79% for FPRs of 10%, 20%, and 30%, including crown-rump length, maternal weight, race, tobacco use, and age.

Vaginal progesterone for preventing preterm birth and adverse perinatal outcomes in twin gestations: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of vaginal progesterone for the prevention of preterm birth and adverse perinatal outcomes in twin gestations. DATA SOURCES: MEDLINE, Embase, LILACS, and CINAHL (from their inception to January 31, 2023), Cochrane databases, Google Scholar, bibliographies, and conference proceedings. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that compared vaginal progesterone to placebo or no treatment in asymptomatic women with a twin gestation. METHODS: The systematic review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was preterm birth <34 weeks of gestation. Secondary outcomes included adverse perinatal outcomes. Pooled relative risks with 95% confidence intervals were calculated. We assessed the risk of bias in each included study, heterogeneity, publication bias, and quality of evidence, and performed subgroup and sensitivity analyses. RESULTS: Eleven studies (3401 women and 6802 fetuses/infants) fulfilled the inclusion criteria. Among all twin gestations, there were no significant differences between the vaginal progesterone and placebo or no treatment groups in the risk of preterm birth <34 weeks (relative risk, 0.99; 95% confidence interval, 0.84-1.17; high-quality evidence), <37 weeks (relative risk, 0.99; 95% confidence interval, 0.92-1.06; high-quality evidence), and <28 weeks (relative risk, 1.00; 95% confidence interval, 0.64-1.55; moderate-quality evidence), and spontaneous preterm birth <34 weeks of gestation (relative risk, 0.97; 95% confidence interval, 0.80-1.18; high-quality evidence). Vaginal progesterone had no significant effect on any of the perinatal outcomes evaluated. Subgroup analyses showed that there was no evidence of a different effect of vaginal progesterone on preterm birth <34 weeks of gestation related to chorionicity, type of conception, history of spontaneous preterm birth, daily dose of vaginal progesterone, and gestational age at initiation of treatment. The frequencies of preterm birth <37, <34, <32, <30, and <28 weeks of gestation and adverse perinatal outcomes did not significantly differ between the vaginal progesterone and placebo or no treatment groups in unselected twin gestations (8 studies; 3274 women and 6548 fetuses/infants). Among twin gestations with a transvaginal sonographic cervical length <30 mm (6 studies; 306 women and 612 fetuses/infants), vaginal progesterone was associated with a significant decrease in the risk of preterm birth occurring at <28 to <32 gestational weeks (relative risks, 0.48-0.65; moderate- to high-quality evidence), neonatal death (relative risk, 0.32; 95% confidence interval, 0.11-0.92; moderate-quality evidence), and birthweight <1500 g (relative risk, 0.60; 95% confidence interval, 0.39-0.88; high-quality evidence). Vaginal progesterone significantly reduced the risk of preterm birth occurring at <28 to <34 gestational weeks (relative risks, 0.41-0.68), composite neonatal morbidity and mortality (relative risk, 0.59; 95% confidence interval, 0.33-0.98), and birthweight <1500 g (relative risk, 0.55; 95% confidence interval, 0.33-0.94) in twin gestations with a transvaginal sonographic cervical length ≤25 mm (6 studies; 95 women and 190 fetuses/infants). The quality of evidence was moderate for all these outcomes. CONCLUSION: Vaginal progesterone does not prevent preterm birth, nor does it improve perinatal outcomes in unselected twin gestations, but it appears to reduce the risk of preterm birth occurring at early gestational ages and of neonatal morbidity and mortality in twin gestations with a sonographic short cervix. However, more evidence is needed before recommending this intervention to this subset of patients.

The long-term outcome following thoraco-amniotic shunting for congenital lung malformations.

