Trends in antenatal corticosteroid administration: did our timing improve?

OBJECTIVES: We aimed to analyze trends in the rate of effective antenatal corticosteroid prophylaxis (ACS) administrations across a spectrum of typical diagnoses associated with preterm birth. METHODS: In this retrospective study we utilized delivery data after ACS from 2014 to 2020 at Charité Berlin, Germany. We evaluated the rate of effective ACS administrations defined as ≤10 days between last dose of ACS and delivery as well as the rate of post-ACS births on/after 37 + 0 weeks. We explored conditions associated with high rates of ineffective ACS administrations (>10 days before delivery). We analyzed the trend of ACS-effectiveness during the study period in the overall cohort and in placental dysfunction and cervical insufficiency diagnoses. RESULTS: The overall rate of effective ACS administrations was 42 % (709/1,672). The overall percentage of deliveries after/at 37 + 0 weeks following ACS administration was 19 % (343). Placenta previa, twin pregnancy and isthmocervical insufficiency were associated with ineffective ACS (19-34 % effective i.e. ≤10 days before delivery). The overall ratio of effective ACS applications rose over time (p=0.002). Over the course of this study ACS effectiveness increased in placental dysfunction and isthmocervical insufficiency diagnoses (p=0.028; p=0.001). CONCLUSIONS: Compared to a previous publication we found a decrease of post-ACS deliveries after/at 37 + 0 weeks (19 vs. 27 %). Ineffective ACS administrations are still frequent in patients with placenta previa, twin pregnancy and isthmocervical insufficiency. It remains to be investigated in future trials if the introduction of new diagnostic tools such as soluble Fms-like tyrosinkinase-1/placental growth factor (sFlt-1/PlGF) testing and placental alpha-microglobulin-1 (PAMG-1) testing directly led to an increased ACS effectiveness.

Pregnancy in myasthenia gravis: a retrospective analysis of maternal and neonatal outcome from a large tertiary care centre in Germany.

PURPOSE: Myasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can affect maternal as well as neonatal outcome with risk of worsening of myasthenic symptoms in the mothers and risk of transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) or foetal acetylcholine receptor antibody-associated disorders (FARAD) in the neonates. METHODS: Retrospective analysis of maternal and neonatal outcome in a cohort of pregnant MG patients treated at a tertiary care centre in Germany. RESULTS: Overall, 66 pregnancies were analysed. During 40 (63%) pregnancies, women experienced a worsening of myasthenic symptoms, of whom 10 patients (15.7%) needed acute therapy with IVIg or plasma exchange. There was no case of myasthenic crisis. Rate of caesarean section was comparable to the overall C-section rate at our centre (38% vs. 40%). However, there was a slightly higher rate for operative vaginal delivery (15% vs. 10%) as potential indicator for fatiguing striated musculature in MG patients during the expulsion stage. Rate of TNMG as well as AMC was 3% (two cases each). CONCLUSIONS: Maternal and neonatal outcome in our cohort was favourable with a low rate of myasthenic exacerbations requiring acute therapies and a low rate of TNMG and AMC/FARAD. Our data might help neurologists and obstetricians to advice MG patients with desire to have children.

European Association of Perinatal Medicine (EAPM), European Board and College of Obstetricians and Gynaecologists (EBCOG), European Midwives Association (EMA). Joint position statement: Substandard and disrespectful care in labour - because words matter.

