Multicentre randomised trial of screening with sFlt1/PlGF and planned delivery to prevent pre-eclampsia at term: protocol of the PE37 study.

INTRODUCTION: Pre-eclampsia affects ~5%-7% of pregnancies. Although improved obstetric care has significantly diminished its associated maternal mortality, it remains a leading cause of maternal morbidity and mortality in the world. Term pre-eclampsia accounts for 70% of all cases and a large proportion of maternal-fetal morbidity related to this condition. Unlike in preterm pre-eclampsia, the prediction and prevention of term pre-eclampsia remain unsolved. Previously proposed approaches are based on combined third-trimester screening and/or prophylactic drugs, but these policies are unlikely to be widely implementable in many world settings. Recent evidence shows that the soluble fms-like tyrosine kinase-1 (s-Flt-1) to placental growth factor (PlGF) ratio measured at 35-37 weeks' gestation predicts term pre-eclampsia with an 80% detection rate. Likewise, recent studies demonstrate that induction of labour beyond 37 weeks is safe and well accepted by women. We hypothesise that a single-step universal screening for term pre-eclampsia based on sFlt1/PlGF ratio at 35-37 weeks followed by planned delivery beyond 37 weeks reduces the prevalence of term pre-eclampsia without increasing the caesarean section rates or worsening the neonatal outcomes. METHODS AND ANALYSIS: We propose an open-label randomised clinical trial to evaluate the impact of a screening of term pre-eclampsia with the sFlt-1/PlGF ratio followed by planned delivery in asymptomatic nulliparous women at 35-37 weeks. Women will be assigned 1:1 to revealed (sFlt-1/PlGF known to clinicians) versus concealed (unknown) arms. A cut-off of >90th centile is used to define the high risk of subsequent pre-eclampsia and offer planned delivery from 37 weeks. The efficacy variables will be analysed and compared between groups primarily following an intention-to-treat approach, by ORs and their 95% CI. This value will be computed using a Generalised Linear Mixed Model for binary response (study group as fixed effect and the centre as intercept random effect). ETHICS AND DISSEMINATION: The study is conducted under the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 20 November 2020. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT04766866.

Enhancing the value of the sFlt-1/PlGF ratio for the prediction of preeclampsia: Cost analysis from the Belgian healthcare payers' perspective.

OBJECTIVE: To evaluate the economic impact of introducing the soluble fms-like tyrosine kinase (sFlt-1) to placental growth factor (PlGF) ratio test into clinical practice in Belgium for the prediction of preeclampsia (PE). STUDY DESIGN: We developed a one-year time-horizon decision tree model to evaluate the short-term costs associated with the introduction of the sFlt-1/PlGF test for guiding the management of women with suspected PE from the Belgian public healthcare payers' perspective. The model estimated the costs associated with the diagnosis and management of PE in pregnant women managed in either a test scenario, in which the sFlt-1/PlGF test is used in addition to current clinical practice, or a no test scenario, in which clinical decisions are based on current practice alone. Test characteristics were derived from PROGNOSIS, a non-interventional study in women presenting with clinical suspicion of PE. Unit costs were obtained from Belgian-specific sources. The main model outcome was the total cost per patient. RESULTS: Introduction of the sFlt-1/PlGF ratio test is expected to result in a cost saving of €712 per patient compared with the no test scenario. These savings are generated mainly due to a reduction in unnecessary hospitalizations. CONCLUSIONS: The sFlt-1/PlGF test is projected to result in substantial cost savings for the Belgian public healthcare payers through reduction of unnecessary hospitalization of women with clinical suspicion of PE that ultimately do not develop the condition. The test also has the potential to ensure that women at high risk of developing PE are identified and appropriately managed.

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.

A multicenter observational survey of management strategies in 442 pregnancies with suspected placenta accreta spectrum.