AIM OF THE STUDY: Insertion of a thoraco amniotic shunt (TAS) during fetal life is a therapeutic option where there is a high risk of death secondary to large congenital lung malformations (CLM). The aim of this study is to present our center's long-term experience. METHODS: Retrospective single center review of the period (Jan 2000-Dec 2020). We included all fetuses that underwent TAS insertion for CLM with detailed analysis of those live newborns managed in our center. Data are quoted as median (range). MAIN RESULTS: Thirty one fetuses underwent 37 TAS insertions at a 25 (20-30) weeks gestational age. This was successful on 1st attempt in 30 (97%) fetuses. In 6 cases a 2nd shunt was required at 6.5 (2-10) weeks following the 1st insertion. Twenty-eight survived to be born. Sixteen (9 male) infants were delivered in our center at 39 (36-41) weeks gestational age and birth weight of 3.1 (2.6-4.2) kg. All infants underwent surgery at 2 (0-535) days (emergency surgery, n = 9; expedited n = 4; elective surgery, n = 3). Final histopathology findings were CPAM Type 1 (n = 14, n.b. associated with mucinous adenocarcinoma, n = 1), CPAM Type 2 (n = 1) and an extralobar sequestration (n = 1). Postoperative stay was 16 (1-70) days with survival in 15/16 (94%). One infant died at 1 day of life secondary to a combination of pulmonary hypoplasia and hypertension. Median follow up period was 10.7 (0.4-20.4) years. Nine (60%) children developed a degree of chest wall deformity though none have required surgical intervention. Clinically, 14/15 (93%) have otherwise normal lung function without limitations of activity, sporting or otherwise. One child has a modest exercise limitation (FVC - 70% predicted). CONCLUSIONS: TAS insertion is associated with high perinatal survival and should be considered in fetuses at risk of hydrops secondary to large cystic lung malformation. Their long term outcome is excellent although most have a mild degree of chest wall deformity.

Effect of race on the measurement of angiogenic factors for prediction and diagnosis of pre-eclampsia.

OBJECTIVE: To examine the effect of self-declared race on serum placental growth factor (PlGF) and sFlt-1/PlGF ratio and the impact on pre-eclampsia (PE) prediction. DESIGN: Prospective observational study. SETTING: Two UK maternity hospitals. POPULATION: 29 035 women with singleton pregnancies attending a routine 35+0 to 36+6 weeks' gestation hospital visit, including 654 (2.3%) who subsequently developed PE. METHODS: The predictive performance of PlGF and sFlt-1/PlGF for PE in minority racial groups (versus white) was examined. MAIN OUTCOME MEASURE: Delivery with PE. RESULTS: Compared with white women, mean PlGF was higher and sFlt-1/PlGF ratio lower in black, South Asian, East Asian and mixed race women. In white women at a PlGF concentration cut-off corresponding to a screen-positive rate (SPR) of 10%, detection rates (DRs) were 49.1% for PE at any time and 72.3% for PE within 2 weeks after screening. In black women, at the same PlGF concentration cut-off for white women, the SPR was 5.5%, and DRs 33.6% and 55.0%, respectively; the number of PE cases was too small to evaluate screening performance in other racial groups. Using a fixed cut-off in sFlt-1/PlGF ratio to identify women at risk of developing PE, similarly diagnostically disadvantaged black women. Bias was overcome by adjusting metabolite concentrations for maternal characteristics and use of the competing risks model to estimate patient-specific risks. CONCLUSION: Screening for PE with fixed cut-offs in PlGF or sFlt-1/PlGF diagnostically disadvantages black women. It is essential that measured levels of PlGF be adjusted for race as well as other maternal characteristics.

Antenatal management of congenital diaphragmatic hernia: What's next ?

Congenital diaphragmatic hernia can be diagnosed in the prenatal period and its severity can be measured by fetal imaging. There is now level I evidence that, in selected cases, Fetoscopic Endoluminal Tracheal Occlusion with a balloon increases survival to discharge from the neonatal unit as well as the risk for prematurity. Both effects are dependent on the time point of tracheal occlusion. Fetoscopic Endoluminal Tracheal Occlusion may also lead to iatrogenic death when the balloon cannot be timely retrieved. The implementation of the findings from our clinical studies, may also vary based on local conditions. These may be different in terms of available skill set, access to fetal therapy, as well as outcome based on local neonatal management. We encourage prior benchmarking of local outcomes with optimal postnatal management, based on large enough numbers and using identical criteria as in the recent trials. We propose to work further on prenatal prediction methods, and the improvement of fetal intervention. In this manuscript, we describe a research agenda from a fetal medicine perspective. This research should be in parallel with innovation in neonatal and pediatric (surgical) management of this condition.