Substandard or disrespectful care during labour should be of serious concern for healthcare professionals, as it can affect one of the most important events in a woman's life. Substandard care refers to the use of interventions that are not considered best-practice, to the inadequate execution of interventions, to situations where best-practice interventions are withheld from patients, or there is lack of adequate informed consent. Disrespectful care refers to forms of verbal and non-verbal communication that affect patients' dignity, individuality, privacy, intimacy, or personal beliefs. There are many possible underlying causes for substandard and disrespectful care in labour, including difficulties in modifying behaviours, judgmental or paternalistic attitudes, personal interests and individualism, and a human tendency to make less arduous, less difficult, or less stressful clinical decisions. The term "obstetric violence" is used in some parts of the world to describe various forms of substandard and disrespectful care in labour, but suggests that it is mainly carried out by obstetricians and is a serious form of aggression, carried out with the intent to cause harm. We believe that this term should not be used, as it does not help to identify the underlying problem, its causes, or its correction. In addition, it is generally seen by obstetricians and other healthcare professionals as an unjust and offensive term, generating a defensive and less collaborative mindset. We reach out to all individuals and institutions sharing the common goal of improving women's experience during labour, to work together to address the underlying causes of substandard and disrespectful care, and to develop common strategies to deal with this problem, based on mutual comprehension, trust and respect.

[Myasthenia gravis-Gender aspects and family planning]. / Myasthenia gravis ­ Genderaspekte und Familienplanung.

BACKGROUND: There is evidence that gender-specific differences can influence the diagnostics, treatment and long-term disease course of myasthenia gravis (MG). In women the diagnosis is often made during childbearing age. OBJECTIVE: Gender-specific differences in MG and relevant aspects in routine clinical practice are presented. In addition, current studies on family planning, pregnancy and childbirth in MG are highlighted and treatment recommendations are derived. MATERIAL AND METHODS: Narrative literature review. RESULTS: In addition to sociodemographic data, gender-specific differences encompass clinical as well as paraclinical factors, such as disease severity and antibody status. With few exceptions pregnancy is possible with good maternal and neonatal outcome. During pregnancy and peripartum, children of MG patients should be closely monitored for early detection and treatment of potential syndromes caused by diaplacental transfer of maternal antibodies. CONCLUSION: Gender-specific factors can influence the course of MG. Adequate medical counselling and multidisciplinary collaboration are essential for MG patients who wish to have children.

Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

EUROPEAN ASSOCIATION OF PERINATAL MEDICINE (EAPM) EUROPEAN MIDWIVES ASSOCIATION (EMA) Joint position statement: Caesarean delivery rates at a country level should be in the 15-20 % range.

While cesarean deliveries performed for health indications can save lives, unnecessary cesareans cause unjustifiable health risks for the mother, newborn, and for future pregnancies. Previous recommendations for cesarean delivery rates at a country level in the 10-15% range are currently unrealistic, and the proposed concept that striving to achieve specific rates is not important has resulted in a confusing message reaching healthcare professionals and the public. It is important to have a clear understanding of when cesarean delivery rates are deviating from internationally acceptable ranges, to trigger the implementation of healthcare policies needed to correct this problem. Based on currently existing scientific evidence, we recommend that cesarean delivery rates at a country level should be in the 15-20% range. This advice is based on the demonstration of decreased maternal and neonatal mortalities when national cesarean delivery rates rise to circa 15%, but values exceeding 20% are not associated with further benefits. It is also based on real-world experiences from northern European countries, where cesarean delivery rates in the 15-20% range are associated with some of the best maternal and perinatal quality indicators in the world. With the increase in cesarean delivery rates projected for the coming years, experience in provision of intrapartum care may come under threat in many hospitals, and recovering from this situation is likely to be a major challenge. Professional and scientific societies, together with healthcare authorities and governments need to prioritize actions to reverse the upward trend in cesarean delivery rates observed in many countries, and to strive to achieve values as close as possible to the recommended range.

Fluid shear stress induces a shift from glycolytic to amino acid pathway in human trophoblasts.

