A case report of metastatic gastric cancer treated with pembrolizumab during pregnancy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are extensively used in present-day clinical practice for treating many types of cancers at different stages. To date, there is scarce data on the use of immunotherapy in pregnancy. Immune-related adverse events (irAE) are a typical consequence of this therapy miming autoimmune diseases. CASE PRESENTATION: A 35-year-old woman (G1P0) diagnosed with gastric carcinoma underwent neoadjuvant chemotherapy followed by surgery. During follow-up, axillary metastasis was discovered, radiotherapy failed, consequently immunotherapy was started. Concurrently, pregnancy was ensued. Despite potential risks, the patient opted to continue immunotherapy and the pregnancy. At 31 weeks, fetal bowel dilation was noted. Subsequently, the fetus also developed fetal growth restriction (FGR). A Cesarean Section (CS) was performed at 35 weeks. The newborn required repeated bowel resections for necrotizing enterocolitis (NEC), necessitating extensive medical intervention. The mother continues pembrolizumab treatment with positive response. CONCLUSION: To the best of our knowledge this might constitute a possible case of fetal immune-related adverse event after immunotherapy in utero exposure.

Reference charts for umbilical Doppler pulsatility index in fetuses with isolated two-vessel cord.

PURPOSE: To determine reference values for umbilical Doppler pulsatility index in fetuses with isolated two-vessel cord and to compare these values with standard umbilical Doppler pulsatility index curves from 23 to 40 gestational weeks. METHODS: A retrospective longitudinal cohort study was conducted between January 2014 and December 2017 in a tertiary referral hospital and included 62 pregnant women with isolated single umbilical artery (two-vessel cord) and 174 measurements. Only uncomplicated term pregnancies were included. A reference curve for umbilical Doppler pulsatility index was built up and compared with a standard curve commonly used for fetuses with three-vessel cord. RESULTS: Umbilical Doppler pulsatility index values were much lower than expected in cases with two-vessel cord compared to 3-vessel cord: mean of the regression equations was 1.02 ± 0.23 vs. 0.86 ± 0.19, respectively (p value < 0.001). This difference was quite constant across the gestational weeks considered, showing that the slopes of the two regressions were very similar. CONCLUSION: Reference curves for umbilical Doppler pulsatility index in two-vessel cord pregnancies were determined. Pulsatility index values were significantly different compared with those commonly used for three-vessel cord. Using lower reference values for umbilical pulsatility index in cases with two-vessel cord may allow a better identification of fetuses affected with intrauterine growth restriction, thus improving fetal surveillance.

Sequential analysis of the normal fetal fissures with three-dimensional ultrasound: a longitudinal study.

OBJECTIVE: To perform a sequential analysis of the main cortical fissures in normal fetuses using 3D ultrasound. METHODS: A cohort of patients with uncomplicated singleton pregnancies underwent three consecutive transabdominal scans at 19-21, 26-28 and 30-34 weeks. Volumes of the fetal head were acquired and searched in the multiplanar mode for the following cortical fissures: sylvian, parieto-occipital, calcarine, hippocampus and cingulate. A qualitative analysis of these sulci was performed in each volume by an experienced operator (A) and a trainee (B). By placing the dot on the sulcus in one plane, it was evaluated whether it was visible also in other planes. RESULTS: Fifty patients were included in the study. At 19-21 weeks, the sylvian and parieto-occipital sulci were visualized on at least one plane by both operators in all cases. At 26-28 weeks, all fissures were visualized by both operators on at least one plane, with no significant difference between the performances of the two operators. At 30-34 weeks, a mild overall decline in the accuracy of identification of all the cerebral fissures was observed. CONCLUSIONS: 3D multiplanar mode allows a systematic evaluation of the cortical fissures in normal fetuses since midtrimester.

Demonstration of the Pericallosal Artery at 11-13 Weeks of Gestation Using 3D Ultrasound.