Chronic hypertension and superimposed preeclampsia: screening and diagnosis.

Superimposed preeclampsia complicates about 20% of pregnancies in women with chronic hypertension and is associated with increased maternal and perinatal morbidity compared with preeclampsia alone. Distinguishing superimposed preeclampsia from chronic hypertension can be challenging because, in chronic hypertension, the traditional criteria for the diagnosis of preeclampsia, hypertension, and significant proteinuria can often predate the pregnancy. Furthermore, the prevalence of superimposed preeclampsia is unlikely to be uniformly distributed across this high-risk group but is related to the severity of preexisting endothelial dysfunction. This has led to interest in identifying biomarkers that could help in screening and diagnosis of superimposed preeclampsia and in the stratification of risk in women with chronic hypertension. Elevated levels of uric acid and suppression of other renal biomarkers, such as the renin-angiotensin aldosterone system, have been demonstrated in women with superimposed preeclampsia but perform only modestly in its prediction. In addition, central to the pathogenesis of preeclampsia is a tendency toward an antiangiogenic state thought to be triggered by an impaired placenta and, ultimately, contributing to the endothelial dysfunction pathognomonic of the disease. In the general obstetrical population, angiogenic factors, such as soluble fms-like tyrosine kinase-1 and placental growth factor, have shown promise in the prediction of preeclampsia. However, soluble fms-like tyrosine kinase-1 and placental growth factor are impaired in women with chronic hypertension irrespective of whether they develop superimposed preeclampsia. Therefore, the differences in levels are less discriminatory in the prediction of superimposed preeclampsia compared with the general obstetrical population. Alternative biomarkers to the angiogenic and renal factors include those of endothelial dysfunction. A characteristic of both preeclampsia and chronic hypertension is an exaggerated systemic inflammatory response causing or augmenting endothelial dysfunction. Thus, proinflammatory mediators, such as tumor necrosis factor-α, interleukin-6, cell adhesion molecules, and endothelin, have been investigated for their role in the screening and diagnosis of superimposed preeclampsia in women with chronic hypertension. To date, the existing limited evidence suggests that the differences between those who develop superimposed preeclampsia and those who do not are, as with angiogenic factors, also modest and not clinically useful for the stratification of women with chronic hypertension. Finally, pro-B-type natriuretic peptide is regarded as a sensitive marker of early cardiac dysfunction that, in women with chronic hypertension, may predate the pregnancy. Thus, it has been proposed that pro-B-type natriuretic peptide could give insight as to the ability of women with chronic hypertension to adapt to the hemodynamic requirements of pregnancy and, subsequently, their risk of developing superimposed preeclampsia. Although higher levels of pro-B-type natriuretic peptide have been demonstrated in women with superimposed preeclampsia compared with those without, current evidence suggests that pro-B-type natriuretic peptide is not a predictor for the disease. The objectives of this review are to, first, discuss the current criteria for the diagnosis of superimposed preeclampsia and, second, to summarize the evidence for these potential biomarkers that may assist in the diagnosis of superimposed preeclampsia.

Maternal Cardiac Function at Midgestation and Development of Preeclampsia.

