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.

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 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.

[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.

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.

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.

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.

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.

The diagnostic value of angiogenic and antiangiogenic factors in differential diagnosis of preeclampsia.

The definition of preeclampsia is changing. However, with the addition of organ symptoms to the presence of hypertension in pregnancy instead of relying only on proteinuria, a more precise detection of women at risk of preeclampsia-associated adverse events has not been achieved. Instead, under the new definitions of the American College of Obstetricians and Gynecologists and of the International Society for the Study of Hypertension in Pregnancy, more women are classified as preeclamptic, with a tendency to milder disease. Furthermore, angiogenic and antiangiogenic factors have emerged as essential tools for predicting and diagnosing preeclampsia at high accuracies. Next to being rooted in the pathophysiology of the disease, they have been proven to be reliable tools for predicting and diagnosing the disease. In addition, 2 cutoffs have been evaluated for the clinical setting. As shown in the Prediction of Short-Term Outcome in Pregnant Women With Suspected Preeclampsia Study, at the soluble fms-like tyrosine kinase-1-to-placental growth factor ratio cutoff of 38, a preeclampsia can be ruled out for 1 week with a negative predictive value of 99.3% (95% confidence interval, 97.9-99.9) and ruled in with a positive predictive value of 36.7% (95% confidence interval, 28.4-45.7). The diagnostic cutoff of 85 has been shown to accurately identify women with preeclampsia, with a sensitivity of up to 88% and a specificity of 99.5%. In this review, we highlight the central role of angiogenic and antiangiogenic factors in the differential diagnosis of women presenting at high risk of the disease, such as patients with chronic hypertension or chronic kidney disease. We will focus on their ability to predict preeclampsia-associated adverse fetal and maternal outcomes. This is only possible when critically reviewing the evolution of the definition of "preeclampsia." We show how changes in this definition shape our clinical picture of the condition and how angiogenic and antiangiogenic biomarkers might be included to better identify women destined to develop preeclampsia-related adverse outcomes.

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.

Differential diagnosis of syndromic craniosynostosis: a case series.

PURPOSE: Syndromic craniosynostosis is a rare genetic disease caused by premature fusion of one or multiple cranial sutures combined with malformations of other organs. The aim of this publication is to investigate sonographic signs of different syndromic craniosynostoses and associated malformations to facilitate a precise and early diagnosis. METHODS: We identified in the period of 2000-2019 thirteen cases with a prenatal suspected diagnosis of syndromic craniosynostosis at our department. We analyzed the ultrasound findings, MRI scans, genetic results as well as the mode of delivery, and postnatal procedures. RESULTS: Eight children were diagnosed with Apert Syndrome, two with Saethre Chotzen syndrome, one with Crouzon syndrome, and one with Greig cephalopolysyndactyly syndrome. One child had a mutation p.(Pro253Leu) in the FGFR2 gene. We identified characteristic changes of the head shape as well as typical associated malformations. CONCLUSION: Second trimester diagnosis of syndromic craniosynostosis is feasible based on the identified sonographic signs. In case of a suspected diagnosis a genetic, neonatal as well as surgical counseling is recommended. We also recommend to offer a fetal MRI. The delivery should be planned in a perinatal center.

Prognostic significance of prenatal ultrasound in fetal arthrogryposis multiplex congenita.

PURPOSE: Fetal arthrogryposis multiplex congenita (AMC) describes a heterogeneous disease entity characterized by multiple contractures affecting at least two different body areas. The aim of our study was to identify additional sonographic abnormalities in fetuses with AMC Type I-III associated with an unfavorable prognosis and to describe when those signs were first detected. METHODS: This retrospective study included 41 pregnancies of suspected AMC diagnosed 1999-2017 at our tertiary referral center. The affected pregnancies were divided into the 3 AMC subgroups; the time of detection and outcome were analyzed. Prenatal sonograms, pediatric charts, genetic tests, and autopsy reports were studied. RESULTS: Pregnancy outcome data were verifiable in 34 out of 41 cases; in 27 cases, AMC was confirmed. Hydrops was present in 50% of postnatally deceased fetuses, 53% of cases resulting in termination of pregnancy vs. 0% of the surviving 8 children. Absent stomach filling was found in 67% of the children with neonatal death. After subcategorization, the limb-involvement-only-group, 8% showed hydrops vs. 100% in system anomaly group vs. 70% in neuromuscular dysfunction cohort (p = 0.001). Scoliosis, nuchal edema, and absent stomach filling were significantly indicating for a neurological etiology. CONCLUSION: In addition to disease-defining sonographic findings, those with prognostic significance were identified. Hydrops, nuchal edema, scoliosis and absent stomach filling were associated with unfavorable outcomes implicating a neuromuscular etiology. This knowledge can help to predict the further course of the disease and support patient counseling.

Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies.

OBJECTIVE: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. METHODS: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. RESULTS: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. CONCLUSIONS: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

Kagami-Ogata syndrome: an important differential diagnosis to Beckwith-Wiedemann syndrome.