OBJECTIVE: To assess the sonographic visualization of the pericallosal arteries in normal fetuses at 11-13 weeks of gestation using 3D ultrasound. METHODS: We prospectively enrolled women with a singleton pregnancy undergoing ultrasound at 11-13 weeks of gestation. A 3D volume with high-definition power Doppler was acquired starting from the sagittal view of the fetal head and stored in the spatiotemporal image correlation mode. The images of the pericallosal arteries were assigned a score of 0 (no visualization), 1 (visualization of the origin) or 2 (visualization of the whole course). A follow-up scan was performed in all cases at 20 weeks of gestation to assess the presence of the corpus callosum. RESULTS: 70 patients were included and the pericallosal arteries were sonographically detectable in all cases. Image scores of 1 and 2 were obtained in 8 and 62 cases, respectively. The whole length of the vessel was between 3.5 and 4.5 mm. The vast majority of those with a score of 2 were beyond 12 completed weeks of gestation. All fetuses showed a normal corpus callosum at midtrimester and no abnormal brain findings after birth. CONCLUSIONS: The pericallosal arteries are sonographically visible since the first trimester in 3D ultrasound scans of fetuses found to have a normal corpus callosum at follow-up.

Uterine artery Doppler longitudinal changes in pregnancies complicated with intrauterine growth restriction without preeclampsia.

OBJECTIVE: The objective of this article is to evaluate the longitudinal changes in uterine artery Doppler pulsatility index (UtA-PI) in pregnancies complicated with early onset intrauterine growth restriction (IUGR). METHOD: Case-control study comparing UtA-PI from 20 to 34 weeks gestation in pregnancies affected by IUGR at 20 to 28 weeks and confirmed at delivery (cases), matched with 1000 controls. Multivariable analyses were used to estimate the UtA-PI as a function of both gestational age and IUGR severity. Finally, bootstrapping technique was used to internally validate the models. RESULTS: We retrospectively retrieved 53 cases and 1000 controls. Regression line having log10 UtA-PI as dependent variable was a function of both gestational age and IUGR. UtA-PI decreased with gestational age in both groups. In IUGR group, UtA-PI was higher from 20 weeks onward and the difference with controls increased with gestational age. In fact, at 20 weeks, the UtA-PI ratio between cases and controls was 1.84, but at 30 weeks it rose to 2.05. Finally, the weight at delivery in the IUGR group was also inversely correlated with the UtA-PI values. CONCLUSION: We presented a reliable multivariable statistical model to evaluate the temporal changes of UtA-PI values as a function of both gestational age and IUGR.

The descent of the fetal head is not modified by mobile epidural analgesia: a controlled sonographic study.

The aim of our study was to assess the sonographic indices of fetal head progression obtained by three-dimensional ultrasound during the second stage of labor in women with and without mobile epidural analgesia. Sonographic volume data sets were obtained with a transperineal approach every 20 min from the beginning of the active second stage until delivery. The ultrasound parameters were calculated off-line from each volume and compared between women with and without epidural analgesia. All the sonographic measurements of the fetal head descent were comparable at each time interval between the two groups. This observation suggests that mobile epidural analgesia is not likely to affect the dynamics of the second stage of labor.

Changes in Artery Diameters and Fetal Growth in Cases of Isolated Single Umbilical Artery.

Background-There are conflicting data in the international literature on the risks of abnormal fetal growth in fetuses presenting an isolated single umbilical artery (SUA), and the pathophysiology of this complication is poorly understood. Objective-To evaluate if changes in diameter of the remaining umbilical artery in fetuses presenting an isolated SUA are associated with different fetal growth patterns. Study design-This was a two-center prospective longitudinal observational study including 164 fetuses diagnosed with a SUA at the 20-22-week detailed ultrasound examination and 200 control fetuses with a three-vessel cord. In all cases, the diameters of the cord vessels were measured in a transverse view of the central portion of the umbilical cord, and the number of cord vessels was confirmed at delivery. Logistic regression and nonparametric receiver operating characteristic (ROC) analysis were carried out to evaluate the association of the umbilical artery diameter in a single artery with small for-gestational age (SGA) and with fetal growth restriction (FGR). The impact of artery dimension was adjusted for maternal BMI, parity, ethnicity, side of the remaining umbilical artery and umbilical resistance index (RI) in the regression model. Results-A significantly (p < 0.001) larger mean diameter was found for the remaining artery in fetuses with SUA compared with controls (3.0 ± 0.9 vs. 2.5 ± 0.6 mm). After controlling for BMI and parity, we found no difference in umbilical resistance and side of the remaining umbilical artery between the SUA and control groups. A remaining umbilical artery diameter of >3.1 mm was found to be associated with a lower risk of FGR, but this association failed to be statistical significant (OR = 0.60, 95% CI = 0.33-1.09, p value = 0.089). We also found that the mean vein-to-artery area ratio was significantly (p < 0.001) increased in the SUA group as compared with the controls (2.4 ± 1.8 vs. 1.8 ± 0.9; mean difference = 0.6; Cohen's d = 0.46). Conclusion-In most fetuses with isolate SUA, the remaining artery diameter at 20-22 weeks is significantly larger than in controls. When there are no changes in the diameter and, in particular, if it remains <3.1 mm, the risk of abnormal fetal growth is higher, and measurements of the diameter of the remaining artery could be used to identify fetuses at risk of FGR later in pregnancy.