BACKGROUND: Preeclampsia (PE) is an independent risk factor for adverse maternal cardiovascular outcomes. The role of maternal cardiac function in the pathophysiology of PE remains unclear. OBJECTIVES: This study sought to describe differences in cardiac function at midgestation between women who develop PE and those with uncomplicated pregnancy and to establish whether routine cardiac assessment at midgestation can improve performance of screening for PE achieved by established biomarkers. METHODS: Mean arterial pressure was measured, medical history was obtained, and left ventricular (LV) systolic and diastolic functions were assessed using standard echocardiography and speckle tracking imaging. Uterine artery pulsatility index and serum placental growth factor and soluble fms-like tyrosine kinase-1 were measured. RESULTS: In 4,795 pregnancies, 126 (2.6%) developed PE. Following multivariable analysis, peripheral vascular resistance was significantly higher and LV global longitudinal systolic strain, ejection fraction, cardiac output, and left atrial area were mildly lower in women who developed PE compared to those who did not. There was a weak association between maternal cardiovascular indices and biomarkers of placental perfusion and function. Cardiac indices did not improve the performance of screening for PE on top of maternal risk factors, mean arterial pressure, and biomarkers of placental perfusion and function. CONCLUSION: Women who develop PE have an increase in peripheral vascular resistance and a mild reduction in LV functional cardiac indices long before PE development. However, cardiac indices do not improve the performance of screening for PE; thus, their routine clinical use is not advocated.

Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus.

Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography-tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11-13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m2 with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m2 (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.

Prevention of preeclampsia with aspirin.

Preeclampsia is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage and is an important cause of maternal and perinatal morbidity and mortality, particularly when of early onset. Although a significant amount of research has been dedicated in identifying preventive measures for preeclampsia, the incidence of the condition has been relatively unchanged in the last decades. This could be attributed to the fact that the underlying pathophysiology of preeclampsia is not entirely understood. There is increasing evidence suggesting that suboptimal trophoblastic invasion leads to an imbalance of angiogenic and antiangiogenic proteins, ultimately causing widespread inflammation and endothelial damage, increased platelet aggregation, and thrombotic events with placental infarcts. Aspirin at doses below 300 mg selectively and irreversibly inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane and inhibiting inflammation and platelet aggregation. Such an effect has led to the hypothesis that aspirin could be useful for preventing preeclampsia. The first possible link between the use of aspirin and the prevention of preeclampsia was suggested by a case report published in 1978, followed by the first randomized controlled trial published in 1985. Since then, numerous randomized trials have been published, reporting the safety of the use of aspirin in pregnancy and the inconsistent effects of aspirin on the rates of preeclampsia. These inconsistencies, however, can be largely explained by a high degree of heterogeneity regarding the selection of trial participants, baseline risk of the included women, dosage of aspirin, gestational age of prophylaxis initiation, and preeclampsia definition. An individual patient data meta-analysis has indicated a modest 10% reduction in preeclampsia rates with the use of aspirin, but later meta-analyses of aggregate data have revealed a dose-response effect of aspirin on preeclampsia rates, which is maximized when the medication is initiated before 16 weeks of gestational age. Recently, the Aspirin for Evidence-Based Preeclampsia Prevention trial has revealed that aspirin at a daily dosage of 150 mg, initiated before 16 weeks of gestational age, and given at night to a high-risk population, identified by a combined first trimester screening test, reduces the incidence of preterm preeclampsia by 62%. A secondary analysis of the Aspirin for Evidence-Based Preeclampsia Prevention trial data also indicated a reduction in the length of stay in the neonatal intensive care unit by 68% compared with placebo, mainly because of a reduction in births before 32 weeks of gestational age with preeclampsia. The beneficial effect of aspirin has been found to be similar in subgroups according to different maternal characteristics, except for the presence of chronic hypertension, where no beneficial effect is evident. In addition, the effect size of aspirin has been found to be more pronounced in women with good compliance to treatment. In general, randomized trials are underpowered to investigate the treatment effect of aspirin on the rates of other placental-associated adverse outcomes such as fetal growth restriction and stillbirth. This article summarizes the evidence around aspirin for the prevention of preeclampsia and its complications.

Ophthalmic artery Doppler in the prediction of preeclampsia.