BACKGROUND: The human placenta, a tissue with a lifespan limited to the period of pregnancy, is exposed to varying shear rates by maternal blood perfusion depending on the stage of development. In this study, we aimed to investigate the effects of fluidic shear stress on the human trophoblast transcriptome and metabolism. RESULTS: Based on a trophoblast cell line cultured in a fluidic flow system, changes caused by shear stress were analyzed and compared to static conditions. RNA sequencing and bioinformatics analysis revealed an altered transcriptome and enriched gene ontology terms associated with amino acid and mitochondrial metabolism. A decreased GLUT1 expression and reduced glucose uptake, together with downregulated expression of key glycolytic rate-limiting enzymes, hexokinase 2 and phosphofructokinase 1 was observed. Altered mitochondrial ATP levels and mass spectrometry data, suggested a shift in energy production from glycolysis towards mitochondrial oxidative phosphorylation. This shift in energy production could be supported by increased expression of glutamic-oxaloacetic transaminase variants in response to shear stress as well as under low glucose availability or after silencing of GLUT1. The shift towards amino acid metabolic pathways could be supported by significantly altered amino acid levels, like glutamic acid, cysteine and serine. Downregulation of GLUT1 and glycolytic rate-limiting enzymes, with concomitant upregulation of glutamic-oxaloacetic transaminase 2 was confirmed in first trimester placental explants cultured under fluidic flow. In contrast, high fluid shear stress decreased glutamic-oxaloacetic transaminase 2 expression in term placental explants when compared to low flow rates. Placental tissue from pregnancies with intrauterine growth restriction are exposed to high shear rates and showed also decreased glutamic-oxaloacetic transaminase 2, while GLUT1 was unchanged and glycolytic rate-limiting enzymes showed a trend to be upregulated. The results were generated by using qPCR, immunoblots, quantification of immunofluorescent pictures, padlock probe hybridization, mass spectrometry and FRET-based measurement. CONCLUSION: Our study suggests that onset of uteroplacental blood flow is accompanied by a shift from a predominant glycolytic- to an alternative amino acid converting metabolism in the villous trophoblast. Rheological changes with excessive fluidic shear stress at the placental surface, may disrupt this alternative amino acid pathway in the syncytiotrophoblast and could contribute to intrauterine growth restriction.

Synapsin autoantibodies during pregnancy are associated with fetal abnormalities.

Anti-neuronal autoantibodies can be transplacentally transferred during pregnancy and may cause detrimental effects on fetal development. It is unclear whether autoantibodies against synapsin-I, one of the most abundant synaptic proteins, are associated with developmental abnormalities in humans. We recruited a cohort of 263 pregnant women and detected serum synapsin-I IgG autoantibodies in 13.3% using cell-based assays. Seropositivity was strongly associated with abnormalities of fetal development including structural defects, intrauterine growth retardation, amniotic fluid disorders and neuropsychiatric developmental diseases in previous children (odds ratios of 3-6.5). Autoantibodies reached the fetal circulation and were mainly of IgG1/IgG3 subclasses. They bound to conformational and linear synapsin-I epitopes, five distinct epitopes were identified using peptide microarrays. The findings indicate that synapsin-I autoantibodies may be clinically useful biomarkers or even directly participate in the disease process of neurodevelopmental disorders, thus being potentially amenable to antibody-targeting interventional strategies in the future.

Accuracy of prenatal detection of facial clefts and relation between facial clefts, additional malformations and chromosomal abnormalities: a large referral-center cohort.