INTRODUCTION: Management options for women with placenta accreta spectrum (PAS) comprise termination of pregnancy before the viable gestational age, leaving the placenta in situ for subsequent reabsorption of the placenta or delayed hysterectomy, manual removal of placenta after vaginal delivery or during cesarean section, focal resection of the affected uterine wall, and peripartum hysterectomy. The aim of this observational study was to describe actual clinical management and outcomes in PAS in a large international cohort. MATERIAL AND METHODS: Data from women in 15 referral centers of the International Society of PAS (IS-PAS) were analyzed and correlated with the clinical classification of the IS-PAS: From Grade 1 (no PAS) to Grade 6 (invasion into pelvic organs other than the bladder). PAS was usually diagnosed antenatally and the operators performing ultrasound rated the likelihood of PAS on a Likert scale of 1 to 10. RESULTS: In total, 442 women were registered in the database. No maternal deaths occurred. Mean blood loss was 2600 mL (range 150-20 000 mL). Placenta previa was present in 375 (84.8%) women and there was a history of a previous cesarean in 329 (74.4%) women. The PAS likelihood score was strongly correlated with the PAS grade (P < .001). The mode of delivery in the majority of women (n = 252, 57.0%) was cesarean hysterectomy, with a repeat laparotomy in 20 (7.9%) due to complications. In 48 women (10.8%), the placenta was intentionally left in situ, of those, 20 (41.7%) had a delayed hysterectomy. In 26 women (5.9%), focal resection was performed. Termination of pregnancy was performed in 9 (2.0%), of whom 5 had fetal abnormalities. The placenta could be removed in 90 women (20.4%) at cesarean, and in 17 (3.9%) after vaginal delivery indicating mild or no PAS. In 34 women (7.7%) with an antenatal diagnosis of PAS, the placenta spontaneously separated (false positives). We found lower blood loss (P < .002) in 2018-2019 compared with 2009-2017, suggesting a positive learning curve. CONCLUSIONS: In referral centers, the most common management for severe PAS was cesarean hysterectomy, followed by leaving the placenta in situ and focal resection. Prenatal diagnosis correlated with clinical PAS grade. No maternal deaths occurred.

Maternal Serum VEGF Predicts Abnormally Invasive Placenta Better than NT-proBNP: a Multicenter Case-Control Study.

The aim of this study was to test if maternal serum vascular endothelial growth factor (VEGF) or N-terminal pro B-type natriuretic peptide (NT-proBNP) predicts abnormally invasive placenta (AIP) better. Secondary objective was to test whether the serum levels of VEGF and NT-proBNP can predict the degree of invasion. In a multicenter case-control study design, gestational age-matched serum samples from pregnant women with AIP (n = 44) and uncomplicated pregnancies (n = 55) who had been enrolled at Charité - Universitätsmedizin Berlin, Germany and Centre Hospitalier Régional de la Citadelle in Liège, Belgium were analyzed. Maternal blood serum VEGF and NT-proBNP levels were immunoassayed from samples taken immediately before delivery (GA median: 35 weeks). Biomarker levels were compared between AIP and control group. The correlation of biomarker levels with the clinical AIP degree was assessed. The predictive biomarker ability was characterized through a multivariate regression model and receiver operating characteristic curves. Women with AIP had significantly lower maternal serum VEGF levels (AIP mean 285 pg/ml, 95% CI 248-322, vs. control: 391 pg/ml, 95% CI 356-426, p < 0.01) and higher NT-proBNP levels (AIP median 329 pg/ml, IQR 287-385, vs. control 295 pg/ml, IQR 273-356, p = 0.03). Maternal serum VEGF levels were able to predict AIP better (AUC = 0.729, 0.622-0.836, p < 0.001; VEGF + number of previous cesarean deliveries: AUC = 0.915, 0.853-0.977, p < 0.001). Maternal serum VEGF levels correlated inversely with the clinical AIP degree (r = - 0.32, p < 0.01). In short, maternal serum VEGF, more than NT-proBNP, can help in predicting AIP and hints at the degree of invasion.

Evidence-based guidelines for the management of abnormally invasive placenta: recommendations from the International Society for Abnormally Invasive Placenta.

The worldwide incidence of abnormally invasive placenta is rapidly rising, following the trend of increasing cesarean delivery. It is a heterogeneous condition and has a high maternal morbidity and mortality rate, presenting specific intrapartum challenges. Its rarity makes developing individual expertise difficult for the majority of clinicians. The International Society for Abnormally Invasive Placenta aims to improve clinicians' understanding and skills in managing this difficult condition. By pooling knowledge, experience, and expertise gained within a variety of different healthcare systems, the Society seeks to improve the outcomes for women with abnormally invasive placenta globally. The recommendations presented herewith were reached using a modified Delphi technique and are based on the best available evidence. The evidence base for each is presented using a formal grading system. The topics chosen address the most pertinent questions regarding intrapartum management of abnormally invasive placenta with respect to clinically relevant outcomes, including the following: definition of a center of excellence; requirement for antenatal hospitalization; antenatal optimization of hemoglobin; gestational age for delivery; antenatal corticosteroid administration; use of preoperative cystoscopy, ureteric stents, and prophylactic pelvic arterial balloon catheters; maternal position for surgery; type of skin incision; position of the uterine incision; use of interoperative ultrasound; prophylactic administration of oxytocin; optimal method for intraoperative diagnosis; use of expectant management; adjuvant therapies for expectant management; use of local surgical resection; type of hysterectomy; use of delayed hysterectomy; intraoperative measures to treat life-threatening hemorrhage; and fertility after conservative management.

Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio and Time to Delivery in Women With Suspected Preeclampsia.

OBJECTIVE: To assess the association of a serum soluble fms-like tyrosine kinase 1-to-placental growth factor (sFlt-1-to-PlGF) ratio of greater than 38 with time to delivery and preterm birth. METHODS: Secondary analysis of an observational cohort study that included women 18 years of age or older from 24 to 36 6/7 weeks of gestation at their first study visit with suspected (not confirmed) preeclampsia. Participants were recruited from December 2010 to January 2014 at 30 sites in 14 countries. A total of 1,041 women were included in time-to-delivery analysis and 848 in preterm birth analysis. RESULTS: Women with an sFlt-1-to-PlGF ratio greater than 38 (n=250) had a 2.9-fold greater likelihood of imminent delivery (ie, delivery on the day of the test) (Cox regression hazard ratio 2.9; P<.001) and shorter remaining time to delivery (median 17 [interquartile range 10-26] compared with 51 [interquartile range 30-75] days, respectively; Weibull regression factor 0.62; P<.001) than women with an sFlt-1-to-PlGF ratio of 38 or less, whether or not they developed preeclampsia. For women who did not (n=842) and did develop preeclampsia (n=199), significant correlations were seen between an sFlt-1-to-PlGF ratio greater than 38 and preterm birth (r=0.44 and r=0.46; both P<.001). Among women who did not develop preeclampsia, those who underwent iatrogenic preterm delivery had higher median sFlt-1-to-PlGF ratios at their first visit (35.3, interquartile range 6.8-104.0) than those who did not (8.4, interquartile range 3.4-30.6) or who delivered at term (4.3, interquartile range 2.4-10.9). CONCLUSIONS: In women undergoing evaluation for suspected preeclampsia, a serum sFlt-1-to-PlGF ratio greater than 38 is associated with a shorter remaining pregnancy duration and a higher risk of preterm delivery.

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.).

Expulsion of a uterine myoma in a patient treated with ulipristal acetate.

Description of a spontaneous expulsion of a submucosal myoma in a patient treated with ulipristal acetate.

Prenatal diagnosis of abnormally invasive placenta reduces maternal peripartum hemorrhage and morbidity.

OBJECTIVE: Abnormally invasive placenta (AIP) poses diagnostic and therapeutic challenges. We analyzed clinical cases with confirmed placenta increta or percreta. DESIGN: Retrospective case series. SETTING: Multicenter study. POPULATION: Pregnant women with AIP. METHODS: Chart review. MAIN OUTCOME MEASURES: Prenatal detection rates, treatment choices, morbidity, mortality and short-term outcome. RESULTS: Sixty-six cases were analyzed. All women and all but three fetuses survived; 57/64 women (89%) had previous uterine surgery. In 26 women (39%) the diagnosis was not known before delivery (Group 1), in the remaining 40 (61%) diagnosis had been made between 14 and 37 weeks of gestation (Group 2). Placenta previa was present in 36 women (54%). In Groups 1 and 2, 50% (13/26) and 62% (25/40) of the women required hysterectomy, respectively. In Group 1 (unknown at the time of delivery) 69% (9/13) required (emergency) hysterectomy for severe hemorrhage in the immediate peripartum period compared with only 12% (3/25) in Group 2 (p = 0.0004). Mass transfusions were more frequently required in Group 1 (46%, 12/26 vs. 20%, 8/40; p = 0.025). In 18/40 women (45%) from Group 2 the placenta was intentionally left in situ; secondary hysterectomies and infections were equally frequent (18%) among these differently treated women. Overall, postpartum infections occurred in 11% and 20% of women in Groups 1 and 2, respectively. CONCLUSIONS: AIP was known before delivery in more than half of the cases. Unknown AIP led to significantly more emergency hysterectomies and mass transfusions during or immediately after delivery. Prenatal diagnosis of AIP reduces morbidity. Future studies should also address the selection criteria for cases appropriate for leaving the placenta in situ.

Hysteroscopic resection of abnormally invasive placenta residuals.

OBJECTIVE: To present our experience in hysteroscopic removal of abnormally invasive placenta (AIP) residuals using bipolar energy. DESIGN: Case series. SETTING: University hospital. POPULATION: Sixteen patients with AIP residuals after 17 pregnancies. METHODS: Cases were identified by ultrasound, treated with hysteroscopic bipolar electrosurgery and oral contraceptives, and followed up by ultrasound or hysteroscopy. Nine subsequent pregnancies were described. MAIN OUTCOME MEASURES AND RESULTS: Complete removal of AIP residuals was achieved by hysteroscopic bipolar electrosurgery in all cases except one. No perioperative complications occurred. AIP residual recurred in one patient after a subsequent pregnancy and was successfully treated using the same procedure. CONCLUSIONS: AIP residual is a rare condition. Management by hysteroscopic resection using bipolar energy is safe and feasible.