The ophthalmic artery is an easily accessible vessel for Doppler assessment that provides information on the less accessible intracranial circulation. In women with preeclampsia, compared with normotensive pregnant women, there is a decrease in impedance to flow and an increase in velocities in the flow velocity waveforms from the ophthalmic arteries. This study aimed to report the methodology for ophthalmic artery Doppler and summarize findings from the clinical implementation of such assessment in the prediction of preeclampsia. The Embase and MEDLINE were searched from inception to November 2020 to identify studies reporting on the use of ophthalmic artery Doppler in the prediction of preeclampsia. Of note, 2 small studies in high-risk pregnancies, one at 11 to 14 weeks' gestation and another at 20 to 28 weeks' gestation, reported differences between women who developed preeclampsia, compared with unaffected pregnancies, in ophthalmic artery Doppler and suggested that this is a useful biomarker for screening for preeclampsia. Another small study in high-risk pregnancies at 18 to 23 weeks' gestation reported that there was no marked difference in ophthalmic artery Doppler indices between the preeclampsia and unaffected groups. In addition, 2 recent, large observational studies in unselected pregnancies at 19 to 23 and 35 to 37 weeks' gestation, respectively, reported that, first, it is necessary to record waveforms from both eyes to get reproducible results; second, the waveform from the ophthalmic arteries is characterized by 2 systolic peaks and the ratio of the second to the first peak systolic velocity was increased in women who developed preeclampsia; third, in the study at 19 to 23 weeks' gestation, the peak systolic velocity ratio was superior to the uterine artery pulsatility index, mean arterial pressure, serum placental growth factor, and soluble fms-like tyrosine kinase-1 as individual biomarkers in the prediction of both preterm and term preeclampsia and the peak systolic velocity ratio improved the prediction of preeclampsia provided by all the other biomarkers; and fourth, in the study at 35 to 37 weeks' gestation, the peak systolic velocity ratio improved the prediction of subsequent development of preeclampsia provided by maternal factors alone and combinations of maternal factors with mean arterial pressure, uterine artery pulsatility index, placental growth factor, and serum placental growth factor. The ophthalmic artery Doppler provides a useful biomarker for the prediction of preeclampsia.

The randomized Tracheal Occlusion To Accelerate Lung growth (TOTAL)-trials on fetal surgery for congenital diaphragmatic hernia: reanalysis using pooled data.

BACKGROUND: Two randomized controlled trials compared the neonatal and infant outcomes after fetoscopic endoluminal tracheal occlusion with expectant prenatal management in fetuses with severe and moderate isolated congenital diaphragmatic hernia, respectively. Fetoscopic endoluminal tracheal occlusion was carried out at 27+0 to 29+6 weeks' gestation (referred to as "early") for severe and at 30+0 to 31+6 weeks ("late") for moderate hypoplasia. The reported absolute increase in the survival to discharge was 13% (95% confidence interval, -1 to 28; P=.059) and 25% (95% confidence interval, 6-46; P=.0091) for moderate and severe hypoplasia. OBJECTIVE: Data from the 2 trials were pooled to study the heterogeneity of the treatment effect by observed over expected lung-to-head ratio and explore the effect of gestational age at balloon insertion. STUDY DESIGN: Individual participant data from the 2 trials were reanalyzed. Women were assessed between 2008 and 2020 at 14 experienced fetoscopic endoluminal tracheal occlusion centers and were randomized in a 1:1 ratio to either expectant management or fetoscopic endoluminal tracheal occlusion. All received standardized postnatal management. The combined data involved 287 patients (196 with moderate hypoplasia and 91 with severe hypoplasia). The primary endpoint was survival to discharge from the neonatal intensive care unit. The secondary endpoints were survival to 6 months of age, survival to 6 months without oxygen supplementation, and gestational age at live birth. Penalized regression was used with the following covariates: intervention (fetoscopic endoluminal tracheal occlusion vs expectant), early balloon insertion (yes vs no), observed over expected lung-to-head ratio, liver herniation (yes vs no), and trial (severe vs moderate). The interaction between intervention and the observed over expected lung-to-head ratio was evaluated to study treatment effect heterogeneity. RESULTS: For survival to discharge, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion was 1.78 (95% confidence interval, 1.05-3.01; P=.031). The additional effect of early balloon insertion was highly uncertain (adjusted odds ratio, 1.53; 95% confidence interval, 0.60-3.91; P=.370). When combining these 2 effects, the adjusted odds ratio of fetoscopic endoluminal tracheal occlusion with early balloon insertion was 2.73 (95% confidence interval, 1.15-6.49). The results for survival to 6 months and survival to 6 months without oxygen dependence were comparable. The gestational age at delivery was on average 1.7 weeks earlier (95% confidence interval, 1.1-2.3) following fetoscopic endoluminal tracheal occlusion with late insertion and 3.2 weeks earlier (95% confidence interval, 2.3-4.1) following fetoscopic endoluminal tracheal occlusion with early insertion compared with expectant management. There was no evidence that the effect of fetoscopic endoluminal tracheal occlusion depended on the observed over expected lung-to-head ratio for any of the endpoints. CONCLUSION: This analysis suggests that fetoscopic endoluminal tracheal occlusion increases survival for both moderate and severe lung hypoplasia. The difference between the results for the Tracheal Occlusion To Accelerate Lung growth trials, when considered apart, may be because of the difference in the time point of balloon insertion. However, the effect of the time point of balloon insertion could not be robustly assessed because of a small sample size and the confounding effect of disease severity. Fetoscopic endoluminal tracheal occlusion with early balloon insertion in particular strongly increases the risk for preterm delivery.