PURPOSE: Facial clefts belong to the most common congenital malformations and their prenatal diagnosis is a constant challenge. The aim of this study was to determine the accuracy of prenatal ultrasound in correctly classifying facial clefts. Furthermore, we aimed to specify the distribution of the type of clefts and underlying genetic conditions. METHODS: All fetuses seen with suspected facial cleft in the Department of Obstetrics, Charité - Universitätsmedizin Berlin during a period of 23 years (1999-2022) were included in this retrospective study. Clefts were classified according to the classification of Nyberg. All additional prenatal findings were assessed and correlated with the outcome. The accuracy of prenatal diagnosis was assessed. RESULTS: 292 patients were included in the study. The most common type of clefts were unilateral cleft lip and palate (CL-P) (53.6%) and bilateral CL-P (30.6%), followed by CL (8.1%), CP (5.1%) and median CL-P (2.6%). The overall pre- and postnatal concordance rate corresponding to a correct prenatal diagnosis was high, 88.9%, ranging from 73.7% (CL) to 93.7% (unilateral CL-P). Most of the median clefts (95.2%) and CP (93.3%) were associated with other sonographic abnormalities, as well as 52.2% of bilateral CL-P. Chromosomal abnormalities, mostly trisomy 13 and trisomy 18, were observed in in the median CL-P (47.6%), bilateral CL-P (31.1%) and CP (26.7%) groups, in contrast to the CL (9.1%) and unilateral CL-P (12.9%) groups. It was exceptional to have a chromosomal abnormality without additional malformations (4.8%). The mortality rate including one late miscarriage, 5 IUFD's, 74 TOPs and 6 palliative cares at birth was 29.8%, particularly high for median clefts (90.5%). CONCLUSION: Prenatal ultrasound exhibited a high accuracy to assess the type of facial clefts with an average rate of 88.9% (73.7%-93.7%) and a concordance rate of up to 93.7%, depending on the type of cleft. The search for additional malformations as well as clarifying underlying genetic conditions is essential. This allows for a targeted counseling of the parents and to best prepare for postnatal care, including surgery by the maxillofacial team.

Pregnancy after Kidney Transplantation-Impact of Functional Renal Reserve, Slope of eGFR before Pregnancy, and Intensity of Immunosuppression on Kidney Function and Maternal Health.

Women of childbearing age show increased fertility after kidney transplantation. Of concern, preeclampsia, preterm delivery, and allograft dysfunction contribute to maternal and perinatal morbidity and mortality. We performed a retrospective single-center study, including 40 women with post-transplant pregnancies after single or combined pancreas-kidney transplantation between 2003 and 2019. Outcomes of kidney function up to 24 months after the end of pregnancy were compared with a matched-pair cohort of 40 transplanted patients without pregnancies. With a maternal survival rate of 100%, 39 out of 46 pregnancies ended up with a live-born baby. The eGFR slopes to the end of 24 months follow-up showed mean eGFR declines in both groups (-5.4 ± 14.3 mL/min in pregnant versus -7.6 ± 14.1 mL/min in controls). We identified 18 women with adverse pregnancy events, defined as preeclampsia with severe end-organ dysfunction. An impaired hyperfiltration during pregnancy was a significant risk contributor for both adverse pregnancy events (p < 0.05) and deterioration of kidney function (p < 0.01). In addition, a declining renal allograft function in the year before pregnancy was a negative predictor of worsening allograft function after 24 months of follow-up. No increased frequency of de novo donor-specific antibodies after delivery could be detected. Overall, pregnancies in women after kidney transplantation showed good allograft and maternal outcomes.

Comparison of the Soluble fms-Like Tyrosine Kinase 1/Placental Growth Factor Ratio Alone versus a Multi-Marker Regression Model for the Prediction of Preeclampsia-Related Adverse Outcomes after 34 Weeks of Gestation.

INTRODUCTION: The objective of this retrospective study was to compare the predictive performance of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio alone or in a multi-marker regression model for preeclampsia-related maternal and/or fetal adverse outcomes in women >34 weeks of gestation. METHODS: We analyzed the data collected from 655 women with suspected preeclampsia. Adverse outcomes were predicted by multivariable and univariable logistic regression models. The outcome of patients was evaluated within 14 days after presentation with signs and symptoms of preeclampsia or diagnosed preeclampsia. RESULTS: The full model integrating available, standard clinical information and the sFlt-1/PlGF ratio had the best predictive performance for adverse outcomes with an AUC of 72.6%, which corresponds to a sensitivity of 73.3% and specificity of 66.0%. The positive predictive value of the full model was 51.4%, and the negative predictive value was 83.5%. 24.5% of patients, who did not experience adverse outcomes but were classified as high risk by sFlt-1/PlGF ratio (≥38), were correctly classified by the regression model. The sFlt-1/PlGF ratio alone had a significantly lower AUC of 65.6%. CONCLUSIONS: Integrating angiogenic biomarkers in a regression model improved the prediction of preeclampsia-related adverse outcomes in women at risk after 34 weeks of gestation.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

Risk factors for anxiety and depression among pregnant women during the COVID-19 pandemic: Results of a web-based multinational cross-sectional study.