Three-dimensional ultrasound is an accurate and reproducible technique for fetal crown-rump length measurement.

OBJECTIVE: The aim of the study was to evaluate the accuracy and reproducibility of fetal crown-rump length (CRL) measurement using three-dimensional ultrasound (3DUS). METHODS: We included a series of women with singleton pregnancy at 6-13 + 6 weeks. Following CRL measurement by the two-dimensional ultrasound (2DUS), a 3DUS volume was acquired. On the reconstructed midsagittal plane, CRL was measured twice by an operator and once by another. The correlation between CRL measured by 3DUS and 2DUS, as well as the intraobserver and interobserver agreement, was then calculated. Furthermore, the agreement between 2DUS and 3DUS CRL measurements together with intraobserver and interobserver agreement was calculated separately for the groups with a midsagittal acquisition plane (MSAP) and non-midsagittal acquisition plane (NMSAP). RESULTS: Overall, 137 pregnancies were included in the analysis. CRL measurements performed using 3DUS showed excellent correlation with 2DUS [intraclass correlation coefficient (ICC) = 0.992]. In addition, the 3DUS showed a high intraobserver and interobserver agreement (ICC = 0.999 and 0.993, respectively). Finally, when we divided the acquired volumes according to the plane of acquisition, excellent 2DUS-3DUS, as well as intraobserver and interobserver agreement, was maintained for both MSAP and NMSAP. CONCLUSION: 3DUS is a highly accurate and reproducible tool for fetal CRL measurement regardless of the fetal position at the time of 3D volume acquisition.

Normal morphometry of fetal posterior fossa at midtrimester: brainstem-tentorium angle and brainstem-vermis angle.

OBJECTIVE: To standardize the evaluation of normal tentorium insertion and normal rotation of the cerebellar vermis over the brainstem, using two novel measurements: the brainstem-tentorium angle (BT angle) and the brainstem-vermis angle (BV angle). We also aimed to test the reproducibility of these measurements. METHODS: Prospective observational study including normal fetuses at routine anomaly scan with confirmed normal follow-up. Three-dimensional volumes of the fetal head were acquired starting from standard trans-cerebellar views. In the sagittal plane, obtained by multiplanar reconstruction, the angle between the brainstem and the tentorium insertion in the fetal skull, and between the brainstem and the lower edge of the vermis were measured twice by two independent operators. Intraobserver and interobserver variations were calculated. RESULTS: Eighty cases were included. The estimated BT and BV angles lie in a wide interval among normal midtrimester fetuses with a median value (min-max) of 25.65 (20.13-47.39) and 9.29 (3.87-19.36) respectively. Intraobserver and interobserver variation were good for both measurements. CONCLUSION: The BT and BV angle may be of help in assessing the fetal posterior fossa at midgestation and gives a standardized and reproducible measurement of normal tentorium insertion and normal rotation of the cerebellar vermis over the brainstem.

Prediction of neonatal coarctation of the aorta at fetal echocardiography: a scoring system.

INTRODUCTION: Coarctation of the aorta (CoA) is common and can lead to neonatal emergency. Despite its burden, antenatal detection of this condition remains inaccurate. OBJECTIVE: To evaluate the diagnostic performance of fetal echocardiography and to design a scoring system for risk stratification of CoA in suspected cases. DESIGN: A retrospective cohort study. SETTING: S. Orsola Hospital, Bologna, Italy. POPULATION: About 140 fetuses referred for suspected CoA to our tertiary center in a 9-year period. METHODS: The following parameters were systematically obtained at fetal echocardiography: ventricular disproportion, great vessels asymmetry, transverse aortic arch hypoplasia, flow turbulence, and Z-scores of the ascending aorta and of the aortic isthmus. Associated anomalies were recorded, if present. When CoA was not confirmed at birth, neonates were followed up for 12 months to identify also a tardive onset of this condition. MAIN OUTCOME MEASURES: The primary outcome was the presence of COA after birth. RESULTS: 108 fetuses were eligible for the purpose of the study. CoA was confirmed postnatally in 55 neonates (50.9%). Arch hypoplasia yielded the highest correlation with CoA. The affected neonates presented also significantly lower Z scores of the ascending aorta and of the aortic isthmus. Earlier gestational age at referral was positively correlated with neonatal CoA. An odds ratio-based multiparametric model was designed to build a scoring system (AUC 0.89). CONCLUSION: In our cohort, no single ultrasound parameter was sufficiently accurate to predict postnatal CoA. The scoring system permitted a better identification of the affected fetuses.