Pravastatin Versus Placebo in Pregnancies at High Risk of Term Preeclampsia.

BACKGROUND: Effective screening for term preeclampsia is provided by a combination of maternal factors with measurements of mean arterial pressure, serum placental growth factor, and serum soluble fms-like tyrosine kinase-1 at 35 to 37 weeks of gestation, with a detection rate of ≈75% at a screen-positive rate of 10%. However, there is no known intervention to reduce the incidence of the disease. METHODS: In this multicenter, double-blind, placebo-controlled trial, we randomly assigned 1120 women with singleton pregnancies at high risk of term preeclampsia to receive pravastatin at a dose of 20 mg/d or placebo from 35 to 37 weeks of gestation until delivery or 41 weeks. The primary outcome was delivery with preeclampsia at any time after randomization. The analysis was performed according to intention to treat. RESULTS: A total of 29 women withdrew consent during the trial. Preeclampsia occurred in 14.6% (80 of 548) of participants in the pravastatin group and in 13.6% (74 of 543) in the placebo group. Allowing for the effect of risk at the time of screening and participating center, the mixed-effects Cox regression showed no evidence of an effect of pravastatin (hazard ratio for statin/placebo, 1.08 [95% CI, 0.78-1.49]; P=0.65). There was no evidence of interaction between the effect of pravastatin, estimated risk of preeclampsia, pregnancy history, adherence, and aspirin treatment. There was no significant between-group difference in the incidence of any secondary outcomes, including gestational hypertension, stillbirth, abruption, delivery of small for gestational age neonates, neonatal death, or neonatal morbidity. There was no significant between-group difference in the treatment effects on serum placental growth factor and soluble fms-like tyrosine kinase-1 concentrations 1 and 3 weeks after randomization. Adherence was good, with reported intake of ≥80% of the required number of tablets in 89% of participants. There were no significant between-group differences in neonatal adverse outcomes or other adverse events. CONCLUSIONS: Pravastatin in women at high risk of term preeclampsia did not reduce the incidence of delivery with preeclampsia. Registration: URL: https://www.isrctn.com; Unique identifier ISRCTN16123934.

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

BACKGROUND: Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking. METHODS: In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women. RESULTS: The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09). CONCLUSIONS: In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.).

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease. METHODS: In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age. RESULTS: In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P = 0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal. CONCLUSIONS: This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.).