OBJECTIVE: To assess risk factors for anxiety and depression among pregnant women during the COVID-19 pandemic using Mind-COVID, a prospective cross-sectional study that compares outcomes in middle-income economies and high-income economies. METHODS: A total of 7102 pregnant women from 12 high-income economies and nine middle-income economies were included. The web-based survey used two standardized instruments, General Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9). RESULT: Pregnant women in high-income economies reported higher PHQ-9 (0.18 standard deviation [SD], P < 0.001) and GAD-7 (0.08 SD, P = 0.005) scores than those living in middle-income economies. Multivariate regression analysis showed that increasing PHQ-9 and GAD-7 scales were associated with mental health problems during pregnancy and the need for psychiatric treatment before pregnancy. PHQ-9 was associated with a feeling of burden related to restrictions in social distancing, and access to leisure activities. GAD-7 scores were associated with a pregnancy-related complication, fear of adverse outcomes in children related to COVID-19, and feeling of burden related to finances. CONCLUSIONS: According to this study, the imposed public health measures and hospital restrictions have left pregnant women more vulnerable during these difficult times. Adequate partner and family support during pregnancy and childbirth can be one of the most important protective factors against anxiety and depression, regardless of national economic status.

New advances in prediction and surveillance of preeclampsia: role of machine learning approaches and remote monitoring.

Preeclampsia, a multisystem disorder in pregnancy, is still one of the main causes of maternal morbidity and mortality. Due to a lack of a causative therapy, an accurate prediction of women at risk for the disease and its associated adverse outcomes is of utmost importance to tailor care. In the past two decades, there have been successful improvements in screening as well as in the prediction of the disease in high-risk women. This is due to, among other things, the introduction of biomarkers such as the sFlt-1/PlGF ratio. Recently, the traditional definition of preeclampsia has been expanded based on new insights into the pathophysiology and conclusive evidence on the ability of angiogenic biomarkers to improve detection of preeclampsia-associated maternal and fetal adverse events.However, with the widespread availability of digital solutions, such as decision support algorithms and remote monitoring devices, a chance for a further improvement of care arises. Two lines of research and application are promising: First, on the patient side, home monitoring has the potential to transform the traditional care pathway. The importance of the ability to input and access data remotely is a key learning from the COVID-19 pandemic. Second, on the physician side, machine-learning-based decision support algorithms have been shown to improve precision in clinical decision-making. The integration of signals from patient-side remote monitoring devices into predictive algorithms that power physician-side decision support tools offers a chance to further improve care.The purpose of this review is to summarize the recent advances in prediction, diagnosis and monitoring of preeclampsia and its associated adverse outcomes. We will review the potential impact of the ability to access to clinical data via remote monitoring. In the combination of advanced, machine learning-based risk calculation and remote monitoring lies an unused potential that allows for a truly patient-centered care.

The additive role of angiogenic markers for women with confirmed preeclampsia.