Pregnancy outcome of monochorionic twins: does amnionicity matter?

OBJECTIVE: To compare the fetal loss rate of monochorionic (MC) twin pregnancies according to their amnionicity. METHODS: A retrospective review of all MC pregnancy outcomes in a tertiary centre. Pregnancy outcomes were compared for monochorionic monoamniotic (MCMA) versus monochorionic diamniotic (MCDA) pregnancies. RESULTS: 29 MCMA and 117 MCDA twin pregnancies were identified. The overall fetal loss rate was significantly higher in MCMA (23/52, 44.2%) compared to MCDA pregnancies (28/233, 12%, Chi squared = 30.03, p < .001). Kaplan-Meier analysis showed that fetal survival rate in MCDA twins were significantly higher than in MCMA twins (Log-rank Chi-squared = 27.9, p < .0005). Early pregnancy ultrasound identified the causes for these fetal losses in some MCMA twins. After exclusion of identifiable causes, the difference in fetal survival was not significant in the two groups (Log-rank chi-squared = 0.373, p = .54). CONCLUSION: The loss rate for MCMA twins is high and occurs mainly due to discordant congenital abnormality, conjoint twins or twin reversed arterial perfusion (TRAP) sequence. Although the fetal loss rate in MCDA is lower than in MCMA pregnancies, the majority of fetal loss in MCDA pregnancies cannot be predicted at the first scan at presentation. The data of this study questions the widespread policy of a difference in the scheduling of elective delivery for MCMA and MCDA twins.

AUditive Direct in Utero Observation (AUDIO): A Randomized Controlled Trial for a Prenatal Demonstration of Fetal Hearing.

INTRODUCTION: The objective of this randomized controlled study was to demonstrate whether acoustic stimulation in utero is associated with fetal reactivity which is documentable by cardiotocography. MATERIALS AND METHODS: A monocentric randomized controlled trial was performed at a single university tertiary hospital between September 2016 and July 2017. This study was registered as a randomized clinical trial on clinicaltrail.gov (registration number NCT04622059). Unselected pregnancies at term of gestation were consecutively recruited for the purpose of this study. After 10 min of normal cardiotocography without accelerations (non-stress-test with a basal frequency between 110 and 150 beats/min, normal variability between 6 and 15 b/min, no accelerations, and no fetal movements), fetuses were randomized at a 1:1 ratio to either of the two groups. Fetuses in group A (n = 105) received acoustic stimulation after 10 min from the beginning of the CTG, whereas fetuses in group B received no stimulation (n = 105). The outcome variables investigated were the lapse of time between the beginning of the CTG and the occurrence of the first acceleration, and the lapse of time between the beginning of the CTG and the first fetal movement noticed. RESULTS: The lapse of time between the beginning of the CTG and the occurrence of the first acceleration was significantly shorter in the group with acoustic stimulation compared to the other group (14.87 ± 5.01 vs. 21.90 ± 6.94 min, p-value < 0.001 log-rank test). Similarly, the lapse of time between the beginning of the CTG and the occurrence of the first fetal movement was significantly shorter in group A compared to group B (17.77 ± 7.62 vs. 23.28 ± 7.61 min, p-value < 0.001, log-rank test). Fetal cardiac acceleration and the occurrence of a fetal movement during the first 20 min of the CTG were more frequently recorded in group A compared to group B (respectively, 15% vs. 5% and 20% vs. 8%). CONCLUSION: This RCT showed an early fetal reaction following auditive stimulus, documentable by cardiotocography. Further research is needed to investigate a possible role of acoustic stimulation in utero for the prenatal diagnosis of congenital hypoacusis.

Prenatal Screening for Developmental Displacement of the Hip: The BUDDHA (Pre-Birth Ultrasound for Developmental Displacement of the Hip Assessment) Study.