Differential expression of Vegfr-2 and its soluble form in preeclampsia.

BACKGROUND: Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (also known as sFlt-1) and soluble endoglin (sEng), as well as to decreased PlGF. Recently, soluble VEGF type 2 receptor (sVEGFR-2) has emerged as a crucial regulator of lymphangiogenesis. To date, however, there is a paucity of information on the changes of VEGFR-2 that occur during the clinical onset of PE. Therefore, the aim of our study was to characterize the plasma levels of VEGFR-2 in PE patients and to perform VEGFR-2 immunolocalization in placenta. METHODOLOGY/PRINCIPAL FINDINGS: By ELISA, we observed that the VEGFR-2 plasma levels were reduced during PE compared with normal gestational age matched pregnancies, whereas the VEGFR-1 and Eng plasma levels were increased. The dramatic drop in the VEGFR-1 levels shortly after delivery confirmed its placental origin. In contrast, the plasma levels of Eng and VEGFR-2 decreased only moderately during the early postpartum period. An RT-PCR analysis showed that the relative levels of VEGFR-1, sVEGFR-1 and Eng mRNA were increased in the placentas of women with severe PE. The relative levels of VEGFR-2 mRNA as well as expressing cells, were similar in both groups. We also made the novel finding that a recently described alternatively spliced VEGFR-2 mRNA variant was present at lower relative levels in the preeclamptic placentas. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the plasma levels of anti-angiogenic factors, particularly VEGFR-1 and VEGFR-2, behave in different ways after delivery. The rapid decrease in plasma VEGFR-1 levels appears to be a consequence of the delivery of the placenta. The persistent circulating levels of VEGFR-2 suggest a maternal endothelial origin of this peptide. The decreased VEGFR-2 plasma levels in preeclamptic women may serve as a marker of endothelial dysfunction.

Thiamine status in humans and content of phosphorylated thiamine derivatives in biopsies and cultured cells.

BACKGROUND: Thiamine (vitamin B1) is an essential molecule for all life forms because thiamine diphosphate (ThDP) is an indispensable cofactor for oxidative energy metabolism. The less abundant thiamine monophosphate (ThMP), thiamine triphosphate (ThTP) and adenosine thiamine triphosphate (AThTP), present in many organisms, may have still unidentified physiological functions. Diseases linked to thiamine deficiency (polyneuritis, Wernicke-Korsakoff syndrome) remain frequent among alcohol abusers and other risk populations. This is the first comprehensive study on the distribution of thiamine derivatives in human biopsies, body fluids and cell lines. METHODOLOGY AND PRINCIPAL FINDINGS: Thiamine derivatives were determined by HPLC. In human tissues, the total thiamine content is lower than in other animal species. ThDP is the major thiamine compound and tissue levels decrease at high age. In semen, ThDP content correlates with the concentration of spermatozoa but not with their motility. The proportion of ThTP is higher in humans than in rodents, probably because of a lower 25-kDa ThTPase activity. The expression and activity of this enzyme seems to correlate with the degree of cell differentiation. ThTP was present in nearly all brain and muscle samples and in ∼60% of other tissue samples, in particular fetal tissue and cultured cells. A low ([ThTP]+[ThMP])/([Thiamine]+[ThMP]) ratio was found in cardiovascular tissues of patients with cardiac insufficiency. AThTP was detected only sporadically in adult tissues but was found more consistently in fetal tissues and cell lines. CONCLUSIONS AND SIGNIFICANCE: The high sensitivity of humans to thiamine deficiency is probably linked to low circulating thiamine concentrations and low ThDP tissue contents. ThTP levels are relatively high in many human tissues, as a result of low expression of the 25-kDa ThTPase. Another novel finding is the presence of ThTP and AThTP in poorly differentiated fast-growing cells, suggesting a hitherto unsuspected link between these compounds and cell division or differentiation.

The efficacy of medical and surgical treatment of endometriosis-associated infertility: arguments in favour of a medico-surgical aproach.

This review discusses the efficacy of a combined, medical (GnRH agonist) and surgical, therapy in endometriosis-associated infertility. Because of the limited information currently available on the activity of lesions in minimal and mild endometriosis, any absolute statement is inappropriate at this time, although some arguments exist in favour of treating endometriosis at laparoscopy. In moderate and severe endometriosis, this review provides arguments in favour of a medico-surgical approach and discusses the possibility of combining medical and surgical therapy.