BACKGROUND: Hypertension complicates 2% to 8% of all pregnancies and is a leading cause of maternal and perinatal morbidity and mortality globally. Given the prognostic role that angiogenic markers play in evaluation of patients with "suspected preeclampsia," the International Society for the Study of Hypertension in Pregnancy incorporated angiogenic imbalance into the 2021 definition of preeclampsia. As women with "suspected preeclampsia" are a heterogeneous group, with some already meeting the diagnostic criteria for preeclampsia, we evaluated whether the soluble fms-like tyrosine kinase-1/placental growth factor ratio adds prognostic value among these women. OBJECTIVE: This study aimed to assess the additive value of soluble fms-like tyrosine kinase-1/placental growth factor ratio when the diagnostic criteria for preeclampsia have already been met. STUDY DESIGN: This was a secondary analysis of a prospective cohort study of patients presenting to obstetrical triage with suspected preeclampsia at ≥20+0 weeks' gestation from July 2009 to June 2012 in Boston, United States. Clinicians were masked to soluble fms-like tyrosine kinase-1/placental growth factor ratio results. Clinical records were reviewed for maternal and neonatal care and outcomes. The value of the soluble fms-like tyrosine kinase-1/placental growth factor ratio (≤38, >38, or >85) was assessed for identifying women at low or high risk of evolving into preeclampsia with severe features within 2 weeks of the triage visit, with preeclampsia with severe features being defined by the American College of Obstetricians and Gynecologists (2013 definition). Based on information in obstetrical triage, preeclampsia among triage patients was defined either by: (1) The International Society for the Study of Hypertension in Pregnancy "restrictive" criteria (ie, new-onset hypertension and proteinuria at ≥20 weeks), or (2) The International Society for the Study of Hypertension in Pregnancy "broad" maternal criteria (ie, new-onset hypertension with proteinuria or one/more relevant maternal end-organ complications). RESULTS: Of 1043 patients included, 459 presented at 20+0 to 34+6 weeks and 584 at ≥35+0 weeks. In triage, 25.8% of women with "suspected preeclampsia" already met the preeclampsia criteria based on the International Society for the Study of Hypertension in Pregnancy broad criteria and 22.0% based on the restrictive criteria. In separate multivariable analyses adjusted for gestational age, a soluble fms-like tyrosine kinase-1/placental growth factor ratio >38 was independently associated with preeclampsia with severe features within 2 weeks even after adjusting for preeclampsia diagnosis in obstetrical triage, whether that preeclampsia were defined restrictively (odds ratio, 15.62; 95% confidence interval, 8.91-27.40) or broadly (odds ratio, 14.56; 95% confidence interval, 8.30-25.56). A soluble fms-like tyrosine kinase-1/placental growth factor ratio ≤38 was good at ruling out development of preeclampsia with severe features within 2 weeks among all patients and among those meeting the restrictive or broad definitions of preeclampsia (negative likelihood ratios, ≤0.16), driven by performance of the ratio before 35 weeks (ie, negative likelihood ratio ≤0.12). A soluble fms-like tyrosine kinase-1/placental growth factor ratio >85 was good at ruling-in preeclampsia with severe features within 2 weeks among women with suspected preeclampsia, either before (positive likelihood ratio, 8.20) or after 35 weeks (positive likelihood ratio, 6.00) and fair at ruling-in preeclampsia with severe features within 2 weeks when preeclampsia had already been confirmed in patients at <35 weeks (restrictively positive likelihood ratio, 3.48, or broadly positive likelihood ratio, 3.40). CONCLUSION: Our findings support the prognostic value of the soluble fms-like tyrosine kinase-1/placental growth factor ratio among patients with confirmed preeclampsia, particularly to identify those both likely and unlikely to progress toward the development of severe features in the next 2 weeks and those who may be most appropriate for expectant and potentially outpatient care. Our findings support the incorporation of angiogenic imbalance into the definition of preeclampsia, particularly at 20-34+0 weeks.

Correlation between placental weight and angiogenic markers sFlt-1 and PlGF in women with preeclampsia and fetal growth restriction.