BACKGROUND: developmental dysplasia of the hip has an incidence of 3-5 out of 1000 children. Currently, only postnatal screening is available. OBJECTIVE: to test the feasibility of a method based on Graf technique application at antenatal ultrasound in assessing the normal development of the hip in unselected term fetuses. METHODS: a prospective cohort study in a single university tertiary hospital from January 2017 to January 2020. Single uncomplicated term pregnancies (37-40 weeks) attending our center for routine ultrasound were consecutively recruited for the purpose of the study. A 3D volume acquisition was launched on the coxofemoral joint of the fetus by a single expert operator, and offline analysis was then performed in the multiplanar mode by two operators (blinded to each other analysis) in order to measure the alpha and beta angles according to our modified Graf technique. Intra- and inter-observer variations were calculated. Reference charts for normal values of both angles were produced. Postnatal ultrasound was then performed to measure the Graf angles in newborns, confirming a normal development of the hip. RESULTS: in the study period, 433 uncomplicated term pregnancies underwent 3D ultrasound for the assessment of the fetal hip. One case was subsequently excluded because of confirmed postnatal diagnosis of developmental dysplasia of the hip. The measurement of our modified Graf angles was feasible at prenatal ultrasound with a good reproducibility. The inter-rater and intra-rater reliability of both angles was substantial. Reference charts for normal values of both angles were produced. CONCLUSIONS: the evaluation of the coxofemoral joint in fetuses at term of gestation has never been attempted before. The Graf technique application, currently employed at postnatal ultrasound, may also be adapted to prenatal ultrasound with a substantial reproducibility. However, there was no evidence of a linear relationship between prenatal and postnatal alpha angles and beta angles. Further research is needed to establish if developmental dysplasia of the hip could be diagnosed antenatally.

Prenatal sonography of the foramen ovale predicts urgent balloon atrial septostomy in neonates with complete transposition of the great arteries.

BACKGROUND: Hypoxia caused by inadequate intracardiac mixing owing to a restrictive foramen ovale is a potentially life-threatening complication in neonates with dextro-transposition of the great arteries. An urgent balloon atrial septostomy is a procedure of choice in such cases, but dependent on the availability of a 24-hour interventional cardiology facility. The prenatal identification of predictors for an urgent balloon atrial septostomy at birth would help in optimizing the management of these neonates, minimizing the risk of hypoxic damage. OBJECTIVE: This study aimed to predict with prenatal echocardiography the need of urgent balloon atrial septostomy in neonates with dextro-transposition of the great arteries. STUDY DESIGN: This was a retrospective cohort study of patients with a prenatal diagnosis of transposition of the great arteries that were delivered in our center between 2010 and 2019, for whom fetal ultrasound echocardiograms obtained at less than 3 weeks before delivery were available. The following parameters were systematically obtained at fetal echocardiography: size and appearance of the foramen ovale, septum primum excursion (foramen ovale flap angle at the maximal excursion), diameters of the atria, and size of the ductus arteriosus. Balloon atrial septostomy was defined as urgent if performed within 12 hours from birth in neonates with restrictive foramen ovale. Neonatal follow-up was obtained through medical records analysis. RESULTS: From November 2007 to April 2019, 160 fetuses with complete transposition of the great arteries were referred to our echocardiography laboratory and 60 of these were included in the analysis; 27 underwent urgent balloon atrial septostomy, 11 elective balloon atrial septostomy, and 22 no balloon atrial septostomy. The size of the foramen ovale was the best predictor of an urgent balloon atrial septostomy. A measurement of >6.5 mm had a sensitivity of 100% and a false positive rate of 45%. CONCLUSION: Fetal echocardiography predicts the need of an urgent balloon atrial septostomy in fetuses with dextro-transposition of the great arteries although with a limited precision. In our experience, a measurement of the foramen ovale within 3 weeks of delivery had the greatest accuracy.

Prenatal diagnosis of congenital heart defects and voluntary termination of pregnancy.