We report the case of a fetus with sonographic characteristics of Beckwith-Wiedemann syndrome (BWS). A 30-year-old gravida 2 para 1 was referred to our fetal medicine unit with an omphalocele. Fetal macrosomia, organomegaly, and polyhydramnios but no macroglossia were detected and BWS was suspected. Genetic testing for BWS did not confirm the suspected diagnosis as the karyotype was normal. Symptomatic polyhydramnios led to repeated amnioreductions. At 35 + 5 weeks of gestation, a female neonate of 3660 g was delivered with APGAR scores of 6/7/8, after 1/5/10 min, respectively. The abnormal shape of the thorax, facial dysmorphism, need for ventilation, and generalized muscular hypotonia led to the suspicion of Kagami-Ogata syndrome (KOS), which was confirmed by genetic testing. KOS in our patient was caused by a large deletion in the MEG3-region on chromosome 14q32 affecting the maternal allele. In this report, we highlight the notion that when sonographic signs suggestive of BWS such as macrosomia, polyhydramnios, and omphalocele are present and genetic testing does not confirm the suspected diagnosis, KOS should be tested for.

Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia.

BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS: We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS: In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS: An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).

Update on the Diagnosis and Prognosis of Preeclampsia with the Aid of the sFlt-1/ PlGF Ratio in Singleton Pregnancies.

Preeclampsia (PE) is involved in a group of obstetrical conditions closely related by the presence of placental dysfunction (PD), which also includes intrauterine growth restriction and placental abruption. The timely and accurate recognition and management of PE are often challenging because diagnostic criteria are still based on nonspecific signs and symptoms and because common severity criteria correlate poorly with adverse maternal and fetal outcomes. The discovery of the role of angiogenesis-related factors - soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) - in the underlying pathophysiology of PD has marked an important step for improving its early diagnosis and prognosis assessment before gestational week 34. Nowadays, an sFlt-1/PlGF ratio cutoff level of ≤38 is widely accepted for ruling out PE in patients with suspicion of the disease, and its use is cost-effective. However, the evidence is more limited regarding the management and prognosis of women with an abnormally high sFlt-1/PlGF ratio. This review summarizes the current evidence of the clinical application of the sFlt-1/PlGF ratio for the diagnosis and prognosis assessment of PE and points out the next challenges for these biomarkers, including their role as target for the development and monitoring of new therapies.

Modeling risk for severe adverse outcomes using angiogenic factor measurements in women with suspected preterm preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a pregnancy-specific syndrome associated with adverse maternal and fetal outcomes. Patient-specific risks based on angiogenic factors might better categorize those who might have a severe adverse outcome. METHODS: Women evaluated for suspected PE at a tertiary hospital (2009-2012) had pregnancy outcomes categorized as 'referent' or 'severe', based solely on maternal/fetal findings. Outcomes that may have been influenced by a PE diagnosis were considered 'unclassified'. Soluble fms-like tyrosine kinase (sFlt1) and placental growth factor (PlGF) were subjected to bivariate discriminant modeling, allowing patient-specific risks to be assigned for severe outcomes. RESULTS: Three hundred twenty-eight singleton pregnancies presented at ≤34.0 weeks' gestation. sFlt1 and PlGF levels were adjusted for gestational age. Risks above 5 : 1 (10-fold over background) occurred in 77% of severe (95% CI 66 to 87%) and 0.7% of referent (95% CI <0.1 to 3.8%) outcomes. Positive likelihood ratios for the modeling and validation datasets were 19 (95% CI 6.2-58) and 15 (95% CI 5.8-40) fold, respectively. CONCLUSIONS: This validated model assigns patient-specific risks of any severe outcome among women attending PE triage. In practice, women with high risks would receive close surveillance with the added potential for reducing unnecessary preterm deliveries among remaining women. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

Update on the pathophysiological implications and clinical role of angiogenic factors in pregnancy.

Angiogenic markers are now being incorporated into clinical practice for the screening, diagnosing, and monitoring of preeclampsia. Pregnancy requires both vasculogenesis and angiogenesis in the fetal compartment and angiogenesis in the maternal compartment. Abnormal angiogenesis in the placenta determines impaired remodeling of the maternal spiral arteries and placental underperfusion that may ultimately lead to fetal growth restriction and maternal preeclampsia. The dysregulation of angiogenesis in the placenta and maternal-fetal circulation has emerged as one of the main pathophysiological features in the development of placental insufficiency and its clinical consequences. Abnormal angiogenesis has also been related to other obstetric and fetal conditions such as peripartum cardiomyopathy and fetal cardiac defects. This opens up new challenges for our understanding of angiogenic involvement in maternal cardiovascular function and fetal cardiac development, and it offers new clinical opportunities. This review summarizes the current knowledge of the pathophysiological implications and the clinical role of angiogenic factors in pregnancy.