OBJECTIVES: The angiogenic factors sFlt-1 (soluble fms-like tyrosine kinase) and PlGF (Placental Growth Factor) play a key role in the pathophysiology, prediction and diagnosis of preeclampsia-associated pregnancy disorders. However, the correlation between maternal serum levels and the placental weight, especially in hypertensive pregnancy disorders is still unclear. STUDY DESIGN: Retrospectively, we analyzed data from a real-world cohort of patients with preeclampsia (PE), intrauterine growth restriction (IUGR), PE + IUGR and controls giving birth within 14 days from inclusion. Herein, correlational analyses were calculated between placental weight, maternal serum levels of sFlt-1, PlGF and the respective sFlt-1/PlGF-ratios. MAIN OUTCOME MEASURES AND RESULTS: This study included n = 328 patients (n = 134 with PE, n = 40 with IUGR and n = 25 showed PE + IUGR) and n = 129 controls. The gestational age-adjusted placental weight was significantly decreased in patients with PE ± IUGR, but not in PE alone, when comparing to controls. Correlation between PlGF and the placental weight was significantly positive and increasing with severity of disease (controls 0.134, p = 0.131, PE 0.419, p < 0.01, IUGR 0.517, p < 0.01, PE + IUGR r = 0.723, p < 0.01). Furthermore, an inverse correlation between the sFlt-1/PlGF-ratio and the placental weight was found. The sFlt-1/PlGF-ratio per gram placental weight was highest in patients with PE + IUGR and lowest in controls (0.6 (IQR 0.4-1.8) vs. 0.05 (IQR 0.02-0.15)). CONCLUSION: A correlation between the serum levels of sFlt-1 and PlGF and the placental weight is present in PE-associated pregnancy disorders. This mirrors the model of an angiogenic continuum in the placenta where the serum sFlt-1 to PlGF ratio increases with severity of the disease.

A machine-learning-based algorithm improves prediction of preeclampsia-associated adverse outcomes.

BACKGROUND: Preeclampsia presents a highly prevalent burden on pregnant women with an estimated incidence of 2% to 5%. Preeclampsia increases the maternal risk of death 20-fold and is one of the main causes of perinatal morbidity and mortality. Novel biomarkers, such as soluble fms-like tyrosine kinase-1 and placental growth factor in addition to a wide span of conventional clinical data (medical history, physical symptoms, laboratory parameters, etc.), present an excellent basis for the application of early-detection machine-learning models. OBJECTIVE: This study aimed to develop, train, and test an automated machine-learning model for the prediction of adverse outcomes in patients with suspected preeclampsia. STUDY DESIGN: Our real-world dataset of 1647 (2472 samples) women was retrospectively recruited from women who presented to the Department of Obstetrics at the Charité - Universitätsmedizin Berlin, Berlin, Germany, between July 2010 and March 2019. After standardization and data cleaning, we calculated additional features regarding the biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor and sonography data (umbilical artery pulsatility index, middle cerebral artery pulsatility index, mean uterine artery pulsatility index), resulting in a total of 114 features. The target metric was the occurrence of adverse outcomes throughout the remaining pregnancy and 2 weeks after delivery. We trained 2 different models, a gradient-boosted tree and a random forest classifier. Hyperparameter training was performed using a grid search approach. All results were evaluated via a 10 × 10-fold cross-validation regimen. RESULTS: We obtained metrics for the 2 naive machine-learning models. A gradient-boosted tree model was performed with a positive predictive value of 88%±6%, a negative predictive value of 89%±3%, a sensitivity of 66%±5%, a specificity of 97%±2%, an overall accuracy of 89%±3%, an area under the receiver operating characteristic curve of 0.82±0.03, an F1 score of 0.76±0.04, and a threat score of 0.61±0.05. The random forest classifier returned an equal positive predictive value (88%±6%) and specificity (97%±1%) while performing slightly inferior on the other available metrics. Applying differential cutoffs instead of a naive cutoff for positive prediction at ≥0.5 for the classifier's results yielded additional increases in performance. CONCLUSION: Machine-learning techniques were a valid approach to improve the prediction of adverse outcomes in pregnant women at high risk of preeclampsia vs current clinical standard techniques. Furthermore, we presented an automated system that did not rely on manual tuning or adjustments.

sFlt-1/PlGF ratio for prediction of preeclampsia in clinical routine: A pragmatic real-world analysis of healthcare resource utilisation.