BACKGROUND: The prenatal diagnosis of an isolated congenital heart defect is a matter of concern for parents. The decision of whether to terminate the pregnancy according to the different types of congenital heart defects has not been investigated yet. OBJECTIVE: This study aimed to evaluate the frequency of voluntary termination of pregnancy after the prenatal diagnosis of a congenital heart defect in a tertiary care center. STUDY DESIGN: This was a retrospective study of patients who were referred to our center from January 2013 to December 2019, underwent fetal echocardiography, and were counseled by a perinatologist and a pediatric cardiologist. The following data were collected: prenatal diagnosis, including genetic testing; gestational age at diagnosis; and outcome of pregnancy. The diagnoses were stratified retrospectively according to the type of congenital heart defect and its severity (low complexity, moderate complexity, and high complexity) by a perinatologist and a pediatric cardiologist. RESULTS: Of 704 women who received a diagnosis of fetal congenital heart defect, 531 (75.4%) were seen before 23 weeks' gestation, which is the upper limit imposed for the termination of pregnancy by the Italian legislation. Congenital heart defects were apparently isolated in 437 of 531 cases (82.3%). Overall, 108 of 531 patients (20.3%) requested a termination of pregnancy. The rate of termination of pregnancy was found to vary according to the severity of congenital heart defects: low complexity, 0%; moderate complexity, 12.1%, and high complexity, 33.2% (P<.001). The presence or absence of associated anomalies or the ethnicity of the couples was not found to have an influence on women's decisions. CONCLUSION: In our population, the decision to terminate a pregnancy after the diagnosis of a fetal congenital heart defect is influenced by the surgical complexity of the congenital heart defect itself. However, most patients, including those with the most severe forms of congenital heart defect, decided to continue the pregnancy.

The prognostic role of uterine artery Doppler studies in patients with late-onset preeclampsia.

OBJECTIVE: To evaluate the usefulness of uterine artery Doppler in the prediction of outcome in patients with late-onset preeclampsia. STUDY DESIGN: Patients with late-onset preeclampsia underwent Doppler interrogation of the uterine arteries. Patients with abnormal uterine artery Doppler were compared with those who had a normal uterine artery Doppler. RESULTS: Ninety-nine patients were included in the study group. Abnormal uterine artery Doppler group presented significantly lower gestational age at admission (36.1 +/- 2.1 weeks vs 37.2 +/- 1.9 weeks; P < .005), lower gestational age at delivery (36.5 +/- 1.9 weeks vs 37.7 +/- 1.7 weeks; P < .005), lower birthweight (2429 +/- 590 g vs 3013 +/- 597 g; P < .0001), and a higher admission rate to neonatal intensive care unit (17/51 vs 6/48; odds ratio, 3.5; 95% confidence interval, 1.2-9.5). No significant difference in the occurrence of maternal complications (10/51 vs 6/48; odds ratio, 1.7; 95% confidence interval, 0.5-4.9) was registered. CONCLUSION: Women with late-onset preeclampsia show a higher risk of perinatal complications if uterine resistance is increased although maternal outcome does not seem to be related to Doppler findings.

Cell-Free Fetal DNA for the Prediction of Pre-Eclampsia at the First and Second Trimesters: A Systematic Review and Meta-Analysis.

OBJECTIVE: A systematic review and pooled analysis was carried out to estimate whether the increase in the quantity of cell-free fetal DNA (cffDNA) before the onset of pre-eclampsia (PE) can predict the disease using real-time polymerase chain reaction (PCR). METHOD: A comprehensive literature search of the PubMed, Scopus, and Web of Knowledge databases was conducted to identify relevant studies that included evaluated cffDNA levels in pregnant women before the clinical onset of PE. A simulation model was generated to calculate the detection rate (DR) of cffDNA for PE, and a random variable was generated using the same number of cases and same statistical measurements of central tendency and dispersion as those reported in the papers considered for the analysis. Simulation of the receiver operating characteristic (ROC) curves was also carried out. RESULTS: Four studies (82 cases and 1315 controls) evaluated cffDNA in early-onset PE, with DRs of 18 and 68.8% at 11-13 and 17-28 weeks, respectively, at a false positive rate of 10%. Nine studies (including two considered for early-onset PE) encompassing 376 cases and 1270 controls were available for the evaluation of 'any PE'. At 11-14 weeks no significant DR was found, while at 15-28 weeks the DR was 37%. CONCLUSION: CffDNA quantification is a marker for predicting the development of both early-onset PE and 'any PE'; however, it can probably only be used from the beginning of the second trimester, otherwise its predictive value is burdened with a DR that is too low or not significant. Due to the heterogeneity and difficulty in interpreting the published data, no conclusion regarding the statistical and clinical relevance, especially for screening 'any PE', can be made at present.