BACKGROUND: We investigated the impact of the soluble fms-like tyrosine kinase 1 (sFlt-1)/placental growth factor (PlGF) ratio to predict short-term risk of preeclampsia on clinical utility and healthcare resource utilisation using real-world data (RWD), and compared findings with health economic modelling from previous studies. METHODS AND FINDINGS: This retrospective analysis compared data from the German population of a multicentre clinical study (PROGNOSIS, n = 203; sFlt-1/PlGF ratio blinded and unavailable for decision-making) with RWD from University Hospital Leipzig, Germany (n = 281; sFlt-1/PlGF ratio used to guide clinical decision-making). A subgroup of the RWD cohort with the same inclusion criteria as the PROGNOSIS trial (RWD prediction only, n = 99) was also included. sFlt-1/PlGF ratio was measured using fully automated Elecsys® sFlt-1 and PlGF immunoassays (cobas e analyser; Roche Diagnostics). A similar proportion of women in the RWD and PROGNOSIS cohorts experienced preeclampsia (14.95% vs. 13.79%; p = 0.7938); a smaller proportion of women in the RWD prediction only cohort experienced preeclampsia versus PROGNOSIS (6.06%; p = 0.0526). In women with preeclampsia, median gestational age at delivery (weeks) was comparable in the RWD and PROGNOSIS cohorts (34.0 vs. 34.3, p = 0.5895), but significantly reduced in the RWD prediction only cohort versus PROGNOSIS (27.1, p = 0.0038). sFlt-1/PlGF ratio at baseline visit was not statistically significantly different for the RWD and PROGNOSIS cohorts, irrespective of preeclampsia outcome. Hospitalisations for confirmed preeclampsia were significantly shorter in the RWD cohort versus PROGNOSIS (median 1 vs. 4 days, p = 0.0093); there was no significant difference between RWD prediction only and PROGNOSIS (3 days, p = 0.9638). All-cause hospitalisations were significantly shorter in the RWD (median 1 day; p<0.0001) and RWD prediction only (1 day; p<0.0001) cohorts versus PROGNOSIS (3 days). CONCLUSIONS: This study supports the findings of previous studies, showing that routine clinical use of the sFlt-1/PlGF ratio may result in shorter duration of hospitalisations, with potential economic benefits.

Clinical interpretation and implementation of the sFlt-1/PlGF ratio in the prediction, diagnosis and management of preeclampsia.

Preeclampsia is associated with significant morbidity and mortality for mother and baby. Although around 30% of all pregnancies are evaluated for preeclampsia, diagnosis is difficult, especially in patients who have overlying symptoms from other diseases. Discovery of circulating angiogenic factors in the pathogenesis of preeclampsia has been a major advance for both diagnosis and prognosis. The anti-angiogenic factor, soluble fms-like tyrosine kinase 1 (sFlt-1) and the pro-angiogenic factor, placental growth factor (PlGF), can be measured in plasma and serum and are usually reported as a ratio, which specifically relates to the onset and severity of preeclampsia. The sFlt-1/PlGF ratio has a very high negative predictive value in ruling out the development of preeclampsia within 7 days among women with suspected preeclampsia. Currently, there is no clear consensus on the practical use of angiogenic biomarkers in the detection and management of preeclampsia in routine clinical practice. While major international clinical guidelines exist, they do not define which specific parameters signal patient admission, or outpatient evaluation of suspected preeclampsia, and most clinicians follow local practices. Better guidance is needed on risk stratification among women with suspected preeclampsia, as well as among women at high risk for preeclampsia. Prediction of adverse outcomes in women, after the clinical diagnosis of preeclampsia, is also important. This report has been developed following a meeting of international experts and aims to guide clinicians in the management of pregnant women at risk of preeclampsia using the sFlt-1/PlGF ratio test.